U.S. patent application number 16/317248 was filed with the patent office on 2019-09-26 for bicyclic heteroaryl substituted compounds.
The applicant listed for this patent is BISTOL-MYERS SQUIBB COMPANY. Invention is credited to J. Alex Bates, Oz Scott Halpern, Eldon Scott Priestley, Samuel Kaye Reznik, Jeremy M. Richter, Xiaojun Zhang.
Application Number | 20190292176 16/317248 |
Document ID | / |
Family ID | 59384258 |
Filed Date | 2019-09-26 |
![](/patent/app/20190292176/US20190292176A1-20190926-C00001.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00002.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00003.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00004.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00005.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00006.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00007.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00008.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00009.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00010.png)
![](/patent/app/20190292176/US20190292176A1-20190926-C00011.png)
View All Diagrams
United States Patent
Application |
20190292176 |
Kind Code |
A1 |
Zhang; Xiaojun ; et
al. |
September 26, 2019 |
BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
Abstract
Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III)
(IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein R3 is a bicyclic heteroaryl group substituted with zero to
3 R.sub.3a; and R.sub.1, R.sub.2, R.sub.3a, R.sub.4, and n are
defined herein. Also disclosed are methods of using such compounds
as PAR4 inhibitors, and pharmaceutical compositions comprising such
compounds. These compounds are useful in inhibiting or preventing
platelet aggregation, and are useful for the treatment of a
thromboembolic disorder or the primary prophylaxis of a
thromboembolic disorder. ##STR00001## ##STR00002##
Inventors: |
Zhang; Xiaojun; (Furlong,
PA) ; Priestley; Eldon Scott; (Yardley, PA) ;
Bates; J. Alex; (Hillborough, NJ) ; Halpern; Oz
Scott; (Robbinsville, NJ) ; Reznik; Samuel Kaye;
(Brooklyn, MA) ; Richter; Jeremy M.; (Yardley,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BISTOL-MYERS SQUIBB COMPANY |
Princeton |
NJ |
US |
|
|
Family ID: |
59384258 |
Appl. No.: |
16/317248 |
Filed: |
July 13, 2017 |
PCT Filed: |
July 13, 2017 |
PCT NO: |
PCT/US2017/041878 |
371 Date: |
January 11, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62362113 |
Jul 14, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/04 20130101;
A61P 7/02 20180101; A61P 9/10 20180101; C07D 405/04 20130101; C07D
403/04 20130101; C07D 519/00 20130101; A61P 43/00 20180101; A61P
11/00 20180101; A61P 7/04 20180101; C07D 471/04 20130101; C07D
405/14 20130101; A61P 13/12 20180101; C07D 487/04 20130101; C07D
417/14 20130101; C07D 513/04 20130101 |
International
Class: |
C07D 417/04 20060101
C07D417/04; C07D 471/04 20060101 C07D471/04; C07D 513/04 20060101
C07D513/04; C07D 405/04 20060101 C07D405/04; A61P 7/04 20060101
A61P007/04; A61P 9/10 20060101 A61P009/10; C07D 487/04 20060101
C07D487/04; C07D 417/14 20060101 C07D417/14; C07D 405/14 20060101
C07D405/14; C07D 519/00 20060101 C07D519/00 |
Claims
1. A compound of Formula (I) to (VIII): ##STR01871## or a salt
thereof; wherein: R.sub.1 is F, Cl, --OH, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 fluorocycloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 fluoroalkoxy, C.sub.2-4 hydroxyalkoxy, C.sub.3-6
cycloalkoxy, (C.sub.1-3 alkoxy)-(C.sub.1-3 alkylene), (C.sub.1-3
alkoxy)-(C.sub.1-3 fluoroalkylene), (C.sub.1-3
deuteroalkoxy)-(C.sub.1-3 deuteroalkylene), (C.sub.1-3
fluoroalkoxy)-(C.sub.1-3 alkylene), (C.sub.1-3
fluoroalkoxy)-(C.sub.1-3 fluoroalkylene),
--(CH.sub.2).sub.1-3O(phenyl), --(CH.sub.2).sub.1-3NR.sub.aR.sub.a,
--C(O)O(C.sub.1-6 alkyl), --C(O)NR.sub.aR.sub.a,
--C(O)NR.sub.bR.sub.b, --NH.sub.2, --NH(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl).sub.2, --NH(C.sub.1-6 hydroxyalkyl),
azetidinyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl,
morpholinyl, piperazinyl, --S(O).sub.2(C.sub.1-3 alkyl),
--S(O).sub.2NR.sub.aR.sub.a, C.sub.1-3 alkylthio, or C.sub.1-3
fluoroalkylthio; R.sub.2, at each occurrence, is independently H,
F, Cl, Br, --OH, --CN, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-3 aminoalkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7
fluorocycloalkyl, C.sub.1-6 alkoxy, C.sub.1-3 fluoroalkoxy,
C.sub.1-3 alkylthio, C.sub.1-3 fluoroalkylthio, (C.sub.1-3
alkoxy)-(C.sub.1-3 alkylene), (C.sub.1-3 fluoroalkoxy)-(C.sub.1-3
alkylene), --C(O)NH.sub.2, --C(O)NH(C.sub.1-6 alkyl),
--C(O)N(C.sub.1-6 alkyl).sub.2, --C(O)O(C.sub.1-6 alkyl),
--C(O)NH(CH.sub.2CH.sub.2O(C.sub.1-3 alkyl)),
--C(O)NR.sub.bR.sub.b, --C(O)(piperidinyl), --CH(OH)(C.sub.3-6
cycloalkyl), --CH(OH)(phenyl), --CH(OH)(pyridyl),
--S(O).sub.2(C.sub.1-3 alkyl), --S(O).sub.2NR.sub.aR.sub.a, or a
cyclic group selected from phenyl, 5-to 6-membered heteroaryl, and
5-to 7-membered heterocyclyl, wherein said cyclic group is
substituted with zero to 5 substituents independently selected from
F, Cl, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, cyclopropyl, and
--CN; R.sub.3 is a bicyclic group selected from indolyl,
benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl,
benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl,
thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl,
4,5,6,7-tetrahydrobenzofuranyl,
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl,
5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl,
5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl,
pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl,
6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl,
4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, and
furo[2,3-b]pyridinyl, each bicyclic group substituted with zero to
3 R.sub.3a; R.sub.3a, at each occurrence, is independently: (i) F,
Cl, --CN, --OH, C.sub.1-3 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6
hydroxyalkyl, C.sub.1-6 hydroxy-deuteroalkyl, C.sub.1-6
hydroxy-fluoroalkyl, C.sub.1-6 alkoxy, C.sub.1-3 fluoroalkoxy,
C.sub.3-6 cycloalkyl, C.sub.3-6 fluorocycloalkyl, 4-to 7-membered
heterocyclyl, --CH(OH)R.sub.y wherein R.sub.y is C.sub.3-6
cycloalkyl, aryl, heteroaryl, or 4-to 7-membered heterocyclyl;
(C.sub.1-3 alkoxy)-(C.sub.1-3 alkylene),
--(CH.sub.2).sub.1-3NR.sub.aR.sub.a,
--(CH.sub.2).sub.1-3NHS(O).sub.2(aryl),
--O(CH.sub.2).sub.1-3(aryl), --O(CH.sub.2).sub.1-3(thiazolyl),
--O(CH.sub.2).sub.1-3(oxazolidinonyl), --O(CH.sub.2).sub.1-3(amino
isoxazolyl), --O(CH.sub.2).sub.1-3(imidazolyl substituted with
phenyl), C.sub.1-6 hydroxyalkoxy, (C.sub.1-3 alkoxy)-(C.sub.1-6
alkoxy), --O(CH.sub.2).sub.1-4O(aryl),
--O(CH.sub.2).sub.1-4O(CH.sub.2).sub.1-3(aryl),
--O(CH.sub.2).sub.1-4NR.sub.aR.sub.a,
--O(CH.sub.2).sub.1-3CHR.sub.aNR.sub.a(methoxy pyrimidinyl),
--O(CH.sub.2).sub.1-4NHS(O).sub.2(C.sub.1-3 alkyl),
--O(CH.sub.2).sub.1-4NHS(O).sub.2(aryl),
--O(CH.sub.2).sub.1-4C(O)OH, --O(CH.sub.2).sub.1-4C(O)O(C.sub.1-6
alkyl), --O(CH.sub.2).sub.1-4C(O)NR.sub.a(CH.sub.2).sub.0-3(aryl),
--O(CH.sub.2).sub.1-4C(O)NR.sub.a(CH.sub.2).sub.0-3(heteroaryl),
--O(CH.sub.2).sub.1-4C(O)(morpholinyl),
--O(CH.sub.2).sub.1-4OC(O)O(C.sub.1-3 alkyl),
--O(CH.sub.2).sub.1-3CHR.sub.aOC(O)NR.sub.a(CH.sub.2).sub.1-4C(O)NR.sub.a-
R.sub.a, --CH.sub.2CHR.sub.dOC(O)NR.sub.a(heteroaryl),
--O(CH.sub.2).sub.1-4OC(O)NR.sub.a(heteroaryl), --O(imidazolyl
substituted with aryl), --C(O)OH, --C(O)O(C.sub.1-6 alkyl),
--NR.sub.aC(O)(furanyl), --NR.sub.aC(O)(pyranyl),
--NR.sub.aC(O)O(C.sub.1-6 alkyl),
--NR.sub.aC(O)O(CH.sub.2).sub.1-4(aryl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(C.sub.1-6 alkyl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(tetrahydropyranyl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(aryl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(heteroaryl),
or
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(tetrahydrofuranyl),
wherein each of said aryl, heteroaryl, and 3- to 6-membered
heterocyclyl is substituted with zero to 5 substituents
independently selected from F, Cl, --CN, C.sub.1-3 alkyl, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-3 alkoxy, --OCF.sub.3,
--OCHF.sub.2, --NH.sub.2, --NH(C.sub.1-6 alkyl), --N(C.sub.1-6
alkyl).sub.2, --C(O)O(C.sub.1-3 alkyl), C.sub.1-3 hydroxyalkoxy,
phenyl, --CONR.sub.cR.sub.c, and --S(O).sub.2NR.sub.cR.sub.c; (ii)
--CH(OH)CR.sub.hR.sub.iR.sub.j wherein R.sub.h and R.sub.i are
independently H, F, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
C.sub.1-3 alkoxy, C.sub.1-3 fluoroalkoxy, or taken together with
the carbon atom to which they are attached, form C.sub.3-8
cycloalkyl or 4- to 7-membered heterocyclyl ring; and R.sub.j is H,
C.sub.1-6 alkyl, C.sub.1-5 fluoroalkyl, (C.sub.1-3
alkoxy)-(C.sub.1-3 alkylene), C.sub.3-8 cycloalkyl, C.sub.3-8
heterocyclyl, aryl, or heteroaryl; (iii)
--O(CH.sub.2).sub.1-4NR.sub.aS(O).sub.2(C.sub.1-4 alkyl) or
--O(CH.sub.2).sub.1-4NR.sub.aS(O).sub.2R.sub.w, wherein R.sub.w is
aryl or heteroaryl, each substituted with zero to 2 substituents
independently selected from F, Cl, cyano, C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, --OCF.sub.3, --OCHF.sub.2, and C.sub.1-3
fluoroalkyl; or (iv) --O(CH.sub.2).sub.1-4OC(O)NR.sub.aR.sub.x,
--OCH(R.sub.d)(CH.sub.2).sub.1-3OC(O)NR.sub.aR.sub.x,
--OCR.sub.dR.sub.d(CH.sub.2).sub.1-3OC(O)NR.sub.aR.sub.x,
--O(CH.sub.2).sub.1-3CH(R.sub.d)OC(O)NR.sub.aR.sub.x,
--O(CH.sub.2).sub.1-3CR.sub.dR.sub.dOC(O)NR.sub.aR.sub.x,
--OCH(R.sub.d)CH(R.sub.d)(CH.sub.2).sub.0-2OC(O)NR.sub.aR.sub.x, or
--OCR.sub.dR.sub.dCR.sub.dR.sub.d(CH.sub.2).sub.0-2OC(O)NR.sub.aR.sub.x,
wherein R.sub.x is selected from H, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, aryl, heteroaryl, and --CH.sub.2(heteroaryl), each
aryl and heteroaryl substituted with zero to 2 substituents
independently selected from F, Cl, Br, --CN, --OH, C.sub.1-3 alkyl,
C.sub.1-3 fluoroalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6
hydroxy-deuteroalkyl, C.sub.1-6 hydroxyalkoxy, C.sub.1-6
hydroxy-fluoroalkoxy, C.sub.1-3 alkoxy, --C(O)OH,
--(CH.sub.2).sub.0-3C(O)O(C.sub.1-3 alkyl),
--(CH.sub.2).sub.1-3OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--C(O)NH.sub.2, --C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl).sub.2, --C(O)NR.sub.a(C.sub.1-6 hydroxyalkyl),
--C(O)NR.sub.bR.sub.b, --S(O).sub.2NR.sub.aR.sub.a, --NH.sub.2,
--NH(C.sub.1-6 alkyl), --NR.sub.a(C.sub.1-6 hydroxyalkyl),
--N(C.sub.1-6 alkyl).sub.2, --NR.sub.aC(O)(C.sub.1-6 alkyl),
--NR.sub.aC(O)(chloro, fluorophenyl),
--NR.sub.aS(O).sub.2(C.sub.1-3 alkyl),
--C(O)NR.sub.a(CH.sub.2).sub.0-1 (hydroxymethyloxetanyl),
--C(O)NR.sub.a(CH.sub.2).sub.0-1 (hydroxymethyl C.sub.3-6
cycloalkyl), --C(O)NR.sub.a(CH.sub.2).sub.0-1 (hydroxy C.sub.3-6
cycloalkyl), --C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl,
thiophenyl, methyl triazolyl, and oxazolidinonyl; R.sub.4 is H, F,
Cl, or --CH.sub.3; R.sub.a, at each occurrence, is independently H,
C.sub.1-4alkyl, or C.sub.1-4 fluoroalkyl; two R.sub.b along with
the nitrogen atom to which they are attached form a 4- to
7-membered heterocyclo ring having 1 to 2 nitrogen atoms and 0-1
oxygen or sulfur atoms; R.sub.c, at each occurrence, is
independently C.sub.1-3 alkyl or C.sub.1-3 hydroxyalkyl, or two
R.sub.c along with the nitrogen atom to which they are attached
form a heterocyclyl or bicyclic heterocyclyl; R.sub.d, at each
occurrence, is independently C.sub.1-6 alkyl, C.sub.1-4
fluoroalkyl, C.sub.1-6 hydroxyalkyl, (C.sub.1-4 alkoxy)-(C.sub.1-3
alkylene), (C.sub.1-2 fluoroalkoxy)-(C.sub.1-2 alkylene),
(C.sub.3-6 cycloalkyl)-(C.sub.0-2 alkylene), aryl-(C.sub.1-2
alkylene), heteroaryl-(C.sub.1-2 alkylene), aryloxy-(C.sub.1-2
alkylene), aryl-CH.sub.2O--(C.sub.1-2 alkylene), or
heteroaryloxy-(C.sub.1-2 alkylene); and n is zero, 1, or 2.
2. The compound according to claim 1 having the structure of
Formula (I) to Formula (IV): ##STR01872##
3. The compound according to claim 1 or a salt thereof; wherein:
R.sub.1 is --OH, C.sub.1-2 alkyl, --CHFCH.sub.3, --CH.dbd.CH.sub.2,
C.sub.1-3 alkoxy, C.sub.1-2 fluoroalkoxy, --OCH.sub.2CH.sub.2OH,
--CH.sub.2O(C.sub.1-2 alkyl), --CD.sub.2OCD.sub.3,
--CH.sub.2OCHF.sub.2, --CF.sub.2OCH.sub.3, --CH.sub.2O(phenyl),
--CH(CH.sub.3)OCH.sub.3, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
--CH.sub.2N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NH(CH.sub.3),
--C(O)N(CH.sub.3).sub.2, --C(O)NH(CH.sub.2CH.sub.2OH),
--C(O)OCH.sub.3, --CH(CH.sub.3)OCH.sub.3, cyclopropyl, furanyl, or
--O(cyclopropyl); R.sub.2, at each occurrence, is independently H,
F, Cl, --CN, --CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--CH(CH.sub.3)OH, --C(CH.sub.3).sub.2OH, --CH(OH)CH.sub.2OH,
--CH.sub.2NH.sub.2, --C(O)NH.sub.2, --C(O)N(CH.sub.3).sub.2,
--C(O)(piperidinyl), --C(O)OCH.sub.3,
--C(O)NH(CH.sub.2CH.sub.2OCH.sub.3), --CH(OH)(cyclopropyl),
--CH(OH)(phenyl), --CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2, or
--C.ident.CH; R.sub.3 is: ##STR01873## R.sub.3a, at each
occurrence, is independently: (i) F, Cl, --CN, --OH, --CH.sub.3,
--CF.sub.3, --CHFC(CH.sub.3).sub.3, cyclopropyl, --CH.sub.2OH,
--CD.sub.2OH, --CH.sub.2CH.sub.2OH, --CH(OH)CH.sub.3,
--C(CH.sub.3).sub.2OH, --CH(OH)C(CH.sub.3).sub.3,
--CD(OH)C(CH.sub.3).sub.3, --CH(OH)CF.sub.3,
--CH(OH)CH.sub.2CF.sub.3, --CH(OH)(cyclopropyl),
--CH(OH)(methylcyclopropyl), --CH(OH)(trifluoromethylcyclopropyl),
--CH(OH)(cyclopropyl substituted with phenyl),
--CH(OH)(cyclobutyl), --CH(OH)(methoxycyclobutyl),
--CH(OH)(ethoxycarbonylcyclobutyl),
--CH(OH)(trifluoromethylcyclobutyl),
--CH(OH)(hydroxymethylcyclobutyl), --CH(OH)(cyclobutyl substituted
with phenyl), --CH(OH)(cyclohexyl), --CH(OH)(methylcyclohexyl),
--CH(OH)(phenyl), --CH(OH)(isopropylphenyl),
--CH(OH)(trifluoromethylphenyl), --CH(OH)(fluoro, methoxyphenyl),
--CH(OH)(pyridinyl), --CH(OH)(thiazolyl),
--CH(OH)(tetrahydropyranyl), --CH(OH)(methyltetrahydropyranyl),
--CH.sub.2OCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2NHS(O).sub.2(phenyl), or --CH(OH)CH.sub.2(phenyl); (ii)
--OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2(phenyl),
--OCH.sub.2(thiazolyl), --OCH.sub.2(oxazolidinonyl),
--OCH.sub.2(amino isoxazolyl), --OCH.sub.2(imidazolyl substituted
with phenyl), --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.3, --OCH(CH.sub.3)CH(OH)CH.sub.3,
--OCH.sub.2C(CH.sub.3).sub.2OH, --OCH.sub.2CH.sub.2O(phenyl),
--OCH.sub.2CH.sub.2OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NH(CH.sub.3), --OCH.sub.2CH(CH.sub.3)NH(methoxy
pyrimidinyl), --OCH.sub.2C(O)OH, --OCH.sub.2C(O)OCH.sub.3,
--OCH.sub.2C(O)OCH.sub.2CH.sub.3,
--OCH.sub.2C(O)OC(CH.sub.3).sub.3, --OCH.sub.2C(O)NH(phenyl),
--OCH.sub.2C(O)NHCH.sub.2(phenyl), --OCH.sub.2C(O)(morpholinyl),
--OCH.sub.2CH.sub.2CH.sub.2C(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2OC(O)OCH.sub.3,
--OCH.sub.2CH(CH.sub.3)OC(O)NHCH.sub.2CH.sub.2C(O)NH.sub.2,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OC(CH.sub.3).sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2(phenyl))OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyrimidinyl),
or --OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(methyl
pyrimidinyl); (iii) --C(O)OH, --C(O)OCH.sub.3, or
--C(O)OC(CH.sub.3).sub.3; (iv) --NHC(O)OCH.sub.3,
--NHC(O)OC(CH.sub.3).sub.3, --NHC(O)OCH.sub.2(phenyl),
--NHC(O)OCH.sub.2(tetrahydrofuranyl), or
--NHC(O)O(tetrahydropyranyl); (v)
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.3,
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydropyranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NHC(O)O(methoxyphenyl),
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2N(CH.sub.3)C(O)NH(methylpyrimidinyl), or
--OCH.sub.2CH(CH.sub.3)OC(O)OCH.sub.2(aminopyridinyl); (vi)
--OCH.sub.2CH.sub.2NHS(O).sub.2CH.sub.3 or
--OCH.sub.2CH.sub.2NHS(O).sub.2R.sub.w wherein R.sub.w is phenyl or
pyridinyl, each substituted with zero to 2 substituents
independently selected from F, Cl, and --CH.sub.3; or (vii)
--OCH.sub.2CH.sub.2OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH.sub.2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2O(isobutyl))OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NHR.sub.z, or
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NHR.sub.z
wherein R.sub.z is H, --CH.sub.2CF.sub.3, phenyl, pyrrolyl,
pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, --CH.sub.2(pyrazolyl),
--CH.sub.2(imidazolyl), or --CH.sub.2(pyridinyl), each substituted
with zero to 2 substituents independently selected from F, Cl, Br,
--CN, --OH, --CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CF.sub.3,
--CH.sub.2OH, --CD.sub.2OH, --CH(CH.sub.3)OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2CH(CH.sub.3)OH, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2CH.sub.2C(O)OCH.sub.3, --CH.sub.2OP(O)(OH).sub.2,
--CH.sub.2CH.sub.2OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--OCH.sub.3, --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2C(CH.sub.3).sub.2OH,
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.2OH, --OCH.sub.2CF.sub.2OH,
--OCH.sub.2CF.sub.2CH.sub.2OH, --C(O)OH, --C(O)OCH.sub.3,
--C(O)NH.sub.2, --C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)NH(CH.sub.2CH(CH.sub.3)OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2CH.sub.2OH),
--C(O)NH(CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)N(CH.sub.3)CH.sub.2CH.sub.2OH,
--C(O)N(CH.sub.3)CH.sub.2C(CH.sub.3).sub.2OH,
--C(O)NHCH.sub.2(hydroxymethyloxetanyl),
--C(O)NH(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2(hydroxycyclobutyl),
--C(O)NHCH.sub.2(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), --NH.sub.2, --N(CH.sub.3).sub.2,
--NHC(O)CH.sub.3, --NHC(O)(chloro, fluorophenyl),
--NH(CH.sub.2C(CH.sub.3).sub.2OH), --N(CH.sub.3)S(O).sub.2CH.sub.3,
pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and
oxazolidinonyl; R.sub.4 is H, F, or --CH.sub.3; and p is zero, 1,
2, or 3.
4. The compound according to claim 1 or a salt thereof, wherein:
R.sub.3 is: ##STR01874##
5. The compound according to claim 1 having the structure of
Formula (I): ##STR01875## or a salt thereof.
6. The compound according to claim 5 or a salt thereof, wherein:
R.sub.1 is --OCH.sub.3, --OCHF.sub.2, --OCH.sub.2CH.sub.3, or
--CH.sub.2OCH.sub.3; R.sub.2, at each occurrence, is independently
H, F, Cl, --CN, --CH.sub.3, --OCH.sub.3, or --CH.sub.2OH; and
R.sub.3 is: ##STR01876##
7. The compound according to claim 1 or a salt thereof, wherein
said compound is selected from Examples 1-129, 131-133, 135-152,
154-176, 178-184, 186-189, 191-511, 516-624, 627-647, 658, 661-669,
671-702, 708-731, 733-738, 740-768, and 805-837.
8. The compound according to claim 1 having the structure of
Formula (II): ##STR01877## or a salt thereof.
9. The compound according to claim 8 or a salt thereof, wherein:
R.sub.1 is --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCHF.sub.2,
--OCH.sub.2CHF.sub.2, --CH.sub.2OCH.sub.3, or --NH(CH.sub.3);
R.sub.2, at each occurrence, is independently F, Cl, --CN,
--CH.sub.3, --CH.sub.2OH, --CH.sub.2F, --CHF.sub.2, or --OCH.sub.3;
R.sub.3 is: ##STR01878## and R.sub.3a, at each occurrence, is
independently F, Cl, --CH.sub.3, --OCH.sub.3,
--CH(OH)(trifluoromethylcyclobutyl),
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z, or
--OCH(CH.sub.3)CH(CH.sub.3)OC(O)NHR.sub.z, wherein R.sub.z is
pyridinyl, pyrimidinyl, or benzo[d]oxazolonyl, each substituted
with zero to 2 substituents independently selected from F, --OH,
--CN, --CH.sub.3, --CF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--OCH.sub.2CH.sub.2OH, --OCH.sub.3, --CH.sub.2CH(CH.sub.3)OH, and
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH.
10. The compound according to claim 1 or a salt thereof, wherein
said compound is selected from Examples 177, 185, 190, 512-515,
625-626, 648-657, 659-660, and 769-804.
11. A pharmaceutical composition, which comprises a
pharmaceutically acceptable carrier and a compound according to
claim 1 or a pharmaceutically acceptable salt thereof, alone or in
combination with another therapeutic agent.
12. A method for the treatment of a thromboembolic disorder or the
primary prophylaxis of a thromboembolic disorder, which comprises
the steps of administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim 1
or a pharmaceutically acceptable salt thereof, wherein the
thromboembolic disorder is selected from the group consisting of
arterial cardiovascular thromboembolic disorders, venous
cardiovascular thromboembolic disorders, and thromboembolic
disorders in the chambers of the heart or in the peripheral
circulation.
13. The method according to claim 8 wherein the thromboembolic
disorder is selected from the group consisting of unstable angina,
an acute coronary syndrome, atrial fibrillation, myocardial
infarction, transient ischemic attack, stroke, atherosclerosis,
peripheral occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial
thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney
embolism, pulmonary embolism, and thrombosis resulting from medical
implants, devices, and procedures in which blood is exposed to an
artificial surface that promotes thrombosis.
14. A method of inhibiting or preventing platelet aggregation,
which comprises the step of administering to a subject in need
thereof a therapeutically effective amount of a compound according
to claim 1 or a salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is entitled to priority pursuant to 35
U.S.C. .sctn. 119(e) to U.S. provisional patent application No.
62/362,113, filed Jul. 14, 2016, which is incorporated herein in
its entirety.
FIELD OF THE INVENTION
[0002] The present invention generally relates to bicyclic
heteroaryl substituted compounds useful as inhibitors of platelet
aggregation. Provided herein are bicyclic heteroaryl substituted
compounds, compositions comprising such compounds, and methods of
their use. The invention further pertains to pharmaceutical
compositions containing at least one compound according to the
invention that are useful in preventing or treating thromboembolic
disorders.
BACKGROUND OF THE INVENTION
[0003] Thromboembolic diseases remain the leading cause of death in
developed countries despite the availability of anticoagulants such
as warfarin (COUMADIN.RTM.), heparin, low molecular weight heparins
(LMWH), synthetic pentasaccharides, and antiplatelet agents such as
aspirin and clopidogrel (PLAVIX.RTM.).
[0004] Current anti-platelet therapies have limitations including
increased risk of bleeding as well as partial efficacy (relative
cardiovascular risk reduction in the 20 to 30% range). Thus,
discovering and developing safe and efficacious oral or parenteral
antithrombotics for the prevention and treatment of a wide range of
thromboembolic disorders remains an important goal.
[0005] Alpha-thrombin is the most potent known activator of
platelet aggregation and degranulation. Activation of platelets is
causally involved in atherothrombotic vascular occlusions. Thrombin
activates platelets by cleaving G-protein coupled receptors termed
protease activated receptors (PARs). PARs provide their own cryptic
ligand present in the N-terminal extracellular domain that is
unmasked by proteolytic cleavage, with subsequent intramolecular
binding to the receptor to induce signaling (tethered ligand
mechanism; Coughlin, S. R., Nature, 407:258-264 (2000)). Synthetic
peptides that mimic the sequence of the newly formed N-terminus
upon proteolytic activation can induce signaling independent of
receptor cleavage. Platelets are a key player in atherothrombotic
events. Human platelets express at least two thrombin receptors,
commonly referred to as PAR1 and PAR4. Inhibitors of PAR1 have been
investigated extensively, and several compounds, including
vorapaxar and atopaxar have advanced into late stage clinical
trials. Recently, in the TRACER phase III trial in ACS patients,
vorapaxar did not significantly reduce cardiovascular events, but
significantly increased the risk of major bleeding (Tricoci, P. et
al., N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a
need to discover new antiplatelet agents with increased efficacy
and reduced bleeding side effects.
[0006] There are several early reports of preclinical studies of
PAR4 inhibitors. Lee, F-Y. et al., "Synthesis of
1-Benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole Analogues as Novel
Antiplatelet Agents", J. Med. Chem., 4-(((22):3746-3749 (2001)
discloses in the abstract that the compound
##STR00003##
"was found to be a selective and potent inhibitor or
protease-activated receptor type 4 (PAR4)-dependent platelet
activation." Compound 58 is also referred to as YD-3 in Wu, C-C. et
al., "Selective Inhibition of Protease-activated Receptor
4-dependent Platelet Activation by YD-3", Thromb. Haemost.,
87:1026-1033 (2002). Also, see Chen, H. S. et al., "Synthesis and
antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate
(YD-3) derivatives", Bioorg. Med. Chem., 16:1262-1278 (2008).
[0007] EP1166785 A1 and EP0667345 disclose various pyrazole
derivatives which are useful as inhibitors of platelet
aggregation.
[0008] The PCT publications WO 2013/163279, WO 2013/163244, and WO
2013/163241 disclose various PAR4 antagonists that are useful as
inhibitors of platelet aggregation.
[0009] There still remains a need for compounds useful as
inhibitors of platelet aggregation.
[0010] Applicants have found potent compounds that have activity as
PAR4 inhibitors. These compounds are provided to be useful as
pharmaceuticals with desirable potency, stability, bioavailability,
therapeutic index, and toxicity values that are important to their
drugability.
SUMMARY OF THE INVENTION
[0011] It has been found that bicyclic heteroaryl substituted
compounds in accordance with the present invention are PAR4
antagonists which inhibit platelet aggregation in gamma-thrombin
induced platelet aggregation assays.
[0012] Accordingly, the present invention provides bicyclic
heteroaryl substituted compounds that are PAR4 antagonists and are
useful as selective inhibitors of platelet aggregation, including
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0013] The present invention also provides processes and
intermediates for making the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof. The present invention also provides
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier and at least one of the compounds of the present
invention or stereoisomers, tautomers, pharmaceutically acceptable
salts, solvates, or prodrugs thereof.
[0014] The present invention also provides a method for the
treatment or prophylaxis of thromboembolic disorders comprising
administering to a patient in need of such treatment or prophylaxis
a therapeutically effective amount of at least one of the compounds
of the present invention or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs
thereof.
[0015] The present invention also provides the compounds of the
present invention or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, for use in
therapy.
[0016] The present invention also provides the use of the compounds
of the present invention or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
for the manufacture of a medicament for the treatment or
prophylaxis of a thromboembolic disorder.
[0017] Other features and advantages of the invention will be
apparent from the following detailed description and claims.
DETAILED DESCRIPTION
[0018] The first aspect of the present invention provides at least
one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII),
or (VIII):
##STR00004## ##STR00005##
or a salt thereof; wherein
[0019] R.sub.1 is F, Cl, --OH, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7
cycloalkyl, C.sub.3-7 fluorocycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
fluoroalkoxy, C.sub.2-4 hydroxyalkoxy, C.sub.3-6 cycloalkoxy,
(C.sub.1-3 alkoxy)-(C.sub.1-3 alkylene), (C.sub.1-3
alkoxy)-(C.sub.1-3 fluoroalkylene), (C.sub.1-3
deuteroalkoxy)-(C.sub.1-3 deuteroalkylene), (C.sub.1-3
fluoroalkoxy)-(C.sub.1-3 alkylene), (C.sub.1-3
fluoroalkoxy)-(C.sub.1-3 fluoroalkylene),
--(CH.sub.2).sub.1-3O(phenyl), --(CH.sub.2).sub.1-3
NR.sub.aR.sub.a, --C(O)O(C.sub.1-6 alkyl), --C(O)NR.sub.aR.sub.a,
--C(O)NR.sub.bR.sub.b, --NH.sub.2, --NH(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl).sub.2, --NH(C.sub.1-6 hydroxyalkyl),
azetidinyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl,
morpholinyl, piperazinyl, --S(O).sub.2(C.sub.1-3 alkyl),
--S(O).sub.2NR.sub.aR.sub.a, C.sub.1-3 alkylthio, or C.sub.1-3
fluoroalkylthio;
[0020] R.sub.2, at each occurrence, is independently H, F, Cl, Br,
--OH, --CN, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, C.sub.1-4
hydroxyalkyl, C.sub.1-3 aminoalkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 fluorocycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-3 fluoroalkoxy, C.sub.1-3 alkylthio,
C.sub.1-3 fluoroalkylthio, (C.sub.1-3 alkoxy)-(C.sub.1-3 alkylene),
(C.sub.1-3 fluoroalkoxy)-(C.sub.1-3 alkylene), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6 alkyl).sub.2,
--C(O)O(C.sub.1-6 alkyl), --C(O)NH(CH.sub.2CH.sub.2O(C.sub.1-3
alkyl)), --C(O)NR.sub.bR.sub.b, --C(O)(piperidinyl),
--CH(OH)(C.sub.3-6 cycloalkyl), --CH(OH)(phenyl),
--CH(OH)(pyridyl), --S(O).sub.2(C.sub.1-3 alkyl),
--S(O).sub.2NR.sub.aR.sub.a, or a cyclic group selected from
phenyl, 5- to 6-membered heteroaryl, and 5- to 7-membered
heterocyclyl, wherein said cyclic group is substituted with zero to
5 substituents independently selected from F, Cl, hydroxy,
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, cyclopropyl, and --CN;
[0021] R.sub.3 is a bicyclic group selected from indolyl,
benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl,
benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl,
thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl,
4,5,6,7-tetrahydrobenzofuranyl,
4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl,
5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl,
5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl,
pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl,
6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl,
4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, and
furo[2,3-b]pyridinyl, each bicyclic group substituted with zero to
3 R.sub.3a;
[0022] R.sub.3a, at each occurrence, is independently:
(i) F, Cl, --CN, --OH, C.sub.1-3 alkyl, C.sub.1-6 fluoroalkyl,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 hydroxy-deuteroalkyl, C.sub.1-6
hydroxy-fluoroalkyl, C.sub.1-6 alkoxy, C.sub.1-3 fluoroalkoxy,
C.sub.3-6 cycloalkyl, C.sub.3-6 fluorocycloalkyl, 4- to 7-membered
heterocyclyl, --CH(OH)R.sub.y wherein R.sub.y is C.sub.3-6
cycloalkyl, aryl, heteroaryl, or 4- to 7-membered heterocyclyl;
(C.sub.1-3 alkoxy)-(C.sub.1-3 alkylene),
--(CH.sub.2).sub.1-3NR.sub.aR.sub.a, --(CH.sub.2).sub.1-3
NHS(O).sub.2(aryl), --O(CH.sub.2).sub.1-3 (aryl),
--O(CH.sub.2).sub.1-3 (thiazolyl), --O(CH.sub.2).sub.1-3
(oxazolidinonyl), --O(CH.sub.2).sub.1-3 (amino isoxazolyl),
--O(CH.sub.2).sub.1-3 (imidazolyl substituted with phenyl),
C.sub.1-6 hydroxyalkoxy, (C.sub.1-3 alkoxy)-(C.sub.1-6 alkoxy),
--O(CH.sub.2).sub.1-4O(aryl),
--O(CH.sub.2).sub.1-4O(CH.sub.2).sub.1-3 (aryl),
--O(CH.sub.2).sub.1-4NR.sub.aR.sub.a,
--O(CH.sub.2).sub.1-3CHR.sub.aNR.sub.a(methoxy pyrimidinyl),
--O(CH.sub.2).sub.1-4 NHS(O).sub.2(C.sub.1-3 alkyl),
--O(CH.sub.2).sub.1-4 NHS(O).sub.2(aryl),
--O(CH.sub.2).sub.1-4C(O)OH, --O(CH.sub.2).sub.1-4C(O)O(C.sub.1-6
alkyl), --O(CH.sub.2).sub.1-4C(O)NR.sub.a(CH.sub.2).sub.0-3 (aryl),
--O(CH.sub.2).sub.1-4C(O)NR.sub.a(CH.sub.2).sub.0-3 (heteroaryl),
--O(CH.sub.2).sub.1-4C(O)(morpholinyl),
--O(CH.sub.2).sub.1-4OC(O)O(C.sub.1-3 alkyl), --O(CH.sub.2).sub.1-3
CHR.sub.aOC(O)NR.sub.a(CH.sub.2).sub.1-4C(O)NR.sub.aR.sub.a,
--CH.sub.2CHR.sub.dOC(O)NR.sub.a(heteroaryl),
--O(CH.sub.2).sub.1-4OC(O)NR.sub.a(heteroaryl), --O(imidazolyl
substituted with aryl), --C(O)OH, --C(O)O(C.sub.1-6 alkyl),
--NR.sub.aC(O)(furanyl), --NR.sub.aC(O)(pyranyl),
--NR.sub.aC(O)O(C.sub.1-6 alkyl),
--NR.sub.aC(O)O(CH.sub.2).sub.1-4(aryl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(C.sub.1-6 alkyl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(tetrahydropyranyl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(aryl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(heteroaryl),
or
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(tetrahydrofuranyl),
wherein each of said aryl, heteroaryl, and 3- to 6-membered
heterocyclyl is substituted with zero to 5 substituents
independently selected from F, Cl, --CN, C.sub.1-3 alkyl, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-3 alkoxy, --OCF.sub.3,
--OCHF.sub.2, --NH.sub.2, --NH(C.sub.1-6 alkyl), --N(C.sub.1-6
alkyl).sub.2, --C(O)O(C.sub.1-3 alkyl), C.sub.1-3 hydroxyalkoxy,
phenyl, --CONR.sub.cR.sub.c, and --S(O).sub.2NR.sub.cR.sub.c; (ii)
--CH(OH)CR.sub.hR.sub.iR.sub.j wherein R.sub.h and R.sub.i are
independently H, F, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
C.sub.1-3 alkoxy, C.sub.1-3 fluoroalkoxy, or taken together with
the carbon atom to which they are attached, form C.sub.3-8
cycloalkyl or 4- to 7-membered heterocyclyl ring; and R.sub.j is H,
C.sub.1-6 alkyl, C.sub.1-5 fluoroalkyl, (C.sub.1-3
alkoxy)-(C.sub.1-3 alkylene), C.sub.3-8 cycloalkyl, C.sub.3-8
heterocyclyl, aryl, or heteroaryl; (iii)
--O(CH.sub.2).sub.1-4NR.sub.aS(O).sub.2(C.sub.1-4 alkyl) or
--O(CH.sub.2).sub.1-4NR.sub.aS(O).sub.2R.sub.w, wherein R.sub.w is
aryl or heteroaryl, each substituted with zero to 2 substituents
independently selected from F, Cl, cyano, C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, --OCF.sub.3, --OCHF.sub.2, and C.sub.1-3
fluoroalkyl; or (iv) --O(CH.sub.2).sub.1-4OC(O)NR.sub.aR.sub.x,
--OCH(R.sub.d)(CH.sub.2).sub.1-3OC(O)NR.sub.aR.sub.x,
--OCR.sub.dR.sub.d(CH.sub.2).sub.1-3OC(O)NR.sub.aR.sub.x,
--O(CH.sub.2).sub.1-3 CH(R.sub.d)OC(O)NR.sub.aR.sub.x,
--O(CH.sub.2).sub.1-3CR.sub.dR.sub.dOC(O)NR.sub.aR.sub.x,
--OCH(R.sub.d)CH(R.sub.d)(CH.sub.2).sub.0-2OC(O)NR.sub.aR.sub.x, or
--OCR.sub.dR.sub.dCR.sub.dR.sub.d(CH.sub.2).sub.0-2OC(O)NR.sub.aR.sub.x,
wherein R.sub.x is selected from H, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, aryl, heteroaryl, and --CH.sub.2(heteroaryl), each
aryl and heteroaryl substituted with zero to 2 substituents
independently selected from F, Cl, Br, --CN, --OH, C.sub.1-3 alkyl,
C.sub.1-3 fluoroalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6
hydroxy-deuteroalkyl, C.sub.1-6 hydroxyalkoxy, C.sub.1-6
hydroxy-fluoroalkoxy, C.sub.1-3 alkoxy, --C(O)OH,
--(CH.sub.2).sub.0-3C(O)O(C.sub.1-3 alkyl),
--(CH.sub.2).sub.1-3OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--C(O)NH.sub.2, --C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl).sub.2, --C(O)NR.sub.a(C.sub.1-6 hydroxyalkyl),
--C(O)NR.sub.bR.sub.b, --S(O).sub.2NR.sub.aR.sub.a, --NH.sub.2,
--NH(C.sub.1-6 alkyl), --NR.sub.a(C.sub.1-6 hydroxyalkyl),
--N(C.sub.1-6 alkyl).sub.2, --NR.sub.aC(O)(C.sub.1-6 alkyl),
--NR.sub.aC(O)(chloro, fluorophenyl),
--NR.sub.aS(O).sub.2(C.sub.1-3 alkyl),
--C(O)NR.sub.a(CH.sub.2).sub.0-1(hydroxymethyloxetanyl),
--C(O)NR.sub.a(CH.sub.2).sub.0-1 (hydroxymethyl C.sub.3-6
cycloalkyl), --C(O)NR.sub.a(CH.sub.2).sub.0-1(hydroxy C.sub.3-6
cycloalkyl), --C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl,
thiophenyl, methyl triazolyl, and oxazolidinonyl;
[0023] R.sub.4 is H, F, Cl, or --CH.sub.3;
[0024] R.sub.a, at each occurrence, is independently H,
C.sub.1-4alkyl, or C.sub.1-4 fluoroalkyl;
[0025] two R.sub.b along with the nitrogen atom to which they are
attached form a 4- to 7-membered heterocyclo ring having 1 to 2
nitrogen atoms and 0-1 oxygen or sulfur atoms;
[0026] R.sub.c, at each occurrence, is independently C.sub.1-3
alkyl or C.sub.1-3 hydroxyalkyl, or two R.sub.c along with the
nitrogen atom to which they are attached form a heterocyclyl or
bicyclic heterocyclyl;
[0027] R.sub.d, at each occurrence, is independently C.sub.1-6
alkyl, C.sub.1-4 fluoroalkyl, C.sub.1-6 hydroxyalkyl, (C.sub.1-4
alkoxy)-(C.sub.1-3 alkylene), (C.sub.1-2 fluoroalkoxy)-(C.sub.1-2
alkylene), (C.sub.3-6 cycloalkyl)-(C.sub.0-2 alkylene),
aryl(C.sub.1-2 alkylene), heteroaryl(C.sub.1-2 alkylene),
aryloxy-(C.sub.1-2 alkylene), aryl-CH.sub.2O--(C.sub.1-2 alkylene),
or heteroaryloxy-(C.sub.1-2 alkylene); and
[0028] n is zero, 1, or 2.
[0029] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein
[0030] R.sub.1 is --OH, C.sub.1-2 alkyl, --CHFCH.sub.3,
--CH.dbd.CH.sub.2, C.sub.1-3 alkoxy, C.sub.1-2 fluoroalkoxy,
--OCH.sub.2CH.sub.2OH, --CH.sub.2O(C.sub.1-2 alkyl),
--CD.sub.2OCD.sub.3, --CH.sub.2OCHF.sub.2, --CF.sub.2OCH.sub.3,
--CH.sub.2O(phenyl), --CH(CH.sub.3)OCH.sub.3, --NH(CH.sub.3),
--N(CH.sub.3).sub.2, --CH.sub.2N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)OCH.sub.3,
--CH(CH.sub.3)OCH.sub.3, cyclopropyl, furanyl, or
--O(cyclopropyl);
[0031] R.sub.2, at each occurrence, is independently H, F, Cl,
--CN, --CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--CH(CH.sub.3)OH, --C(CH.sub.3).sub.2OH, --CH(OH)CH.sub.2OH,
--CH.sub.2NH.sub.2, --C(O)NH.sub.2, --C(O)N(CH.sub.3).sub.2,
--C(O)(piperidinyl), --C(O)OCH.sub.3,
--C(O)NH(CH.sub.2CH.sub.2OCH.sub.3), --CH(OH)(cyclopropyl),
--CH(OH)(phenyl), --CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2, or
--C.ident.CH;
R.sub.3 is:
##STR00006##
[0032] R.sub.3a, at each occurrence, is independently: [0033] (i)
F, Cl, --CN, --OH, --CH.sub.3, --CF.sub.3, --CHFC(CH.sub.3).sub.3,
cyclopropyl, --CH.sub.2OH, --CD.sub.2OH, --CH.sub.2CH.sub.2OH,
--CH(OH)CH.sub.3, --C(CH.sub.3).sub.2OH, --CH(OH)C(CH.sub.3).sub.3,
--CD(OH)C(CH.sub.3).sub.3, --CH(OH)CF.sub.3,
--CH(OH)CH.sub.2CF.sub.3, --CH(OH)(cyclopropyl),
--CH(OH)(methylcyclopropyl), --CH(OH)(trifluoromethylcyclopropyl),
--CH(OH)(cyclopropyl substituted with phenyl),
--CH(OH)(cyclobutyl), --CH(OH)(methoxycyclobutyl),
--CH(OH)(ethoxycarbonylcyclobutyl),
--CH(OH)(trifluoromethylcyclobutyl),
--CH(OH)(hydroxymethylcyclobutyl), --CH(OH)(cyclobutyl substituted
with phenyl), --CH(OH)(cyclohexyl), --CH(OH)(methylcyclohexyl),
--CH(OH)(phenyl), --CH(OH)(isopropylphenyl),
--CH(OH)(trifluoromethylphenyl), --CH(OH)(fluoro, methoxyphenyl),
--CH(OH)(pyridinyl), --CH(OH)(thiazolyl),
--CH(OH)(tetrahydropyranyl), --CH(OH)(methyltetrahydropyranyl),
--CH.sub.2OCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2NHS(O).sub.2(phenyl), or --CH(OH)CH.sub.2(phenyl); [0034]
(ii) --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2(phenyl),
--OCH.sub.2(thiazolyl), --OCH.sub.2(oxazolidinonyl),
--OCH.sub.2(amino isoxazolyl), --OCH.sub.2(imidazolyl substituted
with phenyl), --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.3, --OCH(CH.sub.3)CH(OH)CH.sub.3,
--OCH.sub.2C(CH.sub.3).sub.2OH, --OCH.sub.2CH.sub.2O(phenyl),
--OCH.sub.2CH.sub.2OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NH(CH.sub.3), --OCH.sub.2CH(CH.sub.3)NH(methoxy
pyrimidinyl), --OCH.sub.2C(O)OH, --OCH.sub.2C(O)OCH.sub.3,
--OCH.sub.2C(O)OCH.sub.2CH.sub.3,
--OCH.sub.2C(O)OC(CH.sub.3).sub.3, --OCH.sub.2C(O)NH(phenyl),
--OCH.sub.2C(O)NHCH.sub.2(phenyl), --OCH.sub.2C(O)(morpholinyl),
--OCH.sub.2CH.sub.2CH.sub.2C(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2OC(O)OCH.sub.3,
--OCH.sub.2CH(CH.sub.3)OC(O)NHCH.sub.2CH.sub.2C(O)NH.sub.2,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OC(CH.sub.3).sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2(phenyl))OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyrimidinyl),
or --OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(methyl
pyrimidinyl); [0035] (iii) --C(O)OH, --C(O)OCH.sub.3, or
--C(O)OC(CH.sub.3).sub.3; [0036] (iv) --NHC(O)OCH.sub.3,
--NHC(O)OC(CH.sub.3).sub.3, --NHC(O)OCH.sub.2(phenyl),
--NHC(O)OCH.sub.2(tetrahydrofuranyl), or
--NHC(O)O(tetrahydropyranyl); [0037] (v)
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.3,
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydropyranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NHC(O)O(methoxyphenyl),
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2N(CH.sub.3)C(O)NH(methylpyrimidinyl), or
--OCH.sub.2CH(CH.sub.3)OC(O)OCH.sub.2(aminopyridinyl); [0038] (vi)
--OCH.sub.2CH.sub.2NHS(O).sub.2CH.sub.3 or
--OCH.sub.2CH.sub.2NHS(O).sub.2R.sub.w wherein R.sub.w is phenyl or
pyridinyl, each substituted with zero to 2 substituents
independently selected from F, Cl, and --CH.sub.3; or [0039] (vii)
--OCH.sub.2CH.sub.2OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH.sub.2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2O(isobutyl))OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NHR.sub.z, or
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NHR.sub.z
wherein R.sub.z is H, --CH.sub.2CF.sub.3, phenyl, pyrrolyl,
pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, --CH.sub.2(pyrazolyl),
--CH.sub.2(imidazolyl), or --CH.sub.2(pyridinyl), each substituted
with zero to 2 substituents independently selected from F, Cl, Br,
--CN, --OH, --CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CF.sub.3,
--CH.sub.2OH, --CD.sub.2OH, --CH(CH.sub.3)OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2CH(CH.sub.3)OH, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2CH.sub.2C(O)OCH.sub.3, --CH.sub.2OP(O)(OH).sub.2,
--CH.sub.2CH.sub.2OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--OCH.sub.3, --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2C(CH.sub.3).sub.2OH,
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.2OH, --OCH.sub.2CF.sub.2OH,
--OCH.sub.2CF.sub.2CH.sub.2OH, --C(O)OH, --C(O)OCH.sub.3,
--C(O)NH.sub.2, --C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)NH(CH.sub.2CH(CH.sub.3)OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2CH.sub.2OH),
--C(O)NH(CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)N(CH.sub.3)CH.sub.2CH.sub.2OH,
--C(O)N(CH.sub.3)CH.sub.2C(CH.sub.3).sub.2OH,
--C(O)NHCH.sub.2(hydroxymethyloxetanyl),
--C(O)NH(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2(hydroxycyclobutyl),
--C(O)NHCH.sub.2(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), --NH.sub.2, --N(CH.sub.3).sub.2,
--NHC(O)CH.sub.3, --NHC(O)(chloro, fluorophenyl),
--NH(CH.sub.2C(CH.sub.3).sub.2OH), --N(CH.sub.3)S(O).sub.2CH.sub.3,
pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and
oxazolidinonyl; R.sub.4 is H, F, or --CH.sub.3; and p is zero, 1,
2, or 3.
[0040] One embodiment provides at least one compound of Formulas
(I), (II), (III) or (IV) or a salt thereof, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and n are defined in the first aspect.
Included in this embodiment are compounds in which R.sub.3 is:
##STR00007##
p is zero, 1, 2, or 3; and R.sub.3a is defined in the first aspect.
Also included in this embodiment are compounds in which R.sub.4 is
H, F, or --CH.sub.3.
[0041] One embodiment provides at least one compound of Formulas
(I), (II), (III), or (IV) or a salt thereof, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and n are defined in the first
aspect.
[0042] One embodiment provides at least one compound of Formulas
(I) or (II) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and n are defined in the first aspect.
[0043] One embodiment provides at least one compound of Formula (I)
or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
n are defined in the first aspect.
[0044] One embodiment provides at least one compound of Formula
(II) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
and n are defined in the first aspect.
[0045] One embodiment provides at least one compound of Formula
(III) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, and n
are defined in the first aspect.
[0046] One embodiment provides at least one compound of Formula
(IV) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, and n
are defined in the first aspect.
[0047] One embodiment provides at least one compound of Formula (V)
or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
n are defined in the first aspect.
[0048] One embodiment provides at least one compound of Formula
(VI) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, and n
are defined in the first aspect.
[0049] One embodiment provides at least one compound of Formula
(VII) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and n are defined in the first aspect.
[0050] One embodiment provides at least one compound of Formula
(VIII) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, and n
are defined in the first aspect.
[0051] One embodiment provides at least one compound of Formula (I)
or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
n are defined in the first aspect. Included in this embodiment are
compounds in which R.sub.3 is:
##STR00008##
p is zero, 1, 2, or 3; and R.sub.3a is defined in the first aspect.
Also included in this embodiment are compounds in which R.sub.4 is
H, F, or --CH.sub.3.
[0052] One embodiment provides at least one compound of Formulas
(I) or (II) or a salt thereof, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and n are defined in the first aspect. Included in this
embodiment are compounds in which R.sub.3 is:
##STR00009##
p is zero, 1, 2, or 3; and R.sub.3a is defined in the first
aspect.
[0053] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), or (VIII) or a salt thereof,
wherein R.sub.3 is:
##STR00010##
R.sub.m is H or Cl; R.sub.k is H or F; and R.sub.1, R.sub.2,
R.sub.3a, R.sub.4, and n are defined in the first aspect. Included
in this embodiment are compounds of Formula (I).
[0054] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.3 is:
##STR00011##
and R.sub.1, R.sub.2, R.sub.3a, R.sub.4, and n are defined in the
first aspect. Included in this embodiment are compounds of Formula
(I).
[0055] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1 is --OH, C.sub.1-2 alkyl, --CHFCH.sub.3,
--CH.dbd.CH.sub.2, C.sub.1-3 alkoxy, C.sub.1-2 fluoroalkoxy,
--OCH.sub.2CH.sub.2OH, --CH.sub.2O(C.sub.1-2 alkyl),
--CD.sub.2OCD.sub.3, --CH.sub.2OCHF.sub.2, --CF.sub.2OCH.sub.3,
--CH.sub.2O(phenyl), --CH(CH.sub.3)OCH.sub.3, --NH(CH.sub.3),
--N(CH.sub.3).sub.2, --CH.sub.2N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)OCH.sub.3,
--CH(CH.sub.3)OCH.sub.3, cyclopropyl, furanyl, or --O(cyclopropyl);
and R.sub.2, R.sub.3, R.sub.4, and n are defined in the first
aspect. Included in this embodiment are compounds in which R.sub.1
is --CH.sub.2OCH.sub.3, --OCH.sub.3, or --OCHF.sub.2.
[0056] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.2, at each occurrence, is independently H,
F, Cl, --CN, --CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--CH(CH.sub.3)OH, --C(CH.sub.3).sub.2OH, --CH(OH)CH.sub.2OH,
--CH.sub.2NH.sub.2, --C(O)NH.sub.2, --C(O)N(CH.sub.3).sub.2,
--C(O)(piperidinyl), --C(O)OCH.sub.3,
--C(O)NH(CH.sub.2CH.sub.2OCH.sub.3), --CH(OH)(cyclopropyl),
--CH(OH)(phenyl), --CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2, or
--C.ident.CH; and R.sub.1, R.sub.3, R.sub.4, and n are defined in
the first aspect. Included in this embodiment are compounds in
which R.sub.2 is F, Cl, --CN, --CH.sub.3, or --CH.sub.2OH. Also
included in this embodiment are compounds in which R.sub.2 is
--CH.sub.3.
[0057] One embodiment provides at least one compound of Formula
(I), (II), (V), and (VII) or a salt thereof, wherein R.sub.4 is H,
F, or --CH.sub.3; and R.sub.1, R.sub.2, R.sub.3, and n are defined
in the first aspect. Included in this embodiment are compounds in
which R.sub.4 is H and F. Also included in this compounds in which
R.sub.4 is H.
[0058] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.3a, at each occurrence, is independently,
(i) F, Cl, --CN, --OH, --CH.sub.3, --CF.sub.3,
--CHFC(CH.sub.3).sub.3, cyclopropyl, --CH.sub.2OH, --CD.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH(OH)CH.sub.3, --C(CH.sub.3).sub.2OH,
--CH(OH)C(CH.sub.3).sub.3, --CD(OH)C(CH.sub.3).sub.3,
--CH(OH)CF.sub.3, --CH(OH)CH.sub.2CF.sub.3, --CH(OH)(cyclopropyl),
--CH(OH)(methylcyclopropyl), --CH(OH)(trifluoromethylcyclopropyl),
--CH(OH)(cyclopropyl substituted with phenyl),
--CH(OH)(cyclobutyl), --CH(OH)(methoxycyclobutyl),
--CH(OH)(ethoxycarbonylcyclobutyl),
--CH(OH)(trifluoromethylcyclobutyl),
--CH(OH)(hydroxymethylcyclobutyl), --CH(OH)(cyclobutyl substituted
with phenyl), --CH(OH)(cyclohexyl), --CH(OH)(methylcyclohexyl),
--CH(OH)(phenyl), --CH(OH)(isopropylphenyl),
--CH(OH)(trifluoromethylphenyl), --CH(OH)(fluoro, methoxyphenyl),
--CH(OH)(pyridinyl), --CH(OH)(thiazolyl),
--CH(OH)(tetrahydropyranyl), --CH(OH)(methyltetrahydropyranyl),
--CH.sub.2OCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2NHS(O).sub.2(phenyl), or --CH(OH)CH.sub.2(phenyl); (ii)
--OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2(phenyl),
--OCH.sub.2(thiazolyl), --OCH.sub.2(oxazolidinonyl),
--OCH.sub.2(amino isoxazolyl), --OCH.sub.2(imidazolyl substituted
with phenyl), --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.3, --OCH(CH.sub.3)CH(OH)CH.sub.3,
--OCH.sub.2C(CH.sub.3).sub.2OH, --OCH.sub.2CH.sub.2O(phenyl),
--OCH.sub.2CH.sub.2OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NH(CH.sub.3), --OCH.sub.2CH(CH.sub.3)NH(methoxy
pyrimidinyl), --OCH.sub.2C(O)OH, --OCH.sub.2C(O)OCH.sub.3,
--OCH.sub.2C(O)OCH.sub.2CH.sub.3,
--OCH.sub.2C(O)OC(CH.sub.3).sub.3, --OCH.sub.2C(O)NH(phenyl),
--OCH.sub.2C(O)NHCH.sub.2(phenyl), --OCH.sub.2C(O)(morpholinyl),
--OCH.sub.2CH.sub.2CH.sub.2C(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2OC(O)OCH.sub.3,
--OCH.sub.2CH(CH.sub.3)OC(O)NHCH.sub.2CH.sub.2C(O)NH.sub.2,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OC(CH.sub.3).sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2(phenyl))OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyrimidinyl),
or --OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(methyl
pyrimidinyl); (iii) --C(O)OH, --C(O)OCH.sub.3, or
--C(O)OC(CH.sub.3).sub.3; (iv) --NHC(O)OCH.sub.3,
--NHC(O)OC(CH.sub.3).sub.3, --NHC(O)OCH.sub.2(phenyl),
--NHC(O)OCH.sub.2(tetrahydrofuranyl), or
--NHC(O)O(tetrahydropyranyl); (v)
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.3,
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydropyranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NHC(O)O(methoxyphenyl),
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2N(CH.sub.3)C(O)NH(methylpyrimidinyl), or
--OCH.sub.2CH(CH.sub.3)OC(O)OCH.sub.2(aminopyridinyl); (vi)
--OCH.sub.2CH.sub.2NHS(O).sub.2CH.sub.3 or
--OCH.sub.2CH.sub.2NHS(O).sub.2R.sub.w wherein R.sub.w is phenyl or
pyridinyl, each substituted with zero to 2 substituents
independently selected from F, Cl, and --CH.sub.3; or (vii)
--OCH.sub.2CH.sub.2OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH.sub.2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.0-2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2O(isobutyl))(CH.sub.2).sub.0-2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NHR.sub.z, or
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NHR.sub.z
wherein R.sub.z is H, --CH.sub.2CF.sub.3, phenyl, pyrrolyl,
pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, --CH.sub.2(pyrazolyl),
--CH.sub.2(imidazolyl), or --CH.sub.2(pyridinyl), each substituted
with zero to 2 substituents independently selected from F, Cl, Br,
--CN, --OH, --CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CF.sub.3,
--CH.sub.2OH, --CD.sub.2OH, --CH(CH.sub.3)OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2CH(CH.sub.3)OH, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2CH.sub.2C(O)OCH.sub.3, --CH.sub.2OP(O)(OH).sub.2,
--CH.sub.2CH.sub.2OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--OCH.sub.3, --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2C(CH.sub.3).sub.2OH,
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.2OH, --OCH.sub.2CF.sub.2OH,
--OCH.sub.2CF.sub.2CH.sub.2OH, --C(O)OH, --C(O)OCH.sub.3,
--C(O)NH.sub.2, --C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)NH(CH.sub.2CH(CH.sub.3)OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2CH.sub.2OH),
--C(O)NH(CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)N(CH.sub.3)CH.sub.2CH.sub.2OH,
--C(O)N(CH.sub.3)CH.sub.2C(CH.sub.3).sub.2OH,
--C(O)NHCH.sub.2(hydroxymethyloxetanyl),
--C(O)NH(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2(hydroxycyclobutyl),
--C(O)NHCH.sub.2(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), --NH.sub.2, --N(CH.sub.3).sub.2,
--NHC(O)CH.sub.3, --NHC(O)(chloro, fluorophenyl),
--NH(CH.sub.2C(CH.sub.3).sub.2OH), --N(CH.sub.3)S(O).sub.2CH.sub.3,
pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and
oxazolidinonyl; and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and n are
defined in the first aspect.
[0059] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.3 is substituted with one R.sub.3a selected
from (i) F, Cl, --CN, --OH, --CH.sub.3, --CF.sub.3,
--CHFC(CH.sub.3).sub.3, cyclopropyl, --CH.sub.2OH, --CD.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH(OH)CH.sub.3, --C(CH.sub.3).sub.2OH,
--CH(OH)C(CH.sub.3).sub.3, --CD(OH)C(CH.sub.3).sub.3,
--CH(OH)CF.sub.3, --CH(OH)CH.sub.2CF.sub.3, --CH(OH)(cyclopropyl),
--CH(OH)(methylcyclopropyl), --CH(OH)(trifluoromethylcyclopropyl),
--CH(OH)(cyclopropyl substituted with phenyl),
--CH(OH)(cyclobutyl), --CH(OH)(methoxycyclobutyl),
--CH(OH)(ethoxycarbonylcyclobutyl),
--CH(OH)(trifluoromethylcyclobutyl),
--CH(OH)(hydroxymethylcyclobutyl), --CH(OH)(cyclobutyl substituted
with phenyl), --CH(OH)(cyclohexyl), --CH(OH)(methylcyclohexyl),
--CH(OH)(phenyl), --CH(OH)(isopropylphenyl),
--CH(OH)(trifluoromethylphenyl), --CH(OH)(fluoro, methoxyphenyl),
--CH(OH)(pyridinyl), --CH(OH)(thiazolyl),
--CH(OH)(tetrahydropyranyl), --CH(OH)(methyltetrahydropyranyl),
--CH.sub.2OCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2NHS(O).sub.2(phenyl), or --CH(OH)CH.sub.2(phenyl); (ii)
--OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2(phenyl),
--OCH.sub.2(thiazolyl), --OCH.sub.2(oxazolidinonyl),
--OCH.sub.2(amino isoxazolyl), --OCH.sub.2(imidazolyl substituted
with phenyl), --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.3, --OCH(CH.sub.3)CH(OH)CH.sub.3,
--OCH.sub.2C(CH.sub.3).sub.2OH, --OCH.sub.2CH.sub.2O(phenyl),
--OCH.sub.2CH.sub.2OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NH(CH.sub.3), --OCH.sub.2CH(CH.sub.3)NH(methoxy
pyrimidinyl), --OCH.sub.2C(O)OH, --OCH.sub.2C(O)OCH.sub.3,
--OCH.sub.2C(O)OCH.sub.2CH.sub.3,
--OCH.sub.2C(O)OC(CH.sub.3).sub.3, --OCH.sub.2C(O)NH(phenyl),
--OCH.sub.2C(O)NHCH.sub.2(phenyl), --OCH.sub.2C(O)(morpholinyl),
--OCH.sub.2CH.sub.2CH.sub.2C(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2OC(O)OCH.sub.3,
--OCH.sub.2CH(CH.sub.3)OC(O)NHCH.sub.2CH.sub.2C(O)NH.sub.2,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OC(CH.sub.3).sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2(phenyl))OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyrimidinyl),
or --OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(methyl
pyrimidinyl); (iii) --C(O)OH, --C(O)OCH.sub.3, or
--C(O)OC(CH.sub.3).sub.3; (iv) --NHC(O)OCH.sub.3,
--NHC(O)OC(CH.sub.3).sub.3, --NHC(O)OCH.sub.2(phenyl),
--NHC(O)OCH.sub.2(tetrahydrofuranyl), or
--NHC(O)O(tetrahydropyranyl); (v)
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.3,
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydropyranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NHC(O)O(methoxyphenyl),
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2N(CH.sub.3)C(O)NH(methylpyrimidinyl), or
--OCH.sub.2CH(CH.sub.3)OC(O)OCH.sub.2(aminopyridinyl); (vi)
--OCH.sub.2CH.sub.2NHS(O).sub.2CH.sub.3 or
--OCH.sub.2CH.sub.2NHS(O).sub.2R.sub.w wherein R.sub.w is phenyl or
pyridinyl, each substituted with zero to 2 substituents
independently selected from F, Cl, and --CH.sub.3; or (vii)
--OCH.sub.2CH.sub.2OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH.sub.2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.0-2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2O(isobutyl))(CH.sub.2).sub.0-2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NHR.sub.z, or
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NHR.sub.z
wherein R.sub.z is H, --CH.sub.2CF.sub.3, phenyl, pyrrolyl,
pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, --CH.sub.2(pyrazolyl),
--CH.sub.2(imidazolyl), or --CH.sub.2(pyridinyl), each substituted
with zero to 2 substituents independently selected from F, Cl, Br,
--CN, --OH, --CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CF.sub.3,
--CH.sub.2OH, --CD.sub.2OH, --CH(CH.sub.3)OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2CH(CH.sub.3)OH, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2CH.sub.2C(O)OCH.sub.3, --CH.sub.2OP(O)(OH).sub.2,
--CH.sub.2CH.sub.2OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--OCH.sub.3, --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2C(CH.sub.3).sub.2OH,
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.2OH, --OCH.sub.2CF.sub.2OH,
--OCH.sub.2CF.sub.2CH.sub.2OH, --C(O)OH, --C(O)OCH.sub.3,
--C(O)NH.sub.2, --C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)NH(CH.sub.2CH(CH.sub.3)OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2CH.sub.2OH),
--C(O)NH(CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)N(CH.sub.3)CH.sub.2CH.sub.2OH,
--C(O)N(CH.sub.3)CH.sub.2C(CH.sub.3).sub.2OH,
--C(O)NHCH.sub.2(hydroxymethyloxetanyl),
--C(O)NH(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2(hydroxycyclobutyl),
--C(O)NHCH.sub.2(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), --NH.sub.2, --N(CH.sub.3).sub.2,
--NHC(O)CH.sub.3, --NHC(O)(chloro, fluorophenyl),
--NH(CH.sub.2C(CH.sub.3).sub.2OH), --N(CH.sub.3)S(O).sub.2CH.sub.3,
pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and
oxazolidinonyl; and zero to 2 R.sub.3a independently selected from
F, Cl, --CN, --CH.sub.3, --CF.sub.3, and --OCH.sub.3; and R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and n are defined in the first
aspect.
[0060] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4,
R.sub.a, R.sub.b, R.sub.d, and n are defined in the first aspect
with the proviso that at least one R.sub.3a is F, Cl, --CN, --OH,
C.sub.1-3 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 hydroxyalkyl,
C.sub.1-6 hydroxy-deuteroalkyl, C.sub.1-6 hydroxy-fluoroalkyl,
C.sub.1-6 alkoxy, C.sub.1-3 fluoroalkoxy, C.sub.3-6 cycloalkyl,
C.sub.3-6 fluorocycloalkyl, 3- to 6-membered heterocyclyl,
--CH(OH)R.sub.y wherein R.sub.y is C.sub.3-6 cycloalkyl, aryl,
heteroaryl, or 3- to 6-membered heterocyclyl; (C.sub.1-3
alkoxy)-(C.sub.1-3 alkylene), --(CH.sub.2).sub.1-3NR.sub.aR.sub.a,
--(CH.sub.2).sub.1-3 NHS(O).sub.2(aryl), --O(CH.sub.2).sub.1-3
(aryl), --O(CH.sub.2).sub.1-3 (thiazolyl), --O(CH.sub.2).sub.1-3
(oxazolidinonyl), --O(CH.sub.2).sub.1-3 (amino isoxazolyl),
--O(CH.sub.2).sub.1-3 (imidazolyl substituted with phenyl),
C.sub.1-6 hydroxyalkoxy, (C.sub.1-3 alkoxy)-(C.sub.1-6 alkoxy),
--O(CH.sub.2).sub.1-4O(aryl),
--O(CH.sub.2).sub.1-4O(CH.sub.2).sub.1-3 (aryl),
--O(CH.sub.2).sub.1-4NR.sub.aR.sub.a,
--O(CH.sub.2).sub.1-3CHR.sub.aR.sub.a(methoxy pyrimidinyl),
--O(CH.sub.2).sub.1-4 NHS(O).sub.2(C.sub.1-3 alkyl),
--O(CH.sub.2).sub.1-4NHS(O).sub.2(aryl),
--O(CH.sub.2).sub.1-4C(O)OH, --O(CH.sub.2).sub.1-4C(O)O(C.sub.1-6
alkyl), --O(CH.sub.2).sub.1-4C(O)NR.sub.a(CH.sub.2).sub.0-3 (aryl),
--O(CH.sub.2).sub.1-4C(O)NR.sub.a(CH.sub.2).sub.0-3 (heteroaryl),
--O(CH.sub.2).sub.1-4C(O)(morpholinyl),
--O(CH.sub.2).sub.1-4OC(O)O(C.sub.1-3 alkyl), --O(CH.sub.2).sub.1-3
CHR.sub.aOC(O)NR.sub.a(CH.sub.2).sub.1-4C(O)NR.sub.aR.sub.a,
--CH.sub.2CHR.sub.dOC(O)NR.sub.a(heteroaryl),
--O(CH.sub.2).sub.1-4OC(O)NR.sub.a(heteroaryl), --O(imidazolyl
substituted with aryl), --C(O)OH, --C(O)O(C.sub.1-6 alkyl),
--NR.sub.aC(O)(furanyl), --NR.sub.aC(O)(pyranyl),
--NR.sub.aC(O)O(C.sub.1-6 alkyl), --NR.sub.aC(O)O(CH.sub.2).sub.1-4
(aryl), --O(CH.sub.2).sub.1-4NR.sub.aC(O)O(C.sub.1-6 alkyl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4
(tetrahydropyranyl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4 (aryl),
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4 (heteroaryl),
or
--O(CH.sub.2).sub.1-4NR.sub.aC(O)O(CH.sub.2).sub.0-4(tetrahydrofuranyl),
wherein each of said aryl, heteroaryl, and 3- to 6-membered
heterocyclyl is substituted with zero to 5 substituents
independently selected from F, Cl, --CN, C.sub.1-3 alkyl, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-3 alkoxy, --OCF.sub.3,
--OCHF.sub.2, --NH.sub.2, --NH(C.sub.1-6 alkyl), --N(C.sub.1-6
alkyl).sub.2, --C(O)O(C.sub.1-3 alkyl), C.sub.1-3 hydroxyalkoxy,
phenyl, --CONR.sub.cR.sub.c, and --S(O).sub.2NR.sub.cR.sub.c.
[0061] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4,
R.sub.a, R.sub.b, R.sub.d, and n are defined in the first aspect
with the proviso that at least one R.sub.3a is
--CH(OH)CR.sub.hR.sub.iR.sub.j wherein R.sub.h and R.sub.i are
independently H, F, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, or taken
together with the carbon atom to which they are attached, form
C.sub.3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring; and
R.sub.j is H, C.sub.1-6 alkyl, C.sub.1-5 fluoroalkyl, (C.sub.1-3
alkoxy)-(C.sub.1-3 alkylene), C.sub.3-8 cycloalkyl, C.sub.3-8
heterocyclyl, aryl, or heteroaryl; and p is 1, 2, or 3. Included in
this embodiment are compounds of Formulas (I), (II), (III), or
(IV).
[0062] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4,
R.sub.a, R.sub.b, R.sub.d, and n are defined in the first aspect
with the proviso that at least one R.sub.3a is
--O(CH.sub.2).sub.1-4NR.sub.aS(O).sub.2(C.sub.1-3 alkyl) or
--O(CH.sub.2).sub.1-4NR.sub.aS(O).sub.2R.sub.w, wherein R.sub.w is
aryl or heteroaryl, each substituted with zero to 2 substituents
independently selected from F, Cl, cyano, C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, --OCF.sub.3, --OCHF.sub.2, and C.sub.1-3
fluoroalkyl; and p is 1, 2, or 3. Included in this embodiment are
compounds of Formulas (I), (II), (III), or (IV).
[0063] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4,
R.sub.a, R.sub.b, R.sub.d, and n are defined in the first aspect
with the proviso that at least one R.sub.3a is
--O(CH.sub.2).sub.1-4OC(O)NR.sub.aR.sub.x,
--OCH(R.sub.d)(CH.sub.2).sub.1-3OC(O)NR.sub.aR.sub.x,
--OCR.sub.dR.sub.d(CH.sub.2).sub.1-3OC(O)NR.sub.aR.sub.x,
--O(CH.sub.2).sub.1-3 CH(R.sub.d)OC(O)NR.sub.aR.sub.x,
--O(CH.sub.2).sub.1-3CR.sub.dR.sub.dOC(O)NR.sub.aR.sub.x,
--OCH(R.sub.d)CH(R.sub.d)(CH.sub.2).sub.0-2OC(O)NR.sub.aR.sub.x, or
--OCR.sub.dR.sub.dCR.sub.dR.sub.d(CH.sub.2).sub.0-2OC(O)NR.sub.aR.sub.x,
wherein R.sub.x is selected from H, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, aryl, heteroaryl, and --CH.sub.2(heteroaryl), each
aryl and heteroaryl substituted with zero to 2 substituents
independently selected from F, Cl, Br, --CN, --OH, C.sub.1-3 alkyl,
C.sub.1-3 fluoroalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6
hydroxy-deuteroalkyl, C.sub.1-6 hydroxyalkoxy, C.sub.1-6
hydroxy-fluoroalkoxy, C.sub.1-3 alkoxy, --C(O)OH,
--(CH.sub.2).sub.0-3C(O)O(C.sub.1-3 alkyl),
--(CH.sub.2).sub.1-3OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--C(O)NH.sub.2, --C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl).sub.2, --C(O)NR.sub.a(C.sub.1-6 hydroxyalkyl),
--C(O)NR.sub.bR.sub.b, --S(O).sub.2NR.sub.aR.sub.a, --NH.sub.2,
--NH(C.sub.1-6 alkyl), --NR.sub.a(C.sub.1-6 hydroxyalkyl),
--N(C.sub.1-6 alkyl).sub.2, --NR.sub.aC(O)(C.sub.1-6 alkyl),
--NR.sub.aC(O)(chloro, fluorophenyl),
--NR.sub.aS(O).sub.2(C.sub.1-3 alkyl),
--C(O)NR.sub.a(CH.sub.2).sub.0-1(hydroxymethyloxetanyl),
--C(O)NR.sub.a(CH.sub.2).sub.0-1 (hydroxymethyl C.sub.3-6
cycloalkyl), --C(O)NR.sub.a(CH.sub.2).sub.0-1 (hydroxy C.sub.3-6
cycloalkyl), --C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl,
thiophenyl, methyl triazolyl, and oxazolidinonyl; and p is 1, 2, or
3. Included in this embodiment are compounds of Formulas (I), (II),
(III), or (IV).
[0064] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is F, Cl, --CN, --OH, --CH.sub.3, --CF.sub.3,
--CHFC(CH.sub.3).sub.3, cyclopropyl, --CH.sub.2OH, --CD.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH(OH)CH.sub.3, --C(CH.sub.3).sub.2OH,
--CH(OH)C(CH.sub.3).sub.3, --CD(OH)C(CH.sub.3).sub.3,
--CH(OH)CF.sub.3, --CH(OH)CH.sub.2CF.sub.3, --CH(OH)(cyclopropyl),
--CH(OH)(methylcyclopropyl), --CH(OH)(trifluoromethylcyclopropyl),
--CH(OH)(cyclopropyl substituted with phenyl),
--CH(OH)(cyclobutyl), --CH(OH)(methoxycyclobutyl),
--CH(OH)(ethoxycarbonylcyclobutyl),
--CH(OH)(trifluoromethylcyclobutyl),
--CH(OH)(hydroxymethylcyclobutyl), --CH(OH)(cyclobutyl substituted
with phenyl), --CH(OH)(cyclohexyl), --CH(OH)(methylcyclohexyl),
--CH(OH)(phenyl), --CH(OH)(isopropylphenyl),
--CH(OH)(trifluoromethylphenyl), --CH(OH)(fluoro, methoxyphenyl),
--CH(OH)(pyridinyl), --CH(OH)(thiazolyl),
--CH(OH)(tetrahydropyranyl), --CH(OH)(methyltetrahydropyranyl),
--CH.sub.2OCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2NHS(O).sub.2(phenyl), or --CH(OH)CH.sub.2(phenyl); and p
is 1, 2, or 3. Included in this embodiment are compounds of
Formulas (I), (II), (III), or (IV).
[0065] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2(phenyl), --OCH.sub.2(thiazolyl),
--OCH.sub.2(oxazolidinonyl), --OCH.sub.2(amino isoxazolyl),
--OCH.sub.2(imidazolyl substituted with phenyl),
--OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.3, --OCH(CH.sub.3)CH(OH)CH.sub.3,
--OCH.sub.2C(CH.sub.3).sub.2OH, --OCH.sub.2CH.sub.2O(phenyl),
--OCH.sub.2CH.sub.2OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NH(CH.sub.3), --OCH.sub.2CH(CH.sub.3)NH(methoxy
pyrimidinyl), --OCH.sub.2C(O)OH, --OCH.sub.2C(O)OCH.sub.3,
--OCH.sub.2C(O)OCH.sub.2CH.sub.3,
--OCH.sub.2C(O)OC(CH.sub.3).sub.3, --OCH.sub.2C(O)NH(phenyl),
--OCH.sub.2C(O)NHCH.sub.2(phenyl), --OCH.sub.2C(O)(morpholinyl),
--OCH.sub.2CH.sub.2CH.sub.2C(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2OC(O)OCH.sub.3,
--OCH.sub.2CH(CH.sub.3)OC(O)NHCH.sub.2CH.sub.2C(O)NH.sub.2,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OC(CH.sub.3).sub.3)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2(phenyl))OC(O)NH(pyridinyl),
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(pyrimidinyl),
or --OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NH(methyl
pyrimidinyl); and p is 1, 2, or 3. Included in this embodiment are
compounds of Formulas (I), (II), (III), or (IV).
[0066] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is --C(O)OH, --C(O)OCH.sub.3, or
--C(O)OC(CH.sub.3).sub.3; and p is 1, 2, or 3. Included in this
embodiment are compounds of Formulas (I), (II), (III), or (IV).
[0067] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is --NHC(O)OCH.sub.3, --NHC(O)OC(CH.sub.3).sub.3,
--NHC(O)OCH.sub.2(phenyl), --NHC(O)OCH.sub.2(tetrahydrofuranyl), or
--NHC(O)O(tetrahydropyranyl); and p is 1, 2, or 3. Included in this
embodiment are compounds of Formulas (I), (II), (III), or (IV).
[0068] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is --OCH.sub.2CH.sub.2NHC(O)OCH.sub.3,
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydropyranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(phenyl),
--OCH.sub.2CH.sub.2NHC(O)O(methoxyphenyl),
--OCH.sub.2CH.sub.2NHC(O)O(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)OCH.sub.2(tetrahydrofuranyl),
--OCH.sub.2CH.sub.2NHC(O)NH(pyridinyl),
--OCH.sub.2CH.sub.2N(CH.sub.3)C(O)NH(methylpyrimidinyl), or
--OCH.sub.2CH(CH.sub.3)OC(O)OCH.sub.2(aminopyridinyl); and p is 1,
2, or 3. Included in this embodiment are compounds of Formulas (I),
(II), (III), or (IV).
[0069] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is --OCH.sub.2CH.sub.2NHS(O).sub.2CH.sub.3 or
--OCH.sub.2CH.sub.2NHS(O).sub.2R.sub.w wherein R.sub.w is phenyl or
pyridinyl, each substituted with zero to 2 substituents
independently selected from F, Cl, and --CH.sub.3; and p is 1, 2,
or 3. Included in this embodiment are compounds of Formulas (I),
(II), (III), or (IV).
[0070] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.4, and
n are defined in the first aspect with the proviso that at least
one R.sub.3a is --OCH.sub.2CH.sub.2OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH.sub.2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z,
--OCH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.0-2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2O(isobutyl))(CH.sub.2).sub.0-2OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2CH.sub.3)OC(O)NHR.sub.z,
--OCH.sub.2CH(CH.sub.2OCH.sub.3)OC(O)NHR.sub.z, or
--OCH.sub.2CH(CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2)OC(O)NHR.sub.z
wherein R.sub.z is H, --CH.sub.2CF.sub.3, phenyl, pyrrolyl,
pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, --CH.sub.2(pyrazolyl),
--CH.sub.2(imidazolyl), or --CH.sub.2(pyridinyl), each substituted
with zero to 2 substituents independently selected from F, Cl, Br,
--CN, --OH, --CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CF.sub.3,
--CH.sub.2OH, --CD.sub.2OH, --CH(CH.sub.3)OH, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2CH(CH.sub.3)OH, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2CH.sub.2C(O)OCH.sub.3, --CH.sub.2OP(O)(OH).sub.2,
--CH.sub.2CH.sub.2OP(O)(OH).sub.2, --CH.sub.2(morpholinyl),
--OCH.sub.3, --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH(CH.sub.3)OH,
--OCH.sub.2C(CH.sub.3).sub.2OH,
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, --OCH(CH.sub.3)CH.sub.2OH,
--OCH.sub.2CH(OH)CH.sub.2OH, --OCH.sub.2CF.sub.2OH,
--OCH.sub.2CF.sub.2CH.sub.2OH, --C(O)OH, --C(O)OCH.sub.3,
--C(O)NH.sub.2, --C(O)NH(CH.sub.3), --C(O)N(CH.sub.3).sub.2,
--C(O)NH(CH.sub.2CH.sub.2OH), --C(O)NH(CH.sub.2CH(CH.sub.3)OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)NH(CH.sub.2C(CH.sub.3).sub.2CH.sub.2OH),
--C(O)NH(CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH),
--C(O)N(CH.sub.3)CH.sub.2CH.sub.2OH,
--C(O)N(CH.sub.3)CH.sub.2C(CH.sub.3).sub.2OH,
--C(O)NHCH.sub.2(hydroxymethyloxetanyl),
--C(O)NH(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2(hydroxycyclobutyl),
--C(O)NHCH.sub.2(hydroxymethylcyclobutyl),
--C(O)NHCH.sub.2C(CH.sub.3).sub.2OP(O)(OH).sub.2,
--C(O)(hydroxypiperidinyl), --C(O)(hydroxypyrrolidinyl),
--C(O)(hydroxymethylpyrrolidinyl), --C(O)(morpholinyl),
--C(O)(hydroxymethylmorpholinyl), --NH.sub.2, --N(CH.sub.3).sub.2,
--NHC(O)CH.sub.3, --NHC(O)(chloro, fluorophenyl),
--NH(CH.sub.2C(CH.sub.3).sub.2OH), --N(CH.sub.3)S(O).sub.2CH.sub.3,
pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and
oxazolidinonyl; and p is 1, 2, or 3. Included in this embodiment
are compounds of Formulas (I), (II), (III), or (IV).
[0071] One embodiment provides at least one compound of Formulas
(I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt
thereof, wherein R.sub.3 is substituted with zero to 1 R.sub.3a.
Included in this embodiment are compounds in which R.sub.3 is
unsubstituted.
[0072] One embodiment provides at least one compound of Formula (I)
or a salt thereof, wherein R.sub.1 is --OCH.sub.3, --OCHF.sub.2,
--OCH.sub.2CH.sub.3, or --CH.sub.2OCH.sub.3; R.sub.2, at each
occurrence, is independently H, F, Cl, --CN, --CH.sub.3,
--OCH.sub.3, or --CH.sub.2OH; and
R.sub.3 is:
##STR00012##
[0073] and R.sub.4, R.sub.3a, and p are defined in the first
aspect.
[0074] One embodiment provides at least one compound of Formula
(II) or a salt thereof, wherein R.sub.1 is --OH, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCHF.sub.2, --OCH.sub.2CHF.sub.2,
--CH.sub.2OCH.sub.3, or --NH(CH.sub.3); R.sub.2, at each
occurrence, is independently F, Cl, --CN, --CH.sub.3, --CH.sub.2OH,
--CH.sub.2F, --CHF.sub.2, or --OCH.sub.3;
R.sub.3 is:
##STR00013##
[0075] and R.sub.3a, at each occurrence, is independently F, Cl,
--CH.sub.3, --OCH.sub.3, --CH(OH)(trifluoromethylcyclobutyl),
--OCH.sub.2CH(CH.sub.3)OC(O)NHR.sub.z, or
--OCH(CH.sub.3)CH(CH.sub.3)OC(O)NHR.sub.z, wherein R.sub.z is
pyridinyl, pyrimidinyl, or benzo[d]oxazolonyl, each substituted
with zero to 2 substituents independently selected from F, --OH,
--CN, --CH.sub.3, --CF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--OCH.sub.2CH.sub.2OH, --OCH.sub.3, --CH.sub.2CH(CH.sub.3)OH, and
--OCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH; and R.sub.4 and p are
defined in the first aspect.
[0076] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is indolyl.
Included in this embodiment is a compound of Formula (I) selected
from 2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline
(5).
[0077] One embodiment provides compounds selected from one of the
examples, more preferably, Examples 1 to 837, or stereoisomers,
tautomers, pharmaceutically acceptable salts, or solvates
thereof.
[0078] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is benzofuranyl.
Included in this embodiment is a compound of Formulas (I), (II),
(III), or (IV) selected from: [0079]
5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (1);
[0080]
2-(difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline
(2); [0081]
2-(difluoromethoxy)-5-(4,5-dimethoxybenzofuran-2-yl)-7-methylquino-
xaline (6); [0082]
5-(7-chlorobenzofuran-2-yl)-2-methoxy-7-methylquinoxaline (37);
[0083]
2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)eth-
yl (2-methylpyridin-4-yl)carbamate (38); [0084]
N-(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)-
ethyl)benzenesulfonamide (39); [0085]
2-(difluoromethoxy)-5-(7-methoxybenzofuran-2-yl)-7-methylquinoxaline
(41); [0086]
2-(difluoromethoxy)-5-(4-methoxybenzofuran-2-yl)-7-methylquinoxaline
(42); [0087]
5-(4-(benzyloxy)benzofuran-2-yl)-2-methoxy-7-methylquinoxaline
(43); [0088] 5-(5-(benzyloxy)
benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (44);
methyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethy-
lcarbamate (46); [0089] tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)
acetate (49); [0090]
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)-N-m-
ethylethanamine (54); [0091]
2-methoxy-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline (56);
[0092]
5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline
(120); [0093]
5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methyl-
quinoxaline (121); [0094]
5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxal-
ine (122); [0095]
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)eth-
yl (2-methylpyridin-4-yl)carbamate (123); [0096]
(8-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)-
methanol (124);
(8-(6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol
(125); [0097]
2-((6-fluoro-2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)benzofuran-5-y-
l)oxy)ethyl (2-methylpyridin-4-yl)carbamate (126); [0098]
5-(benzofuran-2-yl)-7-methyl-2-vinylquinoxaline (131); [0099]
5-(benzofuran-2-yl)-2-ethyl-7-methylquinoxaline (132); [0100]
5-(benzofuran-2-yl)-2-(difluoromethoxy)-8-methylquinoxaline (133);
[0101] 5-(benzofuran-2-yl)-2-(furan-3-yl)-7-methylquinoxaline
(135); [0102] 5-(benzofuran-2-yl)-2-methoxy-7-methylquinoxaline
(175); methyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
(176); [0103]
5-(benzofuran-2-yl)-2-(1-methoxyethyl)-7-methylquinoxaline (184);
[0104] 5-(benzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
(195); and [0105] 5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline
(661).
[0106] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
benzo[b]thiophenyl. Included in this embodiment is a compound of
Formula (I) selected from [0107]
5-(benzo[b]thiophen-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
(40).
[0108] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
benzo[d]imidazolyl. Included in this embodiment is a compound of
Formula (I) selected from: [0109]
5-(1H-benzo[d]imidazol-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
(47); and [0110]
2-(difluoromethoxy)-5-(5-methoxy-1H-benzo[d]imidazol-2-yl)-7-methylquinox-
aline (50).
[0111] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
benzo[d]oxazolyl. Included in this embodiment is a compound of
Formula (I) selected from: [0112]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]oxazole
(3).
[0113] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
benzo[d]thiazolyl. Included in this embodiment is a compound of
Formula (I) to (III) selected from: [0114]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(4); [0115]
6-(benzyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thia-
zole (7); [0116]
4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(8); [0117]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d-
]thiazole (10); [0118]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxy-4-methylbenzo[d-
]thiazole (12); [0119]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-difluoro-7-methoxyben-
zo[d]thiazole (13); [0120] tert-butyl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)
carbamate (14); [0121]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(thiazol-4-ylmethoxy)be-
nzo[d]thiazole (15); [0122] tetrahydrofuran-3-yl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)-
oxy)ethyl)carbamate (16); [0123]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-phenoxyethoxy)benzo[-
d]thiazole (17); [0124]
7-(2-(benzyloxy)ethoxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)be-
nzo[d]thiazole (18); [0125] (tetrahydrofuran-2-yl)methyl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (19); [0126]
tetrahydro-2H-pyran-4-yl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (20); [0127]
tetrahydro-2H-pyran-4-yl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-7-yl)carbamate (21); [0128] (tetrahydrofuran-2-yl)
methyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-7-yl)carbamate (22); [0129]
4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yl)oxy)ethyl)benzenesulfonamide (26); [0130]
N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)ethyl) benzenesulfonamide (27); [0131]
N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (28);
[0132]
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylben-
zo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (29); [0133]
N-(2-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)-
oxy) ethyl)-4-fluorobenzenesulfonamide (30); [0134]
N-(2-((2-(2-ethyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)o-
xy)ethyl)-4-fluorobenzenesulfonamide (31); [0135] methyl
5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)--
7-methylquinoxaline-2-carboxylate (32); [0136]
N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-
-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (33); [0137]
4-fluoro-N-(2-((2-(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylben-
zo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (34); [0138]
2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-6-((2-phenyl-1H-imidazol-5-
-yl)methoxy)benzo[d]thiazole (35); [0139]
N-benzyl-2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy)acetamide (36); [0140]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazole
(48); [0141]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzo[d]thiazole
(51); [0142]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
(52); [0143]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazole
(53); [0144]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thia-
zole (55); [0145]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxybenzo[d]thiazole
(58); [0146]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluoro-6-methoxybenzo[d-
]thiazole (59); [0147]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazole
(60); [0148] methyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole-7-carboxy-
late (61); [0149]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
oxy)ethyl) benzenesulfonamide (63);
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)meth-
anol (64); [0150]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(methoxymethyl)benzo[d]-
thiazole (65); [0151]
N-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)m-
ethyl)benzenesulfonamide (66); [0152]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thi-
azol-6-yloxy) ethyl) benzenesulfonamide (67); [0153]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole
(68); methyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy-
)ethylcarbamate (69); [0154] methyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-7-yloxy)ethylcarbamate (70); [0155]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(thiazol-4-ylmethoxy)be-
nzo[d]thiazole (71); [0156]
N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)
benzenesulfonamide (72); [0157]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yloxy) ethyl)benzenesulfonamide (73); [0158]
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy-
)ethanol (74); [0159]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[-
d]thiazole (75); [0160] benzyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbam-
ate (76); [0161]
2-(2-methoxy-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole
(77); [0162]
2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole
(78); [0163]
N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylo-
xy)ethyl) benzenesulfonamide (79); [0164] methyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-7-ylcarbamate (80); [0165]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide (81); [0166]
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-7-yloxy)-N-phenylacetamide (82); [0167]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yloxy) ethyl)-4-(trifluoromethyl) benzenesulfonamide (83);
[0168]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yloxy) ethyl)-2,4-difluorobenzenesulfonamide (84); [0169]
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yloxy) ethyl)-3,4-difluorobenzenesulfonamide (85); [0170]
4-chloro N (2 (2 (2
(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylox-
y)ethyl)benzenesulfonamide (86); [0171]
N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylo-
xy) ethyl)-4-methylbenzenesulfonamide (87); [0172] 4-fluoro N (2 (2
(2
(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl)benzenesulfonamide (89); [0173] 4-fluoro N (2 (2 (2
methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-ylo-
xy)ethyl) benzenesulfonamide (90); [0174]
N-(2-(2-(2-cyclopropyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-
-yloxy)ethyl)-4-fluorobenzenesulfonamide (91); [0175] benzyl
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol--
6-yloxy) ethylcarbamate (92); [0176]
4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazole (93); [0177]
5-(5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
(94); [0178]
N-(2-(4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo-
[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (95); [0179] 2-fluoro N
(2 (2 (2
(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylo-
xy)ethyl) benzenesulfonamide (96); [0180] 3-fluoro N (2 (2 (2
(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl)benzenesulfonamide (97); [0181]
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yloxy) ethyl) methanesulfonamide (98); [0182]
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yloxy) ethyl)benzenesulfonamide (99); [0183]
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yloxy) ethyl)-2-fluorobenzenesulfonamide (100); [0184]
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide (101); [0185]
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yloxy) ethyl)-3-fluorobenzenesulfonamide (102); [0186]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-
-carbonitrile (103); [0187]
N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yloxy)ethyl) benzenesulfonamide (104); [0188]
N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (105); [0189]
N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ylox-
y) ethyl)benzenesulfonamide (106); [0190] 4-fluoro N (2 (2 (2
(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)ben-
zenesulfonamide (107); [0191] 4-fluoro N (2 (2 (2 (1
fluoroethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)eth-
yl)benzenesulfonamide (108); [0192]
N-(2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (109); [0193]
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl phenylcarbamate (110); [0194]
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl pyridin-3-ylcarbamate (111); [0195]
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl 6-methoxypyridin-3-ylcarbamate (112); [0196]
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethylpyridin-4-ylcarbamate (113); [0197]
N-(2-(2-(2-((difluoromethoxy)methyl)-7-methylquinoxalin-5-yl)-4-methylben-
zo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (114);
[0198]
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl
6-methoxypyridin-3-ylcarbamate (115); [0199]
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl 5-cyanopyridin-3-ylcarbamate (116); [0200]
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethyl (6-cyanopyridin-3-yl) carbamate (117); [0201]
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl
(3-cyanophenyl)carbamate (118); [0202]
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethyl (2-chloropyrimidin-5-yl)carbamate (119); [0203]
3-methoxy-8-(6-methoxybenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol
(127); [0204]
2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-
-6-yloxy)ethyl 6-methylpyridin-3-ylcarbamate (128); [0205]
2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-
-6-yloxy)ethyl 2-methylpyridin-4-ylcarbamate (129); [0206] methyl
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxy-
late (152); [0207]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)meth-
anol (154); [0208]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl) methanol (155); [0209]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl) ethanol (156); [0210]
2-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl) propan-2-ol (157); [0211]
cyclopropyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-4-yl)methanol (158); [0212]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-N,N-dimethylmethanamine (159); [0213]
cyclopropyl(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-4-yl) methanol (160); [0214]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl) (phenyl)methanol (161); [0215]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-
-carboxylic acid (162); [0216]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl)(phenyl) methanol (163); [0217]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-2,2-dimethylpropan-1-ol (164); [0218]
cyclohexyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-4-yl)methanol (165); [0219]
cyclobutyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-4-yl)methanol (166); [0220]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl)(pyridin-2-yl)methanol (167); [0221]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl) (pyridin-3-yl)methanol (168); [0222]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-2,2-dimethylpropan-1-ol-1-d.sub.1 (169); [0223]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-2,2-dimethylpropan-1-ol-d.sub.5 (170); [0224]
2,2,2-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl-
)benzo[d]thiazol-4-yl)ethanol (171); [0225]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl)(pyridin-4-yl)methanol (172); [0226]
3,3,3-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl-
)benzo[d]thiazol-4-yl)propan-1-ol (173); [0227]
2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-4-yl) ethanol (174); [0228]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]t-
hiazole (183); [0229]
2-(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methy-
lbenzo[d]thiazole (186); [0230]
6-methoxy-4-methyl-2-(7-methyl-2-(phenoxymethyl)quinoxalin-5-yl)benzo[d]t-
hiazole (187); [0231]
1-(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)-N,-
N-dimethyl methanamine (188); [0232]
2-(2-(ethoxymethyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]th-
iazole (189); [0233]
N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl-
)oxy) ethyl)-4-fluorobenzenesulfonamide (199); [0234]
N-(2-((2-(7-chloro-2-(methoxymethyl)
quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenes-
ulfonamide (200); [0235]
2-(7-chloro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxybenzo[d]thiazole
(201); [0236]
2-(7-chloro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxybenzo[d]thiazole
(202); [0237]
6-methoxy-2-(2-(methoxymethyl)-7-(trifluoromethoxy)quinoxalin-5-yl)-4-met-
hylbenzo[d]thiazole (203); [0238] methyl
8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)
quinoxaline-6-carboxylate (204); [0239] methyl
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)--
3-(methoxy methyl)quinoxaline-6-carboxylate (205); [0240]
2-(7-fluoro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]t-
hiazole (206); [0241]
4-fluoro-N-(2-((2-(7-fluoro-2-(methoxymethyl)quinoxalin-5-yl)-4-methylben-
zo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (207); [0242]
6-methoxy-2-(2-(methoxymethyl)-7-(trifluoromethyl)quinoxalin-5-yl)-4-meth-
ylbenzo[d]thiazole (208); [0243]
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(trifluoromethyl)quinoxalin-5-yl)--
4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
(209);
[0244] 4-chloro-2-(7-chloro-2-(methoxymethyl)
quinoxalin-5-yl)-6-methoxybenzo[d]thiazole (210); [0245]
3-methoxy-8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)quinoxaline-6-carboni-
trile (211); [0246] 4-chloro-6-methoxy-2-(2-(methoxymethyl)
quinoxalin-5-yl)benzo[d]thiazole (212); [0247]
4-fluoro-N-(2-((2-(2-(methoxymethyl)
quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)
benzenesulfonamide (213); [0248]
2-(7-chloro-2-methoxyquinoxalin-5-yl)-4,5-difluoro-6-methoxybenzo[d]thiaz-
ole (214); [0249]
4-chloro-2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluoro-6-methoxybenzo[d]-
thiazole (215); [0250]
4-chloro-5-fluoro-6-methoxy-2-(2-methoxy-6,7-dimethylquinoxalin-5-yl)benz-
o[d]thiazole (216); [0251]
8-(4,5-difluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-car-
bonitrile (217); [0252]
(8-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin--
6-yl)methanol (218); [0253]
(3-methoxy-8-(6-methoxy-4,5-dimethylbenzo[d]thiazol-2-yl)quinoxalin-6-yl)-
methanol (219); [0254]
(8-(4,5-difluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)-
methanol (220); [0255]
8-(5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carboni-
trile (221); [0256]
(8-(5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)meth-
anol (222); [0257]
(8-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-5-fluoro-3-methoxyqu-
inoxalin-6-yl)methanol (224); [0258]
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)--
3-(methoxymethyl)quinoxaline-6-carboxamide (225); [0259]
8-(6-(2-(4-fluorophenylsulfonamido)
ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)-N,N-dimethylquino-
xaline-6-carboxamide (226); [0260]
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(piperidine-1-carbonyl)
quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamid-
e (227); [0261]
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)--
N-(2-methoxyethyl)-3-(methoxymethyl)quinoxaline-6-carboxamide
(228); [0262]
4-fluoro-N-(2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo-
[d]thiazol-6-yl)oxy) ethyl) benzenesulfonamide (229); [0263]
N-(2-((2-(7-ethynyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-y-
l)oxy)ethyl)-4-fluorobenzenesulfonamide (230); [0264]
N-(2-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)-
oxy)ethyl)-4-fluorobenzenesulfonamide (231); [0265]
N-(2-((2-(7-cyano-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiaz-
ol-6-yl) oxy)ethyl)-4-fluorobenzenesulfonamide (232); [0266]
8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-
-carbonitrile (233); [0267]
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-vinylquinoxalin-5-yl)-4-methylbenz-
o[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (234); [0268]
4-fluoro-N-(2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbe-
nzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (235); [0269]
N-(2-((2-(7-(1,2-dihydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[-
d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (236); [0270]
4-fluoro-N-(2-((2-(7-(2-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylb-
enzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (237); [0271]
N-(2-((2-(7-(aminomethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiaz-
ol-6-yl)oxy) ethyl)-4-fluorobenzenesulfonamide (238); [0272]
4-fluoro-N-(2-((2-(7-(1-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylb-
enzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (239); [0273]
4-fluoro-N-(2-((2-(7-(hydroxy
(phenyl)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethyl)benzenesulfonamide (240); [0274]
4-fluoro-N-(2-((2-(2-methoxy-7-(prop-1-en-2-yl)quinoxalin-5-yl)-4-methylb-
enzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (241); [0275]
4-fluoro-N-(2-((2-(7-(2-hydroxypropan-2-yl)-2-methoxyquinoxalin-5-yl)-4-m-
ethylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (242);
[0276]
(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin--
6-yl) methanol (243);
1-(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxali-
n-6-yl) ethanol (244); [0277]
(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin--
6-yl) (phenyl)methanol (245); [0278]
cyclopropyl(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxy-
quinoxalin-6-yl)methanol (246); [0279]
4-fluoro-N-(2-((2-(7-fluoro-2-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yl)oxy)ethyl)benzenesulfonamide (247); [0280]
(8-(5-fluoro-6-isopropoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)m-
ethanol (248); [0281]
N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl-
)oxy) ethyl)pyridine-3-sulfonamide (249); [0282] ethyl
2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y) acetate (250); [0283]
2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)acetic acid (251); [0284]
2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy) ethyl (6-methoxypyridin-3-yl)carbamate (252); [0285]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(253); [0286]
4-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazole (254); [0287]
6-ethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(255); [0288]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(256); [0289]
4,6-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]-
thiazole (257); [0290]
4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
le (258); [0291]
4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(259); [0292]
4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(260); [0293]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
(261); [0294]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-6-(trifluoromethox-
y)benzo[d]thiazole (262); [0295]
6-(difluoromethoxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methy-
lbenzo[d]thiazole (263); [0296] methyl
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole-6--
carboxylate (264); [0297]
4-chloro-7-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-
benzo[d]thiazole (265); [0298]
4-chloro-6-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]th-
iazole (266); [0299]
4,5-difluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo-
[d]thiazole (267); [0300]
5-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazole (268); [0301]
5,6-difluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo-
[d]thiazole (269); [0302]
6-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazole (270); [0303]
5-fluoro-4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo-
[d]thiazole (271); [0304]
6-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(272); [0305]
4-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(273); [0306]
6-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
(274); [0307]
4,6-dichloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
e (275); [0308]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]t-
hiazole (276); [0309]
5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazole (277); [0310]
4,5-difluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ole (278); [0311]
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole
(279); [0312]
5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole
(280); [0313]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-o-
l (281); [0314]
4-chloro-5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazole (282); [0315]
4-chloro-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-
benzo[d]thiazole (283); [0316]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo-
[d]thiazole (284); [0317] methyl
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy)acetate (285); [0318] methyl
2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[-
d]thiazol-6-yl)oxy)acetate (286); [0319] methyl
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)acetate (287); [0320]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy)ethanol (288); [0321]
2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[-
d]thiazol-6-yl)oxy)ethanol (289); [0322]
5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]th-
iazol-6-ol (290); [0323]
4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-ol (291); [0324] methyl
2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)acetate (292); [0325]
2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)ethanol (293); [0326]
5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]-
thiazole (294); [0327]
5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-
benzo[d]thiazole (295); [0328] methyl
2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)acetate (296); [0329]
2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)ethanol (297); [0330]
4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methyl-
benzo[d]thiazole (298); [0331]
4-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]-
thiazole (299); [0332]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]-
thiazol-4-yl)methanol (300); [0333]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]-
thiazol-4-yl)methanol (301); [0334]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy)ethyl (6-fluoropyridin-3-yl)carbamate (302); [0335]
2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[-
d]thiazol-6-yl)oxy)ethyl (6-fluoropyridin-3-yl) carbamate (303);
[0336]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (6-fluoropyridin-3-yl)carbamate (304); [0337]
2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-3-yl)carbamate (305);
[0338]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-o-
l (306); [0339]
6-(benzyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo-
[d]thiazole (307); [0340]
(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)methan-
ol (308); [0341]
6-(methoxymethyl)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]th-
iazole (309); [0342]
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5--
ol (310); [0343]
5,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
le (311); [0344]
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-
-yl) methanol (312); [0345]
6-chloro-5-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazole (313); [0346]
4-cyclopropyl-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin--
5-yl)benzo[d]thiazole (314); [0347]
6-ethoxy-4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
le (315); [0348]
N-(2-((4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide (316); [0349]
N-(2-((4,5-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide (317); [0350]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethanol (318); [0351]
1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)-2-methylpropan-2-ol (319); [0352]
2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)ethyl methyl carbonate (320); [0353]
2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)propan-1-ol (racemate) (321); [0354]
1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)propan-2-ol (racemate) (322); [0355]
3-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thi-
azol-6-yl)oxy)butan-2-ol (diastereomeric) (323); [0356]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)-1-morpholinoethanone (324); [0357]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol--
4-yl) methanol (bis-deuterated) (325); [0358]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[-
d]thiazol-4-yl)ethanol (326); [0359]
2-((4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[-
d]thiazol-6-yl)oxy)ethanol (327); [0360]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[-
d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (racemate) (328); [0361]
5-fluoro-6-isopropoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazole (329); [0362]
N-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (330); [0363]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl pyridin-3-ylcarbamate (331); [0364]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate (332); [0365]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate
(333); [0366]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)ethyl (2,2,2-trifluoroethyl)carbamate (334);
[0367]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl pyridin-4-ylcarbamate (335); [0368]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate (336); [0369]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (5-fluoropyridin-3-yl)carbamate (337); [0370]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl
(6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)carbamate (338);
[0371] 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl pyridin-3-ylcarbamate (339); [0372]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl (6-fluoropyridin-3-yl)carbamate (340); [0373]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl (6-methoxypyridin-3-yl)carbamate (341); [0374]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl pyridin-4-ylcarbamate (342); [0375]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (343);
[0376]
(R)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propyl pyridin-3-ylcarbamate (344); [0377]
(S)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propyl pyridin-3-ylcarbamate (345);
[0378] (S)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)propan-2-ylpyridin-3-ylcarbamate (346);
[0379]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl pyridin-3-ylcarbamate (347); [0380]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-fluoropyridin-3-yl)carbamate (348); [0381]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl pyridin-4-ylcarbamate (349); [0382]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate
(350); [0383]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy) propan-2-yl (6-cyanopyridin-3-yl)carbamate (351);
[0384]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (3-amino-3-oxopropyl) carbamate (352); [0385]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl pyridazin-4-ylcarbamate (353); [0386]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (354);
[0387] (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)propan-2-yl 1H-indol-5-ylcarbamate (355);
[0388]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (1-methyl-1H-indol-5-yl)carbamate (356); [0389]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (357); [0390]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy) ethyl carbamate (358); [0391]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl
1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (359); [0392]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl 1H-indol-5-ylcarbamate (360); [0393] methyl
5-(((2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yl)oxy)ethoxy)carbonyl)amino)picolinate (361); [0394]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (2-methylpyrimidin-5-yl)carbamate (362); [0395]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (5-methoxy-1,2,4-thiadiazol-3-yl)carbamate (363);
[0396]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl 1H-pyrazol-4-ylcarbamate (364); [0397]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy) ethyl (1-methyl-1H-pyrazol-4-yl)carbamate (365); [0398]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (5-methyl-1,3,4-oxadiazol-2-yl) carbamate (366);
[0399]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl
(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate (367); [0400]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy) ethyl (pyridin-3-ylmethyl)carbamate (368); [0401]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (pyridin-4-ylmethyl)carbamate (369); [0402]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl
(5-methyl-1,3,4-thiadiazol-2-yl)carbamate (370); [0403]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate (371);
[0404]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate (372); [0405]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (373); [0406]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl
(6-(trifluoromethyl)pyridin-3-yl)carbamate (374); [0407]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl 3H-pyrrolo[2,3-b]pyridin-5-ylcarbamate
(375); [0408]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propan-2-yl (4-methylpyridin-3-yl) carbamate
(376); [0409]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-methylpyridin-3-yl)carbamate
(377); [0410] methyl
4-(((2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yl)oxy)ethoxy)carbonyl)amino)-1-methyl-1H-pyrrole-2-carboxylate
(378); [0411]
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)-3-isobutoxypropan-2-yl pyridin-3-ylcarbamate (379); [0412]
1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate (380); [0413]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate (racemate)
(381); [0414]
(S)-2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate
(382); [0415]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)ethyl (2-chlorothiazol-4-yl)carbamate (383);
[0416]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl thiazol-5-ylcarbamate (384); [0417]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
(385); [0418]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(386); [0419]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(2-hydroxyethyl)pyridin-3-yl)carbamate (387); [0420]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy) pyridin-4-yl)carbamate
(388); [0421]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (389);
[0422]
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylamino)quinoxalin-5-yl)benzo[d]t-
hiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (390);
[0423]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate (391);
[0424]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-((2-hydroxyethyl)
carbamoyl)pyridin-3-yl)carbamate (392); [0425]
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo-
[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(393); [0426]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)ethyl
((1-methyl-1H-imidazol-4-yl)methyl)carbamate (394); [0427]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate (395); [0428]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl (pyridin-2-ylmethyl)carbamate (396); [0429]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl ((1-methyl-1H-imidazol-4-yl)methyl)carbamate
(397); [0430]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)ethyl ((1-methyl-1H-pyrazol-3-yl)methyl)carbamate
(398); [0431]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)ethyl ((1-methyl-1H-pyrazol-4-yl)methyl)carbamate
(399); [0432]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propan-2-yl (2-cyanopyrimidin-5-yl)carbamate
(400); [0433]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propan-2-yl (2-chloropyrimidin-5-yl)carbamate
(401); [0434]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propan-2-yl
(6-fluoro-5-methylpyridin-3-yl)carbamate (402); [0435]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl (6-bromopyridin-3-yl)carbamate (403);
[0436]
(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (404); [0437]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-methylpyridin-3-yl)carbamate (405); [0438]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (406); [0439]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-methoxypyrimidin-5-yl)carbamate (407);
[0440]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-methoxypyrimidin-5-yl)carbamate (408); [0441]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl pyrimidin-5-ylcarbamate (409); [0442]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl pyrimidin-5-ylcarbamate (410); [0443]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl phenylcarbamate (411); [0444]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-methoxypyridin-4-yl)carbamate (412); [0445]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl pyridazin-4-ylcarbamate (413); [0446]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-propylpyrimidin-5-yl)carbamate (414);
[0447]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(trifluoromethyl)pyrimidin-5-yl)carbamate
(415); [0448]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl (6-methylpyridazin-3-yl)carbamate
(416); [0449]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl (5-methylpyrazin-2-yl)carbamate (417);
[0450]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-methylpyridazin-4-yl)carbamate (418);
[0451]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (5-methylpyridin-3-yl)carbamate (419); [0452]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (5-methoxypyridin-3-yl)carbamate (420); [0453]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (5-cyanopyridin-3-yl)carbamate (421); [0454]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-methoxy-5-methylpyridin-3-yl)carbamate
(422); [0455]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (423); [0456]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl (2-methylpyrimidin-5-yl)carbamate (424); [0457]
(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(425); [0458]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate (426); [0459]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl (2-carbamoylpyridin-4-yl)carbamate
(427); [0460]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propan-2-yl
(2-(methylcarbamoyl)pyridin-4-yl)carbamate (428); [0461]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-carbamoylpyrimidin-5-yl)carbamate (429);
[0462]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(methylcarbamoyl)pyrimidin-5-yl)carbamate
(430); [0463]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(2-(dimethylcarbamoyl)pyrimidin-5-yl)carbamate (431); [0464]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-(methylcarbamoyl)pyridin-3-yl)carbamate (432);
[0465]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-carbamoylpyridin-3-yl)carbamate (433); [0466]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-carbamoylpyridin-3-yl)carbamate (434); [0467]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate
(435); [0468]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(methylcarbamoyl)pyridin-3-yl)carbamate (436); [0469]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(morpholine-4-carbonyl)pyrimidin-5-yl)carbamate (437); [0470]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate
(438); [0471]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (439);
[0472]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(methylcarbamoyl)pyrimidin-5-yl)carbamate
(440); [0473]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (441);
[0474]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(2-((2-hydroxyethyl)carbamoyl)pyridin-4-yl)carbamate (442); [0475]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(methylcarbamoyl)pyridin-4-yl)carbamate (443);
[0476]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-carbamoylpyridin-4-yl)carbamate (444); [0477]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)carbamate (445); [0478]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(6-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-3-yl)carbamate
(446); [0479]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(2-(dimethylcarbamoyl)pyridin-4-yl)carbamate (447); [0480]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
(448); [0481]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate
(449);
[0482]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (450);
[0483]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((2-hydroxyethyl)carbamoyl)pyridin-4-yl)carbamate (451); [0484]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropyl)carbamoyl)pyridin-4-yl)carbamate (452);
[0485]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-carbamoylpyridin-4-yl)carbamate (453);
[0486]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-carbamoylpyrimidin-5-yl)carbamate (454);
[0487]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (455);
[0488]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (456);
[0489]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((2-hydroxy-2-methylpropyl)carbamoyl)pyrimidin-5-yl)carbamate
(457); [0490]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-((3-hydroxy-3-methylbutyl)carbamoyl)pyrimidin-5-yl)carbamate
(458); [0491]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)carbamate
(459); [0492]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
(460); [0493]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(((S)-2-hydroxypropyl)carbamoyl)pyridin-4-yl)carbamate (461);
[0494]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((S)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (462);
[0495]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((1-hydroxycyclobutyl)methyl)carbamoyl)pyrimidin-5-yl)carbamate
(463); [0496]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-3-yl)carbamate
(464); [0497]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-4-yl)carbamate
(465); [0498]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(methylcarbamoyl)pyridin-4-yl)carbamate (466); [0499]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(dimethylcarbamoyl)pyridin-4-yl)carbamate
(467); [0500]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(dimethylcarbamoyl)pyrimidin-5-yl)carbamate (468); [0501]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(2-(2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (469); [0502]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-(((3-(hydroxymethyl)oxetan-3-yl)methyl)carbamoyl)pyridin-3-yl)carbamat-
e (470); [0503]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((2-hydroxyethyl)(methyl)carbamoyl)pyridin-3-yl)carbamate (471);
[0504]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)pyridin-3-yl)carbamate
(472); [0505]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate
(473); [0506]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((2-hydroxy-2-methylpropyl)(methyl)carbamoyl)pyridin-3-yl)carbamate
(474); [0507]
R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)propan-2-yl
(6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(475); [0508]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-((R)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(476); [0509]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((S)-2-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(477); [0510]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(478); [0511]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-((S)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(479); [0512]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((R)-2-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(480); [0513]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(6-((S)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate
(481); [0514]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-((S)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(482); [0515]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(6-((R)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate
(483); [0516]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-((S)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate
(484); [0517]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-((R)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate
(485); [0518]
(2R,3S)-3-((2-(2,7-dimethylquinoxalin-5-yl)-5-fluorobenzo[d]thiazo-
l-6-yl)oxy)butan-2-yl
(6-((R)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(486); [0519]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(6-((S)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(487); [0520]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((R)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(488); [0521]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((S)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(489); [0522]
(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo-
[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(490); [0523]
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-propoxyquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (491);
[0524]
(2R,3S)-3-((5-fluoro-2-(2-isopropoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (492);
[0525]
(2R,3S)-3-((5-fluoro-2-(2-(2-hydroxyethoxy)-7-methylquinoxalin-5-yl)benzo-
[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(493); [0526]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)propan-2-yl
(2-(hydroxymethyl)pyridin-4-yl)carbamate (494); [0527]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(hydroxymethyl)pyridin-4-yl)carbamate (495);
[0528]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (496);
[0529]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)carbamate
(497); [0530]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (498); [0531]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
(499); [0532]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (500); [0533]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)carbamate (501); [0534]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
(502); [0535]
4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole
(503); [0536] 2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole
(504); [0537]
2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
(505); [0538]
4-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazole (506); [0539]
5-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole
(507); [0540]
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
(509); [0541]
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
(510); [0542]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
(512); [0543]
(2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thi-
azol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (513); [0544]
(2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
(514); [0545]
(2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluoro-
benzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (515); [0546]
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)-3-methoxypropan-2-yl pyridin-3-ylcarbamate (rac) (516); [0547]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)butan-2-yl pyridin-3-ylcarbamate (517); [0548]
4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)-N-(pyridin-3-yl)butanamide (518); [0549]
1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thi-
azol-6-yl)oxy) ethyl)-3-(pyridin-3-yl)urea (519); [0550]
1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thi-
azol-6-yl)oxy) ethyl)-1-methyl-3-(2-methylpyrimidin-5-yl)urea
(520); [0551]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy) butan-2-yl
(6-(morpholinomethyl)pyridin-3-yl)carbamate (521); [0552]
(2R,3S)-3-((2-(2-(dimethylamino)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d-
]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(522); [0553]
5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)be-
nzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinic
acid, TFA (523); [0554]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy) butan-2-yl carbamate (524); [0555]
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)-3-isobutoxypropan-2-yl (2-methylpyrimidin-5-yl)carbamate (rac)
(525); [0556]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl
(6-(2-hydroxyethyl)pyridin-3-yl)carbamate (526); [0557]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
(527); [0558]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (528); [0559]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
(529); [0560]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy) propan-2-yl
(6-((2-methyl-2-(phosphonooxy)propyl)carbamoyl)pyridin-3-yl)carbamate,
TFA (530); [0561]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl
(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate, TFA
(531); [0562]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl
(2-((phosphonooxy)methyl)pyrimidin-5-yl)carbamate (532); [0563]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (5-hydroxypyridin-3-yl)carbamate (533); [0564]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy) butan-2-yl (5-(2-hydroxyethoxy)pyridin-3-yl)carbamate
(534); [0565]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl(2-((S)-1-hydroxyethyl)pyrimidin-5-yl)carbamate
(535); [0566]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy) butan-2-yl
(2-(((R)-1-hydroxyethyl)pyrimidin-5-yl)carbamate (536); [0567]
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (537); [0568]
(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (538); [0569]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
(539); [0570]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]th-
iazol-6-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (540); [0571]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (541); [0572]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl
(6-(2-hydroxyethyl)pyridin-3-yl)carbamate (542); [0573]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (543);
[0574]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (5-(hydroxymethyl)-6-methylpyridin-3-yl)carbamate
(544); [0575]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethyl)pyridin-4-yl)carbamate
(545); [0576]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
(546); [0577]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethyl)pyridin-4-yl)carbamate (547); [0578]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)carbamate (549);
[0579]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyridin-4-yl)carbamate (550); [0580]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate
(552);
[0581]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (553);
[0582]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (554);
[0583]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
(555); [0584]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (556); [0585]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (557); [0586]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (558);
[0587]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (559); [0588]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (560);
[0589]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(2-hydroxy-2-methylpropyl)pyridin-4-yl)carbamate (561); [0590]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)carbamate (562); [0591]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (563); [0592]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
(564); [0593]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (565); [0594]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
(566); [0595]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (567); [0596]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
(568); [0597]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (569); [0598]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (570); [0599]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate
(571); [0600]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate
(572); [0601]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (573);
[0602]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (574);
[0603]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(2-hydroxy-2-methylpropoxy)pyrimidin-5-yl)carbamate (575);
[0604]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(2-(2-hydroxy-2-methylpropoxy)pyrimidin-5-yl)carbamate (576);
[0605]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(2-hydroxy-2-methylpropyl)pyrimidin-5-yl)carbamate (577); [0606]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (578); [0607]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
(579); [0608]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (580); [0609]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (581); [0610]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
(582); [0611]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl(2-(((R)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate
(583); [0612]
(2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
(584); [0613]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-((S)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (585); [0614]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl
(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (586); [0615]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(((R)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (587);
[0616]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl(2-((S)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate
(588); [0617]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (589);
[0618]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl (2-methylpyridin-3-yl)carbamate (590);
[0619]
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl pyrimidin-5-ylcarbamate (591); [0620]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-methylpyridin-3-yl)carbamate (592); [0621]
methyl
3-(5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d-
]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidin-2-yl)propanoate
(593); [0622]
(2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (594); [0623]
(2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (595);
[0624] (R)-(5-aminopyridin-2-yl)methyl
(1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yl)oxy)propan-2-yl) carbonate (596); [0625]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (2-(dimethylamino)pyrimidin-5-yl)carbamate (597);
[0626]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(dimethylamino)pyrimidin-5-yl)carbamate
(598); [0627]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(dimethylamino)pyridin-3-yl)carbamate (599); [0628]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(6-(2-oxooxazolidin-3-yl)pyridin-3-yl)carbamate (600); [0629]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-acetamidopyridin-3-yl)carbamate (601);
[0630]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-aminopyridin-3-yl)carbamate (602); [0631]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-morpholinopyridin-3-yl)carbamate (603);
[0632]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl
(2-(3-chloro-4-fluorobenzamido)pyrimidin-5-yl)carbamate (604);
[0633]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(pyrrolidin-1-yl)pyridin-3-yl)carbamate
(605); [0634]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-((2-hydroxy-2-methylpropyl)amino)pyrimidin-5-yl)carbamate (606);
[0635]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(N-methylmethylsulfonamido)pyrimidin-5-yl)carbamate (607);
[0636]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-morpholinopyrimidin-5-yl)carbamate (608);
[0637]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (6-(2-oxooxazolidin-3-yl)pyridin-3-yl)carbamate
(609); [0638]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)propan-2-yl (6-acetamidopyridin-3-yl)carbamate (610);
[0639]
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl (5-(hydroxymethyl)pyridin-3-yl)carbamate (611);
[0640]
(2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-ol (612); [0641]
(2R,3S)-3-((2-(2-carbamoyl-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiaz-
ol-6-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (613);
[0642]
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo-
[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(614); [0643]
(2R,3S)-3-((2-(2-(dimethylcarbamoyl)-7-methylquinoxalin-5-yl)-5-fl-
uorobenzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate (615); [0644]
(2R,3S)-3-((5-fluoro-2-(2-((2-hydroxyethyl)carbamoyl)-7-methylquinoxalin--
5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate (616); [0645]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (5-(hydroxymethyl)pyridin-3-yl)carbamate
(617); [0646]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (618); [0647]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyridin-4-yl)carbamate
(619); [0648]
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(1-hydroxyethyl)pyrimidin-5-yl)carbamate (620); [0649]
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)ethyl isothiazol-5-ylcarbamate (621); [0650]
(R)-5-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yl)oxy)methyl)oxazolidin-2-one (622); [0651]
4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yl)oxy)methyl)oxazol-2-amine (623); [0652]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl
(2-(2-(phosphonooxy)ethyl)pyrimidin-5-yl)carbamate (624); [0653]
2-(6-chloro-3-(methoxymethyl)quinolin-8-yl)-6-methoxy-4-methylbenzo[d]thi-
azole (625); [0654]
2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole
(626); [0655]
2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)pr-
opan-2-ol (627); [0656]
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-2,2-dimethylpropan-1-ol (628); [0657]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)
(phenyl)methanol (629); [0658]
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-
,2-dimethyl propan-1-ol (630); [0659]
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-
-phenylethanol (631); [0660]
1-(5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-4-yl)-2,2-dimethylpropan-1-ol (632); [0661]
2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-4-yl) ethanol (633); [0662]
4-(1-fluoro-2,2-dimethylpropyl)-6-methoxy-2-(2-methoxy-7-methylquinoxalin-
-5-yl)benz o[d]thiazole (634); [0663]
4-(benzyloxy)-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benz-
o[d]thiazole (635); [0664]
1-(2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy
benzo[d]thiazol-4-yl)-2,2-dimethyl propan-1-ol (636); [0665]
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-
,2-dimethyl propan-1-ol (637); [0666]
2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl-
)benzo[d]thiazol-6-yl)oxy)ethyl (5-cyanopyridin-3-yl)carbamate
(638); [0667]
8-(4-(1-hydroxy-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazol-2-yl)-
-3-methoxyquinoxaline-6-carbonitrile (639); [0668]
1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,-
2-dimethylpropan-1-ol (640); [0669]
2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)et-
hanol (641); [0670]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(3-(-
trifluoromethyl)phenyl)methanol (642); [0671]
(2-isopropylphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[-
d]thiazol-4-yl)methanol (643); [0672] ethyl
1-(hydroxy(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)methyl)cyclobutanecarboxylate (644); [0673]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (645); [0674]
(1-(hydroxymethyl)cyclobutyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-
-yl)benzo[d]thiazol-4-yl)methanol (646); [0675]
(2R,3S)-3-((2-(6-chloro-3-ethylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-y-
l)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (647); [0676]
(2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-
-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (648); [0677]
(2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (649); [0678]
(2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d-
]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(650); [0679]
(2R,3S)-3-((2-(6-chloro-3-(2,2-difluoroethoxy)quinolin-8-yl)-5-flu-
orobenzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate (651); [0680]
(2R,3S)-3-((2-(6-chloro-3-(methylamino)quinolin-8-yl)-5-fluorobenzo[d]thi-
azol-6-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (652);
[0681]
(2R,3S)-3-((2-(6-(difluoromethyl)-3-methoxyquinolin-8-yl)-5-fluorobenzo[d-
]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(653); [0682]
(2R,3S)-3-((5-fluoro-2-(6-(fluoromethyl)-3-methoxyquinolin-8-yl)be-
nzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(654); [0683]
(2R,3S)-3-((2-(6-cyano-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thi-
azol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (655);
[0684]
(2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxybenzo[d]thiazol-4-yl)(1-(tr-
ifluoromethyl)cyclobutyl)methanol (656); [0685]
(2R,3S)-3-((2-(3,6-dimethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)o-
xy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (657); [0686]
2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl-
)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate (658);
[0687]
(2R,3S)-3-((2-(3-(difluoromethoxy)-6-methylquinolin-8-yl)-5-fluoro-
benzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate (659); [0688]
(2R,3S)-3-((2-(3-ethoxy-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (660); [0689]
5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline (661); [0690]
4-methoxyphenyl
(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-
-5-yl)oxy)ethyl)carbamate (662); [0691]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tet-
rahydro-2H-pyran-4-yl)methanol (663); [0692]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tet-
rahydro-2H-pyran-4-yl)methanol (664); [0693]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-p-
henylcyclobutyl)methanol (665); [0694]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-m-
ethoxycyclobutyl)methanol (666); [0695]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-(-
trifluoromethyl)cyclopropyl)methanol (667); [0696]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-p-
henylcyclopropyl)methanol (668); [0697]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-(-
trifluoromethyl)cyclobutyl)methanol (669); [0698]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-m-
ethylcyclopropyl)methanol (671); [0699]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-m-
ethylcyclohexyl)methanol (672); [0700]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(thi-
azol-2-yl)methanol (673); [0701]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(4-m-
ethyltetrahydro-2H-pyran-4-yl)methanol (674); [0702]
(3-fluoro-5-methoxyphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl-
)benzo[d]thiazol-4-yl)methanol (675); [0703]
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-m-
ethylcyclohexyl)methanol (676); [0704]
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)et-
han-1-ol (677); [0705]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl (2-methylpyrimidin-5-yl)carbamate (678);
[0706]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl (2-methoxypyrimidin-5-yl)carbamate (679);
[0707]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl pyridin-4-ylcarbamate (680); [0708]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl (6-methylpyridin-3-yl)carbamate (681);
[0709]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl (5-fluoropyridin-3-yl)carbamate (682);
[0710]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (683); [0711]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl pyridin-3-ylcarbamate (684); [0712]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (685); [0713]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl
(2-(3-hydroxypropyl)pyrimidin-5-yl)carbamate (686); [0714]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl
(6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (687);
[0715]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (688); [0716]
methyl
(R)-5-((((1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4--
b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
(689); [0717] methyl
(R)-5-((((1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4--
b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate (690);
[0718]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl(6-(2-hydroxyethyl)pyridin-3-yl)carbamate
(691); [0719]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-
-b]pyridin-5-yl)oxy)
propan-2-yl(2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate
(692); [0720]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(2-(((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate
(693); [0721]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl(6-(hydroxymethyl)pyridin-3-yl)carbamate
(694); [0722]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-
-b]pyridin-5-yl)oxy)
propan-2-yl(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (695);
[0723]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl(2-(2-hydroxyethyl)pyridin-4-yl)carbamate
(696); [0724]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-
-b]pyridin-5-yl)oxy)
propan-2-yl(2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (697); [0725]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl pyridazin-4-ylcarbamate (698); [0726]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate
(699); [0727]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-
-b]pyridin-5-yl)oxy)
propan-2-yl(6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (700); [0728]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (701);
[0729]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate
(702); [0730]
(2R,3S)-3-((5-fluoro-2-(6-fluoro-3-methoxyquinolin-8-yl)benzo[d]th-
iazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (772);
[0731]
(2R,3S)-3-((5-fluoro-2-(6-(hydroxymethyl)-3-methoxyquinolin-8-yl)benzo[d]-
thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (773);
[0732]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (782); [0733]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (6-(trifluoromethyl)pyridin-3-yl)carbamate
(783); [0734]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]th-
iazol-6-yl)oxy)butan-2-yl (6-methoxypyridin-3-yl)carbamate (784);
[0735]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (5-methoxypyridin-3-yl)carbamate (785); [0736]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (5-cyanopyridin-3-yl)carbamate (786); [0737]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (5,6-dimethylpyridin-3-yl)carbamate (787);
[0738]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (788); [0739]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (6-fluoropyridin-3-yl)carbamate (789); [0740]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl pyridin-4-ylcarbamate (790); [0741]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (795); [0742]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (796); [0743]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl (6-fluoropyridin-3-yl)carbamate (797);
[0744]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl pyridin-4-ylcarbamate (798); [0745]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (799); [0746]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl (5,6-dimethylpyridin-3-yl)carbamate
(800); [0747]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorob-
enzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methoxypyridin-3-yl)carbamate
(801); [0748]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorob-
enzo[d]thiazol-6-yl)oxy)butan-2-yl (5-cyanopyridin-3-yl)carbamate
(802); [0749]
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorob-
enzo[d]thiazol-6-yl)oxy)butan-2-yl (5-methoxypyridin-3-yl)carbamate
(803); [0750]
(2R,3S)-3-((4-chloro-5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)b-
enzo[d]thiazol-6-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate
(804); [0751]
1-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-
-yl)-2,2-dimethylpropan-1-ol (806); [0752]
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(methoxymethyl)benzo[d]-
thiazole (808); [0753]
1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,-
2-dimethylpropan-1-ol (817); [0754]
(R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl-
)oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate (818); [0755]
(R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl-
)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (819); [0756]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl(2-methoxypyrimidin-5-yl)carbamate (820);
[0757]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl(6-methoxypyridin-3-yl)carbamate (821); [0758]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl(6-methylpyridin-3-yl)carbamate (822); [0759]
(2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl(6-methylpyridin-3-yl)carbamate (823); [0760]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (824); [0761]
(2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (825); [0762]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl(5-cyanopyridin-3-yl)carbamate (826); [0763]
(2R,3S)-3-((2-(2-(2,2-difluoroethoxy)-7-methylquinoxalin-5-yl)-5-fluorobe-
nzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(827); [0764]
(2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl (6-cyanopyridin-3-yl)carbamate (828);
[0765]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-cyanopyridin-3-yl)carbamate (829); [0766]
methyl
5-(((((2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate (830);
[0767]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
(831); [0768]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(methylcarbamoyl)pyridin-3-yl)carbamate (832); [0769]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy) butan-2-yl (6-carbamoylpyridin-3-yl)carbamate (833);
[0770]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate
(834); [0771]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl
(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (835); [0772]
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
(836); and [0773]
2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]th-
iazole (837);
[0774] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
imidazol[1,2-a]pyridinyl. Included in this embodiment is a compound
of Formula (I) selected from: [0775]
2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-2-yl)-7-methylquinoxa-
line (45).
[0776] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
thiazolo[4,5-b]pyridinyl. Included in this embodiment is a compound
of Formula (I) selected from: [0777]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazolo[4,5-b]pyri-
dine (9); [0778]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxythiazolo[4,5-c]p-
yridine (24); [0779]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine
(146); and [0780]
2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine
(809).
[0781] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
thiazolo[5,4-b]pyridinyl. Included in this embodiment is a compound
of Formula (I) selected from: [0782]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methoxythiazolo[-
5,4-b]pyridine (23); [0783]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
(147); [0784]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
(148); [0785]
7-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyri-
dine (149); [0786]
5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
(150); [0787]
7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine
(151); [0788]
5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]py-
ridine (179); [0789]
6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[-
5,4-b]pyridine (180); [0790]
5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[-
5,4-b]pyridine (181); [0791]
6-fluoro-5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]py-
ridine (182); [0792]
5-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5-
,4-b]pyridine (191); [0793]
(5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]py-
ridin-7-yl) methanol (192); [0794]
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthi-
azolo[5,4-b]pyridin-5-yl)oxy)ethyl) benzenesulfonamide (193);
[0795]
4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,-
4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide (194); [0796]
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)eth yl pyridin-3-ylcarbamate (196); [0797]
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)eth yl (6-cyanopyridin-3-yl)carbamate (197); [0798]
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate (198); [0799]
(3-methoxy-8-(5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-yl)quinoxalin-6--
yl)methanol (223); [0800]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (708); [0801]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (709); [0802]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl (6-methylpyridin-3-yl)carbamate (710);
[0803]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl (2-methoxypyrimidin-5-yl)carbamate
(711); [0804] methyl
5-(((((2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[-
5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxyl-
ate (712); [0805]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl pyridin-4-ylcarbamate (713); [0806]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (714);
[0807] methyl
5-(((((2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)th-
iazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
(715); [0808]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl pyrimidin-5-ylcarbamate (716); [0809]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(2-hydroxyethyl)pyridin-4-yl)carbamate (717); [0810]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (718); [0811]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (719); [0812]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (720); [0813]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (721); [0814]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (722);
[0815]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyridin-4-yl)carbamate (723); [0816]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (724);
[0817]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (725); [0818]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (726);
[0819]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (727); [0820]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (728); [0821]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (729); [0822]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (730); [0823]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(731); [0824]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl pyridin-3-ylcarbamate (733);
[0825]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl(6-fluoro-5-methylpyridin-3-yl)carbamate
(734); [0826]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl(5-cyanopyridin-3-yl)carbamate
(735); [0827]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl(2-chloropyrimidin-5-yl)carbamate
(736); [0828]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl(2-methylpyrimidin-5-yl)carbamate
(737); [0829]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl(2-methoxypyrimidin-5-yl)carbamate
(738); [0830]
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl pyridin-3-ylcarbamate (740);
[0831]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
(741); [0832]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-
-b]pyridin-5-yl)oxy) propan-2-yl [0833]
(6-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate
(742); [0834]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(6-(3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate
(743); [0835]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(744); [0836]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(745); [0837]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(6-(4-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate
(746); [0838]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate
(747); [0839]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)
propan-2-yl(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate
(748); [0840]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl(2-carbamoylpyrimidin-5-yl)carbamate
(749); [0841]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo-
[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (750);
[0842]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-((2-hydroxy-2-methylpropyl)carbamoyl)pyrimidin-5-yl)carbamate
(751); [0843]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo-
[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (752);
[0844]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(((S)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (753);
[0845]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate
(754); [0846]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo-
[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(2-carbamoylpyrimidin-5-yl)carbamate (755); [0847]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate
(756); [0848]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo-
[5,4-b]pyridin-5-yl) oxy)butan-2-yl
(6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(757); [0849]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo-
[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(6-(3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (758);
[0850]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(4-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (759);
[0851]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate
(760); [0852]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo-
[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(6-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate
(761); [0853]
N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyrid-
in-5-yl)oxy) ethyl)-4-methylbenzenesulfonamide (762); [0854]
6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methyl-
thiazolo[5,4-b]pyridine (763); [0855]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (764); [0856]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (765); [0857]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(1-hydroxyethyl)pyridin-3-yl)carbamate (766); [0858]
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]-
pyridin-5-yl)oxy)butan-2-yl
(6-(1-hydroxyethyl)pyridin-3-yl)carbamate (767); [0859]
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy) propan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
(768); [0860]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5-
,4-b]pyridin-5-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(769); [0861]
(R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b-
]pyridin-5-yl)oxy)pro pan-2-yl (2-methylpyrimidin-5-yl)carbamate
(770); [0862]
(2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5-
,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
(771); [0863]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5-
,4-b]pyridin-5-yl)oxy) butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (774); [0864]
(2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (775); [0865]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (776);
[0866]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy) butan-2-yl
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (777); [0867]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy) butan-2-yl
(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (778); [0868]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy) butan-2-yl
(6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (779); [0869]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy) butan-2-yl
(2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (780); [0870]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy) butan-2-yl
(6-(2-hydroxyethyl)pyridin-3-yl)carbamate (781); [0871]
(2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (791);
[0872]
(2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (792); [0873]
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy) butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (793); [0874]
(R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridi-
n-5-yl)oxy)pro pan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
(794); [0875]
1-(5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-7-yl)-2,2-dimethylpropan-1-ol (807); [0876]
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl pyridin-3-ylcarbamate (810); [0877]
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy) ethyl (6-fluoro-5-methylpyridin-3-yl)carbamate (811);
[0878]
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy) ethyl (6-(thiophen-2-yl)pyridin-3-yl)carbamate (812);
[0879]
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (813);
[0880]
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (814); [0881]
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy) propan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (815); [0882]
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (816); and
[0883]
1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-
-yl)-2,2-dimethylpropan-1-ol (817).
[0884] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
4,5,6,7-tetrahydrobenzo[d]thiazolyl. Included in this embodiment is
a compound of Formula (I) selected from: [0885]
2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-
-ol (138); [0886]
7-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d-
]thiazole (139); [0887]
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d-
]thiazole (140); [0888]
2-(2-methoxy-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenz-
o[d]thiazole (141); [0889]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]t-
hiazol-7-ol (143); [0890]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]t-
hiazole (144); [0891]
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrah-
ydrobenzo[d]thiazol-7-ol (145); and [0892]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d-
]thiazole (178).
[0893] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
4,5,6,7-tetrahydrobenzofuranyl. Included in this embodiment is a
compound of Formula (I) selected from: tert-butyl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzof-
uran-4-yl) carbamate (25).
[0894] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
6,7-tetrahydrothiazolo[5,4-c]pyridinyl. Included in this embodiment
is a compound of Formula (I) selected from: tert-butyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c-
]pyridine-5(4H)-carboxylate (11) and methyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c-
]pyridine-5(4H)-carboxylate (62).
[0895] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl. Included in this
embodiment is a compound of Formula (I) selected from: [0896]
2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]-
thiazole (137).
[0897] One embodiment provides compounds of Formulas (I), (II),
(III), or (IV) or a salt thereof, wherein R.sub.3 is
5,6-dihydro-4H-cyclopenta[d]thiazolyl. Included in this embodiment
is a compound of Formula (I) selected from: [0898]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta-
[d]thiazole (136); and
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thia-
zol-5-yl) ethanol (142).
[0899] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. This invention encompasses all combinations of the aspects
and/or embodiments of the invention noted herein. It is understood
that any and all embodiments of the present invention may be taken
in conjunction with any other embodiment or embodiments to describe
additional embodiments. It is also to be understood that each
individual element of the embodiments is meant to be combined with
any and all other elements from any embodiment to describe an
additional embodiment.
Definitions
[0900] The features and advantages of the invention may be more
readily understood by those of ordinary skill in the art upon
reading the following detailed description. It is to be appreciated
that certain features of the invention that are, for clarity
reasons, described above and below in the context of separate
embodiments, may also be combined to form a single embodiment.
Conversely, various features of the invention that are, for brevity
reasons, described in the context of a single embodiment, may also
be combined so as to form sub-combinations thereof. Embodiments
identified herein as exemplary or preferred are intended to be
illustrative and not limiting.
[0901] Unless specifically stated otherwise herein, references made
in the singular may also include the plural. For example, "a" and
"an" may refer to either one, or one or more.
[0902] As used herein, the phase "compounds" refers to at least one
compound. For example, a compound of Formula (I) includes a
compound of Formula (I) and two or more compounds of Formula
(I).
[0903] Unless otherwise indicated, any heteroatom with unsatisfied
valences is assumed to have hydrogen atoms sufficient to satisfy
the valences.
[0904] The definitions set forth herein take precedence over
definitions set forth in any patent, patent application, and/or
patent application publication incorporated herein by
reference.
[0905] Listed below are definitions of various terms used to
describe the present invention. These definitions apply to the
terms as they are used throughout the specification (unless they
are otherwise limited in specific instances) either individually or
as part of a larger group.
[0906] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds.
[0907] In accordance with a convention used in the art,
##STR00014##
is used in structural formulas herein to depict the bond that is
the point of attachment of the moiety or substituent to the core or
backbone structure.
[0908] The terms "halo" and "halogen," as used herein, refer to F,
Cl, Br, and I.
[0909] The term "cyano" refers to the group --CN.
[0910] The term "amino" refers to the group --NH.sub.2.
[0911] The term "alkyl" as used herein, refers to both branched and
straight-chain saturated aliphatic hydrocarbon groups containing,
for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms,
and from 1 to 4 carbon atoms. Examples of alkyl groups include, but
are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl
and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and
t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl),
n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and
4-methylpentyl. When numbers appear in a subscript after the symbol
"C", the subscript defines with more specificity the number of
carbon atoms that a particular group may contain. For example,
"C.sub.1-4 alkyl" denotes straight and branched chain alkyl groups
with one to four carbon atoms.
[0912] The term "fluoroalkyl" as used herein is intended to include
both branched and straight-chain saturated aliphatic hydrocarbon
groups substituted with one or more fluorine atoms. For example,
"C.sub.1-4 fluoroalkyl" is intended to include C.sub.1, C.sub.2,
C.sub.3, and C.sub.4 alkyl groups substituted with one or more
fluorine atoms. Representative examples of fluoroalkyl groups
include, but are not limited to, --CF.sub.3 and
--CH.sub.2CF.sub.3.
[0913] The term "aminoalkyl" as used herein is intended to include
both branched and straight-chain saturated aliphatic hydrocarbon
groups substituted with one or more amino groups. For example,
"C.sub.1-4 aminoalkyl" is intended to include C.sub.1, C.sub.2,
C.sub.3, and C.sub.4 alkyl groups substituted with one or more
amino groups. Representative examples of aminoalkyl groups include,
but are not limited to, --CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2NH.sub.2, and --CH.sub.2CH(NH.sub.2)CH.sub.3.
[0914] The term "hydroxyalkyl" includes both branched and
straight-chain saturated alkyl groups substituted with one or more
hydroxyl groups. For example, "hydroxyalkyl" includes --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, and C.sub.1-4 hydroxyalkyl.
[0915] The term "hydroxy-deuteroalkyl" includes both branched and
straight-chain saturated alkyl groups substituted with one or more
hydroxyl groups and one or more deuterium atoms. Representative
examples of hydroxy-deuteroalkyl groups include, but are not
limited to, --CD.sub.2OH and --CH(CD.sub.3).sub.2OH.
[0916] The term "hydroxy-fluoroalkyl" includes both branched and
straight-chain saturated alkyl groups substituted with one or more
hydroxyl groups and one or more fluorine atoms. Representative
examples of hydroxy-fluoroalkyl groups include, but are not limited
to, --CF.sub.2OH and --CF.sub.2CH.sub.2OH.
[0917] As used herein, "alkylene" refers to a bivalent alkyl
radical having the general formula --(CH.sub.2).sub.n--, where n is
1 to 10. Non-limiting examples include methylene, dimethylene,
trimethylene, tetramethylene, pentamethylene, and hexamethylene.
For example, "C.sub.1-6 alkylene" denotes straight and branched
chain alkylene groups with one to six carbon atoms. Further, for
example, "C.sub.0-4 alkylene" denotes a bond and straight and
branched chain alkylene groups with one to four carbon atoms.
[0918] As used herein, "deuteroalkylene" refers to an alkylene
group in which one or more hydrogen atoms have been replaced with
deuterium atoms. For example, "C.sub.1-6 deuteroalkylene" denotes
straight and branched chain deuteroalkylene groups with one to six
carbon atoms.
[0919] As used herein, "fluoroalkylene" refers to an alkylene group
substituted with one or more fluorine atoms. For example,
"C.sub.1-6 fluoroalkylene" denotes straight and branched chain
fluoroalkylene groups with one to six carbon atoms.
[0920] The term "alkenyl" refers to a straight or branched chain
hydrocarbon radical containing from 2 to 12 carbon atoms and at
least one carbon-carbon double bond. Exemplary such groups include
ethenyl or allyl. For example, "C.sub.2-6 alkenyl" denotes straight
and branched chain alkenyl groups with two to six carbon atoms.
[0921] The term "alkynyl" refers to a straight or branched chain
hydrocarbon radical containing from 2 to 12 carbon atoms and at
least one carbon to carbon triple bond. Exemplary such groups
include ethynyl. For example, "C.sub.2-6 alkynyl" denotes straight
and branched chain alkynyl groups with two to six carbon atoms.
[0922] The term "cycloalkyl," as used herein, refers to a group
derived from a non-aromatic monocyclic or polycyclic hydrocarbon
molecule by removal of one hydrogen atom from a saturated ring
carbon atom. Representative examples of cycloalkyl groups include,
but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.
When numbers appear in a subscript after the symbol "C", the
subscript defines with more specificity the number of carbon atoms
that a particular cycloalkyl group may contain. For example,
"C.sub.3-6 cycloalkyl" denotes cycloalkyl groups with three to six
carbon atoms.
[0923] The term "fluorocycloalkyl" refers to a cycloalkyl group in
which one or more hydrogen atoms are replaced by fluoro
group(s).
[0924] The term "hydroxycycloalkyl" refers to a cycloalkyl group in
which one or more hydrogen atoms are replaced by hydroxyl
group(s).
[0925] The term "alkoxy," as used herein, refers to an alkyl group
attached to the parent molecular moiety through an oxygen atom, for
example, methoxy group (--OCH.sub.3). For example, "C.sub.1-3
alkoxy" denotes alkoxy groups with one to three carbon atoms.
[0926] The terms "fluoroalkoxy" and "--O(fluoroalkyl)" represent a
fluoroalkyl group as defined above attached through an oxygen
linkage (--O--). For example, "C.sub.1-4 fluoroalkoxy" is intended
to include C.sub.1, C.sub.2, C.sub.3, and C.sub.4 fluoroalkoxy
groups.
[0927] The term "hydroxyalkoxy" represent a hydroxyalkyl group as
defined above attached through an oxygen linkage (--O--). For
example, "C.sub.1-4 hydroxyalkoxy" is intended to include C.sub.1,
C.sub.2, C.sub.3, and C.sub.4 hydroxyalkoxy groups.
[0928] The term "hydroxy-fluoroalkoxy" represent a
hydroxy-fluoroalkyl group as defined above attached through an
oxygen linkage (--O--). For example, "C.sub.1-4
hydroxy-fluoroalkoxy" is intended to include C.sub.1, C.sub.2,
C.sub.3, and C.sub.4 hydroxy-fluoroalkoxy groups.
[0929] The term "cycloalkoxy," as used herein, refers to a
cycloalkyl group attached to the parent molecular moiety through an
oxygen atom, for example, cyclopropoxy group
(--O(cyclopropyl)).
[0930] The term "alkoxyalkoxy" as used herein, refers to an alkoxy
group attached through an alkoxy group to the patent molecular
moiety. For example, "(C.sub.1-3 alkoxy)-(C.sub.1-6 alkoxy)"
denotes a C.sub.1-3 alkoxy group attached through a C.sub.1-6
alkoxy group to the parent molecular moiety.
[0931] The term "alkoxyalkylene" as used herein, refers to an
alkoxy group attached through an alkylene group to the patent
molecular moiety. For example, "(C.sub.1-3 alkoxy)-(C.sub.1-3
alkylene)" denotes a C.sub.1-3 alkoxy group attached through a
C.sub.1-3 alkylene to the parent molecular moiety.
[0932] The term "fluoroalkoxyalkylene" as used herein, refers to a
fluoroalkoxy group attached through an alkylene group. For example,
"(C.sub.1-2 fluoroalkoxy)-(C.sub.1-2 alkylene)" denotes a C.sub.1-2
fluoroalkoxy group attached through a C.sub.1-2 alkylene to the
parent molecular moiety.
[0933] The term "alkoxy-fluoroalkylene" as used herein, refers to
an alkoxy group attached through a fluoroalkylene group to the
patent molecular moiety. For example, "(C.sub.1-3
alkoxy)-(C.sub.1-3 fluoroalkylene)" denotes a C.sub.1-3 alkoxy
group attached through a C.sub.1-3 fluoroalkylene to the parent
molecular moiety.
[0934] The term "deuteroalkoxy-deuteroalkylene" as used herein,
refers to a deuteroalkoxy group attached through a deuteroalkylene
group to the patent molecular moiety. For example, "(C.sub.1-3
deuteroalkoxy)-(C.sub.1-3 deuteroalkylene)" denotes a C.sub.1-3
deuteroalkoxy group attached through a C.sub.1-3 deuteroalkylene to
the parent molecular moiety.
[0935] The term "alkylthio," as used herein, refers to an alkyl
group attached to the parent molecular moiety through a sulfur
atom, for example, methylthio group (--SCH.sub.3). For example,
"C.sub.1-3 alkylthio" denotes alkylthio groups with one to three
carbon atoms.
[0936] The term "fluoroalkylthio," as used herein, refers to a
fluoroalkyl group attached to the parent molecular moiety through a
sulfur atom, for example, trifluoromethylthio group (--SCF.sub.3).
For example, "C.sub.1-3 fluoroalkylthio" denotes fluoroalkylthio
groups with one to three carbon atoms.
[0937] The term "aryl," as used herein, refers to a group of atoms
derived from a molecule containing aromatic ring(s) by removing one
hydrogen that is bonded to the aromatic ring(s). Representative
examples of aryl groups include, but are not limited to, phenyl,
naphthyl, indanyl, indenyl, and 1,2,3,4-tetrahydronaphth-5-yl. The
aryl ring may be unsubstituted or may contain one or more
substituents as valence allows.
[0938] The term "benzyl," as used herein, refers to a methyl group
in which one of the hydrogen atoms is replaced by a phenyl group.
The phenyl ring may be unsubstituted or may contain one or more
substituents as valence allows.
[0939] The term "aryloxy," as used herein, refers to an aryl group
attached through an oxygen group.
[0940] The term "phenoxy," as used herein, refers to a phenyl group
attached through an oxygen group (--O-phenyl). The phenyl ring may
be unsubstituted or may contain one or more substituents as valence
allows.
[0941] The term "heteroatom" refers to oxygen (O), sulfur (S), and
nitrogen (N).
[0942] The term "heterocyclo" or "heterocyclyl" may be used
interchangeably and refer to non-aromatic 3- to 7-membered
monocyclic groups and 6- to 11-membered bicyclic groups, in which
at least one of the rings has at least one heteroatom (0, S or N),
said heteroatom containing ring preferably having 1 to 3
heteroatoms independently selected from 0, S, and/or N. Each ring
of such a group containing a heteroatom can contain one or two
oxygen or sulfur atoms and/or from one to four nitrogen atoms
provided that the total number of heteroatoms in each ring is four
or less, and further provided that the ring contains at least one
carbon atom. The nitrogen and sulfur atoms may optionally be
oxidized and the nitrogen atoms may optionally be quaternized. The
fused rings completing the bicyclic group may contain only carbon
atoms and may be saturated, partially saturated, or unsaturated.
The heterocyclo group may be attached at any available nitrogen or
carbon atom. The heterocyclo ring may be unsubstituted or may
contain one or more substituents as valence allows.
[0943] Exemplary monocyclic heterocyclyl groups include oxetanyl,
azetidinyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, 1,3-dioxolane, and
tetrahydro-1,1-dioxothienyl. Exemplary bicyclic heterocyclo groups
include quinuclidinyl.
[0944] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5- or 6-membered monocyclic groups and 9- or
10-membered bicyclic groups which have at least one heteroatom (O,
S or N) in at least one of the rings, said heteroatom-containing
ring preferably having 1, 2, or 3 heteroatoms independently
selected from O, S, and/or N. Each ring of the heteroaryl group
containing a heteroatom can contain one or two oxygen or sulfur
atoms and/or from one to four nitrogen atoms provided that the
total number of heteroatoms in each ring is four or less and each
ring has at least one carbon atom. The fused rings completing the
bicyclic group may contain only carbon atoms and may be saturated,
partially saturated, or unsaturated. The nitrogen and sulfur atoms
may optionally be oxidized and the nitrogen atoms may optionally be
quaternized. Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any ring.
The heteroaryl ring system may be unsubstituted or may contain one
or more substituents.
[0945] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl,
oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and
triazinyl.
[0946] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridyl, dihydroisoindolyl, and tetrahydroquinolinyl.
[0947] The term "heteroaryloxy," as used herein, refers to a
heteroaryl group attached through an oxygen group to the patent
molecular moiety.
[0948] The term "arylalkylene" refers to an aryl group attached
through an alkylene group to the patent molecular moiety. For
example, "aryl(C.sub.1-2 alkylene)" refers to an aryl group
attached through a C.sub.1-2 alkylene to the parent molecular
moiety.
[0949] The term "heteroarylalkylene" refers to a heteroaryl group
attached through an alkylene group to the patent molecular moiety.
For example, "heteroaryl(C.sub.1-2 alkylene)" refers to a
heteroaryl group attached through a C.sub.1-2 alkylene to the
parent molecular moiety.
[0950] The term "aryloxyalkylene" refers to an aryloxy group
attached through an alkylene group to the patent molecular moiety.
For example, "aryloxy-(C.sub.1-2 alkylene)" refers to an aryloxy
group attached through a C.sub.1-2 alkylene to the parent molecular
moiety.
[0951] The term "heteroaryloxyalkylene" refers to a heteroaryloxy
group attached through an alkylene group to the patent molecular
moiety. For example, "heteroaryloxy-(C.sub.1-2 alkylene)" refers to
a heteroaryloxy group attached through a C.sub.1-2 alkylene to the
parent molecular moiety.
[0952] The compounds of the present invention can be provided as
amorphous solids or crystalline solids. Lyophilization can be
employed to provide the compounds as amorphous solids.
[0953] It should further be understood that solvates (e.g.,
hydrates) of the Compounds of the invention are also within the
scope of the present invention. The term "solvate" means a physical
association of a compound of Formulas (I) to (VIII) with one or
more solvent molecules, whether organic or inorganic. This physical
association includes hydrogen bonding. In certain instances the
solvate will be capable of isolation, for example when one or more
solvent molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include hydrates,
ethanolates, methanolates, isopropanolates, acetonitrile solvates,
and ethyl acetate solvates. Methods of solvation are known in the
art.
[0954] In addition, compounds of Formulas (I) to (VIII), subsequent
to their preparation, can be isolated and purified to obtain a
composition containing an amount by weight equal to or greater than
99% of a compound of Formulas (I) to (VIII) ("substantially pure"),
which is then used or formulated as described herein. Such
"substantially pure" compounds of Formulas (I) to (VIII) are also
contemplated herein as part of the present invention.
[0955] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent. The present
invention is intended to embody stable compounds.
[0956] The compounds of the present invention are intended to
include all isotopes of atoms occurring in the present compounds.
Isotopes include those atoms having the same atomic number but
different mass numbers. By way of general example and without
limitation, isotopes of hydrogen include deuterium (D) and tritium
(T). Isotopes of carbon include .sup.13C and .sup.14C.
Isotopically-labeled compounds of the invention can generally be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described herein, using an
appropriate isotopically-labeled reagent in place of the
non-labeled reagent otherwise employed. For example, methyl
(--CH.sub.3) also includes deuterated methyl groups such as
--CD.sub.3.
BIOLOGY
[0957] The term "PAR4 antagonist" denotes an inhibitor of platelet
aggregation which binds PAR4 and inhibits PAR4 cleavage and/or
signaling. Typically, PAR4 activity is reduced in a dose dependent
manner by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
100% compared to such activity in a control cell. The control cell
is a cell that has not been treated with the compound. PAR4
activity is determined by any standard method in the art, including
those described herein (for example calcium mobilization in PAR4
expressing cells, platelet aggregation, platelet activation assays
measuring e.g., calcium mobilization, P-selectin or CD40L release,
or thrombosis and hemostasis models). In certain embodiments,
platelet activation is measured by changes in the platelet
cytoplasm, by changes of the platelet membrane, by changes in the
levels of analytes released by platelets, by the changes in the
morphology of the platelet, by the ability of platelets to form
thrombi or platelet aggregates in flowing or stirred whole blood,
by the ability of platelets to adhere to a static surface which is
derivatized with relevant ligands (e.g., von Willebrand Factor,
collagen, fibrinogen, other extracellular matrix proteins,
synthetic fragments of any of the proteins, or any combination
thereof), by changes in the shape of the platelets, or any
combinations thereof. In one embodiment, platelet activation is
measured by changes in the levels of one or more analytes released
by platelets. For example, the one or more analytes released by
platelets can be P-selectin (CD62p), CD63, ATP, or any combination
thereof. In a particular embodiment, platelet activation is
measured by the level of binding of fibrinogen or GPIIbIIIa
antibodies to platelets. In other embodiments, platelet activation
is measured by the degree of phosphorylation of
vasodilator-stimulated phosphoprotein (VASP) upon platelet
activation. In yet other embodiments, platelet activation is
measured by the level of platelet-leukocyte aggregates. In certain
embodiments, platelet activation is measured by proteomics
profiling. The term "PAR4 antagonist" also includes a compound that
inhibits both PAR1 and PAR4.
[0958] Preferably, compounds of the invention have IC.sub.50s in
the PAR4 FLIPR Assay (described hereinafter) of about 10 .mu.M,
preferably 1 .mu.M or less, more preferably 100 nM or less, and
even more preferably 10 nM or less. PAR4 FLIPR assay data for
compounds of the present invention is presented in the Table.
[0959] In some embodiments, the present invention provides a
pharmaceutical composition, which includes a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of Formula I-VIII, preferably, a compound selected from
one of the examples, more preferably, Examples 1 to 837, or
stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, alone or in combination with another therapeutic
agent.
[0960] In some embodiments, the present invention provides a
pharmaceutical composition which further includes another
therapeutic agent(s). In a preferred embodiment, the present
invention provides a pharmaceutical composition, wherein the
additional therapeutic agent(s) are an anti-platelet agent or a
combination thereof. Preferably, the anti-platelet agent(s) are
P2Y12 antagonists and/or aspirin. Preferably, the P2Y12 antagonists
are clopidogrel, ticagrelor, or prasugrel. In another preferred
embodiment, the present invention provides a pharmaceutical
composition, wherein the additional therapeutic agent(s) are an
anticoagulant or a combination thereof. Preferably, the
anticoagulant agent(s) are a FXa inhibitor, a thrombin inhibitor,
or a FXIa inhibitor. Preferably, the FXa inhibitors are apixaban,
rivaroxaban, edoxaban, or betrixaban. Preferably, the thrombin
inhibitor is dabigatran.
[0961] It is desirable to find compounds with advantageous and
improved characteristics compared with known anti-platelet agents,
in one or more of the following categories that are given as
examples, and are not intended to be limiting: (a) pharmacokinetic
properties, including oral bioavailability, half life, and
clearance; (b) pharmaceutical properties; (c) dosage requirements;
(d) factors that decrease blood concentration peak-to-trough
characteristics; (e) factors that increase the concentration of
active drug at the receptor; (f) factors that decrease the
liability for clinical drug-drug interactions; (g) factors that
decrease the potential for adverse side-effects, including
selectivity versus other biological targets; (h) improved
therapeutic index with less propensity for bleeding; and (h)
factors that improve manufacturing costs or feasibility.
[0962] As used herein, the term "patient" encompasses all mammalian
species.
[0963] As used herein, the term "subject" refers to any human or
nonhuman organism that could potentially benefit from treatment
with a PAR4 antagonist. Exemplary subjects include human beings of
any age with risk factors for cardiovascular disease, or patients
that have already experienced one episode of cardiovascular
disease. Common risk factors include, but are not limited to, age,
male sex, hypertension, smoking or smoking history, elevation of
triglycerides, elevation of total cholesterol or LDL
cholesterol.
[0964] In some embodiments, the subject is a species having a dual
PAR1/PAR4 platelet receptor repertoire. As used herein, the term
"dual PAR1/PAR4 platelet receptor repertoire" means that a subject
expresses PAR1 and PAR4 in platelets or their precursors. Exemplary
subjects having a dual PAR1/PAR4 platelet receptor repertoire
include human beings, non-human primates, and guinea pigs.
[0965] In other embodiments, the subject is a species having a dual
PAR3/PAR4 platelet receptor repertoire. As used herein, the term
"dual PAR3/PAR4 platelet receptor repertoire" means that a subject
expresses PAR3 and PAR4 in platelets or their precursors. Exemplary
subjects having a dual PAR3/PAR4 platelet receptor repertoire
include rodents and rabbits.
[0966] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) inhibiting the disease-state, i.e; arresting its
development; and/or (b) relieving the disease-state, i.e., causing
regression of the disease state.
[0967] As used herein, "prophylaxis" or "prevention" cover the
preventive treatment of a subclinical disease-state in a mammal,
particularly in a human, aimed at reducing the probability of the
occurrence of a clinical disease-state. Patients are selected for
preventative therapy based on factors that are known to increase
risk of suffering a clinical disease state compared to the general
population. "Prophylaxis" therapies can be divided into (a) primary
prevention and (b) secondary prevention. Primary prevention is
defined as treatment in a subject that has not yet presented with a
clinical disease state, whereas secondary prevention is defined as
preventing a second occurrence of the same or similar clinical
disease state.
[0968] As used herein, "risk reduction" covers therapies that lower
the incidence of development of a clinical disease state. As such,
primary and secondary prevention therapies are examples of risk
reduction.
[0969] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention that is effective
when administered alone or in combination to inhibit and/or
antagonize PAR4 and/or to prevent or treat the disorders listed
herein. When applied to a combination, the term refers to combined
amounts of the active ingredients that result in the preventive or
therapeutic effect, whether administered in combination, serially,
or simultaneously.
[0970] The term "thrombosis", as used herein, refers to formation
or presence of a thrombus (pl. thrombi) within a blood vessel that
may cause ischemia or infarction of tissues supplied by the vessel.
The term "embolism", as used herein, refers to sudden blocking of
an artery by a clot or foreign material that has been brought to
its site of lodgment by the blood current. The term
"thromboembolism", as used herein, refers to obstruction of a blood
vessel with thrombotic material carried by the blood stream from
the site of origin to plug another vessel. The term "thromboembolic
disorders" entails both "thrombotic" and "embolic" disorders
(defined above).
[0971] The term "thromboembolic disorders" as used herein includes
arterial cardiovascular thromboembolic disorders, venous
cardiovascular or cerebrovascular thromboembolic disorders, and
thromboembolic disorders in the chambers of the heart or in the
peripheral circulation. The term "thromboembolic disorders" as used
herein also includes specific disorders selected from, but not
limited to, unstable angina or other acute coronary syndromes,
atrial fibrillation, first or recurrent myocardial infarction,
ischemic sudden death, transient ischemic attack, stroke,
atherosclerosis, peripheral occlusive arterial disease, venous
thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. The medical implants or devices include, but
are not limited to: prosthetic valves, artificial valves,
indwelling catheters, stents, blood oxygenators, shunts, vascular
access ports, ventricular assist devices and artificial hearts or
heart chambers, and vessel grafts. The procedures include, but are
not limited to: cardiopulmonary bypass, percutaneous coronary
intervention, and hemodialysis. In another embodiment, the term
"thromboembolic disorders" includes acute coronary syndrome,
stroke, deep vein thrombosis, and pulmonary embolism.
[0972] In another embodiment, the present invention provides a
method for the treatment of a thromboembolic disorder, wherein the
thromboembolic disorder is selected from unstable angina, an acute
coronary syndrome, atrial fibrillation, myocardial infarction,
transient ischemic attack, stroke, atherosclerosis, peripheral
occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial
thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney
embolism, pulmonary embolism, and thrombosis resulting from medical
implants, devices, or procedures in which blood is exposed to an
artificial surface that promotes thrombosis. In another embodiment,
the present invention provides a method for the treatment of a
thromboembolic disorder, wherein the thromboembolic disorder is
selected from acute coronary syndrome, stroke, venous thrombosis,
atrial fibrillation, and thrombosis resulting from medical implants
and devices.
[0973] In another embodiment, the present invention provides a
method for the primary prophylaxis of a thromboembolic disorder,
wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, myocardial
infarction, ischemic sudden death, transient ischemic attack,
stroke, atherosclerosis, peripheral occlusive arterial disease,
venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. In another embodiment, the present invention
provides a method for the primary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from
acute coronary syndrome, stroke, venous thrombosis, and thrombosis
resulting from medical implants and devices.
[0974] In another embodiment, the present invention provides a
method for the secondary prophylaxis of a thromboembolic disorder,
wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, recurrent
myocardial infarction, transient ischemic attack, stroke,
atherosclerosis, peripheral occlusive arterial disease, venous
thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. In another embodiment, the present invention
provides a method for the secondary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from
acute coronary syndrome, stroke, atrial fibrillation and venous
thrombosis.
[0975] The term "stroke", as used herein, refers to embolic stroke
or atherothrombotic stroke arising from occlusive thrombosis in the
carotid communis, carotid interna, or intracerebral arteries.
[0976] It is noted that thrombosis includes vessel occlusion (e.g.,
after a bypass) and reocclusion (e.g., during or after percutaneous
transluminal coronary angioplasty). The thromboembolic disorders
may result from conditions including but not limited to
atherosclerosis, surgery or surgical complications, prolonged
immobilization, arterial fibrillation, congenital thrombophilia,
cancer, diabetes, effects of medications or hormones, and
complications of pregnancy.
[0977] Thromboembolic disorders are frequently associated with
patients with atherosclerosis. Risk factors for atherosclerosis
include but are not limited to male gender, age, hypertension,
lipid disorders, and diabetes mellitus. Risk factors for
atherosclerosis are at the same time risk factors for complications
of atherosclerosis, i.e., thromboembolic disorders.
[0978] Similarly, atrial fibrillation is frequently associated with
thromboembolic disorders. Risk factors for atrial fibrillation and
subsequent thromboembolic disorders include cardiovascular disease,
rheumatic heart disease, nonrheumatic mitral valve disease,
hypertensive cardiovascular disease, chronic lung disease, and a
variety of miscellaneous cardiac abnormalities as well as
thyrotoxicosis.
[0979] Diabetes mellitus is frequently associated with
atherosclerosis and thromboembolic disorders. Risk factors for the
more common type 2 include but are not limited to family history,
obesity, physical inactivity, race/ethnicity, previously impaired
fasting glucose or glucose tolerance test, history of gestational
diabetes mellitus or delivery of a "big baby", hypertension, low
HDL cholesterol, and polycystic ovary syndrome.
[0980] Thrombosis has been associated with a variety of tumor
types, e.g., pancreatic cancer, breast cancer, brain tumors, lung
cancer, ovarian cancer, prostate cancer, gastrointestinal
malignancies, and Hodgkins or non-Hodgkins lymphoma. Recent studies
suggest that the frequency of cancer in patients with thrombosis
reflects the frequency of a particular cancer type in the general
population. (Levitan, N. et al., Medicine (Baltimore),
78(5):285-291 (1999); Levine M. et al., N Engl. J Med.,
334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722
(2005).) Hence, the most common cancers associated with thrombosis
in men are prostate, colorectal, brain, and lung cancer, and in
women are breast, ovary, and lung cancer. The observed rate of
venous thromboembolism (VTE) in cancer patients is significant. The
varying rates of VTE between different tumor types are most likely
related to the selection of the patient population. Cancer patients
at risk for thrombosis may possess any or all of the following risk
factors: (i) the stage of the cancer (i.e., presence of
metastases), (ii) the presence of central vein catheters, (iii)
surgery and anticancer therapies including chemotherapy, and (iv)
hormones and antiangiogenic drugs. Thus, it is common clinical
practice to dose patients having advanced tumors with heparin or
low molecular heparin to prevent thromboembolic disorders. A number
of low molecular weight heparin preparations have been approved by
the FDA for these indications.
[0981] The term "pharmaceutical composition," as used herein, means
any composition, which contains at least one therapeutically or
biologically active agent and is suitable for administration to the
patient. Any of these formulations can be prepared by well-known
and accepted methods of the art. See, for example, Gennaro, A. R.,
ed., Remington: The Science and Practice of Pharmacy, 20th Edition,
Mack Publishing Co., Easton, Pa. (2000).
[0982] The invention includes administering to a subject a
pharmaceutical composition that includes a compound that binds to
PAR4 and inhibits PAR4 cleavage and/or signaling (referred to
herein as a "PAR4 antagonist" or "therapeutic compound").
[0983] The pharmaceutical composition is administered using methods
known in the art. Preferably, the compound is administered orally,
rectally, nasally, by inhalation, topically or parenterally, e.g.,
subcutaneously, intraperitoneally, intramuscularly, and
intravenously. The compound is optionally formulated as a component
of a cocktail of therapeutic drugs to treat a thromboembolic
disorder. In one embodiment, the pharmaceutical composition is
administered orally.
[0984] The therapeutic compounds described herein are formulated
into pharmaceutical compositions utilizing conventional methods.
For example, a PAR4 antagonist is formulated in a capsule or a
tablet for oral administration. Capsules may contain any standard
pharmaceutically acceptable materials such as gelatin or cellulose.
Tablets may be formulated in accordance with conventional
procedures by compressing mixtures of a therapeutic compound with a
solid carrier and a lubricant. Examples of solid carriers include
starch and sugar bentonite. The compound is administered in the
form of a hard shell tablet or a capsule containing a binder, e.g.,
lactose or mannitol, a conventional filler, and a tableting agent.
Other formulations include an ointment, suppository, paste, spray,
patch, cream, gel, resorbable sponge, or foam. Such formulations
are produced using methods well known in the art. The compositions
of the invention are also useful for parenteral administration,
such as intravenous, subcutaneous, intramuscular, and
intraperitoneal. Examples of formulations suitable for parenteral
administration include aqueous solutions of the active agent in an
isotonic saline solution, a 5% glucose solution, or another
standard pharmaceutically acceptable excipient. Standard
solubilizing agents such as PVP or cyclodextrins are also utilized
as pharmaceutical excipients for delivery of the therapeutic
compounds.
[0985] The preferred dose of the PAR4 antagonist is a biologically
active dose. A biologically active dose is a dose that will inhibit
cleavage and/or signaling of PAR4 and have an anti-thrombotic
effect. Desirably, the PAR4 antagonist has the ability to reduce
the activity of PAR4 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 100%, or more than 100% below untreated control
levels. The levels of PAR4 in platelets is measured by any method
known in the art, including, for example, receptor binding assay,
platelet aggregation, platelet activation assays (e.g., p-selectin
expression by FACS), Western blot or ELISA analysis using PAR4
cleavage sensitive antibodies. Alternatively, the biological
activity of PAR4 is measured by assessing cellular signaling
elicited by PAR4 (e.g., calcium mobilization or other second
messenger assays).
[0986] In some embodiments, a therapeutically effective amount of a
PAR4 compound is preferably from about less than 100 mg/kg, 50
mg/kg, 10 mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more
preferred embodiment, the therapeutically effective amount of the
PAR4 compound is less than 5 mg/kg. In a most preferred embodiment,
the therapeutically effective amount of the PAR4 compound is less
than 1 mg/kg. Effective doses vary, as recognized by those skilled
in the art, depending on route of administration and excipient
usage.
[0987] The activity of the PAR4 antagonists of the present
invention can be measured in a variety of in vitro assays.
Exemplary assays are shown below.
[0988] The Fluorometric Imaging Plate Reader (FLIPR) assay is an
exemplary in vitro assay for measuring the activity of the PAR4
antagonists of the present invention. In this assay, intracellular
calcium mobilization is induced in PAR4 expressing cells by a PAR4
agonist and calcium mobilization is monitored.
[0989] AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist
is H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2. As
shown in Example B of WO2013/163279,
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 was
validated as a PAR4 agonist in the FLIPR assay. A side-by-side
comparison of the IC.sub.50 values of .about.180 compounds were
performed using AYPGKF versus
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2. The
results demonstrated a strong correlation between the two assays.
Additionally,
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 has
improved agonist activity as compared to AYPGKF with an EC.sub.50
that is 10 fold lower than the EC.sub.50 for AYPGKF in the FLIPR
assay. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 can
be synthesized using methods well known to those of skill in the
art.
[0990] The FLIPR assay can also be used as a counterscreen to test
agonist activity or PAR1 antagonist activity in a cell line that
expresses both PAR1 and PAR4. The PAR1 antagonist activity can be
tested by the ability of the compound to inhibit calcium
mobilization induced by the PAR1 agonist peptide SFLLRN or other
PAR1 agonist peptides.
[0991] The compounds of the current invention can be tested in
vitro for their ability to inhibit platelet aggregation induced by
gamma-thrombin as shown below. Gamma-thrombin, a proteolytic
product of alpha-thrombin which no longer interacts with PAR1,
selectively cleaves and activates PAR4 (Soslau, G. et al., "Unique
pathway of thrombin-induced platelet aggregation mediated by
glycoprotein Ib", J. Biol. Chem., 276:21173-21183 (2001)). Platelet
aggregation can be monitored in a 96-well microplate aggregation
assay format or using standard platelet aggregometer. The
aggregation assay can also be employed to test the selectivity of
the compound for inhibiting platelet aggregation induced by PAR4
agonist peptides, PAR1 agonist peptide, ADP, or thromboxane
analogue U46619.
[0992] The compounds of the current invention can be tested in
vitro for their ability to inhibit platelet aggregation induced by
alpha-thrombin as shown below. Alpha-thrombin activates both PAR1
and PAR4. The ability of a selective PAR4 antagonist of the present
invention to inhibit platelet aggregation can be measured using a
standard optical aggregometer.
[0993] The compounds of the current invention can be tested in
vitro for their ability to inhibit platelet aggregation induced by
tissue factor as shown below. The conditions in this assay mimic
the physiological events during thrombus formation. In this assay,
platelet aggregation in human platelet rich plasma (PRP) is
initiated by the addition of tissue factor and CaCl.sub.2. Tissue
factor, the initiator of the extrinsic coagulation cascade, is
highly elevated in human atherosclerotic plaque. Exposure of blood
to tissue factor at the atherosclerotic site triggers a robust
generation of thrombin and induces the formation of obstructive
thrombi.
[0994] The activity of the PAR4 antagonists of the present
invention can also be measured in a variety of in vivo assays.
Exemplary mammals that can provide models of thrombosis and
hemostasis to test the effectiveness of the PAR4 antagonists of the
present invention as antithrombotic agents include, but are not
limited to, guinea pigs and primates. Relevant efficacy models
include, but are not limited to, electrically-induced carotid
arterial thrombosis, FeCl.sub.3-induced carotid artery thrombosis
and arteriovenous-shunt thrombosis. Models of kidney bleeding time,
renal bleeding time and other bleeding time measurements can be
used to assess the bleeding risk of the antithrombotic agents
described in the current invention.
ASSAYS
Materials
[0995] 1) PAR1 and PAR4 Agonist Peptides
[0996] SFFLRR is a known high affinity PAR1 selective agonist
peptide. (Reference: Seiler, S. M., "Thrombin receptor
antagonists", Seminars in Thrombosis and Hemostasis, 22(3):223-232
(1996).) The PAR4 agonist peptides AYPGKF and
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 were
synthesized.
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 showed
improved PAR4 agonist activity over AYPGKF in the FLIPR assay
(EC.sub.50 value of 8 .mu.M for
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 and 60
.mu.M for AYPGKF) and in washed platelet aggregation assay
(EC.sub.50 value of 0.9 .mu.M for
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2 and 12
.mu.M for AYPGKF).
2) PAR4 Expressing Cells
[0997] HEK293 cells stably expressing PAR4 were generated by a
standard method of transfection of human PAR4 (F2R23) cDNA
expression vector and selected based on PAR4 protein expression or
mRNA expression. Those cells demonstrated functional responses to
PAR4 agonist peptide-induced intracellular calcium elevation using
FLIPR.RTM. (Fluorometric Imaging Plate Reader; Molecular Devices
Corp.). These cells also express endogenous PAR1 and can elicit
calcium signal upon stimulation with PAR1 agonist peptide.
Therefore, the same cells were also used to determine selectivity
against PAR1 and agonist activity for both receptors. Cells from
HEK293 PAR4 Clone 1.2A (BMS Arctic ID 383940) were propagated and
used for calcium mobilization studies.
3) Preparation of Platelet Rich Plasma (PRP)
[0998] Human blood was collected in 3.8% sodium citrate at a ratio
of 1 ml per 9 ml blood and centrifuged in a Sorvall.RTM. RT6000B
centrifuge at 900 revolution per minute (rpm) at room temperature
(RT) for 15 minutes. PRP was collected and used for aggregation
assay. Refludan (Berlex Labs, Wayne, N.J.), a recombinant hirudin,
at a final concentration of 1 unit/mL was added to the sample to
selectively prevent PAR1 activation induced by residual
alpha-thrombin contamination. The remaining blood sample was
centrifuged at 2500 rpm at room temperature for 5 minutes to
collect platelet-poor plasma (PPP).
4) Preparation of Washed Platelets (WP)
[0999] Human blood was collected in ACD (85 mM tri-sodium citrate,
78 mM citric acid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml
per 10 ml blood. PRP was isolated by centrifugation at 170 g for 14
minutes and platelets were further pelleted by centrifugation at
1300 g for 6 minutes. Platelets were washed once with 10 ml ACD
containing 1 mg/ml bovine serum albumin. Platelets were resuspended
at .about.2.5.times.10.sup.8/ml in Tyrode's Buffer (137 mM NaCl, 2
mM KCl, 1.0 mM MgCl.sub.2, 1 mM CaCl.sub.2, 5 mM glucose, 20 mM
HEPES pH 7.4).
FLIPR Assay in PAR4-Expressing HEK293 Cells
[1000] FLIPR-based calcium mobilization assay in HEK293 cells was
used to measure PAR4 antagonism, agonism, and selectivity against
PAR1. The activity of the PAR4 antagonists of the present invention
were tested in PAR4 expressing cells by monitoring
H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2-induced
intracellular calcium mobilization. Counter screens for agonist
activity and PAR1 antagonist activity were also performed. Briefly,
PAR1/PAR4-expressing HEK293 cells were grown in DMEM (Life
Technology, Grand Island, N.Y.) containing 10% heat-inactivated
FBS, 1% Penicillin-Streptomycin, 10 .mu.g/mL blasticidin, and 100
.mu.g/mL Zeocin at 37.degree. C. with 5% CO.sub.2. Cells were
plated overnight prior to the experiment in a black 384-well
Purecoat Amine clear bottom plate (Becton Dickinson Biosciences,
San Jose, Calif.) at 10,000 cells/well in 30 .mu.L growth medium
and incubated in a humidified chamber at 37.degree. C. with 5%
CO.sub.2 overnight. Prior to compound addition, the cell medium was
replaced with 40 .mu.L of 1.times. calcium and magnesium-containing
Hank's Balanced Saline Solution (HBSS) (with 20 mM HEPES) and
1:1000 diluted fluorescent calcium indicator (Codex Biosolutions,
Gaithersburg, Md.). After a 30 minute incubation period at
37.degree. C. and a further 30 minute incubation and equilibration
period at room temperature, 20 .mu.L test compound (diluted in
1.times.HBSS buffer) was added at various concentrations at 0.17%
dimethyl sulfoxide (DMSO) final concentration. Changes in
fluorescence intensity were measured using a Functional Drug
Screening System (FDSS, Hamamatsu, Japan) to determine agonist
activities. The cells were then incubated for 30 minutes at room
temperature followed by addition of 20 .mu.L of agonist peptide for
antagonist activity measurement. The PAR4 agonist peptide
(H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH.sub.2) and the
PAR1 agonist peptide (SFFLRR) were routinely tested to ensure a
proper response at the EC.sub.50 value in the assay (.about.5 .mu.M
for PAR4 agonist peptide and -2 .mu.M for PAR1 agonist peptide).
Compound potency was derived from 11-point concentration-response
curves.
Gamma Thrombin Induced Platelet Aggregation Assays
[1001] The ability of the compounds of the current invention to
inhibit platelet aggregation induced by gamma-thrombin was tested
in a 96-well microplate aggregation assay format. Briefly, 90 .mu.L
of PRP or washed platelets were pre-incubated for 5 minutes at
37.degree. C. with 3-fold serially diluted test compound, which was
prepared as a 100-fold stock solution in dimethyl sulfoxide (DMSO).
Aggregation was initiated by addition of 10 .mu.L of gamma-thrombin
(Haematologic Technologies, Inc. Essex Junction, Vt.) at 50-100 nM
final concentration, which was titrated daily to achieve 80%
platelet aggregation. The plate was then placed into a
SpectraMax.RTM. Plus Plate Reader (Molecular Devices) at 37.degree.
C. Platelet aggregation was monitored at a wavelength of 405 nm
using a kinetic analysis mode. Prior to the first data collection
time point, the plate was shaken for 10 seconds to allow thorough
mixing. Data was subsequently collected every 10 seconds for up to
7 minutes total. Data was collected using SoftMax.RTM. 5.4.1
software and exported to Microsoft Excel for analysis. The optical
density (OD) values at the time point that achieved 75% platelet
activation by agonist alone were used for analysis. The OD value
from a PRP sample without any treatment served as ODmaximum, and
the OD value from a PPP sample containing no platelets served as
the ODminimum. Inhibition of platelet aggregation (IPA) was
calculated based on the formula: %
IPA=(100-100*[ODcompound-ODminimum]/[ODmaximum-ODminimum]). The
IC.sub.50 value of the test compound was calculated by fitting the
% IPA values to the one-site concentration response equation:
Y=A+(B-A)/{1+(C/X){circumflex over ( )}D]}, using XLfit for 32 bit
Excel.RTM. Version 2 Build 30 (ID Business Solutions Limited).
[1002] The aggregation assays were also employed to test the
selectivity of the compound against other platelet receptors by
using SFFLRR for PAR1, collagen (Chrono-Log, Havertown, Pa.) for
collagen receptors, ADP for P2Y1 and P2Y12 and U46619 (Cayman
Chemical, Ann Arbor, Mich.) for thromboxane receptors.
Alpha-thrombin Induced Platelet Aggregation Assays
[1003] The ability of PAR4 antagonists to inhibit platelet
aggregation induced by alpha-thrombin can be tested using human
washed platelets. The antagonists are pre-incubated with washed
platelets for 20 min. Aggregation is initiated by addition of 1.5
nM alpha-thrombin (Haematologic Technologies, Essex Junction, Vt.)
to 300 .mu.l of washed platelets at stirring speed of 1000 rpm.
Platelet aggregation is monitored using an Optical Aggregometer
(Chrono-Log, Havertown, Pa.) and the area under the curve (AUC) at
6 min was measured. IC.sub.50 values are calculated using vehicle
control as 0% inhibition.
Tissue Factor-Induced Platelet Aggregation Assay
[1004] The ability of PAR1 or PAR4 antagonists to inhibit platelet
aggregation induced by endogenous thrombin can be tested in a
tissue factor driven aggregation assay. Aggregation is initiated by
addition of CaCl.sub.2 and recombinant human tissue factor, which
results in the generation of thrombin through activation of the
coagulation pathway in the plasma. Anticoagulant agents such as
corn trypsin inhibitor (Haematologic Technologies, Essex Junction,
Vt.) at 50 .mu.g/ml and PEFABLOC.RTM. FG (Centerchem, Norwalk,
Conn.) are also added to the sample to prevent fibrin clot
formation during the time of the study. Platelet aggregation is
monitored using standard instrumentation including optical
aggregometer or impedance aggregometer.
[1005] The following table sets out the results obtained employing
various compounds of the invention tested in the PAR4 FLIPR
assay.
TABLE-US-00001 TABLE PAR4 FLIPR assay (IC50, Ex. No. nM) 1 29 2 11
3 240 4 17 5 880 6 130 7 800 8 8.1 9 220 10 2.2 11 1700 12 2.0 13
3.5 14 6.8 15 38 16 80 17 13 18 98 19 41 20 30 21 3.3 22 1.8 23 5.3
24 2.0 25 130 26 3.3 27 5.4 28 3.0 29 1.4 30 4.7 31 240 32 3.0 33
120 34 1.6 35 54 36 7.7 37 22 38 2.1 39 10 40 36 41 400 42 5.2 43
170 44 220 45 99 46 17 47 34 48 2.1 49 9.7 50 92 51 180 52 4.7 53
9.8 54 94 55 14 56 4.7 58 3.0 59 5.0 60 19 61 43 62 100 63 2.9 64
7.4 65 31 66 28 67 2.9 68 120 69 36 70 34 71 160 72 1.0 73 2.3 74
9.3 75 14 76 2.1 77 130 78 39 79 2.2 80 21 81 1.5 82 280 83 11 84
2.5 85 8.5 86 7.2 87 2.0 89 1.4 90 84 91 62 92 2.0 93 0.3 94 1.4 95
0.8 96 1.1 97 1.7 98 0.3 99 0.6 100 0.5 101 0.2 102 0.9 103 2.5 104
1.7 105 8.1 106 1.6 107 2.8 108 1100 109 8.3 110 12 111 1.1 112 2.0
113 3.0 114 1600 115 1.3 116 1.4 117 0.5 118 2.2 119 16 120 28 121
0.7 122 3.9 123 1.5 124 1.8 125 2.0 126 1.2 127 8.3 128 2.2 129 3.2
130 460 131 890 132 59 133 570 134 120 135 2200 136 29 137 29 138
33 139 3.9 140 21 141 80 142 5.6 143 36 144 0.3 145 4.5 146 7.0 147
1.7 148 48 149 4.2 150 94 151 2000 152 38 153 16 154 3.8 155 0.8
156 1.4 157 31 158 0.7 159 25 160 1.2 161 0.7 162 270 163 0.5 164
0.5 165 1.2 166 2.8 167 4.5 168 2.0 169 0.4 170 0.3 171 0.6 172 1.7
173 2.7 174 3.0 175 23 176 980 177 190 178 13 179 18 180 2.7 181
1.2 182 22 183 0.6 184 2300 185 6.5 186 17 187 390 188 580 189 140
190 1700 191 6.4 192 2.8 193 1.2 194 2.5 195 32 196 2.3 197 1.3 198
0.6 199 2.5 200 1.6 201 1.3 202 0.9 203 4.1 204 3.1 205 51 206 0.7
207 0.9 208 1.1 209 1.1 210 0.3 211 21 212 2.4 213 5.8 214 4.3 215
2.9 216 160 217 18 218 2.5 219 5.5 220 2.6 221 21 222 1.0 223 10
224 15 225 54 226 140 227 160 228 890 229 3.9 230 2.2 231 1.0 232
0.7 233 0.4 234 1.4 235 2.2 236 140 237 170 238 1300 239 7.9 240 72
241 5.4 242 120 243 1.2
244 2.0 245 92 246 140 247 19 248 19 249 6.9 250 31 251 17 252 0.5
253 0.6 254 1.5 255 0.8 256 1.2 257 2.1 258 2.8 259 14 260 4.8 261
1.2 262 0.8 263 0.8 264 8.3 265 6.8 266 2.2 267 0.8 268 0.9 269 3.6
270 17 271 1.5 272 3.2 273 4.3 274 5.7 275 0.9 276 1.2 277 9.0 278
4.6 279 18 280 4.3 281 3.6 282 1.1 283 1.9 284 5.9 285 16 286 0.5
287 8.5 288 8.6 289 1.3 290 6.0 291 11 292 0.8 293 1.0 294 5.2 295
0.7 296 1.2 297 5.7 298 2.1 299 10 300 0.9 301 15 302 3.2 303 0.9
304 2.3 305 1.0 306 1.0 307 0.9 308 3.6 309 3.3 310 9.1 311 93 312
6.7 313 2.9 314 10 315 3.3 316 4.9 317 4.5 318 7.8 319 7.3 320 3.4
321 3.1 322 5.1 323 15 324 42 325 0.7 326 1.1 327 5.2 328 1.4 329
1.1 330 57 331 9.2 332 2.4 333 1.7 334 29 335 2.5 336 5.5 337 0.7
338 2.0 339 1.6 340 1.5 341 15 342 11 343 0.7 344 11 345 0.6 346
3.7 347 0.8 348 4.4 349 2.7 350 2.8 351 2.7 352 390 353 22 354 1.2
355 17 356 2.1 357 6.7 358 270 359 170 360 160 361 5.5 362 4.1 363
1700 364 19 365 2.5 366 550 367 12 369 13 370 5.8 371 1.8 372 1.3
373 0.9 374 110 375 1.7 376 72 377 4.3 378 8.7 379 1.7 380 2.3 381
1.4 382 1.3 383 590 384 18 385 2.3 386 7.8 387 1.5 388 0.7 389 0.4
390 3.6 391 2.0 392 3.1 393 30 394 130 395 5.8 396 4.6 397 210 398
8.6 399 3.9 400 2.0 401 2.7 402 3.7 403 1.7 404 2.2 405 1.9 406 3.5
407 0.9 408 3.2 409 0.4 410 0.3 411 4.4 412 0.3 413 3.4 414 7.0 415
3.1 416 32 417 11 418 1.3 419 2.0 420 2.2 421 1.8 422 2.2 423 4.2
426 5.4 427 7.6 428 5.9 429 0.5 430 0.9 431 1.1 432 0.4 433 0.6 434
1.4 435 0.9 436 1.5 437 4.9 438 1.9 439 0.9 440 0.8 441 0.9 442 0.8
443 0.6 444 0.8 445 3.2 446 2.3 447 21 448 2.1 449 0.3 450 0.5 451
0.7 452 0.4 453 0.6 454 1.3 455 0.8 456 0.7 457 0.4 458 0.5 459 0.9
460 0.9 461 0.4 462 0.2 463 0.7 464 1.5 465 1.4 466 0.7 467 1.9 468
0.8 470 2.2 471 5.2 472 4.6 473 3.4 474 11 475 4.8 476 10 477 3.0
478 9.1 479 1.4 480 3.4 481 0.6 482 0.6 483 0.8 484 1.0 485 1.6 486
1.5 487 1.3 488 14 489 9.1 490 5.1 491 0.4 492 7.4 493 21 494 1.8
495 15 496 1.9 497 1.3 498 1.3
499 4.4 500 3.8 501 4.0 502 1.7 512 1.2 513 1.1 514 1.9 515 2.6 516
2.0 517 1.1 518 13 519 16 520 77 521 24 522 20 523 2.6 524 84 525
2.3 526 2.0 527 1.4 528 5.0 529 0.9 530 1.8 531 0.7 532 1.7 533 0.7
534 0.9 535 5.2 536 4.9 539 6.5 540 3.0 541 3.4 542 1.6 543 1.3 544
34 545 1.5 546 14 547 5.2 549 1.0 550 0.4 552 0.7 553 1.2 554 0.7
555 1.1 556 0.7 557 0.7 558 1.5 559 0.9 560 1.4 561 53 562 1.6 563
2.8 564 3.7 565 3.0 566 1.8 567 5.9 568 2.4 569 8.2 570 6.6 571 1.0
572 0.9 573 1.6 574 2.0 575 0.6 576 1.2 577 1.0 578 5.8 579 3.3 580
1.1 581 4.1 582 5.3 589 0.8 590 25 591 7.0 592 0.7 596 130 597 15
598 3.7 599 5.6 600 2.4 601 3.5 602 6.4 603 2.1 604 17 605 0.7 606
0.4 607 0.2 608 0.5 609 1.9 610 4.3 611 2.1 613 65 614 30 615 870
616 4200 618 3.8 621 8.0 622 350 623 320 624 0.7 625 1.8 626 7.2
627 1400 628 1.4 629 2.2 630 1.4 631 5.3 632 10 633 2.6 634 44 635
10 636 3.0 637 2.1 638 2.7 639 1.4 640 8.0 641 250 642 4.6 643 5.3
644 21 645 4.9 646 3.8 647 19 648 3.0 649 7.4 650 5.6 651 4.3 652
11 653 0.83 654 1.0 655 1.1 656 2.4 657 1.1 658 3.0 659 2.1 660 2.0
661 55 662 77 663 7.0 664 0.9 665 1.7 666 1.1 667 5.6 668 7.3 669
2.3 671 1.9 672 1.9 673 39 674 20 675 10 676 3.2 677 3.8 678 1.0
679 2.5 680 0.8 681 0.4 682 0.9 683 0.7 684 0.7 685 1.7 686 9.9 687
0.9 688 4.5 689 0.3 690 0.3 691 0.9 692 1.8 693 1.3 694 2.1 695 1.0
696 2.6 697 2.9 698 17 699 1.1 700 0.9 701 2.7 702 4.3 708 2.6 709
0.4 710 1.8 711 2.4 712 3.2 713 1.8 714 1.2 715 0.9 716 2.0 717 1.6
718 1.7 719 1.7 720 3.2 721 2.6 722 1.4 723 2.4 724 2.1 725 0.8 726
1.2 727 1.7 728 2.4 729 2.8 730 13 731 0.9 733 1.1 734 1.0 735 1.1
736 5.3 737 8.1 738 10 740 0.9 741 2.1 747 2.4 748 2.9 749 4.3 750
1.1 751 4.7 752 14 753 12 754 0.3 755 0.3 762 1.4 763 4.0 764 1.7
765 0.8 766 2.9 767 3.4 768 10 769 3.2 770 1.9 771 6.3 772 1.5 773
11 774 1.2 775 0.8 776 2.5 777 8.6 778 3.4 779 3.3 780 5.0 781 6.0
782 2.7 783 4.2 784 2.8 785 3.5 786 2.2 787 2.9 788 3.1 789 2.4 790
4.4 791 2.3 792 11 793 24 794 10
795 0.8 796 1.3 797 3.1 798 2.5 799 2.9 800 2.5 801 2.6 802 2.0 803
3.5 804 2.8 806 6.6 807 2.6 808 2.0 809 54 810 6.9 811 1.5 812 7.0
813 1.0 814 7.2 815 6.4 816 10 817 3.6 818 1.8 819 1.2 820 1.7 821
4.6 822 1.6 823 5.1 824 1.5 825 8.0 826 1.9 827 6.2 828 0.7 829 0.6
830 1.6 831 2.2 832 2.5 833 1.6 834 3.0 835 0.5 836 1.2 837 17
Methods of Preparation
[1006] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or by variations thereon as appreciated by those skilled in the
art. Preferred methods include, but are not limited to, those
described below. The reaction mixtures are performed in a solvent
or solvent mixture appropriate to the reagents and materials
employed and suitable for the transformations being effected. It
will be understood by those skilled in the art of organic synthesis
that the functionality present on the molecule should be consistent
with the transformations proposed. This will sometimes require a
judgment to modify the order of the synthetic steps or to select
one particular process scheme over another in order to obtain a
desired compound of the invention.
[1007] It will also be recognized that another major consideration
in the planning of any synthetic route in this field is the
judicious choice of the protecting group used for protection of the
reactive functional groups present in the compounds described in
this invention. An authoritative account describing the many
alternatives to the trained practitioner is Wuts et al. (Greene's
Protective Groups In Organic Synthesis, 4th Edition,
Wiley-Interscience (2006).
[1008] Compounds of Formula I of this invention can be obtained by
palladium catalyzed cross coupling of aryl halides of Formula Ia
with organometallic species R.sub.3-M as shown in Scheme 1.
##STR00015##
[1009] Alternatively, compounds of Formula I can also be prepared
from palladium catalyzed cross coupling of arylboronic acids of
Formula Ib with halides R.sub.3--X shown in Scheme 2.
##STR00016##
[1010] One way to prepare the quinoxalines of Formula Ia and Ib is
through the condensation reaction of the diamine Ic with
ketoaldehyde Id, as shown in Scheme 3. In general, the condensation
will give two regioisomers that may be separated by chromatography.
Structure of Formula Ia can be converted to boronic acid Ib via
Suzuki-Miyaura reaction.
##STR00017##
[1011] A regio specific synthesis of quinoxalines of Formula Ia and
Ib is shown in Scheme 4. A properly protected ortho-nitro aniline
Ie is alkylated with methyl bromoacetate to yield compound If.
Deprotection of compound If and reduction of compound Ig should
initiate cyclization to give rise to compound Ih. Compound Ih can
be oxidized to quinoxaline-2-one of Formula Ii, which can be
converted to the intermediate Ij with oxophosphorus halides. The
halides in compound Ij can be displaced with a nucleophile
containing an R.sub.1 group to compound Ia, and compounds of
Formula Ia can be converted to corresponding boronic acids of
Formula Ib via Suzuki-Miyaura reaction. Intermediate Ii could also
be converted to Ik by condensation reaction with sodium
chlorodifluoroacetate in the presence of a base such as
K.sub.2CO.sub.3. The difluoroalkoxy may be displaced with a
nucleophile containing an R.sub.1 group to compound Ia.
##STR00018##
[1012] Compounds of Formula II of this invention can be obtained as
shown in Scheme 5. Compound IIa can be condensed with dicarbonyl
IIb to give compound IIc. Acid catalyzed cyclization provides the
key bromide IId. Palladium catalyzed cross coupling reaction with
an appropriate boronic acid furnishes compound II.
##STR00019##
[1013] Compounds of Formula III of this invention can be obtained
as shown in Scheme 6. Compound IIIa can be condensed with
dimethylacetal IIIb to give compound IIIc. Acid catalyzed
cyclization and triflate formation provides the key coupling
partner IIId. Palladium catalyzed cross coupling reaction with an
appropriate boronic acid furnishes the compound of Formula III
##STR00020##
[1014] Compounds of Formula IV of this invention can be obtained as
shown in Scheme 7. Compound IVa can be condensed with
dimethylacetal IVb to give compound IVc. Acid catalyzed cyclization
and triflate formation provides the key coupling partner IVd.
Palladium catalyzed cross coupling reaction with an appropriate
boronic acid furnishes the compound of Formula IV.
##STR00021##
[1015] Compounds of Formula V of this invention can be obtained as
shown in Scheme 8. Compound Va can be condensed with acid chloride
Vb to give compound Vc. Acid catalyzed cyclization and carbonyl
alkylation provides the key bromide Vd. Palladium catalyzed cross
coupling reaction with an appropriate boronic acid furnishes the
compound of Formula V.
##STR00022##
[1016] Compounds of Formula VI of this invention can be obtained as
shown in Scheme 9. Compound VIa can be condensed with dicarbonyl
compound VIb to give compound VIc. Palladium catalyzed cross
coupling reaction with an appropriate boronic acid furnishes the
compound of Formula VI.
##STR00023##
[1017] In this invention, compounds of Formula VII can be obtained
through the synthetic route shown in Scheme 10. Beginning with aryl
chloride VIIa, palladium catalyzed cross coupling of various
boronic acids or stannanes yields substituted anilines of structure
VIIb. Nitration of compound VIIb and reduction of compound VIIc
allows access to compounds of Formula VIId. Base mediated
condensation of dianiline VIId with substituted bromo-ketones
provides heterocycles of Formula VIIe. A final palladium-catalyzed
cross coupling with aryl boronic acids or stannanes then furnishes
the compounds of Formula VII.
##STR00024##
[1018] Compounds of Formula VIII of this invention can be obtained
by palladium catalyzed cross coupling of aryl boronic acids or
stannanes with aryl chloride VIIIc as shown in Scheme 11. Compound
Villa can be condensed with amidines to give compound VIIIb.
Phosphorous oxychloride conversion of compound VIIIb to aryl
chloride VIIIc followed by palladium-catalyzed cross coupling with
aryl boronic acids or stannanes furnishes the compound of Formula
VIII.
##STR00025##
[1019] A synthesis of 2-halo benzothiazole XXI is shown in Scheme
12. Beginning with the appropriately substituted aniline XIX, the
2-amino benzothiazole XX is formed via addition and oxidative
cyclization of a thiocyanate. Subsequent Sandmeyer chemistry is
employed to generate the desired 2-halo benzothiazole XXI. With XXI
in hand, various compounds of Formula I with structure XXIIa are
prepared with boronic acid Ib via Suzuki cross-coupling.
Intermediates for preparation of compounds of Formulas I-VIII
containing bicyclic R.sub.3 groups other than benzothiazole are
commercially available or can be prepared by one skilled in the
art, and can be incorporated into compounds of Formulas I-VIII via
cross coupling chemistry as shown in Scheme 12.
##STR00026##
[1020] When compounds of structure XXIIb are used as a starting
material, several compounds of Formula I with structure XXIII are
prepared through either alkylation or Mitsunobu chemistry as shown
in Scheme 13. Compounds XXIVa are accessed via epoxide opening of a
variety of mono-substituted epoxides, and compounds XXIVb are
accessed through the opening of di-substituted cyclic sulfates.
##STR00027## ##STR00028##
[1021] Substitution at the 4-position of the benzothiazole R.sub.3
group can be accomplished from intermediates XXVa and XXVb as shown
in Scheme 14. Lithiation of XXVa followed by its addition to a
variety of aldehydes provides XXVI, as does Grignard addition to
benzaldehyde XXVb. XXVI is then coupled to Ib as described above to
provide compounds of Formula I with structure XXVII.
##STR00029##
[1022] Many compounds derived from the core structures depicted
above can be either acylated or sulfonylated using the strategy
shown in Scheme 15. Thus, chloroformate XXIX is synthesized from
compounds with formulas analogous to XXVIII using phosgene. These
chloroformates are then reacted with a variety of nucleophiles to
generate compounds of structure XXX. Compounds of structure XXXII
are synthesized from amines such as XXXI using sulfonyl chloride
reagents.
##STR00030##
General Methods
[1023] The following methods were used in the exemplified Examples,
except where noted otherwise.
[1024] Products were analyzed by reverse phase analytical HPLC
carried out on a Shimadzu Analytical HPLC system running Discovery
VP software using one of the following methods
[1025] Method A: PHENOMENEX.RTM. Luna C18 column (4.6.times.50 mm
or 4.6.times.75 mm) eluted at 4 mL/min with 2, 4 or 8 min gradient
from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B:
10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
[1026] Method B: PHENOMENEX.RTM. Luna C18 column (4.6.times.50 mm)
eluted at 4 mL/min with a 4 min gradient from 100% A to 100% B (A:
10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9%
acetonitrile, 0.1% TFA, UV 220 nm).
[1027] Method C: PHENOMENEX.RTM. Luna C18 column (4.6.times.50 mm
or 4.6.times.75 mm) eluted at 4 mL/min with a 2, 4 or 8 min
gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1%
H.sub.3PO.sub.4; B: 10% water, 89.9% methanol, 0.1%
H.sub.3PO.sub.4, UV 220 nm).
[1028] Method D: PHENOMENEX.RTM. Luna C18 column (4.6.times.50 mm
or 4.6.times.75 mm) eluted at 4 mL/min with a 2, 4 or 8 min
gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1%
NH.sub.4OAc; B: 10% water, 89.9% methanol, 0.1% NH.sub.4OAc, UV 220
nm).
[1029] Method E: BEH C18 2.1.times.50 mm; A: water+0.05% TFA; B:
acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0%
B to 100% B in 1 minute, gradient time 1.5 min.
[1030] Method F: BEH C18 2.1.times.50 mm; A: water+0.05% TFA; B:
acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0%
B to 50% B in 1 minute, gradient time 1.5 min.
[1031] Method G: BEH C18 2.1.times.50 mm; A: water+0.05% TFA; B:
acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min;
50% B to 100% B in 1 minute, gradient time 1.5 min.
[1032] Reverse phase preparative HPLC was carried out using a
Shimadzu Preparative HPLC system running Discovery VP software
using one of the following methods.
[1033] Method A: PHENOMENEX.RTM. Axia Luna 5 .mu.M C18 30.times.75
mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B
(A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9%
acetonitrile, 0.1% TFA, UV 220 nm).
[1034] Method B: YMC Sunfire 5 .mu.M C18 30.times.100 mm column
with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10%
methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1%
TFA, UV 220 nm).
[1035] Method C: XBridge C18, 19.times.200 mm column, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%
trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with
0.1% trifluoroacetic acid; Flow: 20 mL/min.
[1036] Method D: Waters XBridge C18, 19.times.100 mm column,
5-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water with
10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water
with 10-mM ammonium acetate; Flow: 20 mL/min.
[1037] Method E: PHENOMENEX.RTM. Luna 5 .mu.M C18 30.times.100 mm
column with a 10 min gradient at 40 mL/min from 100% A to 100% B
(A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9%
acetonitrile, 0.1% TFA, UV 220 nm).
[1038] Method F: PHENOMENEX.RTM. Luna 5 .mu.M C18 30.times.100 mm
column with a 10 min gradient at 40 mL/min from 100% A to 100% B
(A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9%
methanol, 0.1% TFA, UV 220 nm).
[1039] Method G: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% formic
acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% formic
acid; Flow: 20 mL/min.
[1040] LCMS chromatograms were obtained on a Shimadzu HPLC system
running Discovery VP software, coupled with a Waters ZQ mass
spectrometer running MassLynx version 3.5 software using
[1041] Method A: A linear gradient using solvent A (10%
acetonitrile, 90% water, 0.1% of TFA) and solvent B (90%
acetonitrile, 10% water, 0.1% of TFA); 0-100% of solvent B over 2
min and then 100% of solvent B over 1 min. Column: PHENOMENEX.RTM.
Luna 3 u C18(2) (2.0.times.30 mm). Flow rate was 5 ml/min. And UV
detection was set to 220 nm. The LC column was maintained at room
temperature.
[1042] Method B: A linear gradient using solvent A (10% methanol,
90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water,
0.1% of TFA); 0-100% of solvent B over 4 min and then 100% of
solvent B over 1 min. Column: PHENOMENEX.RTM. Luna 5 u C18
(4.5.times.30 mm). Flow rate was 4 ml/min. And UV detection was set
to 220 nm. The LC column was maintained at room temperature.
[1043] Method C: A linear gradient using solvent A (10% methanol,
90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water,
0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of
solvent B over 1 min. Column: PHENOMENEX.RTM. Luna 3 u C18(2)
(2.0.times.30 mm). Flow rate was 1 ml/min. And UV detection was set
to 220 nm. The LC column was maintained at room temperature.
[1044] Method D: A linear gradient using solvent A (10% methanol,
90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water,
0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of
solvent B over 1 min. Column: PHENOMENEX.RTM. Luna 3 u C18(2)
(4.5.times.30 mm). Flow rate was 5 ml/min. And UV detection was set
to 220 nm. The LC column was maintained at room temperature.
[1045] Method E: 30-95% acetonitrile in water with 0.1% TFA in 8
min run, Waters Xbridge 4.6.times.50 mm 5 um C18, flow rate 1.2
mL/min and UV detection was set to 220 nm. The LC column was
maintained at room temperature.
[1046] Method F: 10-95% methanol in water, 0.1% TFA in a 10 min
run, PHENOMENEX.RTM. Onyx Monolithic 4.6.times.100 mm 5 um C18,
flow rate 2.0 mL/mL and UV detection was set to 220 nm. The LC
column was maintained at room temperature.
[1047] Method G: 5-95% acetonitrile in water, 10 mM of modifier in
6 min run, Waters Xbridge 2.1.times.50 mm 5 um C18, flow rate 1.0
mL/min and UV detection was set to 220 nm. The LC column was
maintained at room temperature.
[1048] Method H: BEH C18 2.1.times.50 mm; A: water+0.05% TFA; B:
acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min;
gradient time 1.5 min; 2 to 98% B.
[1049] Method I: BEH C18 2.1.times.50 mm; A: water+0.05% TFA; B:
acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min;
gradient time 1.5 min; 2 to 52% B.
[1050] Method J: BEH C18 2.1.times.50 mm; A: water+0.05% TFA; B:
acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min;
gradient time 1.5 min; 48 to 98% B.
[1051] Method K: Column: Waters Acquity UPLC BEH C18, 2.1.times.50
mm, 1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water
with 10 mM ammonium acetate; Mobile Phase B: 95:5
acetonitrile:water with 10 mM ammonium acetate; Temperature:
50.degree. C.; Gradient: 0-100% B over 3 minutes, then a
0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220
nm.
[1052] Method L: Column: Waters Acquity UPLC BEH C18, 2.1.times.50
mm, 1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water
with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5
acetonitrile:water with 0.1% trifluoroacetic acid; Temperature:
50.degree. C.; Gradient: 0-100% B over 3 minutes, then a
0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220
nm.
[1053] In addition, the following orthogonal HPLC conditions were
used to check the purity of the compounds
[1054] Method A: Two analytical LC/MS injections were used to
determine the final purity. Injection1 condition: A linear gradient
using solvent A (5% acetonitrile, 95% water, 0.05% TFA) and solvent
B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent B
over 10 min and then 100% of solvent B over 5 min. Column: Sunfire
C18 3.5 um (4.6.times.150 mm). Flow rate was 2 ml/min. And UV
detection was set to 220 nm. The LC column was maintained at room
temperature. Injection 2 conditions: A linear gradient using
solvent A (5% acetonitrile, 95% water, 0.05% TFA) and solvent B
(95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent B over
10 min and then 100% of solvent B over 5 min. Column: Xbridge
Phenyl 3.5 um (4.6.times.150 mm). Flow rate was 2 ml/min. And UV
detection was set to 220 nm. The LC column was maintained at room
temperature.
[1055] Method B: Two analytical LC/MS injections were used to
determine the final purity. Injection 1 conditions: Column: Waters
Acquity UPLC BEH C18, 2.1.times.50 mm, 1.7-.mu.m particles; Mobile
Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium
acetate; Temperature: 50.degree. C.; Gradient: 0-100% B over 3
minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min;
Detection: UV at 220 nm. Injection 2 conditions: Column: Waters
Acquity UPLC BEH C18, 2.1.times.50 mm, 1.7-.mu.m particles; Mobile
Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;
Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic
acid; Temperature: 50.degree. C.; Gradient: 0-100% B over 3
minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min;
Detection: UV at 220 nm.
General Procedures
[1056] The following procedures were used during the synthesis of
the Examples and Intermediates where indicated below.
[1057] Procedure A: 5-bromo-2-chloropyrimidine (1.0 equiv.) was
solvated in DMF (0.2 M) along with the appropriate diol (2.0
equiv.). 60% sodium hydride in mineral oil (3.0 equiv.) was added
to the reaction mixture portion-wise at 0.degree. C., then the
reaction mixture allowed to warm to room temperature and stirred
for 30 minutes. The reaction mixture was then quenched with
saturated ammonium chloride and diluted with EtOAc. The organic
layer was washed with 10% aqueous LiCl solution (3.times.), brine
(1.times.), dried with sodium sulfate, filtered and concentrated.
The resulting residue was dissolved in methylene chloride before
being purified by silica gel chromatography to provide the desired
material.
[1058] Procedure B: To a vial containing the appropriate
5-bromopyrimidine (1.0 equiv.), palladium(II) acetate (0.1 equiv.),
BINAP (0.2 equiv.), cesium carbonate (1.2 equiv.) and
diphenylmethanimine (1.1 equiv.) was added toluene (0.5 M). The
vial was sealed, evacuated and backfilled with Ar 3.times., and the
reaction mixture was heated to 105.degree. C. for 18 hours. The
reaction mixture was then diluted with EtOAc and washed with 1M
aqueous NaOH (1.times.) and brine (1.times.). The organic layer was
dried with sodium sulfate, filtered and concentrated. The resulting
residue was dissolved in methylene chloride before being purified
by silica gel chromatography to provide the desired material.
[1059] Procedure C: The 4-((diphenylmethylene)amino)pyrimidine
intermediate (1.0 equiv.) was dissolved in 1:1 MeOH/THF (0.06M). 1M
aqueous HCl (2.5 equiv.) was added to the reaction mixture at room
temperature. The reaction mixture was allowed to stir at room
temperature for 1 hour then diluted with water and extracted with
5:1 EtOAc/Hexanes (3.times.). The aqueous phase was concentrated
and azeotroped with toluene 3.times. to yield the desired
4-aminopyrimidine which was brought forward without further
purification.
[1060] Procedure D: 4-bromo-2-fluoropyridine (1.0 equiv.) was
dissolved in DMF (1.1 M) along with the appropriate diol (1.5
equiv.). 60% sodium hydride in mineral oil (2.0 equiv.) was added
to the reaction mixture portion-wise at 0.degree. C. and the
reaction mixture was allowed to warm to room temperature and
stirred at room temperature for 4 hours. The reaction mixture was
then quenched with saturated ammonium chloride solution and
extracted with EtOAc (3.times.). The organic layer was washed with
brine, dried with sodium sulfate, filtered and concentrated. The
resulting residue was dissolved in methylene chloride before being
purified by silica gel chromatography to provide the desired
material.
[1061] Procedure E: N1,N2-dimethylethane-1,2-diamine (1.0 equiv.),
2,2,2-trifluoroacetamide (2.0 equiv.), copper(I) iodide (0.2
equiv.), potassium carbonate (2.0 equiv.) and the
4-boromo-2-alkoxypyridine intermediate (1.0 equiv.) were dissolved
in dioxane (0.6 M) in a sealed vial. The vial was evacuated and
backfilled with Ar 3.times. then the reaction mixture was stirred
at 75.degree. C. for 2 hours. 3 mL of 1:1 MeOH/H.sub.2O was added
to the mixture which was stirred at room temperature for 2 h then
at 40.degree. C. for 1 h. The reaction mixture was then diluted
with water and extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with sodium sulfate,
filtered and concentrated. The resulting residue was dissolved in a
small amount of methylene chloride before being purified by silica
gel chromatography to provide the desired material.
[1062] Procedure F: The ester (1.0 equiv.) was dissolved in THF
(0.2 M) and the solution was cooled to -78.degree. C. 1M DIBAL-H in
toluene (3.0 equiv.) was added to the mixture which was allowed to
warm to room temperature and stirred at room temperature for 30
minutes. The reaction mixture was then quenched saturated
Rochelle's salt and allowed to stir for 18 h at room temperature.
The mixture was then diluted with water and extracted with EtOAc
(3.times.). The combined organic layer was washed with brine
(1.times.), dried with sodium sulfate, filtered and concentrated
yield the desired product.
[1063] Procedure G: The ester (1.0 equiv.) was dissolved in THF
(0.2 M) and cooled to -78.degree. C. To the cooled reaction mixture
was added 1M DIBAL-H in toluene (3.0 equiv.) and the reaction
mixture was allowed to stir at -78.degree. C. for 1 hour. The
reaction mixture was then quenched saturated Rochelle's salt and
allowed to stir for 2 h at room temperature. The mixture was then
diluted with water and extracted with EtOAc (3.times.). The
combined organic layer was washed with brine (1.times.), dried with
sodium sulfate, filtered and concentrated. The resulting aldehyde
intermediate was then re-subjected to the conditions described
above to ultimately yield the desired alcohol product.
[1064] Procedure H: To the ester (1.0 equiv.) dissolved in THF
(0.06 M) at -78.degree. C. was added methylmagnesium bromide (10.0
equiv.). The reaction mixture was allowed to warm to room
temperature and stirred for 30 minutes at room temperature. The
reaction mixture was then quenched with saturated ammonium
chloride, diluted with water and extracted with EtOAc (3.times.).
The combined organic layer was washed with brine (1.times.), dried
with sodium sulfate, filtered and concentrated. The resulting
residue was purified by reverse phase preparative HPLC to yield the
desired product.
[1065] Procedure I: The alcohol (1.0 equiv.), imidazole (2.2
equiv.) and TBS-Cl (2.0 equiv.) were dissolved in THF or DCM (0.1
M). The reaction mixture was allowed to stir at room temperature
for 18 h. The reaction mixture was then diluted with 1.5 M
dipotassium phosphate solution and extracted with EtOAc (3.times.).
The combined organic layer was washed with brine (1.times.), dried
with sodium sulfate, filtered and concentrated. The resulting
residue was dissolved in a small amount of methylene chloride and
purified by silica gel chromatography to yield the desired
product.
[1066] Procedure J: The silyl protected intermediate (1.0 equiv.)
was dissolved in a mixture of 20:1 MeOH/concentrated aqueous HCl
(0.01 M), and the reaction mixture was stirred at room temperature.
The reaction was monitored by LCMS, and after completion of the
reaction (10 min-12 hours) the reaction mixture was concentrated,
dissolved in DMF and purified by preparative HPLC to yield the
desired example.
[1067] Procedure K: The acetonide intermediate (1.0 equiv.) was
dissolved in a mixture of 4:3:2 THF/MeOH/concentrated aqueous HCl
(0.01 M), and the solution was stirred at room temperature. The
resulting mixture was monitored by LCMS, and after completion of
the reaction (10 min-12 hours) the mixture was diluted with EtOAc,
washed with 1.5 M K.sub.2HPO.sub.4, dried over sodium sulfate,
filtered, concentrated, dissolved in DMF and purified by
preparative HPLC to yield the desired example.
EXAMPLES
[1068] The invention is further defined in the following Examples.
It should be understood that the Examples are given by the way of
illustration only. From the above discussion and the Examples, one
skilled in the art can ascertain the essential characteristics of
the invention, and without departing from the spirit and scope
thereof, can make various changes and modifications to adapt the
invention to various uses and conditions. As a result, the
invention is not limited by the illustrative examples set forth
herein below, but rather is defined by the claims appended
hereto.
ABBREVIATIONS
[1069] AcOH acetic acid [1070] ACN acetonitrile [1071] BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthylene [1072] Boc
tert-butoxycarbonyl [1073] BOC.sub.2O di(tert-butoxycarbonyl) ether
[1074] BuLi butyl lithium [1075] DCE dichloroethane [1076] DCM
dichloromethane [1077] DIAD diisopropyl azodicarboxylate [1078]
DIBAL-H diisobutylaluminium hydride [1079] DIEA
diisopropylethylamine [1080] DMAP dimethylaminopyridine [1081] DMF
dimethylformamide [1082] DMSO dimethylsulfoxide [1083] EtOAc ethyl
acetate [1084] EtOH ethanol [1085] HOBt hydroxybenzotriazole [1086]
mCPBA 3-chloroperbenzoic acid [1087] MeCN acetonitrile [1088] MeOH
methanol [1089] NH.sub.4OAc ammonium acetate [1090] NMP
N-methylpyrrolidinone [1091] PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
dichloromethane adduct [1092] Pd(OAc).sub.2 palladium acetate
[1093] Pd(Ph.sub.3P).sub.4 tetrakis(triphenylphosphine)palladium
[1094] TBAF tetrabutylammonium fluoride [1095] TBDMS-Cl
tert-butyldimethylsilyl chloride [1096] TEA triethylamine [1097]
TFA trifluoroacetate [1098] THF tetrahydrofuran [1099] HPLC high
pressure liquid chromatography [1100] MS mass spectrometry [1101] g
gram(s) [1102] h or hr hour(s) [1103] min. minute(s) [1104] mL
milliliter(s) [1105] mmol millimole(s) [1106] RT retention time
INTERMEDIATE I-1
2-(difluoromethoxy)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l) quinoxaline
##STR00031##
[1107] Intermediate I-1A: tert-butyl
N-(2-bromo-4-methyl-6-nitrophenyl)-N-[(tert-butoxy)
carbonyl]carbamate
##STR00032##
[1109] To a solution of 2-bromo-4-methyl-6-nitroaniline (9.6 g,
41.6 mmol) in THF (60 mL) was added DMAP (0.508 g, 4.16 mmol),
followed by BOC.sub.2O (22.67 g, 104 mmol) as a solid. The mixture
was stirred at room temperature overnight. Solvent was removed by
vacuum. The crude product was dissolved in a small amount of
chloroform and charged to a 120 g silica gel cartridge (2 separate
columns) which was eluted with 5% EtOAc in hexanes for 4 min., then
a 12 min gradient from 5% to 30% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate I-1A
(17.12 g, 39.7 mmol, 96% yield) as a white solid. .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.80-7.79 (m, 1H), 7.73 (dd, J=1.9, 0.8
Hz, 1H), 2.48 (s, 3H), 1.42 (s, 18H); LC-MS: method A, RT=1.90 min,
MS (ESI) m/z: 230.0 and 232.0 (M-2 Boc).sup.+.
Intermediate I-1B: tert-butyl
(2-bromo-4-methyl-6-nitrophenyl)carbamate
##STR00033##
[1111] To a solution of Intermediate I-1A (17.1 g, 39.6 mmol) in
dichloromethane (60 mL) was added TFA (6.11 mL, 79 mmol) and the
mixture was stirred at room temperature for 1.0 h. The reaction
mixture was quenched by addition of saturated sodium bicarbonate,
extracted with dichloromethane (3.times.), dried over sodium
sulfate. After evaporation of solvent, Intermediate I-1B was
obtained as a yellow solid (12.88 g, 88% yield): .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.71 (d, J=1.1 Hz, 1H), 7.68 (dd, J=1.9,
0.8 Hz, 1H), 2.42 (s, 3H), 1.51 (s, 9H); LC-MS: method A, RT=1.53
min, MS (ESI) m/z: 231.0 and 233.0 (M-Boc).sup.+.
Intermediate I-1C: methyl
2-((2-bromo-4-methyl-6-nitrophenyl)(tert-butoxycarbonyl)
amino)acetate
##STR00034##
[1113] Intermediate I-1B (12 g, 26.3 mmol) was dissolved in DMF (80
mL), cooled with a water bath. Cs.sub.2CO.sub.3 (25.8 g, 79 mmol)
was added. The dark brown solution was stirred at room temperature
for 10 min, then methyl 2-bromoacetate (4.37 mL, 47.6 mmol) was
added dropwise. After addition of methyl bromoacetate, the brown
color faded to yellow. The mixture was stirred at room temperature
for 1.0 h, diluted with EtOAc, quenched with water. The organic
layer was collected, washed with brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform and charged to a 330 g silica gel
cartridge which was eluted with 5% EtOAc in hexanes for 5 min.,
then a 12 min gradient from 5% to 50% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate I-1C
(15.2 g, 37.7 mmol, 95% yield) as an yellow oil. .sup.1H NMR (500
MHz, chloroform-d) indicated a mixture of rotamers: .delta.
7.75-7.67 (m, 2H), 4.61-3.97 (m, 2H), 3.76 and 3.69 (s, 3H), 2.48
and 2.43 (s, 3H), 1.55 and 1.37 (s, 9H); LC-MS: method A, RT=1.70
min, MS (ESI) m/z: 303.0 and 305.0 (M-Boc).sup.+.
Intermediate I-1D: methyl
2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate
##STR00035##
[1115] To Intermediate I-1C (15.2 g, 37.7 mmol) was added 4.0 N HCl
in dioxane (47.1 ml, 188 mmol) and the mixture was stirred at room
temperature overnight. Solvent was removed under vacuum, chased
with EtOAc (2.times.) to give Intermediate I-1D (13.6 g, 40.1 mmol,
106% yield) as a yellow solid. .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 7.88 (dd, J=1.9, 0.6 Hz, 1H), 7.80 (dd,
J=1.9, 0.6 Hz, 1H), 4.47 (d, J=17.3 Hz, 1H), 4.08 (d, J=17.1 Hz,
1H), 3.69 (s, 3H), 2.46 (s, 3H); LC-MS: Method A, RT=1.94 min, MS
(ESI) m/z: 303.1 and 305.1 (M+H).sup.+.
Intermediate I-1E:
5-bromo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
##STR00036##
[1117] To a solution of Intermediate I-1D (13.6 g, 40.1 mmol) in
MeOH (100 mL) in a 1 L flask cooled with water bath was added
concentrated HCl (13.35 mL, 160 mmol), followed by tin(II) chloride
dihydrate (36.1 g, 160 mmol). The mixture was stirred at 68.degree.
C. for 2.5 h. MeOH was removed by vacuum. The crude was partitioned
in water (100 mL)/EtOAc (200 mL), and the pH was adjusted to
neutral with 4.0 N NaOH (ca 90 mL). The white precipitate formed
was very fine particle that was very hard to remove by filtration.
The mixture was transferred to a separatory funnel. The organic
layer was collected. The aqueous was further extracted (2.times.200
mL) with EtOAc. The combined organic layer was washed with water
(2.times.) and brine (2.times.), dried over sodium sulfate. After
evaporation of solvent, Intermediate I-1E (8.36 g, 34.7 mmol, 87%
yield) was obtained as a pale yellow solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.37 (s, 1H), 6.87 (dd, J=1.8, 0.7 Hz, 1H),
6.56 (dd, J=1.1, 0.6 Hz, 1H), 5.46 (s, 1H), 3.76 (d, J=2.2 Hz, 2H),
2.14 (s, 3H); LC-MS: method A, RT=1.66 min, MS (ESI) m/z: 241.0 and
243.0 (M+H).sup.+.
Intermediate I-1F: 5-bromo-7-methylquinoxalin-2-ol
##STR00037##
[1119] To a suspension of Intermediate I-1E (6.7 g, 27.8 mmol) in
MeOH (50 mL) in a 1 L flask was added 30% hydrogen peroxide (28.4
mL, 278 mmol), followed by 4.0 N NaOH (20.84 mL, 83 mmol). The
mixture was stirred at room temperature for 5 min, then gently
heated at 60.degree. C. After 15 min heating, the reaction mixture
turned strongly exothermic, suggesting an initiation of the
reaction mixture. The heating bath was removed and stirring
continued for 30 min until the mixture turned completely clear.
After cooling to room temperature with a water bath, MeOH was
removed by vacuum. The mixture was then neutralized with 2.0 N HCl
(to pH 2-3) and ice cooling. The precipitate formed was collected
by filtration, washed with water, dried under vacuum in the air for
1.0 h and then at vacuum at 60.degree. C. for 2.0 h, and under high
vacuum to give Intermediate I-1F (6.55 g, 27.4 mmol, 99% yield) as
an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.52 (br. s., 1H), 8.17 (s, 1H), 7.49 (d, J=1.1 Hz, 1H), 7.08 (s,
1H), 2.40 (s, 3H; LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 239.0
and 241.0 (M+H).sup.+.
Intermediate I-1G:
5-bromo-2-(difluoromethoxy)-7-methylquinoxaline
##STR00038##
[1121] A mixture of Intermediate I-1F (7.4 g, 26.9 mmol) and
potassium carbonate (18.56 g, 134 mmol) in DMF (120 mL) was heated
at 100.degree. C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate
(16.40 g, 107.6 mmol) was added in one portion, and the mixture was
stirred at 100.degree. C. for 10 min. The mixture turned from
yellow slurry to brown. The mixture was cooled to room temperature,
diluted with EtOAc and water, extracted with EtOAc (3.times.). The
combined organic layer was washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform/toluene and purified with
a 330 g ISCO column eluted with 5% dichloromethane in hexanes for 3
min, then 5-70% DCM/hexanes for 40 min (12 min gradient time). The
desired fractions were combined, concentrated to give Intermediate
I-1G (6.0 g, 20.76 mmol, 77% yield) as a slightly yellow solid.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 8.64 (s, 1H), 7.89 (d,
J=1.7 Hz, 1H), 7.68 (dd, J=1.8, 1.0 Hz, 1H), 7.63 (t,
J.sub.HF=71.80 Hz, 1H), 2.59 (s, 3H); .sup.19F NMR (471 MHz,
chloroform-d) .delta. -89.82 (s, 2F); LC-MS: method A, RT=2.09 min,
MS (ESI) m/z: 289.0 and 291.0 (M+H).sup.+.
Intermediate I-1
[1122] A mixture of Intermediate I-1G (1.04 g, 3.60 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.370
g, 5.40 mmol), potassium acetate (0.883 g, 8.99 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (0.147 g, 0.180 mmol) in dioxane
(14 mL) was degassed by bubbling argon for 10 min. The reaction
mixture vial was sealed and heated in microwave reactor at
135.degree. C. for 30 min. The mixture was diluted with
EtOAc/water, insoluble material was removed by filtration. The
filtrate was extracted with EtOAc, washed with brine and dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of toluene and charged to a 40 g silica
gel cartridge which was eluted with 5% EtOAc in hexanes for 2 min.,
then a 18 min gradient from 5% to 75% EtOAc in hexanes. The desired
fractions were concentrated and lyophilized to give Intermediate
I-1 (0.93 g, 72% yield) as a pale solid. .sup.1H NMR was
complicated by the presence of two sets of signals. .sup.19F NMR
indicated a single compound. .sup.19F NMR (471 MHz, chloroform-d)
.delta. -89.64 (s., 2F). LC-MS: method A, RT=2.01 min, MS (ESI)
m/z: 225.0 (boronic acid).sup.+.
Intermediate I-2
2-(methoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
quinoxaline
##STR00039##
[1123] Intermediate I-2A: 1-diazo-3-methoxypropan-2-one
##STR00040##
[1125] To 2-methoxyacetyl chloride (2.4 g, 22.12 mmol) in MeCN (40
mL) cooled with ice-bath was added (diazomethyl)trimethylsilane 2.0
M in diethyl ether (19.35 mL, 38.7 mmol). The mixture was allowed
to stir at room temperature overnight. Solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 50% EtOAc in hexane
over 18 min using a 40 g silica gel cartridge). The desired
fractions were combined and concentrated (bath temp below
35.degree. C.) to yield Intermediate I-2A (1.82 g, 15.95 mmol,
72.1% yield) as a yellow liquid. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 5.73 (br. s., 1H), 3.97 (br. s., 2H), 3.43
(s, 3H); LC-MS: method A, RT=0.43 min, MS (ESI) m/z: 137.0
(M+Na).sup.+.
Intermediate I-2B: 1-bromo-3-methoxypropan-2-one
##STR00041##
[1127] To Intermediate I-2A (1.6 g, 14.02 mmol) in diethyl ether
(20 mL) at 0.degree. C. was added aqueous HBr 48% (2.380 mL, 21.03
mmol) dropwise. After stirring at 0.degree. C. for 5 min and at
room temperature for 10 min, the reaction mixture was diluted with
EtOAc, washed with water, saturated sodium bicarbonate (2.times.)
and brine. The organic layer was dried over sodium sulfate,
concentrated (keep bath temp below 30.degree. C.) to give
Intermediate I-2B (1.5 g, 8.98 mmol, 64.1% yield) as a slightly
yellow liquid. .sup.1H NMR indicated >92% purity. The compound
was used immediately for the next step without further
purification. .sup.1H NMR (500 MHz, chloroform-d) .delta. 4.24 (s,
2H), 4.03 (s, 2H), 3.45 (s, 3H), consistent with literature report
(I Org. Chem. 1981, 217).
Intermediate I-2C: tert-butyl
(2-bromo-4-methyl-6-nitrophenyl)(3-methoxy-2-oxopropyl)carbamate
##STR00042##
[1129] To Intermediate I-1B (1.98 g, 5.98 mmol) in DMF (20 mL) at
0.degree. C. was added Cs.sub.2CO.sub.3 (3.41 g, 10.46 mmol). The
brown solution was stirred at 0.degree. C. for 10 min, followed by
addition of Intermediate I-2B (1.498 g, 8.97 mmol) in acetonitrile
(5.0 mL). The brown solution turned yellow. The mixture was stirred
at 0.degree. C. for 15 min., diluted with EtOAc, washed with water,
brine, dried over sodium sulfate and concentrated. The crude
product was purified by flash chromatography (loading in
chloroform, 0% to 60% EtOAc in hexane over 18 min using a 80 g
silica gel cartridge). The desired fractions were combined and
concentrated to yield Intermediate I-2C (2.4 g, 5.75 mmol, 96%
yield) as a yellow oil. .sup.1H NMR indicated presence of two
rotamers. .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.70-7.65 (m,
2H), 4.55 (d, J=17.9 Hz, 1H), 4.18 (d, J=17.9 Hz, 1H), 4.32 and
4.14 (d, J=1.4 Hz, 2H), 3.44 and 3.40 (s, 3H), 2.45 and 2.40 (s,
3H), 1.49 and 1.35 (s, 9H); LC-MS: method A, RT=1.89 min, MS (ESI)
m/z: 317 and 319 (M-Boc).sup.+.
Intermediate I-2D
6-bromo-3-hydroxy-3-(methoxymethyl)-8-methyl-1-oxo-1,3,4,5-tetrahydrobenzo-
[c][1,2,5]oxadiazepin-1-ium
##STR00043##
[1131] To Intermediate I-2C (1.67 g, 4.00 mmol) in ethyl acetate
(10 mL) was added 4.0 N HCl in dioxane (10.01 mL, 40.0 mmol) and
the mixture was stirred at room temperature for 20 min. Solvent was
removed under vacuum, chased with EtOAc once to give Intermediate
I-2D (1.25 g, 99%) as a yellow oil. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.75-7.66 (m, 2H), 4.13-3.98 (m, 1H),
3.78-3.56 (m, 3H), 3.50 and 3.44 (m, 3H), 2.39 (s, 3H); LC-MS:
method A, RT=1.47 min, MS (ESI) m/z: 317.0 and 319.0
(M+H).sup.+.
Intermediate I-2E:
5-bromo-2-(methoxymethyl)-7-methylquinoxaline
##STR00044##
[1133] Intermediate I-2D (1.25 g, 3.9 mmol) was dissolved in THF
(30 mL). Concentrated HCl (0.986 mL, 12.01 mmol) was added,
followed by tin(II) chloride dihydrate (3.61 g, 16.01 mmol). The
mixture was placed and stirred in an oil bath pre-heated at
40.degree. C. for 4.0 h. The reaction mixture was diluted with
EtOAc/water, The organic phase was neutralized with saturated
sodium bicarbonate and stirred at room temperature for 15 min, the
precipitate was removed by filtration with a pad of wet celite. The
filtrate was collected. The organic layer was washed with brine,
dried over sodium sulfate and concentrated. The crude product was
purified by flash chromatography (loading in chloroform, 0% to 60%
EtOAc in hexane over 20 min using a 120 g silica gel cartridge).
The desired fractions were combined and concentrated to yield
Intermediate I-2D (0.57 g, 1.920 mmol, 48.0% yield) as a brown
solid: .sup.1H NMR (400 MHz, chloroform-d) .delta. 9.03 (s, 1H),
7.95 (d, J=1.5 Hz, 1H), 7.84 (dd, J=1.8, 1.1 Hz, 1H), 4.84 (s, 2H),
3.56 (s, 3H), 2.60 (s, 3H); Intermediate I-2D was contaminated with
ca 10% of a side product 5-bromo-2,7-dimethylquinoxaline.
Intermediate I-2
[1134] A mixture of Intermediate I-2E (900 mg, 3.37 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1369
mg, 5.39 mmol), potassium acetate (661 mg, 6.74 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (110 mg, 0.135 mmol) in dioxane
(15 mL) was degassed by bubbling argon for 10 min. The reaction
vial was sealed and heated in microwave reactor at 130.degree. C.
for 30 min. The mixture was diluted with EtOAc/water, insoluble
material was removed by filtration. The filtrate was extracted with
EtOAc, washed with brine and dried over sodium sulfate,
concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 20% dichloromethane in
MeOH over 15 min using a 40 g silica gel cartridge). The desired
fractions were combined and concentrated and further purified by
prep HPLC (method A, 10-80% B in 8 mins; with a flow rate of 40
mL/min). The desired fractions were placed in a SpeedVac overnight
to remove solvent. The material was dissolved in EtOAc, washed with
diluted saturated sodium bicarbonate (to remove TFA), brine, dried
over sodium sulfate, concentrated and lyophilized to give
Intermediate I-2 (360 mg, 1.550 mmol, 46% yield) as a slightly
colored solid. LC-MS: method A, RT=1.73 min, MS (ESI) m/z: 233.1
boronic acid (M+H).sup.+.
Intermediate I-3
2-bromo-6-methoxy-4-methylbenzo[d]thiazole
##STR00045##
[1135] Intermediate I-3A:
6-methoxy-4-methylbenzo[d]thiazol-2-amine
##STR00046##
[1137] To 4-methoxy-2-methylaniline (209 mg, 1.524 mmol) in
acetonitrile (8 mL) was added ammonium thiocyanate (174 mg, 2.285
mmol). The mixture was stirred at room temperature for 10 min. Then
it was cooled with tap water, and benzyltrimethylammonium
tribromide (594 mg, 1.524 mmol) in acetonitrile (3.0 mL) was added
dropwise. The mixture was then stirred at room temperature
overnight. HPLC and LCMS indicated a clean reaction. The mixture
was diluted with EtOAc/saturated sodium bicarbonate. The organic
layer was collected, washed with brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform/MeOH, and charged to a 24 g silica gel
cartridge which was eluted with 5% EtOAc in hexanes for 3 min.,
then a 12 min gradient from 5% to 50% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate I-3A
(240 mg, 1.235 mmol, 81% yield) as a pale solid. .sup.1H NMR (500
MHz, methanol-d.sub.4) .delta. 7.03 (d, J=2.5 Hz, 1H), 6.71 (d,
J=1.9 Hz, 1H), 3.79 (s, 3H), 2.46 (s, 3H); LC-MS: method A, RT=1.22
min, MS (ESI) m/z: 195.0 (M+H).sup.+.
Intermediate I-3
[1138] t-Butyl nitrite (0.969 mL, 8.15 mmol) was added to
copper(II) bromide (1820 mg, 8.15 mmol) in dry acetonitrile (20 mL)
under argon. The mixture was stirred at room temperature for 10
min. A suspension of Intermediate I-3A (931 mg, 4.79 mmol) in
acetonitrile (30 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 1.0 h. LCMS indicated a clean
reaction. Acetonitrile was removed under vacuum, the reaction
mixture was diluted with EtOAc (30 mL) and 20 mL of 0.5M HCl
(aqueous). After separation, organic layer was washed with 0.5 N
HCl (20 mL.times.2), saturated sodium bicarbonate (15 mL), brine
(15 mL) and dried over sodium sulfate. After evaporation of the
solvent, the crude product was purified by ISCO (80 g silica gel
column, 20% EtOAc/hexanes). Removing solvent gave Intermediate I-3
as white solid (1.13 g, 91%). .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.29 (d, J=2.5 Hz, 1H), 6.95-6.87 (m,
1H), 3.84 (s, 3H), 2.60 (s, 3H); LC-MS: (BEH C18 2.1.times.50 mm;
A: 10% MeCN-90% H.sub.2O -0.1% TFA; B: 90% MeCN-10% H.sub.2O -0.1%
TFA; wavelength 220/254 nm; flow rate 5 mL/min; gradient time 2
min; 2 to 98% B) 1.11 min, [M+1].sup.+=258.0, 260.0;
Intermediate I-4
2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethanamine
##STR00047##
[1139] Intermediate I-4A: 2-chlorobenzo[d]thiazol-6-ol
##STR00048##
[1141] Aluminum chloride (3.07 g, 22.99 mmol) was added to a
solution of 2-chloro-6-methoxybenzo[d]thiazole (1.53 g, 7.66 mmol)
in toluene (50 mL). The mixture was heated at 110.degree. C. for
1.5 h. TLC indicated a complete conversion of starting material.
The reaction mixture was cooled to room temperature, quenched with
ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min.
The precipitate was collected by filtration, washed with water
(3.times.), saturated sodium bicarbonate (3.times.), water
(3.times.) and air-dried for 1.0 h under vacuum. It was further
dried under high vacuum overnight to give Intermediate I-4A (1.18
g, 6.36 mmol, 83% yield) as a pale brown solid. .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.82 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.5
Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 5.53 (s, 1H); LC-MS: method
A, RT=1.62 min, MS (ESI) m/z: 186.0 and 188.0 (M+H).sup.+.
Intermediate I-4B:
6-((tert-butyldimethylsilyl)oxy)-2-chlorobenzo[d]thiazole
##STR00049##
[1143] To a stirred solution of Intermediate I-4A (1.15 g, 6.20
mmol) in DMF (20 mL) was added TBDMS-Cl (1.307 g, 8.67 mmol) and
imidazole (0.738 g, 10.84 mmol). After stirring at room temperature
for 1.0 h, the reaction mixture was partitioned between
EtOAc/water. The organic layer was washed with brine and dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 24 g
silica gel cartridge which was eluted with hexanes for 3 min., then
a 15 min gradient from 0% to 15% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate I-4B
(1.78 g, 5.94 mmol, 96% yield) as a clear brownish oil. .sup.1H NMR
(500 MHz, chloroform-d) .delta. 7.81 (d, J=8.8 Hz, 1H), 7.22 (d,
J=2.2 Hz, 1H), 7.01 (dd, J=8.8, 2.5 Hz, 1H), 1.04 (s, 9H), 0.26 (s,
6H); LC-MS: Method A, 50 to 100% B. RT=2.34 min, MS (ESI) m/z:
300.0 and 302.0 (M+H).sup.+.
Intermediate I-4C
6-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-
-5-yl)benzo[d]thiazole
##STR00050##
[1145] To Intermediate I-1 (1.45 g, 4.31 mmol), Intermediate I-4B
(1.488 g, 4.96 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (0.176 g, 0.216 mmol) was added
toluene (9 mL) and EtOH (3 mL). The mixture was sonicated for 1
min, and flushed with argon. To this was added sodium carbonate, 2M
(4.53 mL, 9.06 mmol). The reaction mixture was heated in a
microwave at 130.degree. C. for 80 min. HPLC and LCMS indicated a
clean reaction. To the reaction mixture was added EtOAc/water. The
organic layers were collected, dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of toluene/chloroform and charged to a 80 g silica gel
cartridge which was eluted with 5% dichloromethane in hexanes for 3
min., then a 18 min gradient from 5% to 75% dichloromethane in
hexanes (flow rate 50 mL/min). The desired fractions were combined
and concentrated to give Intermediate I-4C (1.65 g, 3.48 mmol, 81%
yield) as a bright yellow solid. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 8.76 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 8.01
(d, J=8.8 Hz, 1H), 7.80 (dd, J=1.8, 1.0 Hz, 1H), 7.68 (t,
J.sub.HF=71.80 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.07 (dd, J=8.7,
2.3 Hz, 1H), 2.70 (s, 3H), 1.07-1.05 (m, 9H), 0.30-0.28 (m, 6H);
.sup.19F NMR (471 MHz, chloroform-d) .delta. -89.74 (s, 2F); LC-MS:
method A, RT=2.89 min, MS (ESI) m/z: 474.1 (M+H).sup.+.
Intermediate I-4D:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
##STR00051##
[1147] To a solution of Intermediate I-4C (1.65 g, 3.48 mmol) in
THF (15 mL) at room temperature was added acetic acid (0.439 mL,
7.66 mmol), followed by addition of 1.0 N TBAF in THF (4.53 mL,
4.53 mmol) dropwise. The mixture was stirred at room temperature
for 40 min. HPLC and LCMS indicated a completion of reaction. The
mixture was diluted with EtOAc, washed with water, saturated sodium
bicarbonate (2.times.), brine, and dried over sodium sulfate. After
evaporation of the solvent, the crude product was triturated with
EtOAc/hexanes (1:4). The precipitate was collected by filtration to
give Intermediate I-4D (1.13 g) of the desired product. .sup.1H NMR
(500 MHz, chloroform-d) .delta. 8.58 (d, J=1.9 Hz, 1H), 8.53 (s,
1H), 7.76 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.22 (d, J=2.5 Hz, 1H),
7.50 (t, J.sub.HF=71.80 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, J=8.8, 2.5
Hz, 1H), 2.52 (s, 3H); .sup.19F NMR (471 MHz, chloroform-d) .delta.
-89.75 (s, 2F); LC-MS: method A, RT=2.24 min, MS (ESI) m/z: 360.0
(M+H).sup.+.
Intermediate I-4E: tert-butyl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)o-
xy)ethyl)carbamate
##STR00052##
[1149] A solution of tert-butyl (2-hydroxyethyl)carbamate (1.252 g,
7.76 mmol) and DIAD (1.510 mL, 7.76 mmol) in THF (6 mL) was added
to a mixture of Intermediate I-4D (0.93 g, 2.59 mmol) and
triphenylphosphine (1.358 g, 5.18 mmol) in THF (10 mL) heated at
70.degree. C. dropwise with a syringe pump in 3 h. At the end of
addition, HPLC and LCMS indicated a complete conversion of starting
material to the product. The mixture was diluted with EtOAc, washed
with saturated sodium bicarbonate (2.times.), brine. The organic
layers were collected, dried over sodium sulfate. After evaporation
of solvent, the crude product was dissolved in a small amount of
chloroform and charged to a 80 g silica gel cartridge which was
eluted with dichloromethane for 5 min., then a 18 min gradient from
0% to 25% EtOAc in dichloromethane, flow rate 60 mL/min. The
desired fractions were combined and purified with a second ISCO (80
g) column, to give Intermediate I-4E (1.0 g, 1.990 mmol, 77% yield)
as a yellow solid. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.80
(d, J=1.7 Hz, 1H), 8.71 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.81 (dd,
J=1.8, 1.0 Hz, 1H), 7.68 (t, J.sub.HF=71.68 Hz, 1H), 7.43 (d, J=2.5
Hz, 1H), 7.15 (dd, 2.5 Hz, 1H), 4.19-4.12 (m, 2H), 3.63 (d, J=5.0
Hz, 2H), 2.71 (s, 3H), 1.53-1.48 (s, 9H); .sup.19F NMR (471 MHz,
chloroform-d) .delta. -89.75 (s, 2F); LC-MS: Method A, 50 to 100%
B. RT=2.20 min, MS (ESI) m/z: 503.0 (M+H).sup.+.
Intermediate I-4
[1150] Intermediate I-4E (1.2 g, 2.388 mmol) was added 4.0 N HCl in
dioxane (41.8 ml, 167 mmol), followed by addition of EtOAc (10 mL)
to rinse the solid residue on the flask wall. The mixture was left
stirring at room temperature overnight. HPLC and LCMS indicated a
clean reaction. Solvent was removed, chased twice with EtOAc, once
with MeOH, and then dried under high vacuum over the weekend to
give Intermediate I-4 (1.0 g, 2.279 mmol, 95% yield) as a bright
yellow solid. .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.75
(d, J=1.7 Hz, 1H), 8.73 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.91-7.89
(m, 1H), 7.69 (t, J.sub.HF=71.53 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H),
7.29 (dd, J=8.9, 2.3 Hz, 1H), 4.38 (t, J=5.0 Hz, 2H), 3.42 (t,
J=4.5 Hz, 2H), 2.71 (s, 3H); LC-MS: method A, RT=1.90 min, MS (ESI)
m/z: 403.0 (M+H).sup.+.
Intermediate I-5
N-(2-((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulf-
onamide
##STR00053##
[1151] Intermediate I-5A: tert-butyl
(2-(3-methyl-4-nitrophenoxy)ethyl)carbamate
##STR00054##
[1153] In a round bottom flask, tert-butyl
(2-hydroxyethyl)carbamate (3.0 g, 18.61 mmol) was dissolved in DMF
(20 mL) and mixed with 4-fluoro-2-methyl-1-nitrobenzene (2.89 g,
18.61 mmol). K.sub.2CO.sub.3 (7.72 g, 55.8 mmol) was added. Then
the mixture was stirred at 100.degree. C. overnight. On the next
day, the reaction mixture was poured into ice water (50 mL) and was
extracted with EtOAc (50 mL.times.2). The combined organic phases
were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give a crude product that was purified by flash
chromatography (80 g silica gel column, eluted with 0-100%
EtOAc/Hexane gradient). Collecting desired fractions and removing
solvent gave the desired product as a yellow oil. (2.44 g, 8.2
mmol, 44.2%). .sup.1H NMR (400 MHz, chloroform-d): .delta.
8.19-7.94 (m, 1H), 6.91-6.70 (m, 2H), 4.95 (br s, 1H), 4.14-4.05
(m, 2H), 3.56 (q, J=5.3 Hz, 2H), 2.64 (s, 3H), 1.46 (s, 9H); LC-MS:
method H, RT=1.13 min, MS (ESI) m/z: 241.1
([M+H--(CH.sub.3).sub.3C].sup.+).
Intermediate I-5B: tert-butyl
(2-(4-amino-3-methylphenoxy)ethyl)carbamate
##STR00055##
[1155] Intermediate I-5A (3.94 g, 13.30 mmol) was dissolved in MeOH
(50 mL) and mixed with wet Pd--C (0.708 g, 0.665 mmol). After
applying vacuum and refilling with H2 3.times., the mixture was
treated with 1 atm H.sub.2 for 4 h. The resulting mixture was
filtered over celite and washed with a small amount of MeOH several
times. Solvent was removed in vacuo to give Intermediate I-5B as
yellow oil. (3.28 g, 93%). .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. 6.67 (s, 1H), 6.62 (d, J=1.7 Hz, 2H), 5.00 (br. s., 1H),
3.95 (t, J=5.1 Hz, 2H), 3.49 (d, J=5.0 Hz, 2H), 3.37 (br. s., 2H),
2.16 (d, J=0.6 Hz, 3H), 1.46 (s, 9H); LC-MS: method H, RT=0.79 min,
MS (ESI) m/z: 267.3).
Intermediate I-5C: tert-butyl
(2-((2-amino-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
##STR00056##
[1157] To Intermediate I-5B (3.28 g, 12.3 mmol) in acetonitrile (30
mL) was added ammonium thiocyanate (1.406 g, 18.5 mmol). The
mixture was stirred at room temperature for 10 min, cooled in an
ice water bath, and benzyltrimethylammonium tribromide (4.80 g,
12.3 mmol) in acetonitrile (20 mL) was added dropwise. The mixture
was stirred at room temperature for 2 h, and then diluted with
EtOAc/saturated sodium bicarbonate (100 mL/30 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (30
mL.times.2). Then organic phases were combined, washed with
saturated NaHCO.sub.3(aqueous, 30 mL) and brine (30 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated on a rotary evaporator
to give Intermediate I-5C (3.972 g, 12.3 mmol, 100%) as a brown
solid. The crude product was used in the next step without further
purification. .sup.1H NMR (400 MHz, chloroform-d): .delta. 6.97 (d,
J=2.4 Hz, 1H), 6.75 (s, 1H), 5.13 (br s, 2H), 5.00 (br s, 1H), 4.02
(t, J=5.1 Hz, 2H), 3.53 (d, J=4.8 Hz, 2H), 2.53 (d, J=0.4 Hz, 3H),
1.46 (s, 9H); LC-MS: method H, RT=1.04 min, MS (ESI) m/z:
324.2.
Intermediate I-5D: tert-butyl
(2((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
##STR00057##
[1159] In a round bottom flask charged with a stirring bar, copper
(II) bromide (441 mg, 1.976 mmol), and dry acetonitrile (5 mL)
under argon, tert-butyl nitrite (204 mg, 1.976 mmol) was added. The
mixture was stirred at room temperature for 10 min. A suspension of
Intermediate I-5C (376 mg, 1.163 mmol) in dry acetonitrile (5 mL)
was added dropwise. The reaction mixture was stirred at room
temperature for 1.0 h, and the acetonitrile was removed under
vacuum. The reaction mixture was diluted with EtOAc (50 mL) and 40
mL of 0.5M HCl (aqueous). After separation, the organic layer was
washed with 0.5 N HCl (aqueous, 30 mL.times.2), saturated sodium
bicarbonate (aqueous, 30 mL), brine (20 mL), dried over sodium
sulfate, filtered, and concentrated on a rotary evaporator. The
residue was purified by flash chromatography (40 g silica gel
column, 0-50% EtOAc/hexane) to give the desired product as a
colorless oil (340 mg, 1.50 mmol, 76%). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.08 (d, J=2.2 Hz, 1H), 6.88 (d, J=1.5 Hz,
1H), 4.98 (br s, 1H), 4.06 (t, J=5.1 Hz, 2H), 3.56 (d, J=5.1 Hz,
2H), 2.67 (s, 3H), 1.46 (s, 9H); LC-MS: method H, RT=1.37 min, MS
(ESI) m/z: 387.0, 389.0.
Intermediate I-5E: tert
2((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethanamine
##STR00058##
[1161] In a round bottom flask charged with a stirring bar,
Intermediate I-5D (940 mg, 2.43 mmol) was dissolved in DCM (4 mL)
and treated with TFA (2 ml, 26.0 mmol) at room temperature for 1
hour. Solvent and extra TFA were removed on a rotary evaporator and
the residue was dissolved in 30 mL of DCM and was washed with 20 mL
of saturated NaHCO.sub.3, 20 mL of brine, and dried over
Na.sub.2SO.sub.4. Removing solvent gave the crude product used
without purification in the next step. (657 mg, 2.28 mmol, 94%)
LC-MS: method H, RT=0.85 min, MS (ESI) m/z: 87.0, 289.0.
Intermediate I-5
[1162] Intermediate I-5E (534 mg, 1.86 mmol) was dissolved in a
mixture of THF (5 mL) and DIEA (1.30 mL, 7.45 mmol).
4-Fluorobenzene-1-sulfonyl chloride (362 mg, 1.862 mmol) in THF (5
mL) was added dropwise, and the mixture was stirred at room
temperature for 30 minutes. Solvent was removed on a rotary
evaporator and the residue was purified by flash chromatography (40
g silica gel column, 0-100% EtOAc/hexane gradient) to give the
title compound as a white solid (666 mg, 1.49 mmol, 80%). .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.96-7.87 (m, 2H), 7.23-7.14
(m, 2H), 6.99 (d, J=2.2 Hz, 1H), 6.79-6.76 (m, 1H), 4.05 (t, J=5.1
Hz, 2H), 3.46-3.36 (m, 2H), 2.66 (s, 3H); LC-MS: method H, RT=1.37
min, MS (ESI) m/z: 444.9 and 446.9.
Intermediate I-9
(2-methoxy-7-methylquinoxalin-5-yl)boronic acid
##STR00059##
[1163] Intermediate I-9A: 5-bromo-2-methoxy-7-methylquinoxaline
##STR00060##
[1165] To Intermediate I-1G (3.13 g, 10.83 mmol) dissolved in THF
(20 mL) and MeOH (15 mL) at room temperature was added 4.3 M sodium
methoxide in MeOH (7.55 mL, 32.5 mmol). The reaction mixture was
stirred at room temperature overnight. Methanol was removed under
vacuum. The reaction mixture was diluted with EtOAc, quenched with
0.5 N HCl (30.0 mL). The organic layer was washed with saturated
sodium bicarbonate, brine, dried and concentrated to give
Intermediate I-9A (2.7 g, 10.67 mmol, 99% yield) as a slightly
yellow solid. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.48 (s,
1H), 7.72 (d, J=1.7 Hz, 1H), 7.60 (dd, J=1.8, 1.0 Hz, 1H), 4.10 (s,
3H), 2.53 (s, 3H); LC-MS: Method A, 30 to 100% B. RT=1.71 min, MS
(ESI) m/z: 253.0 and 255.0 (M+H).sup.+.
Intermediate I-9
[1166] A mixture of Intermediate I-9A (700 mg, 2.77 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1053
mg, 4.15 mmol), potassium acetate (679 mg, 6.91 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (113 mg, 0.138 mmol) in dioxane
(14 mL) was degassed by bubbling argon for 5 min. It was then
heated at 130.degree. C. for 40 min. The reaction mixture was mixed
with EtOAc/water and stirred at room temperature for 15 min. The
insoluble material was removed by filtration through a pad of wet
celite. The organic layer was washed with brine, dried over sodium
sulfate and concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 5% to 100% EtOAc in hexane
over 15 min using a 80 g silica gel cartridge). The desired
fractions were combined, concentrated and lyophilized to yield to
yield Intermediate I-9 (362 mg, 1.659 mmol, 60 yield) as a solid.
.sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.41 (s, 1H), 7.69
(br. s., 1H), 7.49 (br. s., 1H), 4.10 (s, 3H), 2.56 (s, 3H). LC-MS:
method H, RT=0.83 min, MS (ESI) m/z: 219.1 (M+H).sup.+.
Intermediate I-12
2-methoxy-7-methylquinoxaline-5-carbothioamide
##STR00061##
[1167] Intermediate I-12A:
2-methoxy-7-methylquinoxaline-5-carbonitrile
##STR00062##
[1169] Intermediate I-9A (0.458 g, 1.810 mmol) and copper(I)
cyanide (0.600 g, 6.70 mmol) were dissolved in DMF (18.10 mL) and
heated to reflux for 20 hours. The reaction mixture was cooled to
ambient temperature. The reaction mixture was diluted with
saturated NaHCO.sub.3 and extracted with EtOAc. The organic layer
was further washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate I-12A (247 mg, 1.24 mmol, 68.5%) as a white solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.55 (s, 1H), 7.86 (d,
J=0.8 Hz, 1H), 7.78 (s, 1H), 4.11 (s, 3H), 2.58 (s, 3H); LC-MS:
Method H, RT=0.92 min, MS (ESI) m/z: 200.1 (M+H).sup.+.
Intermediate I-12
[1170] Intermediate I-12A (0.247 g, 1.240 mmol), sodium
hydrosulfide (1.043 g, 18.60 mmol), and magnesium chloride (1.771
g, 18.60 mmol) were dissolved in DMF (12.40 mL) and stirred for 18
hours. The reaction mixture was diluted with water, which formed
copious amounts of precipitates. The reaction mixture was extracted
thrice with EtOAc. The combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The solid was sonicated with DCM then filtered. The
resulting solution was concentrated in vacuo to give Intermediate
I-12 (111 mg, 0.476 mmol, 38.4%) as an orange solid: .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 11.86 (br. s., 1H), 9.04 (d, J=2.0
Hz, 1H), 8.40 (s, 1H), 8.32 (br. s., 1H), 7.82 (dd, J=1.9, 0.9 Hz,
1H), 4.11 (s, 3H), 2.61 (s, 3H); LC-MS: Method H, RT=0.88 min, MS
(ESI) m/z: 234.0 (M+H).sup.+.
Intermediate I-14
5-iodo-7-methylquinoxalin-2(1H)-one
##STR00063##
[1171] Intermediate I-14A: 2-iodo-4-methyl-6-nitroaniline
##STR00064##
[1173] Iodine (4.59 g, 18.07 mmol) was dissolved in EtOH (65.7 mL).
Next, 4-methyl-2-nitroaniline (2.5 g, 16.43 mmol) and then silver
sulfate (5.64 g, 18.07 mmol) were added and the reaction mixture
was allowed to stir for 18 hours. The reaction mixture was diluted
with EtOAc, filtered through a sintered glass funnel, and
concentrated in vacuo. The crude material was redissolved in EtOAc
and washed with saturated Na.sub.2S.sub.2O.sub.3, saturated
NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate I-14A (4.65 g, 16.72
mmol, 100%) as an orange solid: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.97 (d, J=1.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 6.49 (br.
s., 2H), 2.26 (s, 3H); LC-MS: Method H, RT=0.98 min, MS (ESI) m/z:
279.0 (M+H).sup.+.
Intermediate I-14B: bis-tert-butyl
(2-iodo-4-methyl-6-nitroaniline)bis carbamate
##STR00065##
[1175] Intermediate I-14A (4.65 g, 16.72 mmol), DMAP (0.204 g,
1.672 mmol), and Boc.sub.2O (9.71 mL, 41.8 mmol) were dissolved in
THF (27.9 mL) and stirred for 18 hours. The reaction mixture was
diluted with water and extracted with EtOAc. The organic layer was
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 220 g silica gel column, 50 minute gradient
from 0 to 100% EtOAc in hexanes), to give Intermediate I-14B (5.4
g, 11.29 mmol, 67.5%) as a light yellow solid: .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 7.94 (s, 1H), 7.78 (s, 1H), 2.43 (s,
3H), 1.40 (s, 18H); LC-MS: Method H, RT=1.10 min, MS (ESI) m/z:
(bis-deboc mass observed) 278.9 (M+H).sup.+.
Intermediate I-14C: methyl
2-((tert-butoxycarbonyl)(2-iodo-4-methyl-6-nitrophenyl)amino)acetate
##STR00066##
[1177] Intermediate I-14B (5.4 g, 11.29 mmol) was dissolved in DCM
(18.82 mL) and TFA (1.740 mL, 22.58 mmol) and stirred for 30
minutes. The reaction mixture was diluted with DCM, quenched with
saturated NaHCO.sub.3, washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
dissolved in DMF (18.82 mL). Cs.sub.2CO.sub.3 (9.20 g, 28.2 mmol)
was added and stirred for 15 minutes. The reaction mixture turned
deep red. Methyl bromoacetate (1.249 mL, 13.55 mmol) was added and
the reaction mixture was allowed to stir 24 hours. The reaction
mixture turned from deep red to yellow. The reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 220 g silica
gel column, 50 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate I-14C (3.51 g, 7.80 mmol, 69.1%) as an orange
solid: LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: (deboc mass
observed) 350.9 (M+H).sup.+.
Intermediate I-14D: methyl
2-((2-iodo-4-methyl-6-nitrophenyl)amino)acetate
##STR00067##
[1179] Intermediate I-14C (3.51 g, 7.80 mmol) was dissolved in HCl
in dioxane (4 M, 9.75 mL, 39.0 mmol) and stirred for 1 hour. The
reaction mixture was concentrated in vacuo to give Intermediate
I-14D, which was used directly in the subsequent step without
purification: LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 350.9
(M+H).sup.+.
Intermediate I-14E:
5-iodo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
##STR00068##
[1181] Intermediate I-14D (2.73 g, 7.80 mmol) was dissolved in MeOH
(28.4 mL). HCl (2.60 mL, 31.2 mmol) then tin(II) chloride dihydrate
(7.04 g, 31.2 mmol) were added and the reaction mixture was heated
to 65.degree. C. for 3.5 hours. The reaction mixture was cooled to
ambient temperature, neutralized with 10 N NaOH and diluted with
brine then EtOAc. Vigorous stirring was allowed for 15 minutes. The
mixture was filtered through celite and concentrated in vacuo to
give Intermediate I-14E (1.77 g, 6.14 mmol, 79.0%) as an orange
solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.57 (br. s.,
1H), 7.17 (s, 1H), 6.48 (s, 1H), 4.17 (br. s., 1H), 4.02 (d, J=1.8
Hz, 2H), 2.21 (s, 3H); LC-MS: Method H, RT=0.82 min, MS (ESI) m/z:
289.0 (M+H).sup.+.
Intermediate I-14
[1182] Intermediate I-14E (1.7696 g, 6.14 mmol) was suspended in
MeOH (17.86 mL). 1 N NaOH (18.43 mL, 18.43 mmol) then
H.sub.2O.sub.2 (30%)(3.23 mL, 36.9 mmol) were added and the
reaction mixture stirred 24 hours. More H.sub.2O.sub.2 (3.23 mL,
36.9 mmol) was added and the reaction mixture was stirred for 24
hours. More H.sub.2O.sub.2 (3.23 mL, 36.9 mmol) was added and the
reaction mixture was stirred for 24 hours. The reaction mixture was
diluted with ca 50 mL of water then about 50 mL of brine. The
mixture was evaporated under a nitrogen stream to remove MeOH. The
aqueous material was extracted thrice with EtOAc. During the
extractions, an off-white solid precipitated. This precipitate was
collected by suction filtration as to give Intermediate I-14 (1.35
g, 4.72 mmol, 77.0%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.44 (br. s., 1H), 8.11 (s, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.09 (s,
1H), 2.37 (s, 3H); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z:
287.0 (M+H).sup.+.
Intermediate I-15
(2-(ethoxycarbonyl)-7-methylquinoxalin-5-yl)boronic acid
##STR00069##
[1183] Intermediate I-15A: 3-bromo-5-methylbenzene-1,2-diamine
##STR00070##
[1185] 2-bromo-4-methyl-6-nitroaniline (5.00 g, 21.64 mmol) was
dissolved in MeOH (148 mL) and THF (18.50 mL). Ammonium chloride
(23.15 g, 433 mmol) then zinc (14.15 g, 216 mmol) were added and
the reaction mixture was heated to 40.degree. C. for 1 h. The
reaction mixture was cooled to ambient temperature, concentrated in
vacuo, re-dissolved in EtOAc and saturated Na.sub.2CO.sub.3, and
stirred vigorously for 10 minutes. The mixture was filtered through
a sintered glass funnel and washed with more EtOAc. The organic
layer was further washed twice with water, washed with brine, dried
with sodium sulfate, filtered, and concentrated in vacuo to yield
Intermediate I-15A (4.35 g, 21.63 mmol, 100% yield). .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 6.81 (s, 1H), 6.48 (s, 1H), 3.66
(br. s., 2H), 3.46 (br. s., 2H), 2.19 (s, 3H). LC-MS: method H,
RT=0.93 min, MS (ESI) m/z: 201.0 (M+H).sup.+.
Intermediate I-15B: ethyl
5-bromo-7-methylquinoxaline-2-carboxylate
##STR00071##
[1187] Intermediate I-15A (4.35 g, 21.63 mmol) and ethyl
3-bromo-2-oxopropanoate (3.63 mL, 26.0 mmol) were dissolved in NMP
(72.1 mL) and allowed to stir at room temperature for 18 h open to
air. The reaction mixture was diluted with water and EtOAc. The
layers were separated and the aqueous layer was back extracted with
EtOAc (.times.3). The combined organic layer was washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure.
The reaction mixture was purified by ISCO column using 0-40% EtOAc
in hexanes on a 220 g column to yield a mixture of regioisomers.
The reaction mixture was purified by SFC on a Chiralcel OD-H,
30.times.250 mm, 5 micron column using 20% IPA/80% CO.sub.2 with 85
mL/min, 100 Bar, 40.degree. C. to yield Intermediate I-15B (0.936
g, 3.17 mmol, 14.66% yield) as a yellow solid. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.48 (s, 1H), 8.01 (s, 1H), 7.99 (s,
1H), 4.53 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.44 (t, J=7.2 Hz, 3H).
LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 295.1 (M+H).sup.+.
Intermediate I-15
[1188] A mixture of Intermediate I-15B (0.100 g, 0.339 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.129
g, 0.508 mmol), potassium acetate (0.083 g, 0.847 mmol) in dioxane
(3.39 mL) were degassed by bubbling argon for 5 min.
PdCl.sub.2(dppf)-CH.sub.2Cl adduct (0.014 g, 0.017 mmol) was added
and the mixture was sealed and heated in microwave at 130.degree.
C. for 30 min. The reaction mixture was diluted with water and
EtOAc. The layers were separated and the organic layer was washed
with brine, dried with sodium sulfate, and concentrated under
reduced pressure to yield a brown oil. The reaction mixture was
purified on Prep HPLC using Method A to yield Intermediate I-15
(0.027 g, 0.104 mmol, 30.6% yield) as an off white solid. LC-MS:
method H, RT=1.15 min, MS (ESI) m/z: 261.2 (M+H).sup.+.
Intermediate I-16
(2-bromo-5-methoxy-7-methylthiazolo[5,4-b]pyridine
##STR00072##
[1189] Intermediate I-16A:
1-(6-methoxy-4-methylpyridin-3-yl)thiourea
##STR00073##
[1191] To a solution of 6-methoxy-4-methylpyridin-3-amine (0.150 g,
1.086 mmol) in acetone (1 mL) was added dropwise benzoyl
isothiocyanate (0.161 mL, 1.194 mmol). The reaction mixture was
allowed to stir at room temperature for 2.5h. The reaction mixture
was concentrated under reduced pressure and re-dissolved in
tetrahydrofuran (1 mL). To this solution was added sodium methoxide
(0.5 M in MeOH) (3.26 mL, 1.628 mmol), and the reaction mixture was
allowed to stir at room temperature for 30 min. The reaction
mixture was diluted with water and EtOAc. The layers were separated
and the organic layer was washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure. The reaction
mixture was triturated with Et.sub.2O and filtered. The solid was
collected to yield Intermediate I-16A (0.148 g, 0.750 mmol, 69.1%
yield) as a brown solid. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 8.04 (s, 1H), 7.54 (br. s., 1H), 6.69 (s, 1H), 6.51-5.18
(m, 2H), 3.93 (s, 3H), 2.28 (s, 3H). LC-MS: method H, RT=0.93 min,
MS (ESI) m/z: 198.1 (M+H).sup.+.
Intermediate I-16B:
5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-amine
##STR00074##
[1193] To a solution of Intermediate I-16A (0.146 g, 0.740 mmol) in
tetrahydrofuran (1 mL) was added benzyltrimethylammonium tribromide
(0.289 g, 0.740 mmol). The reaction mixture was allowed to stir at
room temperature for 2 hours. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with saturated aqueous NaHCO.sub.3, washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure.
The reaction mixture was purified on ISCO using 0-100% EtOAc in
hexanes gradient on a 24 g column to yield Intermediate I-16B
(0.035 g, 0.179 mmol, 24.22% yield) as a white solid. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 6.53 (d, J=0.7 Hz, 1H), 5.00 (br.
s., 2H), 3.91 (s, 3H), 2.49 (d, J=0.9 Hz, 3H). LC-MS: method H,
RT=0.93 min, MS (ESI) m/z: 196.1 (M+H).sup.+.
Intermediate I-16
[1194] Copper (II) bromide (0.068 g, 0.305 mmol) and t-butyl
nitrite (0.036 mL, 0.305 mmol) were dissolved in MeCN (0.717 mL)
and allowed to stir 10 minutes. Intermediate I-16B (0.035 g, 0.179
mmol) was dissolved in MeCN (1.076 mL) and the copper solution was
added. The reaction mixture was allowed to stir at room temperature
for 2 h. The reaction mixture was diluted with EtOAc, washed with 1
N HCl, saturated aqueous NaHCO.sub.3, washed with brine, dried with
sodium sulfate, filtered, and concentrated in vacuo to yield
Intermediate I-16 (0.030 g, 0.116 mmol, 64.6% yield). .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 6.64 (d, J=1.1 Hz, 1H), 3.96 (s,
3H), 2.62 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=0.93 min, MS (ESI)
m/z: 359.1 (M+H).sup.+.
Intermediate I-17
2-bromo-6-fluoro-5-methoxythiazolo[5,4-b]pyridine
##STR00075##
[1195] Intermediate I-17A:
N-((5-fluoro-6-methoxypyridin-3-yl)carbamothioyl)benzamide
##STR00076##
[1197] To a solution of 5-fluoro-6-methoxypyridin-3-amine (0.100 g,
0.704 mmol) in acetone (1 mL) was added dropwise benzoyl
isothiocyanate (0.104 mL, 0.774 mmol). The reaction mixture was
allowed to stir at room temperature for 3 h. The reaction mixture
was diluted with water and EtOAc. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate I-17A
(0.215 g, 0.704 mmol, 100% yield): .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 12.48 (br. s., 1H), 9.12 (br. s., 1H), 8.06
(d, J=2.0 Hz, 1H), 8.01 (dd, J=10.8, 2.2 Hz, 1H), 7.91 (d, J=1.1
Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.60-7.54 (m,
2H), 4.06 (s, 3H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z:
306.1 (M+H).sup.+.
Intermediate I-17B: 1-(5-fluoro-6-methoxypyridin-3-yl)thiourea
##STR00077##
[1199] To a solution of Intermediate I-17A (0.215 g, 0.704 mmol) in
tetrahydrofuran (1 mL) was added dropwise sodium methoxide (0.5 M
in MeOH) (2.112 mL, 1.056 mmol). The reaction mixture was allowed
to stir at room temperature for 18 h. The reaction mixture was
diluted with water and EtOAc. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure. The residue was triturated
with Et.sub.2O, and the solid was collected to yield Intermediate
I-17B (0.09 g, 0.447 mmol, 63.5% yield) as a pale yellow solid.
LC-MS: method H, RT=0.81 min, MS (ESI) m/z: 202.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.86 (d, J=2.2 Hz, 1H),
7.63 (br. s., 2H), 7.32 (s, 1H), 4.03 (s, 3H).
Intermediate I-17C:
6-fluoro-5-methoxythiazolo[5,4-b]pyridin-2-amine
##STR00078##
[1201] To a solution of Intermediate I-17B (0.078 g, 0.338 mmol) in
tetrahydrofuran (1 mL) was added benzyltrimethylammonium tribromide
(0.151 g, 0.388 mmol). The reaction mixture was allowed to stir at
room temperature for 2 hours. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with saturated aqueous NaHCO.sub.3, washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure.
The reaction mixture was purified on Prep HPLC using Method A to
yield Intermediate I-17C (0.028 g, 0.141 mmol, 36.3% yield) as a
white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.87 (br.
s., 2H), 7.59 (d, J=9.7 Hz, 1H), 4.05 (s, 3H) LC-MS: method H,
RT=0.84 min, MS (ESI) m/z: 200.1 (M+H).sup.+.
[1202] Intermediate I-17
[1203] Copper (II) bromide (0.055 g, 0.247 mmol) and t-butyl
nitrite (0.029 mL, 0.247 mmol) were dissolved in MeCN (0.582 mL)
and allowed to stir 10 minutes. Intermediate I-17C (0.029 g, 0.146
mmol) was dissolved in MeCN (0.873 mL) and the copper solution was
added. The reaction mixture was diluted with EtOAc, washed with 1 N
HCl, saturated aqueous NaHCO.sub.3, then brine, dried with sodium
sulfate, filtered, and concentrated in vacuo to yield Intermediate
I-17 (0.035 g, 0.133 mmol, 91% yield). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.86 (d, J=9.9 Hz, 1H), 4.09 (s, 3H). LC-MS:
method H, RT=1.23 min, MS (ESI) m/z: 263.0 (M+H).sup.+.
Intermediate I-20
2-bromo-6-methoxybenzo[d]thiazole-4-carbaldehyde
##STR00079##
[1204] Intermediate I-20A: Methyl 2-amino-5-methoxybenzoate
##STR00080##
[1206] 2-amino-5-methoxybenzoic acid (250 mg, 1.496 mmol) was
dissolved in MeOH (7478 .mu.L). Thionyl chloride (327 .mu.L, 4.49
mmol) was added and the reaction mixture was heated to reflux for 3
days. The reaction mixture was concentrated in vacuo. The crude
material was dissolved in EtOAc and washed with 1 N NaOH, then
water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate I-20A (190 mg, 1.049
mmol, 70.1%) as a brown oil: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.38 (d, J=3.1 Hz, 1H), 6.98 (dd, J=9.0, 3.1 Hz, 1H), 6.66
(d, J=8.8 Hz, 1H), 5.43 (br. s., 2H), 3.90 (s, 3H), 3.79 (s, 3H);
LC-MS: Method H, RT=0.89 min, MS (ESI) m/z: 182.1 (M+H).sup.+.
Intermediate I-20B: Methyl
2-amino-6-methoxybenzo[d]thiazole-4-carboxylate
##STR00081##
[1208] Intermediate I-20A (190 mg, 1.049 mmol) was dissolved in
MeCN (5243 .mu.L). Ammonium thiocyanate (120 mg, 1.573 mmol) was
added, followed by benzyltrimethylammonium tribromide (409 mg,
1.049 mmol). After 4 hours, the reaction mixture was diluted with
EtOAc, washed with saturated NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate I-20B (100 mg, 0.42 mmol, 40%) as a brown solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.51 (d, J=2.6 Hz, 1H),
7.35 (d, J=2.6 Hz, 1H), 5.89 (br. s., 2H), 3.99 (s, 3H), 3.88 (s,
3H); LC-MS: Method H, RT=0.82 min, MS (ESI) m/z: 239.1
(M+H).sup.+.
Intermediate I-20C: Methyl
2-bromo-6-methoxybenzo[d]thiazole-4-carboxylate
##STR00082##
[1210] Copper(II) bromide (159 mg, 0.713 mmol) and t-butyl nitrite
(85 .mu.L, 0.713 mmol) were dissolved in MeCN (1679 .mu.L) and
allowed to stir 10 minutes. Intermediate I-20B (100 mg, 0.420 mmol)
was dissolved in MeCN (2518 .mu.L) and the copper solution was
added. After 2 hours, the reaction mixture was diluted with EtOAc,
washed with 1 N HCl, saturated NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate I-20C (100.6 mg, 0.333 mmol, 79%) as a red solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.68 (d, J=2.6 Hz, 1H),
7.46 (d, J=2.6 Hz, 1H), 4.05 (s, 3H), 3.93 (s, 3H); LC-MS: Method
H, The compound did not ionize.
Intermediate I-20D:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)methanol
##STR00083##
[1212] Intermediate I-20C (93.5 mg, 0.309 mmol) was dissolved in
toluene (2063 .mu.L) and THF (1032 .mu.L) and cooled to -78.degree.
C. DIBAL-H (681 .mu.L, 0.681 mmol) was added and the reaction
mixture was warmed to ambient temperature for 1 hour. The reaction
was quenched with 1 N HCl (1 mL), diluted with EtOAc, filtered
through celite, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate I-20D (28.1 mg, 0.103 mmol, 33%) as an off-white
solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.17 (d, J=2.6
Hz, 1H), 7.04 (d, J=2.6 Hz, 1H), 5.05 (d, J=6.6 Hz, 2H), 3.87 (s,
3H), 3.00 (t, J=6.5 Hz, 1H); LC-MS: Method H, RT=1.06 min, MS (ESI)
m/z: 274/276 (M+H).sup.+.
Intermediate I-20
[1213] Intermediate I-20D (188.8 mg, 0.689 mmol) was dissolved in
CHCl.sub.3 (4591 .mu.L). Manganese dioxide (359 mg, 4.13 mmol) was
added and the reaction mixture was allowed to stir for 24 hours.
More manganese dioxide (359 mg, 4.13 mmol) was added and the
reaction mixture was allowed to stir for 3 days. The reaction
mixture was filtered through celite and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 12 g
silica gel column, 17 minute gradient from 0 to 100% EtOAc in
hexanes) to give Intermediate I-20 (136.3 mg, 0.501 mmol, 72.7%) as
a white solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
10.90-10.84 (m, 1H), 7.63-7.59 (m, 1H), 7.57-7.51 (m, 1H), 3.93 (s,
3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 272/274
(M+H).sup.+.
Intermediate I-22
4-bromo-6-methoxybenzo[d]thiazol-2-amine
##STR00084##
[1215] 2-Bromo-4-methoxyaniline (10 g, 49.5 mmol) was dissolved in
MeCN (247 mL). Ammonium thiocyanate (5.65 g, 74.2 mmol) was added,
followed by benzyltrimethylammonium tribromide (19.3 g, 49.5 mmol).
After stirring for 2 days, the reaction mixture was diluted with
saturated NaHCO.sub.3 and the resulting solid was collected by
suction filtration. The solid was washed with water to give
Intermediate I-22 (10.75 g, 41.5 mmol, 84% yield) as a light brown
solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.19 (d, J=2.4
Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 3.78 (s, 3H); LC-MS: Method H,
RT=0.70 min, MS (ESI) m/z: 259/261 (M+H).sup.+.
Intermediate I-25
2-(methoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinoxaline, D.sub.5
##STR00085##
[1216] Intermediate I-25A:
(5-bromo-7-methylquinoxalin-2-yl)methanol
##STR00086##
[1218] NaBH.sub.4 (135 mg, 3.56 mmol) and calcium chloride (197 mg,
1.779 mmol) were dissolved in THF (5270 .mu.l). A solution of
Intermediate I-15B (500 mg, 1.779 mmol) in THF (1318 .mu.l) was
added dropwise, and the reaction mixture was allowed to stir at
room temperature for 18 h. The reaction mixture was diluted with
EtOAc, washed with water, washed with brine, dried with sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude material was purified by column chromatography (ISCO, 40 g
silica gel column, 19 minute gradient from 0 to 100% EtOAc in
hexanes) to yield Intermediate I-25A (0.263 g, 1.04 mmol, 58%) as a
yellow solid. .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.85 (s,
1H), 7.92 (d, J=1.7 Hz, 1H), 7.79 (dd, J=1.7, 1.1 Hz, 1H), 5.04 (s,
2H), 3.73 (br. s., 1H), 2.58 (s, 3H). LC-MS: method H, RT=0.93 min,
MS (ESI) m/z: 253.1 (M+H).sup.+.
Intermediate I-25B: (5-bromo-7-methylquinoxalin-2-yl)methyl
methanesulfonate
##STR00087##
[1220] Intermediate I-25A (262.5 mg, 1.037 mmol) and TEA (0.434 mL,
3.11 mmol) were dissolved in DCM (20 mL) and methanesulfonic
anhydride (217 mg, 1.245 mmol) was added. The reaction mixture was
stirred at room temperature for 1 h. The reaction mixture was
diluted with DCM and washed with saturated NaHCO.sub.3, dried with
sodium sulfate, filtered, and concentrated in vacuo to yield
Intermediate I-25B (0.343 g, 1.04 mmol, 100%) as an orange solid.
The material will be used crude in the next step. LC-MS: method H,
RT=1.00 min, MS (ESI) m/z: 331.0 (M+H).sup.+.
Intermediate I-25C: 5-bromo-2-(methoxymethyl)-7-methylquinoxaline,
d.sub.5
##STR00088##
[1222] CD.sub.3ONa was prepared by dissolving sodium metal (60 mg,
2.500 mmol) in CD.sub.3OD (0.405 mL, 10 mmol) for 30 minutes.
Intermediate I-25B (207 mg, 0.625 mmol) was dissolved in THF (12
mL). CD.sub.3ONa (71.3 mg, 1.250 mmol) was added, and the reaction
mixture was allowed to stir at room temperature for 18 h. The
reaction mixture was partially concentrated in vacuo to remove THF,
diluted with EtOAc and washed with water, washed with brine, dried
with sodium sulfate, filtered, and concentrated in vacuo to yield
Intermediate I-25C (0.118 g, 0.432 mmol, 69% yield). .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.01 (s, 1H), 7.93 (d, J=1.5 Hz,
1H), 7.82 (dd, J=1.8, 0.9 Hz, 1H), 2.58 (s, 3H). LC-MS: method H,
RT=0.90 min, MS (ESI) m/z: 272.1 (M+H).sup.+.
Intermediate I-25
[1223] Intermediate I-25C (117.6 mg, 0.432 mmol),
bis(pinacolato)diboron (165 mg, 0.648 mmol), and potassium acetate
(106 mg, 1.080 mmol) were dissolved in dioxane (4321 .mu.l) and
degassed for 5 minutes by bubbling with argon.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (28.2 mg, 0.035 mmol) was
added and the reaction mixture was degassed for an additional 10
minutes. The reaction mixture was heated to 130.degree. C. in the
microwave for 45 minutes. The reaction mixture was diluted with
EtOAc and water and filtered. The reaction mixture was further
extracted twice with EtOAc. The combined organic layers were washed
with brine, dried with sodium sulfate, filtered, and concentrated
in vacuo to yield Intermediate I-25 (0.097 g, 0.302 mmol, 70%
yield). LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 238.2
(M+H).sup.+. Observed the mass of the boronic acid in LC/MS.
Intermediate I-26
(R)-(2-chloro-4-methyl-7,8-dihydro-[1,4]dioxino[2',3':
3,4]benzo[1,2-d]thiazol-7-yl)methyl acetate
##STR00089##
[1224] Intermediate I-26A:
(R)-5-methyl-2-(oxiran-2-ylmethoxy)benzaldehyde
##STR00090##
[1226] To a solution of 2-hydroxy-5-methylbenzaldehyde (5 g, 36.7
mmol) in DMF (80 mL) was added (R)-oxiran-2-ylmethyl
3-nitrobenzenesulfonate (10.47 g, 40.4 mmol) and Cs.sub.2CO.sub.3
(35.9 g, 110 mmol). The mixture was stirred at room temperature
overnight. LCMS indicated a completion of the reaction mixture. The
mixture was diluted with EtOAc and water, extracted with EtOAc. The
combined organic layer was washed with brine, dried over MgSO.sub.4
and concentrated. The crude sample was purified with a 120 g ISCO
column eluted with 0-100% EtOAc/hexanes for 40 min. The desired
fractions were collected and concentrated to give Intermediate
I-26A (7 g, 36.4 mmol, 99% yield) as a colorless oil. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 10.50 (s, 1H), 7.65 (d, J=2.2 Hz,
1H), 7.35 (ddd, J=8.6, 2.4, 0.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H),
4.36 (dd, J=11.1, 3.0 Hz, 1H), 4.05 (dd, J=11.1, 5.6 Hz, 1H), 3.40
(ddt, J=5.6, 4.1, 2.8 Hz, 1H), 2.94 (dd, J=4.7, 4.1 Hz, 1H), 2.80
(dd, J=4.8, 2.6 Hz, 1H), 2.32 (s, 3H); LC-MS: method C, RT=1.59
min, MS (ESI) m/z: 193.0 (M+H).sup.+.
Intermediate I-26B:
(S)-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol
##STR00091##
[1228] To a stirred solution of Intermediate I-26A (7 g, 36.4 mmol)
in dichloromethane (100 mL) cooled with an ice bath was added mCPBA
(12.36 g, 53.7 mmol). Next, trifluoroacetic acid (2.81 mL, 36.4
mmol) in dichloromethane (10 mL) was added dropwise. Ice bath was
removed and the mixture was stirred at room temperature for 1.0 h.
TLC and LCMS indicated no starting material remaining. The reaction
mixture was quenched by addition of saturated sodium bicarbonate,
followed by 10% sodium thiosulfite (20.0 mL), extracted with
dichloromethane. The organic layers were collected, washed with
saturated sodium bicarbonate, brine and dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in
MeOH (100 mL), and K.sub.2CO.sub.3 (15.10 g, 109 mmol) was added.
The mixture was stirred overnight at room temperature. The reaction
mixture was diluted with EtOAc and water, extracted with EtOAc, the
combined organic layer was washed with brine, dried over MgSO.sub.4
and concentrated. The crude sample was purified with a 120 g ISCO
column eluted with 0-100% EtOAc/hexanes for 40 min. The desired
fractions were combined and concentrated to give Intermediate I-26B
(4.65 g, 25.8 mmol, 70.9% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 6.78 (d, J=8.1 Hz, 1H), 6.73 (d, J=1.3 Hz,
1H), 6.69-6.63 (m, 1H), 4.33-4.21 (m, 2H), 4.15-4.05 (m, 1H),
3.96-3.76 (m, 2H), 2.26 (s, 3H). LC-MS: method C, RT=1.55 min, MS
(ESI) m/z: 209.0 (M+H).sup.+.
Intermediate I-26C:
(R)-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl
acetate
##STR00092##
[1230] To a solution of Intermediate I-26B (4.6 g, 25.5 mmol) in
THF (100 mL) at 0.degree. C. was added TEA (8.89 mL, 63.8 mmol),
followed by acetyl chloride in DCM (31.9 mL, 31.9 mmol) dropwise.
The mixture was stirred at 0.degree. C. for 10 min, and at room
temperature for 1.0 h. The mixture was diluted with EtOAc, washed
with water. The organic layer was washed with 0.5 N HCl, saturated
sodium bicarbonate, brine and dried over sodium sulfate. After
evaporation of solvent, Intermediate I-26C (5.3 g, 23.85 mmol, 93%
yield) was obtained as a yellow oil. It was used for the next step
without further purification. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 6.76 (d, J=8.1 Hz, 1H), 6.72 (d, J=1.3 Hz, 1H), 6.68-6.61
(m, 1H), 4.40-4.33 (m, 1H), 4.30 (dd, J=5.1, 4.4 Hz, 2H), 4.25 (dd,
J=11.3, 2.3 Hz, 1H), 4.03 (dd, J=11.4, 6.8 Hz, 1H), 2.25 (s, 3H),
2.11 (s, 3H). LC-MS: method C, RT=1.92 min, MS (ESI) m/z: 245.0
(M+H).sup.+.
Intermediate I-26D:
(R)-(7-methyl-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl
acetate
##STR00093##
[1232] To a solution of Intermediate I-26C (4.15 g, 18.67 mmol) in
acetic acid (40 mL) cooled at 0.degree. C. with an ice-bath was
added fuming nitric acid (4.36 mL, 93 mmol) dropwise. The mixture
was stirred at 0.degree. C. for 1 h, then at room temperature for
30 min. TLC (PMA stain) indicated a completion of the reaction. It
was quenched with ice water. The aqueous was removed and the
organic layer was washed with saturated sodium bicarbonate
(3.times.), brine and dried over sodium sulfate. After evaporation
of solvent, Intermediate I-26D (4.6 g, 17.21 mmol, 92% yield) was
obtained as an off-white solid which was used for the next step
without further purification. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.71 (s, 1H), 6.83 (s, 1H), 4.54-4.45 (m, 1H), 4.39-4.28
(m, 3H), 4.09 (dd, J=11.9, 7.0 Hz, 1H), 2.55 (d, J=0.4 Hz, 3H),
2.13 (s, 3H). LC-MS: method C, RT=1.90 min, MS (ESI) m/z: 290.0
(M+H).sup.+.
Intermediate I-26E:
(R)-(6-amino-7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl
acetate
##STR00094##
[1234] To a solution of Intermediate I-26D (5.3 g, 19.83 mmol) in
MeOH (80 mL) and THF (80 mL) cooled with an ice bath was added
ammonium chloride (16.97 g, 317 mmol) and zinc dust (10.37 g, 159
mmol). The mixture was stirred at 0.degree. C. for 30 min, and at
room temperature for 1.0 h. MeOH and THF were removed under vacuum.
The residue was diluted with EtOAc/saturated sodium bicarbonate and
stirred at room temperature for 3 min. The mixture was filtered
through a pad of wet celite to remove insoluble material. The
filtrate was collected, organic layer was washed with brine, dried
over sodium sulfate, concentrated to give Intermediate I-26E (4.7
g, 19.81 mmol, 100% yield) as off-white solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 6.63 (s, 1H), 6.25 (s, 1H), 4.38-4.20
(m, 4H), 4.06-3.95 (m, 1H), 3.35 (br. s., 2H), 2.11 (s, 3H), 2.09
(s, 3H). LC-MS: method C, RT=1.14 min, MS (ESI) m/z: 238.0
(M+H).sup.+.
Intermediate I-26F
(R)-(2-amino-4-methyl-7,8-dihydro-[1,4]dioxino[2',3':3,4]benzo[1,2-d]thiaz-
ol-7-yl)methyl acetate
##STR00095##
[1236] To Intermediate I-26E (4.7 g, 19.81 mmol) dissolved in
acetonitrile (120 mL) was added ammonium thiocyanate (2.262 g, 29.7
mmol). The mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (8.11 g, 20.80 mmol) in
acetonitrile (20 mL) was added dropwise (5 min). The reaction
mixture was stirred at room temperature overnight, diluted with
EtOAc/THF/saturated sodium bicarbonate. The insoluble material was
removed by filtration. The organic layer of the filtrate was
collected, washed with brine, dried over sodium sulfate. After
evaporation of solvent, Intermediate I-26F (5.8 g, 19.71 mmol, 99%
yield) was obtained as a yellow solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 6.73 (d, J=0.7 Hz, 1H), 5.10 (s, 2H),
4.47-4.28 (m, 4H), 4.14 (dd, J=11.3, 6.9 Hz, 1H), 2.45 (d, J=0.7
Hz, 3H), 2.12 (s, 3H). LC-MS: method C, RT=1.46 min, MS (ESI) m/z:
295.0 (M+H).sup.+.
Intermediate I-26
[1237] To a suspension of Intermediate I-26F (5.8 g, 19.71 mmol) in
dry acetonitrile (80 mL) was added copper (II) chloride (4.5 g,
33.5 mmol), followed by tert-butyl nitrite (4.56 mL, 34.5 mmol)
dropwise. The reaction mixture was stirred at room temperature for
2 h. LCMS indicated a completion of the reaction. Acetonitrile was
removed under vacuum, the reaction mixture was diluted with EtOAc,
quenched with 1.0 N HCl. The organic layer was collected, washed
with 0.5 N HCl (2.times.), saturated sodium bicarbonate, brine and
dried over sodium sulfate. After evaporation of solvent, the crude
product was purified with a 220 g ISCO column eluted with 0% to 70%
EtOAc in hexanes over 60 min. The desired fraction was collected
and concentrated to yield Intermediate I-26 (3.9 g, 12.43 mmol,
63.1% yield) as an off-white solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 6.89 (d, J=0.7 Hz, 1H), 4.55-4.28 (m, 4H),
4.18 (dd, J=11.4, 7.0 Hz, 1H), 2.59 (s, 3H), 2.13 (s, 3H). LC-MS:
method C, RT=2.18 min, MS (ESI) m/z: 314.0 (M+H).sup.+.
Intermediate I-27
7-((tert-butyldimethylsilyloxy)methyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,-
3,2-dioxaborolan-2-yl)quinoxaline
##STR00096##
[1238] Intermediate I-27A:
8-bromo-3-methoxyquinoxaline-6-carbaldehyde
##STR00097##
[1240] To a solution of Intermediate I-9A (1 g, 3.95 mmol) in
CCl.sub.4 (20 mL) was added NBS (1.547 g, 8.69 mmol) and benzoic
peroxide (0.115 g, 0.474 mmol). The mixture was heated at reflux
(95.degree. C. oil bath) for 3 h. TLC and LCMS indicated a
completion of the reaction. The mixture was cooled to room
temperature and filtered. The filtrate was concentrated to a yellow
solid. The crude sample was dissolved in THF (10 ml) and silver
nitrate (6.71 g, 39.5 mmol) in water (10 ml) was added. The mixture
was stirred at 95.degree. C. for 1 h. LCMS indicated a completion
of the reaction. The mixture was cooled to room temperature and
poured to 60 ml of water. The mixture was filtered and the filter
cake was washed with CHCl.sub.3 for 3 times. The combined filtrate
was extracted with CHCl.sub.3 and the organic layer was combined,
washed with NaHCO.sub.3 and brine dried over MgSO.sub.4 and
concentrated to Intermediate I-27A (1 g, 3.74 mmol, 95% yield). The
crude sample was used for next step without purification. LC-MS:
method C, RT=1.84 min, MS (ESI) m/z: 267 and 269 (M+H).sup.+.
Intermediate I-27B: (8-bromo-3-methoxyquinoxalin-6-yl)methanol
##STR00098##
[1242] Intermediate I-27A (1.055 g, 3.95 mmol) suspended in THF (10
mL) and MeOH (10 mL) was treated with NaBH.sub.4 (0.149 g, 3.95
mmol) at room temperature for 15 min. The reaction mixture turned
to a clear solution. LCMS indicated a completion of the reaction.
Saturated NH.sub.4Cl was added to quench the reaction. After
stirring at room temperature for 10 min, it was diluted with EtOAc
and water. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated. The crude product was purified with a
120 g ISCO column eluted with 0-100% EtOAc in hexanes. The desired
fraction was collected and concentrated to give Intermediate I-27B
(380 mg, 1.412 mmol, 35.7% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.54 (s, 1H), 8.01-7.77 (m, 2H), 4.90 (s,
2H), 4.13 (s, 3H). LC-MS: method C, RT=1.64 min, MS (ESI) (m/z) 269
and 271 (M+H).sup.+.
Intermediate I-27C
5-bromo-7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxaline
##STR00099##
[1244] To a stirred solution of Intermediate I-27B (380 mg, 1.412
mmol) in DMF (5 mL) was added TBDMS-Cl (319 mg, 2.118 mmol) and
imidazole (173 mg, 2.54 mmol). The reaction mixture was stirred at
room temperature for 1.0 h. TLC and LCMS indicated a clean
reaction. The mixture was partitioned between EtOAc/water. The
organic layer was washed with water, brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
silica gel cartridge which was eluted with hexanes for 3 min., then
a 20 min gradient from 0% to 15% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate I-27C
(480 mg, 1.252 mmol, 89% yield) as a white solid. LC-MS: method C,
RT=2.74 min, MS (ESI) (m/z) 383 and 385 (M+H).sup.+.
Intermediate I-27
[1245] A mixture of Intermediate I-27C (100 mg, 0.261 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (99 mg,
0.391 mmol), potassium acetate (64.0 mg, 0.652 mmol) in dioxane (2
mL) was degassed with argon for 5 min,
then[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (10.65 mg, 0.013 mmol) was
added. The mixture was sealed and heated in microwave reactor at
130.degree. C. for 30 min. LCMS indicated a clean reaction. The
mixture was diluted with EtOAc/water, insoluble material was
removed by filtration. The filtrate was extracted with EtOAc,
washed with brine, dried over sodium sulfate. After evaporation of
solvent, the crude product was dissolved in a small amount of
toluene and charged to a 40 g silica gel cartridge which was eluted
with 5% EtOAc in hexanes for 2 min., then a 18 min gradient from 5%
to 75% EtOAc in hexanes. The desired fractions were combined,
concentrated and lyophilized to give Intermediate I-27 (105 mg,
0.244 mmol, 94% yield) as a pale solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.39 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.96
(dt, J=2.0, 1.0 Hz, 1H), 4.96 (s, 2H), 4.13 (s, 3H), 1.45 (s, 12H),
1.00 (s, 9H), 0.16 (s, 6H). LC-MS: method C, RT=2.73 min, MS (ESI)
(m/z) 349 (M+H).sup.+ (boronic acid).
Intermediate I-28
7-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxal-
ine
##STR00100##
[1246] Intermediate I-28A: 2-bromo-4-chloro-6-nitroaniline
##STR00101##
[1248] A solution of 4-chloro-2-nitroaniline (10 g, 57.9 mmol) in
acetic acid (50 mL) was cooled to 0.degree. C. with an ice bath.
Bromine (3.28 mL, 63.7 mmol) was added dropwise, and the mixture
was stirred at room temperature for 1 hr, and then poured into ice
water. The precipitated solid was filtered and was washed with
water several times. The filter cake was re-dissolved in EtOAc,
dried over sodium sulfate, filtered and concentrated in vacuo to
give the title compound as a yellow solid (14.66 g, 100%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.08 (d, J=2.4 Hz, 1H), 8.02
(d, J=2.6 Hz, 1H), 7.27 (br s, 2H); LC-MS: method H, RT=1.15 min,
MS (ESI) m/z: 250.9 and 252.9 (M+H).sup.+.
Intermediate I-28B: tert-butyl
N-(2-bromo-4-chloro-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
##STR00102##
[1250] In a round bottom flask charged with a stirring bar,
Intermediate I-28A (5 g, 19.88 mmol) was dissolved in THF (30 mL).
DMAP (0.243 g, 1.988 mmol) was added, followed by di-tert-butyl
dicarbonate (11.54 mL, 49.7 mmol). The reaction mixture was stirred
at room temperature for 1 hour, and then solvent was removed on a
rotary evaporator. The residue was purified by flash chromatography
(120 g silica gel column eluted with 0-100% EtOAc/Hexane) to give
the title compound as a white solid (8.2 g, 18.1 mmol, 91%).
.sup.1H NMR (400 MHz, chloroform-d): 7.97 (d, J=2.4 Hz, 1H), 7.90
(d, J=2.4 Hz, 1H), 1.42 (s, 18H); LC-MS: method H, RT=1.04 min, MS
(ESI) m/z: 250.9 and 252.9 (M+H-2Boc).sup.+.
Intermediate I-28C: tert-butyl
(2-bromo-4-chloro-6-nitrophenyl)carbamate
##STR00103##
[1252] To a solution of Intermediate I-28B (8.2 g, 18.15 mmol) in
DCM (50 mL) was added TFA (2.80 mL, 36.3 mmol) and the mixture was
stirred at room temperature for 1 hour. Saturated
NaHCO.sub.3(aqueous 30 mL) was added to the mixture. After stirring
at room temperature for 10 minutes, the layers were separated and
the aqueous layer was extracted by DCM (30 mL.times.2). The
combined organic solution was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the title compound as a
yellow solid (6.32 g, 18.0 mmol, 99%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.45 (br s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.12
(d, J=2.4 Hz, 1H), 1.43 (br s, 9H); LC-MS: method H, RT=0.82 min,
MS (ESI) m/z: 250.9 and 252.9 (M+H-Boc).sup.+.
Intermediate I-28D: methyl
2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate
##STR00104##
[1254] To a solution of Intermediate I-28C (6.32 g, 18.0 mmol) in
DMF (30 mL) was added Cs.sub.2CO.sub.3 (14.64 g, 44.9 mmol. Methyl
2-bromoacetate (5.50 g, 36.0 mmol) was added dropwise and the
mixture was stirred at room temperature for 30 minutes. The
reaction mixture was diluted with 100 mL of EtOAc and 50 mL of
water. After separation, the aqueous layer was extracted by EtOAc
(50 mL), and the combined organic layers were washed with brine and
concentrated. The residue was purified by flash chromatography (120
g silica gel column, eluted with 0-50% EtOAc/Hex) to give the title
compound (7.55 g, 17.8 mmol, 99%) as a yellow oil. .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.92-7.81 (m, 2H), 4.58 (d, J=17.6 Hz,
1H), 3.99 (d, J=17.4 Hz, 1H), 3.69 (s, 3H), 1.38 (s, 9H); LC-MS:
method H, RT=1.23 min, MS (ESI) m/z: 366.9 and 368.9
(M+H-56).sup.+.
Intermediate I-28E: methyl
2-((2-bromo-4-chloro-6-nitrophenyl)amino)acetate, TFA salt
##STR00105##
[1256] Intermediate I-28D (5.6 g, 13.22 mmol) was dissolved in DCM
(30 mL) and was treated with TFA (10.18 mL, 132 mmol) at room
temperature overnight. On the next day, the solvent was removed and
the crude product was used in the next step without purification.
LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 323.0 and 324.9
(M+H).sup.+.
Intermediate I-28F:
5-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one
##STR00106##
[1258] In a round bottom flask charged with a stirring bar,
Intermediate I-28E (6.0 g, 18.55 mmol) was dissolved in MeOH (60
mL), and concentrated HCl (4.64 mL, 55.6 mmol) was added, followed
by SnCl.sub.2 (14.07 g, 74.2 mmol). The reaction mixture was
stirred at 60.degree. C. overnight. On the next day, after cooling
to room temperature, another 2 equivalents of SnCl.sub.2 was added
to the reaction mixture. After 2 h at 60.degree. C., the reaction
mixture was cooled to room temperature; the precipitate was
filtered, washed with small amount of MeOH, and dried to give a
white solid as desired product. The filtrate was concentrated on a
rotary evaporator and then partitioned between 150 mL of EtOAc and
30 mL of water. Next, 4M NaOH (aqueous) was added to adjust the pH
to 12. The solid was filtered on a Celite pad and the filter cake
was washed with EtOAc. The layers were separated and the aqueous
phase was extracted twice with EtOAc. The combined organic phases
were washed with saturated NaHCO.sub.3(aqueous), brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give
additional product. Combining material gave
5-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one (3.55 g, 13.58
mmol, 73.2% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.53 (s, 1H), 7.12 (d, J=2.2 Hz, 1H),
6.85-6.66 (m, 1H), 5.83 (s, 1H), 3.82 (d, J=2.0 Hz, 2H); LC-MS:
method H, RT=1.02 min, MS (ESI) m/z: 261.0 and 263.0
(M+H).sup.+.
Intermediate I-28G: 5-bromo-7-chloroquinoxalin-2-ol
##STR00107##
[1260] In 1 L round bottom flask charged with a stirring bar,
Intermediate I-28F (3.84 g, 14.7 mmol) was suspended in MeOH (50
mL), and H.sub.2O.sub.2 (15.00 mL, 147 mmol, 30% in water) was
added, followed by 4N NaOH (11.01 mL, 44.1 mmol). The mixture was
stirred at room temperature for 5 minutes, and then heated at
60.degree. C. for 15 minutes. Heating was removed and the reaction
mixture was stirred at room temperature over the weekend. Another 5
mL of H.sub.2O.sub.2 was added and the mixture was stirred at room
temperature for 2 h. The reaction mixture was concentrated on a
rotary evaporator. The residual mixture was cooled in an ice bath,
and 6 N HCl was added to adjust the pH value to 2-3, followed by
200 mL of EtOAc. After shaking and separation, the aqueous layer
was extracted with EtOAc (50 mL.times.2). The combined organic
phases were combined and dried over Na.sub.2SO.sub.4. Removing
solvent in vacuo gave the title compound as a brown solid. (2.51 g,
9.70 mmol, 66%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.63
(br s, 1H), 8.23 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0
Hz, 1H); LC-MS: method H, RT=1.01 min, MS (ESI) m/z: 258.9 and
260.9 (M+H).sup.+.
Intermediate I-28H: 5-bromo-7-chloro-2-methoxyquinoxaline
##STR00108##
[1262] In a round bottom flask charged with a stirring bar,
Intermediate I-28G (1.60 g, 6.17 mmol) was suspended in POCl.sub.3
(10 mL, 107 mmol), and the mixture was refluxed for 2 h. Excess
POCl.sub.3 was removed on a rotary evaporator and the residue was
dried in vacuo for 30 minutes to give a brown solid. This brown
solid was suspended in MeOH (30 mL), and anhydrous K.sub.2CO.sub.3
(1.704 g, 12.33 mmol) was added. The mixture was stirred at room
temperature for 10 minutes, and then refluxed for 2 h. After
cooling to room temperature, the solvent was removed on a rotary
evaporator. The residue was dissolved in 100 ml of EtOAc, washed
with water, brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give the crude product. The crude product was
purified by flash chromatography (80 g silica gel column, 0-50%
EtOAc/Hexane) to give Intermediate I-28H (1.02 g, 3.73 mmol, 60.5%
yield) as a yellow solid. .sup.1H NMR (400 MHz, chloroform-d):
.delta. 8.53 (s, 1H), 7.87-7.83 (m, 2H), 4.12 (s, 3H); LC-MS:
method J, RT=0.96 min, MS (ESI) m/z: 273.0 and 275.0
(M+H).sup.+.
Intermediate I-28
[1263] In a microwave vial charged with a stirring bar,
Intermediate I-28H (330 mg, 1.207 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (460
mg, 1.810 mmol), potassium acetate (296 mg, 3.02 mmol) were mixed
with 1,4-dioxane (10 mL). After degassing with bubbling N.sub.2 for
10 minutes, PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (49.3 mg,
0.060 mmol) was added. The vial was sealed and was heated by
microwave to 120.degree. C. for 60 minutes. After cooling to room
temperature, the reaction mixture was diluted by adding 40 mL of
EtOAc and 30 mL of water. After separation, the aqueous layer was
extracted with EtOAc (20 mL.times.2). The combined organic layers
were dried over Na.sub.2SO.sub.4 and concentrated on a rotary
evaporator. The residue was purified by flash chromatography (40 g
silica gel column, 0-100% EtOAc/hexane gradient in 10 minutes, 100%
EtOAc for 10 minutes) to give Intermediate I-28 as a yellow solid.
(293 mg, 76%). .sup.1H NMR (400 MHz, chloroform-d): 8.53 (s, 1H),
7.92-7.85 (m, 2H), 4.08 (s, 3H), 1.45 (s, 12H); LC-MS: method H,
RT=1.09 min, MS (ESI) m/z: 239.1 (M+H-82).sup.+.
Intermediate I-29
7-chloro-2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
quinoxaline
##STR00109##
[1264] Intermediate I-29A: tert-butyl
(2-bromo-4-chloro-6-nitrophenyl)(3-methoxy-2-oxopropyl)carbamate
##STR00110##
[1266] To Intermediate I-28C (2.0 g, 5.69 mmol) in DMF (20 mL) at
0.degree. C. was added cesium carbonate (3.24 g, 9.96 mmol). The
brown solution was stirred at 0.degree. C. for 10 min, followed by
addition of Intermediate I-2B (1.140 g, 6.83 mmol) in DMF (5.0 mL).
The brown solution turned yellow. The mixture was stirred at
0.degree. C. for 15 min. The mixture was diluted with EtOAc, washed
with water, brine, dried over sodium sulfate and concentrated. The
crude product was purified by flash chromatography (80 g silica gel
column, 0% to 60% EtOAc/hexane over 18 min) to yield the desired
product (2.01 g, 81%) as a yellow oil. .sup.1H NMR (400 MHz,
chloroform-d): .delta. 7.95-7.80 (m, 2H), 4.65 (d, J=18.3 Hz, 1H),
4.22 (d, J=18.0 Hz, 1H), 4.09 (s, 2H), 3.42 (s, 3H), 1.37 (s, 9H);
LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 383.0
(M+H-54).sup.+.
Intermediate I-29B:
5-bromo-7-chloro-2-(methoxymethyl)quinoxaline
##STR00111##
[1268] To Intermediate I-29A (2.0 g, 4.57 mmol) in ethyl acetate
(10 mL) was added HCl in 1,4-dioxane (11.42 mL, 45.7 mmol) and the
mixture was stirred at room temperature for 20 min. LCMS indicated
a clean reaction. Solvent was removed under vacuum, and chased with
EtOAc once to give the deprotected intermediate as yellow oil. The
deprotected intermediate was dissolved in THF (40 mL). Concentrated
HCl (aqueous) (1.142 mL, 13.71 mmol) was added, followed by
SnCl.sub.2 (3.47 g, 18.28 mmol). The mixture was stirred in an oil
bath at 40.degree. C. for 4.0 h. After cooling to room temperature,
the reaction mixture was diluted with EtOAc (100 mL)/water (50 mL).
The organic phase was neutralized with saturated sodium
bicarbonate, stirred at room temperature for 15 min, and the
precipitate was removed by filtration with a pad of wet Celite. The
organic solution was washed with brine, dried over sodium sulfate
and concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 40% EtOAc in hexane
over 20 min using an 80 g silica gel cartridge) to yield a brown
solid (0.48 g, 36.5%). .sup.1H NMR (400 MHz, chloroform-d) .delta.
9.07 (s, 1H), 8.06 (s, 2H), 4.83 (s, 2H), 3.56 (s, 3H); LC-MS:
method J, RT=1.20 min, MS (ESI) m/z: 287.1, 289.0 (M+H).sup.+.
Intermediate I-29
[1269] In a microwave vial charged with a stirring bar,
Intermediate I-29B (475 mg, 1.652 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (629
mg, 2.478 mmol) and potassium acetate (405 mg, 4.13 mmol) were
mixed in 1,4-dioxane (10 mL). After degassing with bubbling N.sub.2
for 10 minutes, Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (67.5 mg,
0.083 mmol) was added. The vial was sealed and was irradiated in
the microwave at 120.degree. C. for 60 minutes. Solvent was removed
and the residue was purified by flash chromatography (24 g silica
gel column, 0-100% EtOAc/Hexane) to give Intermediate I-29 (432 mg,
76%) as an off-white solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 9.07 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.08 (d, J=2.2 Hz,
1H), 4.78 (s, 2H), 3.51 (s, 3H), 1.24 (s, 12H); LC-MS: method J,
RT=1.20 min, MS (ESI) m/z: 253.0 (M+H-82).sup.+.
Intermediate I-30 to Intermediate I-34
[1270] Intermediate I-30 to Intermediate I-34 were synthesized by
following the general procedures described in Intermediate I-28 and
I-29.
TABLE-US-00002 LCMS LCMS [M + H].sup.+ RT (Min)/ Intermediate
Structure m/z Method NMR I-30 ##STR00112## 237.1* 1.00/H I-31
##STR00113## 287.2* 0.61/J I-32 ##STR00114## 303.2* 0.73/J I-33
##STR00115## 277.1* 0.92/J I-34 ##STR00116## 219.1* 0.86/H *(M +
H).sup.+ of boronic acid
Intermediate I-35
(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)boronic acid
##STR00117##
[1271] Intermediate I-35A: 4-bromo-2-chloro-6-nitroaniline
##STR00118##
[1273] A mixture of 4-bromo-2-nitroaniline (10.82 g, 49.9 mmol) and
NCS (8.32 g, 62.3 mmol) in DMF (100 mL) was heated to 100.degree.
C. for 1 h. After cooling to room temperature, the solution was
poured into ice water. The yellow precipitate was collected by
filtration and was washed with water. The solid was dissolved in
dichloromethane (100 mL) and the organic phase was washed with
water and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated to yield the title compound (11.54 g, 45.9 mmol, 92%
yield) as a yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.26 (d, J=2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 6.57 (br s,
2H).
Intermediate I-35B: tert-butyl
N-(4-bromo-2-chloro-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
##STR00119##
[1275] Intermediate I-35B (11.75 g, 87%) was made as a yellow solid
from Intermediate I-35A (7.52 g, 29.9 mmol) via the same procedure
as Intermediate I-28B. .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.08 (d, J=2.2 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 1.42 (s, 18H).
Intermediate I-35C: tert-butyl
(4-bromo-2-chloro-6-nitrophenyl)carbamate
##STR00120##
[1277] Intermediate I-35C (5.2 g, 14.8 mmol, 98%) was made as a
brown waxy solid from Intermediate I-35B (6.8 g, 15.0 mmol) via the
same procedure as Intermediate I-28C. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.00 (d, J=2.2 Hz, 1H), 7.81 (d, J=2.2 Hz,
1H), 6.92 (br s, 1H), 1.50 (s, 9H)
Intermediate I-35D: methyl
2-((4-bromo-2-chloro-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
##STR00121##
[1279] Intermediate I-35D (5.4 g, 12.8 mmol, 87%) was made as a
yellow oil from Intermediate I-35C (5.2 g, 14.8 mmol) via the same
procedure as Intermediate I-28D. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.99 (d, J=2.2 Hz, 1H), 7.88-7.85 (m, 1H),
4.49 (d, J=17.4 Hz, 1H), 4.07 (d, J=17.4 Hz, 1H), 3.71-3.67 (m,
3H), 1.37 (s, 9H); LC-MS: method H, RT=1.04 min, MS (ESI) m/z:
323.0 and 325.0 (M+H-100).sup.+.
Intermediate I-35E: methyl
2-((4-bromo-2-chloro-6-nitrophenyl)amino)acetate
##STR00122##
[1281] Intermediate I-35E (4.15 g, 12.8 mmol, 100%) was made as a
brown oil from Intermediate I-35D (5.44 g, 12.8 mmol) via the same
procedure as Intermediate I-28E. LC-MS: method H, RT=1.0 min, MS
(ESI) m/z: 323.1 and 325.0 (M+H).sup.+.
Intermediate I-35F:
7-bromo-5-chloro-3,4-dihydroquinoxalin-2(1H)-one
##STR00123##
[1283] Intermediate I-35F (3.02 g, 11.55 mmol, 73%) was made as a
white solid from Intermediate I-35E (5.1 g, 15.8 mmol) via the same
procedure as Intermediate I-28F. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.54 (s, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.83
(d, J=2.2 Hz, 1H), 6.02 (s, 1H), 3.82 (d, J=1.8 Hz, 2H); LC-MS:
method H, RT=0.84 min, MS (ESI) m/z: 261.0 and 263.0
(M+H).sup.+.
Intermediate I-35G: 7-bromo-5-chloroquinoxalin-2(1H)-one
##STR00124##
[1285] Intermediate I-35G (3.40 g, 13.10 mmol, 70%) was made as an
off-white solid from Intermediate I-35F (4.85 g, 18.5 mmol) via the
same procedure as Intermediate I-28G. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.76 (s, 1H), 7.21 (d, J=2.2 Hz, 1H), 7.11
(d, J=2.2 Hz, 1H); LC-MS: method H, RT=1.08 min, MS (ESI) m/z:
259.1 and 261.1 (M+H).sup.+.
Intermediate I-35H: 7-bromo-5-chloro-2-methoxyquinoxaline
##STR00125##
[1287] Intermediate I-35H (2.13 g, 7.79 mmol, 86%) was made as a
yellow solid from Intermediate I-35G (2.34 g, 9.02 mmol) via the
same procedure as Intermediate I-28H. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.55 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.80
(d, J=2.0 Hz, 1H), 4.12 (s, 3H); LC-MS: method H, RT=1.07 min, MS
(ESI) m/z: 273.1 and 275.1 (M+H).sup.+.
Intermediate I-35I: 5-chloro-2-methoxy-7-vinylquinoxaline
##STR00126##
[1289] To a vial charged with a stirring bar was added Intermediate
I-35H (0.7 g, 2.56 mmol), potassium vinyltrifluoroborate (0.377 g,
2.82 mmol), cesium carbonate (1.668 g, 5.12 mmol),
(s)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.159 g, 0.256
mmol) and diacetoxypalladium (0.029 g, 0.128 mmol). After applying
vacuum and refilling with N.sub.2 3 times, DMF (10 mL) was added
and N.sub.2 was bubbled through the solution for 10 minutes. The
vial was sealed, stirred at room temperature for 10 minutes, and
then heated at 80.degree. C. for 3 h. After cooling to room
temperature, the reaction mixture was diluted with 60 mL of EtOAc,
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude product was purified by flash
chromatography (0-50% EtOAc/Hexane in 12 minutes, 50-100%
EtOAc/hexane in 6 minutes, 40 g silica gel column) to give the
title compound (470 mg, 2.130 mmol, 83% yield) as an off-white
solid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.51 (s, 1H),
7.79 (d, J=2.0 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 6.83 (dd, J=17.5,
10.9 Hz, 1H), 5.96 (d, J=17.4 Hz, 1H), 5.48 (d, J=11.0 Hz, 1H),
4.12 (s, 3H); LC-MS: method H, RT=1.02 min, MS (ESI) m/z:
221.1.
Intermediate I-35J:
8-chloro-3-methoxyquinoxaline-6-carbaldehyde
##STR00127##
[1291] In a round bottom flask charged with a stirring bar,
Intermediate I-351 (470 mg, 2.130 mmol) was dissolved in THF (20
mL)/water (6 mL), and treated with sodium periodate (1367 mg, 6.39
mmol) and osmium tetroxide (4% by wt. in water) (0.271 mL, 0.043
mmol). The mixture was stirred at room temperature for 4 h, and
then reaction mixture was diluted by adding 40 mL of EtOAc and 20
mL of water. The organic phase was washed with saturated
Na.sub.2S.sub.2O.sub.3 (aqueous, 3.times.) and brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated on a
rotary evaporator to give the title compound (457 mg, 2.053 mmol,
96% yield) as a yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 10.17 (s, 1H), 8.67 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.16
(d, J=1.8 Hz, 1H), 4.17 (s, 3H); LC-MS: method H, RT=0.88 min, MS
(ESI) m/z: 223.2.
Intermediate I-35K: (8-chloro-3-methoxyquinoxalin-6-yl)methanol
##STR00128##
[1293] In a round bottom flask charged with a stirring bar,
Intermediate I-35J (421 mg, 1.89 mmol) was dissolved in toluene (10
mL) and mixed with sodium triacetoxyborohydride (882 mg, 4.16
mmol). The mixture was stirred at 60.degree. C. for 4 h. After
cooling to room temperature, the solvent was removed on a rotary
evaporator. The residue was dissolved in 30 mL of EtOAc and 20 mL
of water. The organic phase was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator
to give the title compound (0.415 g, 1.847 mmol, 98% yield) as an
off-white solid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.55
(s, 1H), 7.79-7.75 (m, 1H), 7.70 (d, J=1.8 Hz, 1H), 4.89 (s, 2H),
4.12 (s, 3H), 1.94 (br s, 1H); LC-MS: method H, RT=0.75 min, MS
(ESI) m/z: 225.2.
Intermediate I-35
[1294] A microwave tube was charged with Pd.sub.2(dba).sub.3 (48.9
mg, 0.053 mmol), X-Phos (102 mg, 0.214 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (814
mg, 3.21 mmol), and potassium acetate (315 mg, 3.21 mmol). The tube
was capped and then evacuated and backfilled with argon 3 times.
Intermediate I-35K (240 mg, 1.068 mmol) in 1,4-dioxane (10 mL) was
added via syringe, followed by flushing the reaction mixture with
N.sub.2 for 10 minutes. The reaction mixture was heated at
110.degree. C. in a microwave reactor for 30 minutes. After cooling
to room temperature, the reaction mixture was concentrated in vacuo
and the residue was purified by flash chromatography (40 g silica
gel, 0-100% EtOAc, then 0-10% MeOH/DCM) to give Intermediate I-35
(121 mg, 0.517 mmol, 48.4% yield) as a grey solid. LC-MS: method H,
RT=0.75 min, MS (ESI) m/z: 235.2.
Intermediate I-36
2-methoxy-6,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quin-
oxaline
##STR00129##
[1295] Intermediate I-36A: 2-bromo-3,4-dimethyl-6-nitroaniline
##STR00130##
[1297] From commercially available 4,5-dimethyl-2-nitroaniline
(5.76 g, 34.7 mmol), Intermediate I-36A was prepared as a yellow
solid (7.78 g, 31.7 g, 114%) via the same procedure as Intermediate
I-28A. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.90 (s, 1H),
7.11 (br s, 2H), 2.38 (s, 3H), 2.26 (s, 3H); LC-MS: method H,
RT=1.22 min, MS (ESI) m/z: 245.1 and 247.0 (M+H).sup.+.
Intermediate I-36B: t-butyl
N-(2-bromo-3,4-dimethyl-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
##STR00131##
[1299] Intermediate I-36B (9.2 g, 19.2 mmol, 65.1%) was made as a
yellow solid from Intermediate I-36A (7.78 g, 20.66 mmol) via the
same procedure as Intermediate I-28B. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.83 (s, 1H), 2.51 (s, 3H), 2.46 (s, 3H),
1.41 (s, 18H); LC-MS: method J, RT=1.03 min, MS (ESI) m/z: 445.1
and 447.0 (M+H).sup.+.
Intermediate I-36C: tert-butyl
(2-bromo-3,4-dimethyl-6-nitrophenyl)carbamate
##STR00132##
[1301] Intermediate I-36C (6.6 g, 19.1 mmol, 93%) was made as a
yellow solid from Intermediate I-36B (9.2 g, 1.30 mmol) via the
same procedure as Intermediate I-28C. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.18 (br s, 1H), 7.80 (s, 1H), 2.42 (s, 3H),
2.39 (s, 3H), 1.50-1.22 (m, 9H); LC-MS: method J, RT=0.88 min, MS
(ESI) m/z: 245.0 and 247.0 (M+H-100).sup.+.
Intermediate I-36D: methyl
2-((2-bromo-3,4-dimethyl-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
##STR00133##
[1303] Intermediate I-36D (3.21 g, 7.69 mmol, 87%) was made as an
orange oil from Intermediate I-36C (3.05 g, 8.84 mmol) via the same
procedure as Intermediate I-28D. LC-MS: method H, RT=1.27 min, MS
(ESI) m/z: 317.0 and 319.1 (M+H-100).sup.+.
Intermediate I-36E: methyl
2-((2-bromo-3,4-dimethyl-6-nitrophenyl)amino)acetate
##STR00134##
[1305] Intermediate I-36E (2.43 g, 7.67 mmol, 100%) was made as a
brown solid from Intermediate I-36D (3.2 g, 7.67 mmol) via the same
procedure as Intermediate I-28E. LC-MS: method H, RT=1.22 min, MS
(ESI) m/z: 317.0 and 319.0 (M+H).sup.+.
Intermediate I-36F:
5-bromo-6,7-dimethyl-3,4-dihydroquinoxalin-2(1H)-one
##STR00135##
[1307] Intermediate I-36F (1.69 g, 6.62 mmol, 86%) was made as a
white solid from Intermediate I-36E (2.43 g, 7.67 mmol) via the
same procedure as Intermediate I-28F. LC-MS: method H, RT=1.04 min,
MS (ESI) m/z: 255.1 and 257.0 (M+H).sup.+.
Intermediate I-36G: 5-bromo-6,7-dimethylquinoxalin-2(1H)-one
##STR00136##
[1309] Intermediate I-36G (1.12 g, 4.43 mmol, 86%) was made as a
white solid from Intermediate I-36F (1.26 g, 4.94 mmol) via the
same procedure as Intermediate I-28G. LC-MS: method H, RT=1.03 min,
MS (ESI) m/z: 253.0 and 255.1 (M+H).sup.+.
Intermediate I-36H: 5-bromo-2-methoxy-6,7-dimethylquinoxaline
##STR00137##
[1311] Intermediate I-36H (0.79 g, 2.97 mmol, 67.2%) was made as a
white solid from Intermediate I-36G (1.12 g, 4.43 mmol) via the
same procedure as Intermediate I-28H. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.48 (s, 1H), 7.61 (s, 1H), 4.10 (s, 3H),
2.61 (s, 3H), 2.53 (s, 3H); LC-MS: method H, RT=1.19 min, MS (ESI)
m/z: 267.0 and 268.8 (M+H).sup.+.
Intermediate I-36
[1312] Intermediate I-36 (0.50 g, 2.14 mmol, 72.5%) was made as a
brown solid from Intermediate I-36H (0.79 g, 2.96 mmol) via the
same procedure as Intermediate I-281. LC-MS: method H, RT=0.96 min,
MS (ESI) m/z: 232.9 (M+H-82).sup.+.
Intermediate I-37
2
(5-fluoro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quino-
xalin-6-yl) methanol
##STR00138##
[1313] Intermediate I-37A:
4-bromo-6-chloro-3-fluoro-2-nitroaniline
##STR00139##
[1315] A mixture of 4-bromo-3-fluoro-2-nitroaniline (1.0 g, 4.26
mmol), NCS (0.710 g, 5.32 mmol) in DMF (10 mL) was heated to
100.degree. C. for 1 h. After cooling to room temperature, the
reaction mixture was diluted by adding 40 mL of DCM and 30 mL of
water. After shaking and separation, aqueous layer was extracted
with DCM (20 mL.times.2). Then organic phases were combined and
washed with brine, dried over Na.sub.2SO.sub.4, filtered
concentrated on a rotary evaporator, dried on a high vacuum pump to
give 4-bromo-6-chloro-3-fluoro-2-nitroaniline (1.22 g, 4.53 mmol,
106% yield) as brown oil. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.64 (d, J=6.4 Hz, 1H), 6.02 (br s, 2H); .sup.19F NMR (376
MHz, chloroform-d) .delta. -109.56 (s, 1F)
Intermediate I-37B: t-butyl
N-(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carb-
amate
##STR00140##
[1317] Intermediate I-37A (1.22 g, 4.53 mmol) was dissolved in THF
(10 mL) and mixed with di-tert-butyl dicarbonate (1.976 g, 9.06
mmol) at room temperature, DMAP (0.055 g, 0.453 mmol) was added.
The mixture was stirred at room temperature overnight. the next
day, solvent was removed on a rotary evaporator and residue was
purified by flash chromatography for purification (40 g silica gel
column, 0-50% EtOAc/Hexane gradient) to give the title compound
(1.141 g, 2.429 mmol, 53.7% yield) as a white solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 7.86 (d, J=6.4 Hz, 1H), 1.43 (s,
18H); .sup.19F NMR (376 MHz, chloroform-d) .delta. -114.28 (s,
1F).
Intermediate I-37C: tert-butyl
(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)carbamate
##STR00141##
[1319] Intermediate I-37C (0.85 g, 2.3 mmol, 95%) was made as a
yellow solid from Intermediate I-37B (9.2 g, 1.30 mmol) via the
same procedure as Intermediate I-28C. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.82 (d, J=6.4 Hz, 1H), 6.61 (br s, 1H), 1.50
(s, 9H); .sup.19F NMR (376 MHz, chloroform-d) .delta. -112.58 (br
s, 1F).
Intermediate I-37D: methyl
2-((4-bromo-6-chloro-3-fluoro-2-nitrophenyl)(tert-butoxycarbonyl)amino)ac-
etate
##STR00142##
[1321] Intermediate I-37D (0.68 g, 1.55 mmol, 68%) was made as a
colorless oil from Intermediate I-37C (0.85 g, 2.30 mmol) via the
same procedure as Intermediate I-28D. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.85 (d, J=6.4 Hz, 1H), 4.44 (d, J=17.4 Hz,
1H), 3.96-3.89 (m, 1H), 3.74 (s, 3H), 1.40 (s, 9H); .sup.19F NMR
(376 MHz, chloroform-d) .delta. -114.08 (s, 1F); LC-MS: method H,
RT=1.05 min, MS (ESI) m/z: 341.1 and 343.0 (M+H-100).sup.+.
Intermediate I-37E: methyl
2-((4-bromo-6-chloro-3-fluoro-2-nitrophenyl)amino)acetate
##STR00143##
[1323] Intermediate I-37E (0.53 g, 1.55 mmol, 100%) was made as
brown oil from Intermediate I-37D (0.68 g, 1.55 mmol) via the same
procedure as Intermediate I-28E. LC-MS: method H, RT=1.01 min, MS
(ESI) m/z: 341.1 and 343.0 (M+H).sup.+.
Intermediate I-37F:
7-bromo-5-chloro-8-fluoro-3,4-dihydroquinoxalin-2(1H)-one
##STR00144##
[1325] Intermediate I-37F (0.34 g, 1.22 mmol, 79%) was made as a
yellow oil from Intermediate I-37E (0.53 g, 1.55 mmol) via the same
procedure as Intermediate I-28F. .sup.1H NMR (400 MHz, Acetone)
.delta. 9.51 (br s, 1H), 7.17 (d, J=6.4 Hz, 1H), 5.72 (br s, 1H),
4.05-3.97 (m, 2H); .sup.19F NMR (376 MHz, Acetone) .delta. 47.90
(br s, 1F); LC-MS: method I, RT=1.17 min, MS (ESI) m/z: 279.0 and
281.1 (M+H).sup.+.
Intermediate I-37G:
7-bromo-5-chloro-8-fluoroquinoxalin-2(1H)-one
##STR00145##
[1327] Intermediate I-37G (0.31 g, 1.10 mmol, 90%) was made as a
yellow solid from Intermediate I-37F (0.34 g, 1.22 mmol) via the
same procedure as Intermediate I-28G. LC-MS: method H, RT=0.77 min,
MS (ESI) m/z: 277.0 and 279.0 (M+H).sup.+.
Intermediate I-37H:
7-bromo-5-chloro-8-fluoro-2-methoxyquinoxaline
##STR00146##
[1329] Intermediate I-37G (306 mg, 1.103 mmol) was treated with
POCl.sub.3 (3 mL, 32.2 mmol) and heated to refluxing for 1 hour.
After cooling to room temperature, extra POCl.sub.3 was removed on
a rotary evaporator and the residue was dried on HVAC for 1 hour.
Then the material was dissolved in anhydrous MeOH (10 mL) and
K.sub.2CO.sub.3 (517 mg, 3.74 mmol) was added. After stirring at
room temperature for 10 minutes, the mixture was refluxed for 2 h.
Then reaction mixture was cooled to room temperature. Most of MeOH
was removed on a rotary evaporator and residue was dissolved in 30
mL of EtOAc and 15 mL of H.sub.2O. After separation, organic phase
was washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated on a rotary evaporator. The residue was purified by
flash chromatography column (40 g silica gel, 0-100% EtOAc/Hexane
gradient). Removing solvent gave
7-bromo-5-chloro-8-fluoro-2-methoxyquinoxaline (85 mg, 0.292 mmol,
26.4% yield) as a yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.60 (s, 1H), 7.82 (d, J=6.2 Hz, 1H), 4.18 (s, 3H);
.sup.19F NMR (376 MHz, chloroform-d) .delta. -119.01 (s, 1F);
LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 291.0 and 293.1
(M+H).sup.+.
Intermediate I-37I:
5-chloro-8-fluoro-2-methoxy-7-vinylquinoxaline
##STR00147##
[1331] To a vial charged with a stirring bar was added Intermediate
I-37H (83 mg, 0.285 mmol), potassium trifluoro(vinyl)borate (36.2
mg, 0.270 mmol), cesium carbonate (186 mg, 0.569 mmol),
(s)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (35.5 mg, 0.057
mmol) and Pd(OAc).sub.2 (6.39 mg, 0.028 mmol). After applying
vacuum and refilling with N.sub.2 3 times, DMF (1.0 mL) was added
and the mixture was degassed with bubbling N.sub.2 for 10 minutes.
The vial was sealed and the reaction mixture was stirred at room
temperature for 10 minutes, then heated at 120.degree. C. for 2 h.
After cooling to room temperature, the reaction mixture was diluted
by adding 20 mL of EtOAc and washed with water and brine, dried
over Na.sub.2SO.sub.4 and filtered. Removing solvent gave crude
product that was purified by flash chromatography (24 g silica gel
column, 0-100% EtOAc/Hexane gradient in 10 minutes). Removing
solvent gave 5-chloro-8-fluoro-2-methoxy-7-vinylquinoxaline (43 mg,
0.180 mmol, 63.3% yield) as a yellow solid. LC-MS: method H,
RT=1.05 min, MS (ESI) m/z: 239.0 (M+H).sup.+.
Intermediate I-37J:
8-chloro-5-fluoro-3-methoxyquinoxaline-6-carbaldehyde
##STR00148##
[1333] Intermediate I-37I (43 mg, 0.180 mmol) was dissolved in THF
(3 mL))/water (1 mL). Sodium periodate (116 mg, 0.541 mmol) was
added, followed by osmium tetroxide (0.023 mL, 3.60 .mu.mol). The
mixture was stirred at room temperature for 6 h. Then the reaction
mixture was diluted by adding 30 mL of EtOAc and 20 mL of water.
After separation, organic phase was washed with saturated
Na.sub.2S.sub.2O.sub.3 (aqueous) 3 times, brine, dried over
Na.sub.2SO.sub.4 and filtered. Concentration on a rotary evaporator
gave 8-chloro-5-fluoro-3-methoxyquinoxaline-6-carbaldehyde (32 mg,
0.133 mmol, 73.8% yield) as light yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 10.58 (s, 1H), 8.70 (s, 1H), 8.07 (d,
J=5.9 Hz, 1H), 4.22 (s, 3H); LC-MS: method H, RT=0.90 min, MS (ESI)
m/z: 241.0 (M+H).sup.+.
Intermediate I-37K:
(8-chloro-5-fluoro-3-methoxyquinoxalin-6-yl)methanol
##STR00149##
[1335] Intermediate I-37J (32 mg, 0.133 mmol) was dissolved in
toluene (1 mL) and mixed with sodium triacetoxyborohydride (62.0
mg, 0.293 mmol). The mixture was stirred at 60.degree. C. for 4
hour. Then reaction mixture was cooled to room temperature, solvent
was removed on a rotary evaporator. The residue was dissolved in 20
mL of EtOAc and 10 mL of water. After separation, organic phase was
washed with brine, passed over Na.sub.2SO.sub.4, concentrated on a
rotary evaporator to give
(8-chloro-5-fluoro-3-methoxyquinoxalin-6-yl)methanol (26 mg, 0.107
mmol, 81% yield) as a solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.58 (s, 1H), 7.80 (d, J=6.2 Hz, 1H), 4.97 (d, J=4.4 Hz,
2H), 4.17 (s, 3H), 2.10-2.03 (m, 1H); LC-MS: method H, RT=0.75 min,
MS (ESI) m/z: 243.0 (M+H).sup.+.
Intermediate I-37
[1336] In a microwave tube was charged with Pd.sub.2(dba).sub.3
(4.91 mg, 5.36 .mu.mol), XPhos (10.22 mg, 0.021 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (82 mg,
0.321 mmol) and potassium acetate (31.5 mg, 0.321 mmol). The
microwave tube was capped, evacuated and backfilled with argon
(this sequence was carried out two times). Intermediate I-37J (26
mg, 0.107 mmol) in 1,4-dioxane (1 ml) was added via syringe,
followed by flushing the reaction mixture with N.sub.2 for 10
minutes. The microwave tube was sealed and the reaction mixture was
heated at 130.degree. C. in a microwave reactor for 30 minutes.
After cooling to room temperature, the reaction mixture was
removed. The crude material Intermediate I-37 was used without
purification in the next step. LC-MS: method H, RT=0.65 min, MS
(ESI) m/z: 253.1 (M+H).sup.+.
Intermediate I-38
3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-6-car-
bonitrile
##STR00150##
[1337] Intermediate I-38A:
8-bromo-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
##STR00151##
[1339] Intermediate I-38A was synthesized from
4-amino-3-nitrobenzonitrile via the route described for
Intermediate I-28. LC-MS: method I, RT=0.94 min, MS (ESI) m/z:
252.0 and 253.9 (M+H).sup.+.
Intermediate I-38B:
8-bromo-3-oxo-3,4-dihydroquinoxaline-6-carbonitrile
##STR00152##
[1341] In a round bottom flask charged with a stirring bar,
Intermediate I-38A (394 mg, 1.563 mmol) was suspended in DMF (10
mL), and manganese dioxide (1359 mg, 15.63 mmol) was added. The
mixture was stirred at room temperature for 60 minutes. LCMS showed
starting material remained. Another 10 equivalents of manganese
dioxide (1359 mg, 15.63 mmol) was added, and the mixture was
stirred at room temperature overnight. The next day, the solid was
filtered and solvent was removed on a rotary evaporator and dried
on HVAC to give the title compound (100 mg, 0.400 mmol, 25.6%
yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.32 (s, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.65 (s, 1H); LC-MS:
method A, RT=2.42 min, MS (ESI) m/z: 248.0 and 250.0
(M+H).sup.+.
Intermediate I-38
[1342] Intermediate I-38 was synthesized in two steps from
Intermediate I-38B via the route described in Intermediate I-28.
LC-MS: method A, RT=0.97 min, MS (ESI) m/z: 230.1 (M+H).sup.+ of
boronic acid.
Intermediate I-39
Ethyl 2-((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)acetate
##STR00153##
[1344] Intermediate I-39 was made from Intermediate I-40 following
the procedure described in I-49. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.08 (d, J=2.2 Hz, 1H), 6.95-6.92 (m, 1H),
4.66 (s, 2H), 4.29 (q, J=7.3 Hz, 2H), 2.67 (s, 3H), 1.31 (t, J=7.2
Hz, 3H; LC-MS: method H, RT=1.37 min, MS (ESI) m/z: 330.0 and
332.0.
Intermediate I-40
2-bromo-4-methylbenzo[d]thiazol-6-ol
##STR00154##
[1346] Intermediate I-3 (100 mg, 0.387 mmol) was solvated in DCM
(3.87 mL) and cooled to 0.degree. C. Boron tribromide (1.0 M in
Hexanes) (0.415 mL, 0.415 mmol) was slowly added dropwise. After 1
h of stirring, the reaction mixture was allowed to thaw to room
temperature. Once at room temperature, the reaction mixture was
recooled to 0.degree. C. and quenched with saturated NH.sub.4Cl.
The resulting mixture was extracted twice with DCM and the organic
phase was dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 18
min. Product at 18%) to give clean Intermediate I-40 (54 mg, 0.221
mmol, 57.1% yield) as a white solid. LC-MS: Method H, RT=1.10 min,
MS (ESI) m/z: 244.0, 246.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.06 (d, J=2.2 Hz, 1H), 6.79 (s, 1H),
2.57 (s, 1H).
Intermediate I-41
2-bromo-4,5-difluoro-6-methoxybenzo[d]thiazole
##STR00155##
[1347] Intermediate I-41A: 2,3-difluoro-4-methoxyaniline
##STR00156##
[1349] Degussa grade Pd/C (1.125 g, 1.058 mmol) was added to a 250
mL round bottom flask previously purged with argon. The Pd was
carefully wetted with a few milliliters of MeOH before the full
amount of solvent (42.3 ml) was added. The head space of the flask
was evacuated until the solvent began to slightly bubble and then
back-filled 3.times. with N.sub.2.
2,3-difluoro-1-methoxy-4-nitrobenzene (2.0 g, 10.58 mmol) was added
to the black suspension, and a balloon of Hz gas was attached. The
heterogeneous mixture was sparged with H.sub.2 for 30 min, before
being allowed to stir under an atmosphere of H.sub.2 for an
additional 4 h. The reaction mixture was then filtered over celite
to remove Pd/C. The celite was rinsed with EtOAc, and the filtrate
was concentrated to afford Intermediate I-41A (1.63 g, 10.24 mmol,
97% yield) as a purple solid. LC-MS: Method H, RT=0.83 min, MS
(ESI) m/z: 160.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 6.59 (td, J=8.6, 2.2 Hz, 1H), 6.49-6.43 (m, 1H), 3.83 (s,
3H), 3.51 (br. s., 2H).
Intermediate I-41B:
4,5-difluoro-6-methoxybenzo[d]thiazol-2-amine
##STR00157##
[1351] To a solution of Intermediate I-41A (1.63 g, 10.24 mmol) in
acetonitrile (51.2 ml) was added ammonium thiocyanate (1.014 g,
13.32 mmol). The mixture was stirred at room temperature for 10 min
followed by the addition of benzyltrimethylammonium tribromide
(4.39 g, 11.27 mmol). After 16 h, the reaction mixture was
concentrated down and retaken in DCM. The organic phase was washed
with saturated NaHCO.sub.3, concentrated and purified by ISCO (120
g, 0-100% EtOAc/Hexanes, 16 min. Product from 55%-100%) to afford
Intermediate I-41B (398 mg, 1.843 mmol, 18% yield). LC-MS: Method
H, RT=0.93 min, MS (ESI) m/z: 217.2 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 6.96 (dd, J=6.9, 2.1 Hz, 1H), 5.19 (br.
s., 2H), 3.92 (s, 3H).
Intermediate I-41
[1352] To a solution of copper (II) bromide (289 mg, 1.295 mmol)
and Intermediate I-41B (280 mg, 1.295 mmol) in acetonitrile (10 mL)
was added t-Butyl nitrite (0.222 mL, 1.684 mmol) at room
temperature. After 30 min, the crude mixture was diluted with EtOAc
and washed with 1 M HCl. The organic phase was dried over
MgSO.sub.4, filtered, concentrated and purified by ISCO flash
chromatography (0-20% EtOAc/Hex, 19 min, 40 g silica gel cartridge.
Product from 12% to 20%) to afford Intermediate I-41 (271 mg, 0.968
mmol, 74.7% yield) as an off-white solid. LC-MS: Method H, RT=1.21
min, MS (ESI) m/z: 280.1, 282.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.11 (dd, J=6.6, 2.0 Hz, 1H), 3.98 (s,
3H).
Intermediate I-42
2-bromo-4,5-difluorobenzo[d]thiazol-6-ol
##STR00158##
[1354] A solution of Intermediate I-41 (220 mg, 0.785 mmol)
solvated in DCM (20 ml) was cooled to 0.degree. C. A solution of
BBr.sub.3 (1.0 M hexanes) (1.571 ml, 1.571 mmol) was then added
dropwise. After 5 min, the mixture was allowed to thaw to room
temperature. After an additional 18 h, the reaction mixture was
quenched with 1 M HCl (20.0 mL) and stirred vigorously for 20 min
to fully cleave the boronate complex. The mixture was diluted with
EtOAc and extracted. The organic phase was dried over MgSO.sub.4,
filtered and concentrated to give Intermediate I-42 (208 mg, 0.785
mmol, 100% yield) which was taken forward without further
purification. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 266.0,
268.0 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.24 (dd, J=7.2, 2.1 Hz, 1H).
Intermediate I-43
2-bromo-4-chloro-5-fluoro-6-methoxybenzo[d]thiazole
##STR00159##
[1355] Intermediate I-43A:
2-chloro-3-fluoro-4-methoxy-1-nitrobenzene
##STR00160##
[1357] To a 0.degree. C. solution of
1-chloro-2-fluoro-3-methoxybenzene (1.606 g, 10 mmol) in acetic
acid (5.00 ml) was added fuming nitric acid (0.933 ml, 20.00 mmol)
followed by the dropwise addition of sulfuric acid (2.132 ml, 40.0
mmol). After 30 min, the reaction mixture was poured into water and
diluted with ethyl acetate. The organic phase was separated and
washed 2.times. with saturated NaHCO.sub.3 followed by a final
brine wash. The organic solution was then dried over MgSO.sub.4,
filtered, concentrated and purify by ISCO (120 g, 10-50%
EtOAc/Hexanes, 25 min. Desired regioisomer eluted second) affording
Intermediate I-43A (1.10 g, 5.35 mmol, 53% yield) as a yellow
solid. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: No Ionization
Observed (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.89 (dd, J=9.2, 2.2 Hz, 1H), 6.95 (dd, J=9.4, 7.6 Hz, 1H), 4.00
(s, 3H). Regiochemistry confirmed through NMR analysis of both
regioisomeric products.
Intermediate I-43B: 2-chloro-3-fluoro-4-methoxyaniline
##STR00161##
[1359] To a solution of Intermediate I-43A (1.10 g, 5.35 mmol) in
MeOH (26.7 mL, 0.2 M) was added NH.sub.4Cl (5.72 g, 107 mmol) and
zinc dust (3.50 g, 53.5 mmol). The resulting mixture was allowed to
stir at room temperature overnight. After 14 h, the MeOH solvent
was removed in vacuo. The resulting residue was diluted with EtOAc
and saturated sodium bicarbonate (0.2 M of each) and stirred
vigorously for 1 hr and then filtered over celite. The organic
layer was then separated, washed with brine, dried over MgSO.sub.4,
filtered and concentrated to give Intermediate I-43B (710 mg, 4.04
mmol, 76% yield) as a dark brown solid. This material was taken on
without further purification. LC-MS: Method H, RT=0.95 min, MS
(ESI) m/z: 176.1, 178.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.76 (t, J=8.7 Hz, 1H), 6.49 (dd, J=9.0, 2.2
Hz, 1H), 3.86 (br. s, 2H), 3.82 (s, 3H).
Intermediate I-43C:
4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-amine
##STR00162##
[1361] To a solution of Intermediate I-43B (820 mg, 3.74 mmol) in
acetonitrile (18.700 mL) was added ammonium thiocyanate (370 mg,
4.86 mmol). The mixture was stirred at room temperature for 10 min
and then benzyltrimethylammonium tribromide (1457 mg, 3.74 mmol)
was added. The resulting heterogeneous mixture was stirred
vigorously overnight. After 16 h, the reaction mixture was
concentrated and retaken in 30 mL saturated NaHCO.sub.3. This
suspension was stirred vigorously and then filtered. The collected
solid was washed with water and transferred to a new flask using
acetone. This solution was concentrated in vacuo to afford
Intermediate I-43C (863 mg, 3.67 mmol, 99% yield) as a yellow
solid. This material was taken on without further purification.
LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 233.1, 235.1
(M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.34
(d, J=7.5 Hz, 1H), 3.88 (s, 3H).
Intermediate I-43
[1362] To a solution of copper (II) bromide (835 mg, 3.74 mmol) and
Intermediate I-43C (870 mg, 3.74 mmol) in acetonitrile (18.700 mL)
was added t-butyl nitrite (0.642 mL, 4.86 mmol) at room
temperature. After 30 min, the reaction mixture was diluted with
EtOAc and washed with 1 M HCl followed by 1 M K.sub.2HPO.sub.4,
then brine. The organic phase was concentrated and purified by ISCO
flash chromatography (0-20% EtOAc/Hex over 30 min, 120 g silica gel
cartridge-product at 10%) to afford Intermediate I-43 (723 mg,
2.267 mmol, 60.6% yield) as a yellow solid. LC-MS: Method H,
RT=1.23 min, MS (ESI) m/z: 295.9, 297.9, 299.9 (M+H).sup.+. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 7.23 (d, J=7.3 Hz, 1H), 3.96
(s, 3H).
Intermediate I-44
2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-ol
##STR00163##
[1364] To a solution of Intermediate I-43 (72 mg, 0.243 mmol) in
toluene (2428 .mu.l) was added AlCl.sub.3 (97 mg, 0.728 mmol) and
the mixture was heated to reflux. After 2 h, the solution was
allowed to cool to room temperature, and the resulting mixture was
diluted with 1 M HCl followed by EtOAc. The organic phase was
separated, dried over MgSO.sub.4, filtered and concentrated to give
Intermediate I-44 (38 mg, 0.135 mmol, 55.4% yield) as a brown
solid. The isolated material was taken on without further
purification. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 281.9,
284.0, 285.9 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.39 (d, J=7.7 Hz, 1H).
Intermediate I-45
2-bromo-5-fluoro-6-methoxy-4-methylbenzo[d]thiazole
##STR00164##
[1365] Intermediate I-45A:
1-chloro-3-fluoro-2-methoxy-4-methyl-5-nitrobenzene
##STR00165##
[1367] A solution of 1-chloro-3-fluoro-2-methoxy-4-methylbenzene (1
g, 5.73 mmol) in acetic acid (2.86 ml) was cooled to 0.degree. C.
To this cooled solution was added fuming nitric acid (0.535 ml,
11.45 mmol) followed by sulfuric acid (1.221 ml, 22.91 mmol)
dropwise. After 30 min, the reaction mixture was poured into ice
water and extracted with ethyl acetate. The organic phase was
washed with 1 M K.sub.2HPO.sub.4 and then concentrated in vacuo to
give Intermediate I-45A (1.26 g, 5.16 mmol, 90% yield) as a dark
orange oil. This material was taken forward without further
purification. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: None
Observed (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.91 (d, J=2.2 Hz, 1H), 4.08 (d, J=2.4 Hz, 3H), 2.50 (d, J=2.9 Hz,
3H).
Intermediate I-45B: 5-chloro-3-fluoro-4-methoxy-2-methylaniline
##STR00166##
[1369] A 250 mL round bottom flask containing Intermediate I-45A
(1.26 g, 5.74 mmol) was evacuated and back-filled with N.sub.2.
Degussa grade Pd/C (0.611 g, 0.574 mmol) was then added to the
orange oil. This mixture was carefully wet with a few mL of MeOH
before the full solvent volume (28.7 ml) was added. The head space
of the flask was evacuated until the solvent began to slightly
bubble and then back-filled with N.sub.2. A balloon of hydrogen gas
was attached and the mixture was sparged with H.sub.2 for about 15
minutes through a vent needle. The vent was removed and the
reaction mixture was stirred vigorously under an atmosphere of
H.sub.2 overnight. After 14 h, the reaction mixture was filtered
over Celite and rinsed with EtOAc to afford Intermediate I-45B (890
mg, 5.74 mmol, 100% yield) as a tan solid. This material was taken
on to the next reaction without further purification. LC-MS: Method
H, RT=0.71 min, MS (ESI) m/z: 156.0 (M+H).sup.+. .sup.1H NMR (400
MHz, METHANOL-d.sub.4) .delta. 7.18-6.95 (m, 2H), 3.88 (s, 3H),
2.27 (d, J=2.4 Hz, 3H).
Intermediate I-45C:
5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-amine
##STR00167##
[1371] To a solution of Intermediate I-45B (1.03 g, 6.64 mmol) in
acetonitrile (33.2 ml) was added ammonium thiocyanate (0.657 g,
8.63 mmol) followed by benzyltrimethylammonium tribromide (2.59 g,
6.64 mmol). The resulting mixture was stirred vigorously for 4 h
before being diluted with saturated NaHCO.sub.3 and extracted
2.times. with DCM. The organic phase was dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford Intermediate I-45C
(920 mg, 4.33 mmol, 65.3% yield). This material was taken on
without further purification. LC-MS: Method H, RT=0.84 min, MS
(ESI) m/z: 213.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.39 (br. s., 2H), 7.35 (d, J=8.1 Hz, 1H), 3.80 (s, 3H),
2.33 (d, J=2.2 Hz, 3H).
Intermediate I-45
[1372] To a heterogeneous solution of Intermediate I-45C (920 mg,
4.33 mmol) in acetonitrile (43.3 ml) was added copper (II) bromide
(0.968 g, 4.33 mmol) followed by t-butyl nitrite (0.745 ml, 5.64
mmol). After 30 min, the reaction mixture was diluted with 1 M HCl
and extracted 2.times. with EtOAc. The organic phase was dried over
MgSO.sub.4, filtered over celite, concentrated and purified by ISCO
(120 g, 0-10% EtOAc/Hexanes, 35 min. Product at 4%) to afford
Intermediate I-45 (750 mg, 2.72 mmol, 62.7% yield) as a beige
solid. LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 276.0, 278.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.15 (d,
J=7.5 Hz, 1H), 3.93 (s, 3H), 2.61 (dd, J=2.4, 0.4 Hz, 3H).
Intermediate I-46
2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-ol
##STR00168##
[1374] To a solution of Intermediate I-45 (155 mg, 0.561 mmol) in
toluene (2807 .mu.l) was added AlCl.sub.3 (225 mg, 1.684 mmol). The
mixture was heated to 90.degree. C. for 30 min and then allowed to
cool room temperature. The resulting mixture was diluted with EtOAc
and washed 2.times. with 1 M HCl followed by Brine. The organic
phase was dried over MgSO.sub.4, filtered and concentrated in vacuo
to afford Intermediate I-46 (123 mg, 0.399 mmol, 71.1% yield) as a
brown solid. This material was taken on without further
purification. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 262.0,
264.0 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.23 (dd, J=7.9, 0.4 Hz, 1H), 2.54 (dd, J=2.4, 0.4 Hz, 3H).
Intermediate I-47
2-bromo-6-methoxy-4,5-dimethylbenzo[d]thiazole
##STR00169##
[1375] Intermediate I-47A: 4-methoxy-2,3-dimethylaniline
##STR00170##
[1377] A 250 mL round bottom flask containing
1-methoxy-2,3-dimethyl-4-nitrobenzene (1 g, 5.52 mmol) was
evacuated and back-filled with N.sub.2. The flask was then charged
with Degussa grade Pd/C (0.587 g, 0.552 mmol). This mixture was
carefully wet with a few milliliters of MeOH before the full
solvent volume (27.6 ml) was added. The head space of the flask was
evacuated until the solvent began to slightly bubble and then
back-filled with N.sub.2. A balloon of hydrogen gas was attached
and the mixture was sparged with H.sub.2 for about 15 minutes
through a vent needle. The vent was removed and the reaction
mixture was stirred vigorously under an atmosphere of H.sub.2
overnight. After 14 h, the reaction mixture was filtered over
celite and rinsed with EtOAc to afford Intermediate I-47B (820 mg,
5.42 mmol, 98% yield) as a dark brown solid. This material was
taken on to the next reaction without further purification. LC-MS:
Method H, RT=0.71 min, MS (ESI) m/z: 152.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 6.66-6.47 (m, 2H), 3.75 (s, 3H),
3.34 (br. s., 2H), 2.17 (s, 3H), 2.10 (s, 3H).
Intermediate I-47B:
6-methoxy-4,5-dimethylbenzo[d]thiazol-2-amine
##STR00171##
[1379] To a solution of Intermediate I-47A (100 mg, 0.661 mmol) in
acetonitrile (18.700 mL) was added ammonium thiocyanate (370 mg,
4.86 mmol). The mixture was stirred at room temperature for 10 min
and then benzyltrimethylammonium tribromide (1457 mg, 3.74 mmol)
was added. After 2 h of vigorous stirring, the reaction mixture was
concentrated and retaken in 5 mL saturated NaHCO.sub.3. This
suspension was stirred vigorously and then filtered. The collected
solid was washed with water and transferred to a new flask using
acetone. This solution was concentrated in vacuo to afford
Intermediate I-47B (136 mg, 0.654 mmol, 99% yield) as a tan solid.
This material was taken on without further purification. LC-MS:
Method H, RT=0.88 min, MS (ESI) m/z: 209.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.03 (s, 1H), 3.79 (s, 3H),
2.42 (s, 3H), 2.17 (s, 3H).
Intermediate I-47
[1380] To a heterogeneous solution of crude Intermediate I-47B (136
mg, 0.65 mmol) in acetonitrile (6600 .mu.l) was added copper (II)
bromide (145 mg, 0.65 mmol) followed by t-butyl nitrite (113 .mu.l,
0.858 mmol). After 30 min, the reaction mixture was diluted with 1
M HCl and EtOAc. The organic phase was dried over MgSO.sub.4,
filtered, concentrated and purified by ISCO (24 g, 0-20%
EtOAc/Hexanes, 25 min. Product at 5%) to afford Intermediate I-47
(45 mg, 0.165 mmol, 25.05% yield) as a beige solid. LC-MS: Method
H, RT=1.34 min, MS (ESI) m/z: 272.1, 274.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.05 (s, 1H), 3.87 (s, 3H), 2.64
(s, 3H), 2.25 (s, 3H).
Intermediate I-48
2-bromo-4,5-dimethylbenzo[d]thiazol-6-ol
##STR00172##
[1382] To a solution of Intermediate I-47 (600 mg, 2.205 mmol) in
toluene (22.000 mL) was added AlCl.sub.3 (588 mg, 4.41 mmol). The
mixture was heated to 90.degree. C. under an atmosphere of N.sub.2
for 1 h. The solution was then cooled to room temperature and 22 mL
of 1 M HCl was added. The resulting mixture was stirred vigorously
at room temperature for 1 h. The solution was then filtered to
collect the off-white solid which had precipitated out of the
mixture. These solids were washed with water, retaken in toluene
and concentrated in vacuo to afford Intermediate I-48 (350 mg,
2.205 mmol, 61.5% yield), which was taken on without further
purification. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 258.0,
260.0 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.06 (s, 1H), 2.57 (s, 3H), 2.24 (s, 3H).
Intermediate I-49
methyl 2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetate
##STR00173##
[1384] To a solution of Intermediate I-48 (240 mg, 0.930 mmol)
solvated in DMF (9297 .mu.l) was added methyl 2-bromoacetate (132
.mu.l, 1.395 mmol) followed by K.sub.2CO.sub.3 (257 mg, 1.859
mmol). The resulting mixture was stirred vigorously at room
temperature for 30 min, before being diluted EtOAc, filtered over
celite, concentrated and purified by ISCO (40 g, 0-30%
EtOAc/Hexanes, 19 min. Product at 15%) to afford Intermediate I-49
(268 mg, 0.812 mmol, 87% yield) as a light pink solid. LC-MS:
Method H, RT=1.29 min, MS (ESI) m/z: 333.0, 332.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.96 (s, 1H), 4.69 (s,
2H), 3.82 (s, 3H), 2.65 (s, 3H), 2.33 (s, 3H).
Intermediate I-50
methyl 2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propanoate
(racemate)
##STR00174##
[1386] To a solution of Intermediate I-48 (30 mg, 0.116 mmol)
solvated in DMF (1162 .mu.l) was added methyl 2-bromopropanoate
(38.9 .mu.l, 0.349 mmol) followed by K.sub.2CO.sub.3 (48.2 mg,
0.349 mmol). The mixture was stirred vigorously for 1.5 h before
being diluted with EtOAc, filtered over celite, concentrated and
purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 16 min. Product at
15%) to afford Intermediate I-50 (rac) (37 mg, 0.107 mmol, 92%
yield) as a light pink solid. LC-MS: Method H, RT=1.31 min, MS
(ESI) m/z: 344.1, 346.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.93 (s, 1H), 4.76 (q, J=6.8 Hz, 1H), 3.76
(s, 3H), 2.64 (s, 3H), 2.31 (s, 3H), 1.67 (d, J=6.6 Hz, 3H).
Intermediate I-51
2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethanol
##STR00175##
[1388] A solution of Intermediate I-49 (170 mg, 0.515 mmol) in
toluene (3432 .mu.l) and THF (1716 .mu.l) was cooled to -78.degree.
C. under an atmosphere of N.sub.2. To this cold solution was added
DIBAL-H (1 M in Toluene) (1.13 mL, 1.13 mmol) dropwise. After 5 min
of stirring, the reaction mixture was allowed to thaw to room
temperature. Once this solution reached room temperature, 5 mL of 1
M HCl was added. The resulting slurry was stirred vigorously for 1
hr to fully cleave the aluminate complexes. The mixture was then
diluted with EtOAc, extracted, washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by ISCO (40 g, 0-100% EtOAc/Hexanes, 19 min. Product at
47%) to afford 2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)
ethanol (156 mg, 0.516 mmol, 100% yield) as an off-white, amorphous
solid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 302.1, 304.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.08 (s,
1H), 4.15-4.09 (m, 2H), 4.06-3.99 (m, 2H), 2.65 (s, 3H), 2.29 (s,
3H), 1.94 (t, J=6.3 Hz, 1H).
Intermediate I-52
Methyl
2((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)acetate
##STR00176##
[1390] To a solution of Intermediate I-46 (105 mg, 0.341 mmol)
solvated in DMF (3405 .mu.l) was added methyl 2-bromoacetate (48.4
.mu.l, 0.511 mmol) followed by K.sub.2CO.sub.3 (94 mg, 0.681 mmol).
The reaction mixture was stirred vigorously at room temperature for
1 h before being diluted with EtOAc, filtered over celite and
concentrated. The crude material was purified by ISCO (24 g, 0-50%
EtOAc/Hexanes, 20 min. Product at 18%) to afford Intermediate I-52
(81 mg, 0.242 mmol, 71% yield) as a pink solid. LC-MS: Method H,
RT=1.20 min, MS (ESI) m/z: 334.0, 336.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.15 (d, J=7.5 Hz, 1H), 4.74 (s,
2H), 3.82 (s, 3H), 2.62 (dd, J=2.4, 0.4 Hz, 3H).
Intermediate I-53
2-((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol
##STR00177##
[1392] This intermediate was prepared in a manner analogous to
Intermediate I-51. Thus, Intermediate I-52 was reacted to afford
Intermediate I-53 (82% yield) as an off-white, amorphous solid.
LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 306.0, 308.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.19 (d,
J=7.5 Hz, 1H), 4.20-4.15 (m, 2H), 4.02 (dt, J=6.2, 4.5 Hz, 2H),
2.61 (d, J=2.4 Hz, 3H), 2.08 (t, J=6.4 Hz, 1H).
Intermediate I-54
(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)methanol
##STR00178##
[1393] Intermediate I-54A: methyl
3-methoxy-2-methyl-6-nitrobenzoate
##STR00179##
[1395] This intermediate was prepared in a manner analogous to
Intermediate I-43A. Thus, methyl 3-methoxy-2-methylbenzoate was
reacted to afford Intermediate I-54A (56% yield) as the major
regioisomer isolated from the reaction mixture (second eluting on
silica gel). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: None
Observed (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.13 (d, J=9.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 3.97 (s, 3H), 3.95
(s, 3H), 2.20 (s, 3H).
Intermediate I-54B: methyl 6-amino-3-methoxy-2-methylbenzoate
##STR00180##
[1397] This intermediate was prepared in a manner analogous to
Intermediate I-47A. Thus, Intermediate I-54A was reacted to afford
Intermediate I-54B (100% yield) as a brown oil. LC-MS: Method H,
RT=0.60 min, MS (ESI) m/z: 196.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.82 (d, J=8.8 Hz, 1H), 6.53 (dd, J=8.7, 0.6
Hz, 1H), 4.38 (br. s., 2H), 3.90 (s, 3H), 3.75 (s, 3H), 2.26 (s,
3H).
Intermediate I-54C: methyl
2-amino-6-methoxy-5-methylbenzo[d]thiazole-4-carboxylate
##STR00181##
[1399] This intermediate was prepared in a manner analogous to
Intermediate I-47B. Thus, Intermediate I-54B was reacted to afford
Intermediate I-54C (60% yield) as a brown solid. LC-MS: Method H,
RT=0.66 min, MS (ESI) m/z: 252.9 (M+H).sup.+. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.29 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H),
2.17 (s, 3H).
Intermediate I-54D: methyl
2-bromo-6-methoxy-5-methylbenzo[d]thiazole-4-carboxylate
##STR00182##
[1401] This intermediate was prepared in a manner analogous to
Intermediate I-47. Thus, Intermediate I-54C was reacted to afford
Intermediate I-54D (70% yield) as a bright yellow solid. LC-MS:
Method H, RT=0.99 min, MS (ESI) m/z: 315.7, 317.7 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.22 (s, 1H), 4.03 (s,
3H), 3.90 (s, 3H), 2.29 (s, 3H).
Intermediate I-54
[1402] A solution of Intermediate I-54D (390 mg, 1.234 mmol) in
toluene (8223 .mu.l) and THF (4112 .mu.l) was cooled to -78.degree.
C. under an atmosphere of N.sub.2. To this cooled solution was
added DIBAL-H (1 M in toluene) (2714 .mu.l, 2.71 mmol) dropwise.
After 5 min of stirring, the mixture was allowed to thaw to room
temperature. Once at room temperature, the reaction was quenched
with 12 mL 1 M HCl and stirred vigorously for 30 min to fully
cleave any aluminate complexes. The mixture was then diluted with
EtOAc, extracted, washed with brine, dried over MgSO.sub.4,
filtered and concentrated. The crude product was purified by ISCO
(80 g, 0-100% EtOAc/Hexanes, 33 min. SM peak recovered at 20%,
Product peak) to afford Intermediate I-54 (213 mg, 0.739 mmol,
59.9% yield) as white powder. LC-MS: Method H, RT=0.88 min, MS
(ESI) m/z: 287.8, 289.8 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.14 (s, 1H), 5.14 (d, J=6.4 Hz, 2H), 3.89
(s, 3H), 3.42 (t, J=6.3 Hz, 1H), 2.33 (s, 3H).
Intermediate I-55
2-bromo-6-methoxy-5-methylbenzo[d]thiazole-4-carbaldehyde
##STR00183##
[1404] To a solution of Intermediate I-54 (80 mg, 0.278 mmol) in
DCE (2776 .mu.l) was added manganese(IV) oxide (241 mg, 2.78 mmol).
The solution was heated to reflux under an atmosphere of N.sub.2
for 4 h. The reaction mixture was allowed to cool to room
temperature before being filtered over celite and washed with
EtOAc. The filtrate was concentrate in vacuo to afford Intermediate
I-55 (61 mg, 0.213 mmol, 77% yield) as an off-white solid. This
material was taken on without further purification. LC-MS: Method
H, RT=1.04 min, MS (ESI) m/z: 285.7, 287.7 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 11.12 (s, 1H), 7.42 (s, 1H), 3.93
(s, 3H), 2.63 (s, 3H).
Intermediate I-56
2-bromo-4-chloro-6-methoxy-5-methylbenzo[d]thiazole
##STR00184##
[1405] Intermediate I-56A:
2-chloro-4-methoxy-3-methyl-1-nitrobenzene
##STR00185##
[1407] This intermediate was prepared in a manner analogous to
Intermediate I-43A. Thus 1-chloro-3-methoxy-2-methylbenzene was
reacted to afford Intermediate I-56A (52% yield) as the major
regioisomer isolated from the reaction mixture (second eluting on
silica gel). LC-MS: Method H, RT=0.85 min, MS (ESI) m/z: None
Observed (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.80 (d, J=8.8 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.93 (s, 3H), 2.34
(s, 3H).
Intermediate I-56B: 2-chloro-4-methoxy-3-methylaniline
##STR00186##
[1409] This intermediate was prepared in a manner analogous to
Intermediate I-43B. Thus, Intermediate I-56A was reacted to afford
Intermediate I-56B (42% yield) as a purple oil. LC-MS: Method H,
RT=0.91 min, MS (ESI) m/z: 172.1, 174.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 6.68-6.58 (m, 2H), 3.77 (br. s.,
2H), 3.76 (s, 3H), 2.27 (s, 3H).
Intermediate I-56C:
4-chloro-6-methoxy-5-methylbenzo[d]thiazol-2-amine
##STR00187##
[1411] This intermediate was prepared in a manner analogous to
Intermediate I-43C. Thus, Intermediate I-56B was reacted to afford
Intermediate I-56C (81% yield) as a purple oil. LC-MS: Method H,
RT=1.06 min, MS (ESI) m/z: 229.1, 231.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.50 (s, 1H), 7.34 (s, 1H), 3.79
(s, 3H), 2.24 (s, 3H).
Intermediate I-56
[1412] This intermediate was prepared in a manner analogous to
Intermediate I-43. Thus, Intermediate I-56C was reacted to afford
Intermediate I-56 (51% yield) as a beige solid. LC-MS: Method H,
RT=1.36 min, MS (ESI) m/z: 292.0, 294.0, 295.9 (M+H).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.50 (s, 1H), 7.34 (s, 1H),
3.79 (s, 3H), 2.24 (s, 3H).
Intermediate I-57
methyl
2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)acetate
##STR00188##
[1413] Intermediate I-57A:
2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-ol, hydrobromide
##STR00189##
[1415] A suspension of Intermediate I-43C (100 mg, 0.430 mmol) in
acetic acid (2 mL) and HBr (48% in water) (2 mL, 17.68 mmol) was
heated to 125.degree. C. After 3 h of heating, the mixture was
cooled to room temperature and concentrated in vacuo to give
Intermediate I-57A (116 mg, 0.387 mmol, 90% yield) as its HBr salt.
LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 218.9, 220.8
(M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.36
(d, J=7.3 Hz, 1H).
Intermediate I-57B: methyl
2-((2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) acetate
##STR00190##
[1417] To a solution of Intermediate I-57A (129 mg, 0.431 mmol) in
DMF (5 mL) was added Cs.sub.2CO.sub.3 (631 mg, 1.938 mmol) followed
by methyl bromoacetate (0.044 mL, 0.474 mmol). The reaction mixture
was stirred vigorously for 30 min before being quenched with AcOH
(0.247 mL, 4.31 mmol) followed by 5 mL deionized water. This
solution was diluted with DCM and extracted 3.times.. The organic
phase was concentrated and the crude residue was purified by ISCO
(40 g, 0-10% DCM/MeOH, 17 min. Product at 5%) to afford
Intermediate I-57B (135 mg, 0.418 mmol, 97% yield). LC-MS: Method
H, RT=0.90 min, MS (ESI) m/z: 290.8, 292.7 (M+H).sup.+. .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.33 (d, J=7.5 Hz, 1H), 4.77
(s, 2H), 3.78 (s, 3H).
Intermediate I-57C: methyl
2-((2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) acetate
##STR00191##
[1419] This intermediate was prepared in a manner analogous to
Intermediate I-43. Thus, Intermediate I-57B was reacted to afford
Intermediate I-57C (57% yield) as a beige solid. LC-MS: Method H,
RT=1.00 min, MS (ESI) m/z: 353.9, 356.0, 357.9 (M+H).sup.+. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 7.25 (d, 1H-buried under
CDCl.sub.3), 4.77 (s, 2H), 3.82 (s, 3H).
Intermediate I-58
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)acetic acid
##STR00192##
[1421] To a mixture of Intermediate I-57 (88 mg, 0.248 mmol) in THF
(3.5 mL) and water (1.0 mL) was added LiOH monohydrate (51.2 mg,
1.241 mmol). After 30 min the reaction mixture was diluted with
EtOAc and washed with 1 M HCl. The organic phase was concentrated
to afford Intermediate I-58 (88 mg, 0.258 mmol, 104% yield) as a
beige solid. This material was taken forward without further
purification. LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 340.0,
342.0, 344.0 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.62 (d, J=7.5 Hz, 1H), 4.83 (s, 2H).
Intermediate I-59
2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol
##STR00193##
[1423] This intermediate was prepared in a manner analogous to
Intermediate I-51. Intermediate I-57 was reacted to afford
Intermediate I-59 (77% yield) as a yellow solid. LC-MS: Method H,
RT=1.07 min, MS (ESI) m/z: 326.0, 327.9, 329.9 (M+H).sup.+. .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.68 (d, J=7.3 Hz, 1H),
4.25-4.15 (m, 2H), 4.00-3.89 (m, 2H).
Intermediate I-60
2-bromo-5-fluorobenzo[d]thiazol-6-ol
##STR00194##
[1425] A solution of Intermediate 277B (502 mg, 1.915 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was cooled to 0.degree. C. To this mixture
was slowly added BBr.sub.3 (1 M in Hexanes) (5.75 mL, 5.75 mmol)
over 5 minutes. After this addition, the reaction mixture was
allowed to thaw to room temperature overnight. After 16 h, the
reaction mixture was poured into ice. The mixture was diluted with
30 mL of EtOAc and stirred vigorously for 10 min. The organic phase
was separated and the aqueous phase was washed 2.times. with EtOAc.
The combined organic phase was dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford Intermediate I-60 (468 mg, 1.887
mmol, 98% yield) as an off-white solid. LC-MS: Method H, RT=0.85
min, MS (ESI) m/z: 248.0, 249.9 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.48 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.62
(d, J=8.4 Hz, 1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-135.05 (s, 1F).
Intermediate I-61
2((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol
##STR00195##
[1427] Intermediate I-61A: methyl
2-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)acetate
##STR00196##
[1428] This intermediate was prepared in a manner analogous to
Intermediate I-52. Thus, Intermediate I-60 was reacted to afford
Intermediate I-61A (96% yield) as a white solid. LC-MS: Method H,
RT=0.92 min, MS (ESI) m/z: 320.1, 322.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.72 (d, J=11.0 Hz, 1H), 7.33 (d,
J=7.7 Hz, 1H), 4.76 (s, 2H), 3.82 (s, 3H).
Intermediate I-61
[1429] This intermediate was prepared in a manner analogous to
Intermediate I-51. Thus, Intermediate I-61A was reacted to afford
Intermediate I-61 (98% yield) as an off-white, amorphous solid.
LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 292.1, 294.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.70 (d,
J=11.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.04
(dt, J=6.2, 4.5 Hz, 2H), 2.10-2.04 (m, 1H).
Intermediate I-62
2-((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl
(6-fluoropyridin-3-yl) carbamate
##STR00197##
[1431] To a solution of Intermediate I-53 (22 mg, 0.072 mmol) in
THF (1.5 mL) was added DIEA (0.065 mL, 0.370 mmol) followed by a
solution of phosgene (15% by wt. in toluene) (0.253 mL, 0.359 mmol)
at room temperature. After 2 h of stirring, the crude chlorofomate
intermediate was concentrated to remove excess phosgene and retaken
in THF (1 mL). Another batch of DIEA (0.065 mL, 0.370 mmol) was
added followed by 6-fluoropyridin-3-amine (24.90 mg, 0.222 mmol).
After 15 min, the crude reaction mixture was concentrated and
purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min. Product at
35%) to afford Intermediate I-62 (28 mg, 0.070 mmol, 95% yield) as
an off-white solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z:
443.1, 445.2 (M+H).sup.+. .sup.1H NMR (400 MHz, THF) .delta. 9.10
(br. s., 1H), 8.07 (br. s., 1H), 8.02-7.91 (m, 1H), 7.40 (t, J=7.7
Hz, 1H), 6.80 (dd, J=8.8, 3.5 Hz, 1H), 4.46-4.38 (m, 2H), 4.26-4.18
(m, 2H), 2.44 (dd, J=3.6, 2.5 Hz, 3H).
Intermediate I-63
2((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-
-3-yl) carbamate
##STR00198##
[1433] This intermediate was prepared in a manner analogous to
Intermediate I-62. Thus, Intermediate I-59 was reacted to afford
Intermediate I-63 (90% yield) as an off-white solid. LC-MS: Method
H, RT=1.18 min, MS (ESI) m/z: 464.0, 466.0, 468.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, THF) .delta. 9.22 (br. s., 1H), 8.19 (br. s.,
1H), 8.12-8.02 (m, 1H), 7.70 (d, J=7.3 Hz, 1H), 6.92 (dd, J=8.8,
3.5 Hz, 1H), 4.56-4.53 (m, 2H), 4.41-4.37 (m, 2H).
Intermediate I-64
5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
##STR00199##
[1434] Intermediate I-64A:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-ol
##STR00200##
[1436] A microwave vial was charged with Intermediate I-1 (106 mg,
0.314 mmol), Intermediate I-60 (65 mg, 0.262 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (17.12 mg, 0.021 mmol). A
solvent mixture of toluene (1638 .mu.l), EtOH (546 .mu.l) and 2.0 M
Na.sub.2CO.sub.3 (197 .mu.l, 0.393 mmol) was then added, and the
resulting solution was sparged with argon for 10 min before being
sealed and then heated in the microwave at 130.degree. C. for 30
min. The crude reaction mixture was diluted with EtOAc and filtered
over celite before being concentrated and purified by ISCO (24 g,
0-100% EtOAc/Hexanes, 16 min. Product at 35%.) to afford
Intermediate I-64A (95 mg, 0.252 mmol, 96% yield) as a dark yellow
solid. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 378.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.76 (d,
J=2.0 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=10.8 Hz, 1H), 7.80 (s, 1H),
7.66 (t, J=71.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 5.30 (d, J=5.1 Hz,
1H), 2.68 (s, 3H).
Intermediate I-64
[1437] To a solution of Intermediate I-64A (20 mg, 0.053 mmol) in
THF (1 mL) was added a 0.5 M NaOMe solution in MeOH (0.530 mL,
0.265 mmol). After 1 h, the reaction mixture was diluted with EtOAc
and quenched with 1.0 N HCl. The organic phase was extracted, dried
over MgSO.sub.4, filtered and concentrated in vacuo to afford
Intermediate I-64 (18 mg, 0.053 mmol, 99% yield) as a yellow solid.
This material was taken on without further purification. LC-MS:
Method H, RT=1.08 min, MS (ESI) m/z: 342.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, THF) .delta. 8.95 (br. s., 1H), 8.70 (d, J=1.3 Hz, 1H),
8.54 (s, 1H), 7.80-7.67 (m, 2H), 7.46 (d, J=8.6 Hz, 1H), 4.10 (s,
3H), 2.63 (s, 3H).
Intermediate I-65
4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-o-
l
##STR00201##
[1438] Intermediate I-65A
4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]t-
hiazol-6-ol
##STR00202##
[1440] This intermediate was prepared in a manner analogous to
Intermediate I-64A. Thus, Intermediate I-1 was reacted with
Intermediate I-44 to afford Intermediate I-65A (81% yield) as a
bright yellow solid. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z:
412.0, 414.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.94-9.01 (m, 1H), 8.69-8.78 (m, 1H), 7.72-8.10 (m, 2H),
7.64-7.70 (m, 1H), 2.70 (s, 3H).
Intermediate I-65
[1441] This intermediate was prepared in a manner analogous to
Intermediate I-64. Thus, Intermediate I-65A was reacted to afford
Intermediate I-65 (100% yield) as a dark orange solid. LC-MS:
Method H, RT=1.36 min, MS (ESI) m/z: 376.0, 378.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.94-9.01 (m, 1H),
8.69-8.78 (m, 1H), 7.72-8.10 (m, 2H), 7.64-7.70 (m, 1H), 2.70 (s,
3H).
Intermediate I-66
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy-
)ethanol
##STR00203##
[1442] Intermediate I-66A:
2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiaz-
ol-6-yl)oxy)ethanol
##STR00204##
[1444] This intermediate was prepared in a manner analogous to
Intermediate I-64A. Thus, Intermediate I-1 was reacted with
Intermediate I-61 to afford Intermediate I-66A (75% yield) as a
yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 422.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.76 (d,
J=1.8 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.80 (dd,
J=1.8, 0.9 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.50 (d, J=7.7 Hz,
1H), 4.29-4.23 (m, 2H), 4.10-4.03 (m, 2H), 2.69 (s, 3H), 2.14 (t,
J=6.4 Hz, 1H).
Intermediate I-66
[1445] This intermediate was prepared in a manner analogous to
Intermediate I-64. Intermediate I-66A was reacted to afford
Intermediate I-66 (43% yield) as a dark orange solid. LC-MS: Method
H, RT=1.08 min, MS (ESI) m/z: 386.1 (M+H).sup.+. .sup.1H NMR (400
MHz, THF) .delta. 8.71 (d, J=1.8 Hz, 1H), 8.55 (s, 1H), 7.77-7.73
(m, 2H), 7.71 (d, J=8.1 Hz, 1H), 4.22-4.16 (m, 2H), 4.10 (s, 3H),
3.93-3.85 (m, 2H), 2.64 (s, 3H).
Intermediate I-67
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)propan-2-ol
##STR00205##
[1447] To a suspension of Intermediate I-64 (30 mg, 0.088 mmol)
neat in (R)-2-methyloxirane (1 mL, 14.29 mmol) was added
tetrabutylammonium bromide (56.7 mg, 0.176 mmol) followed by
K.sub.2CO.sub.3 (36.4 mg, 0.264 mmol). The reaction vessel was
sealed, heated to 65.degree. C. and stirred vigorously for 4 h. The
reaction mixture was then cooled to room temperature and quenched
with a few drops of AcOH. The resulting mixture was concentrated
and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min. Product at
38%) to afford Intermediate I-67 (27 mg, 0.068 mmol, 77% yield) as
a bright yellow solid. LC-MS: Method H, RT=1.16 min, MS (ESI) m/z:
400.1 (M+H).sup.+. .sup.1H NMR (400 MHz, THF) .delta. 8.70 (d,
J=1.8 Hz, 1H), 8.56 (s, 1H), 7.78-7.73 (m, 2H), 7.71 (d, J=8.1 Hz,
1H), 4.10 (s, 3H), 4.16-4.07 (m, 1H), 4.07-4.00 (m, 1H), 4.00-3.92
(m, 1H), 2.64 (s, 3H), 2.55 (br. s, 1H), 1.26 (d, J=6.4 Hz,
3H).
Intermediate I-68
(S)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)propan-2-ol
##STR00206##
[1449] This intermediate was prepared in a manner analogous to
Intermediate I-67. Intermediate I-64 was reacted with
(S)-2-methyloxirane to afford Intermediate I-68 (73% yield) as a
bright yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z:
422.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.76
(d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.80 (dd,
J=1.8, 0.9 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.50 (d, J=7.7 Hz,
1H), 4.29-4.23 (m, 2H), 4.10-4.03 (m, 2H), 2.69 (s, 3H), 2.14 (t,
J=6.4 Hz, 1H).
Intermediate I-69
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thi-
azol-6-yl)oxy)propan-2-ol
##STR00207##
[1451] This intermediate was prepared in a manner analogous to
Intermediate I-67. Thus, Intermediate I-65 was reacted with
(R)-2-methyloxirane to afford Intermediate I-69 (74% yield) as a
bright yellow solid. LC-MS: Method H, RT=1.20 min, MS (ESI) m/z:
434.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.78
(s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.88 (s,
1H), 5.00 (d, J=4.2 Hz, 1H), 4.10 (s, 3H), 4.10-4.00 (m, 3H), 2.67
(s, 3H), 1.22 (d, J=5.9 Hz, 3H).
Intermediate I-70
(S)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)propan-1-ol
##STR00208##
[1452] Intermediate I-70A:
(S)-6-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-fluoro-2-(2-me-
thoxy-7-methyl quinoxalin-5-yl)benzo[d]thiazole
##STR00209##
[1454] A solution of Intermediate I-64 (30 mg, 0.088 mmol) and
triphenylphosphine (92 mg, 0.352 mmol) in THF (1.0 mL) was heated
to 65.degree. C. To this mixture was added a solution of
(R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (84 mg, 0.439 mmol)
mixed with DIAD (0.085 mL, 0.439 mmol) in THF (1.0 mL) dropwise
over 1 h via syringe pump. At the end of addition, the crude
mixture was allowed to cool to room temperature then was
concentrated and purified by ISCO (12 g, 0-10% EtOAc/Hexanes, 16
min. Product at 7%) to afford Intermediate I-70A (31 mg, 0.060
mmol, 68.7% yield) as a yellow oil. LC-MS: Method H, RT=1.56 min,
MS (ESI) m/z: 514.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.61 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.80
(d, J=11.2 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H),
4.52 (sxt, J=5.9 Hz, 1H), 4.13 (s, 3H), 3.89 (dd, J=10.7, 5.8 Hz,
1H), 3.75 (dd, J=10.7, 5.0 Hz, 1H), 2.65 (s, 3H), 1.39 (d, J=6.2
Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).
Intermediate I-70
[1455] To a solution of Intermediate I-70A (20 mg, 0.039 mmol) in
THF (0.8 mL) and methanol (0.2 mL) was added several drops of
concentrated HCl (12.1M, 0.016 mL, 0.195 mmol). After stirring for
5 min at room temperature, the reaction mixture was quenched with
saturated NaHCO.sub.3. This solution was then diluted with DCM and
extracted. The organic phase was dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford Intermediate I-70 (15 mg, 0.039
mmol, 100% yield), which was taken on without further purification.
LC-MS(ESI) m/z: 400.2 (M+H).sup.+. RT=1.11 min (1 min gradient,
ACN/water/TFA). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72
(s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.94 (d,
J=11.6 Hz, 1H), 7.82 (d, J=0.8 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H),
4.63-4.55 (m, 1H), 4.08 (s, 3H), 3.68-3.61 (m, 1H), 3.61-3.55 (m,
1H), 2.63 (s, 3H), 2.51 (dt, J=3.5, 1.7 Hz, 8H), 1.30 (d, J=6.1 Hz,
3H).
Intermediate I-71
(R)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)propan-1-ol
##STR00210##
[1456] Intermediate I-71A:
(R)-6-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-fluoro-2-(2-me-
thoxy-7-methyl quinoxalin-5-yl)benzo[d]thiazole
##STR00211##
[1458] This intermediate was prepared in a manner analogous to
Intermediate I-70A. Intermediate I-64 was reacted with
(S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol to afford
Intermediate I-71A (61% yield) as a yellow oil. LC-MS: Method H,
RT=1.56 min, MS (ESI) m/z: 514.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.61 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.80
(d, J=11.2 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H),
4.52 (sxt, J=5.9 Hz, 1H), 4.13 (s, 3H), 3.89 (dd, J=10.7, 5.8 Hz,
1H), 3.75 (dd, J=10.7, 5.0 Hz, 1H), 2.65 (s, 3H), 1.39 (d, J=6.2
Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).
Intermediate I-71
[1459] This intermediate was prepared in a manner analogous to
Intermediate I-70. Thus, Intermediate I-71A was reacted to afford
Intermediate I-71 (94% yield). LC-MS(ESI) m/z: 400.2 (M+H).sup.+.
RT=1.11 min (1 min gradient, ACN/water/TFA). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.99
(d, J=8.3 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.82 (d, J=0.8 Hz, 1H),
4.96 (t, J=5.6 Hz, 1H), 4.63-4.55 (m, 1H), 4.08 (s, 3H), 3.68-3.61
(m, 1H), 3.61-3.55 (m, 1H), 2.63 (s, 3H), 2.51 (dt, J=3.5, 1.7 Hz,
8H), 1.30 (d, J=6.1 Hz, 3H).
Intermediate I-72
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-ol
##STR00212##
[1460] Intermediate I-72A:
(2R,3S)-3((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
##STR00213##
[1462] To a solution of Intermediate I-60 (1.0 g, 4.03 mmol) in THF
(26.9 ml) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane
2,2-dioxide (0.736 g, 4.84 mmol) followed by potassium carbonate
(0.669 g, 4.84 mmol). The reaction mixture was sealed and heated to
65.degree. C. for 16 h. The reaction mixture was cooled to
0.degree. C. and concentrated sulfuric acid (0.430 ml, 8.06 mmol)
was added (caution: significant bubbling observed) followed by
water (0.218 ml, 12.09 mmol). The reaction mixture was allowed to
thaw to room temperature for 10 min before being quenched with 1.5
M K.sub.2HPO.sub.4, extracted with EtOAc, washed with brine, dried
over MgSO.sub.4, filtered over celite and concentrated down to
afford Intermediate I-72A (1.29 g, 4.03 mmol) as beige solid. The
crude material was taken on without further purification. LC-MS:
Method H, RT=0.96 min, MS (ESI) m/z: 319.9, 321.9 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.96 (d, J=8.1 Hz, 1H),
7.89 (d, J=11.4 Hz, 1H), 4.86 (d, J=5.3 Hz, 1H), 4.35-4.25 (m, 1H),
3.84-3.73 (m, 1H), 1.26 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -132.96.
Intermediate I-72B
(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[-
d]thiazol-6-yl)oxy)butan-2-ol
##STR00214##
[1464] To a 250 mL round bottom flask charged with Intermediate I-1
(787 mg, 2.342 mmol) and Intermediate I-72A (750 mg, 2.342 mmol)
was added toluene (8784 .mu.l) and EtOH (2928 .mu.l) followed by a
2M solution of sodium carbonate (1757 .mu.l, 3.51 mmol). The
mixture was stirred vigorously and sparged with argon for 10
minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium
(II) complex with dichloromethane (1:1) (191 mg, 0.234 mmol) was
then added and the mixture was sparged with argon for an additional
5 min. The reaction mixture was heated to reflux under an
atmosphere of argon. After 2 h of heating, the reaction mixture was
diluted with EtOAc and filtered through celite before being
concentrated, dry loaded onto celite and purified by ISCO (120 g,
0-100% DCM/EtOAc, Product at 25%) to afford Intermediate I-72B (470
mg, 1.046 mmol, 44.6% yield) as a bright yellow solid. LC-MS:
Method H, RT=1.19 min, MS (ESI) m/z: 450.9 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.76 (d, J=2.0 Hz, 1H), 8.69 (s,
1H), 7.83 (d, J=11.4 Hz, 1H), 7.80 (dd, J=1.9, 1.0 Hz, 1H), 7.66
(t, J=71.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 4.40 (qd, J=6.3, 3.3
Hz, 1H), 4.18-4.06 (m, 1H), 2.69 (s, 3H), 2.14 (d, J=4.8 Hz, 1H),
1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H). .sup.19F NMR (376
MHz, CHLOROFORM-d) .delta. -89.77, -132.68.
Intermediate I-72
[1465] Intermediate I-72B (470 mg, 1.046 mmol) was co-evaporated
with toluene to removed adventitious water. The crude solid was
retake in THF (20.900 mL) and a 0.5 M solution sodium methoxide in
MeOH (20.91 mL, 10.46 mmol) was added causing the solution to turn
dark red. The reaction mixture was quenched after 30 min with 1.0 N
HCl (21 mL) causing the solution to return to a bright yellow
color. The reaction mixture was diluted with 150 mL EtOAc,
extracted and washed with brine. The organic phase was dried over
MgSO.sub.4, filtered over a pad of SiO.sub.2 gel and concentrated
to afford Intermediate I-72 (430 mg, 1.040 mmol, 99% yield) as a
yellow solid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 414.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.62 (d,
J=1.8 Hz, 1H), 8.55 (s, 1H), 7.83 (d, J=11.2 Hz, 1H), 7.77 (d,
J=0.9 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 4.43-4.34 (m, 1H), 4.13 (s,
3H), 2.65 (s, 3H), 2.15 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.2 Hz, 3H),
1.29 (d, J=6.6 Hz, 3H). .sup.19F NMR (376 MHz, CHLOROFORM-d)
.delta. -133.04.
Intermediate I-73
(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[-
d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate
##STR00215##
[1467] To a solution of Intermediate I-72B (170 mg, 0.332 mmol) in
THF (6.5 mL) was added a 15% phosgene solution in toluene (2354
.mu.l, 3.34 mmol). The resulting slurry was allowed to stir at room
temperature for 16 h before being concentrated down to the crude
chloroformate intermediate. This crude residue was retaken in THF
(6.5 mL) and 2-methylpyrimidin-5-amine (39.9 mg, 0.365 mmol)
followed by pyridine (0.134 mL, 1.660 mmol) were added to the
reaction mixture. After 10 min, the reaction mixture was
concentrated and purified by ISCO (40 g, 0-100% EtOAc/Hex, Product
at 85%) to afford Intermediate I-73 (182 mg, 0.311 mmol, 94% yield)
as a yellow solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z:
585.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.76
(d, J=2.0 Hz, 1H), 8.72 (br. s., 2H), 8.69 (s, 1H), 7.86-7.78 (m,
2H), 7.66 (t, J=71.8 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 6.49 (br. s.,
1H), 5.21-5.12 (m, 1H), 4.63 (dd, J=6.4, 3.3 Hz, 1H), 2.69 (s, 3H),
2.68 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.44 (d, J=6.4 Hz, 3H).
.sup.19F NMR (376 MHz, CHLOROFORM-d) .delta. -89.78 (s, 3F),
-132.17 (s, 1F)
Intermediate I-74
Methyl
5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
##STR00216##
[1469] To a solution of Intermediate I-72 (30 mg, 0.073 mmol) in
THF (1.5 mL) was added a 15% phosgene solution in toluene (512
.mu.l, 0.726 mmol). The resulting slurry was allowed to stir at
room temperature for 16 h before being concentrated down to the
crude chloroformate intermediate. This crude residue was retaken in
THF (1.5 mL) and methyl 5-aminopicolinate (13.25 mg, 0.087 mmol)
was added followed by pyridine (0.059 mL, 0.726 mmol). After 10
min, the reaction mixture was concentrated and loaded directly onto
an ISCO column (12 g, 0-60%, DCM/EtOAc, Product at 28%) to afford
Intermediate I-74 (40 mg, 0.068 mmol, 93% yield) as a light yellow
solid. LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 592.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.64-8.59
(m, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.6 Hz, 1H), 8.51 (s,
1H), 8.18-8.11 (m, 1H), 8.10-8.06 (m, 1H), 7.79 (d, J=11.2 Hz, 1H),
7.74 (d, J=0.9 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.18 (s, 1H), 5.16
(qd, J=6.5, 3.1 Hz, 1H), 4.65-4.57 (m, 1H), 4.12 (s, 3H), 3.95 (s,
3H), 2.63 (s, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.42 (d, J=6.4 Hz,
3H).
Intermediate I-75
Methyl
5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
##STR00217##
[1470] Intermediate I-75A: (ethyl
5-(5-fluoro-6-(((2S,3R)-3-hydroxybutan-2-yl)oxy)
benzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate
##STR00218##
[1472] This intermediate was prepared in a manner analogous to
Intermediate I-70A. Thus, Intermediate I-72A was reacted with
Intermediate I-15 and purified by ISCO (0-100% EtOAc/Hex, Product
at 60%) to afford Intermediate I-75A (79% yield) as a dark yellow
solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 456.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.62 (s,
1H), 8.99 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J=11.2 Hz, 1H),
7.56 (d, J=7.9 Hz, 1H), 4.67-4.58 (m, 2H), 4.47-4.36 (m, 1H),
4.17-4.08 (m, 1H), 2.74 (s, 3H), 2.14 (d, J=4.6 Hz, 1H), 1.56-1.53
(m, 3H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H).
Intermediate I-75
[1473] This intermediate was prepared in a manner analogous to
Intermediate I-73. Thus Intermediate I-75A was reacted to afford
Intermediate I-75 (50% yield) as a yellow solid. LC-MS: Method H,
RT=1.08 min, MS (ESI) m/z: 591.8 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.97 (br. s., 1H), 9.46 (s, 1H), 8.85 (br.
s., 1H), 8.73 (br. s., 2H), 8.18 (br. s., 1H), 8.05 (d, J=7.6 Hz,
1H), 7.94 (d, J=11.6 Hz, 1H), 5.12 (br. s., 1H), 4.84 (br. s., 1H),
4.49 (d, J=6.7 Hz, 2H), 2.69 (br. s., 3H), 2.56 (s, 3H), 1.56-1.34
(m, 9H).
Intermediate I-76
(2R,3S)-3((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
##STR00219##
[1474] Intermediate I-76A: (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane
2-oxide
##STR00220##
[1476] To a solution of thionyl chloride (5.37 ml, 73.5 mmol) in
DCM (235 ml) was added (2R,3R)-butane-2,3iol (5.37 ml, 58.8 mmol).
The reaction mixture immediately became opaque and bubbled. Over
time, the solution became clear once again. After 30 min, the
reaction mixture was carefully concentrated [Note: This product is
volatile]. Intermediate I-76A (8.01 g, 58.8 mmol, 100% yield) was
isolated as a light tan oil mixed with some residual DCM. The
product was taken on to the subsequent sulfur oxidation without
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.68 (dq,
J=9.0, 6.2 Hz, 1H), 4.11 (dq, J=8.9, 6.3 Hz, 1H), 1.57 (d, J=6.2
Hz, 3H), 1.48 (d, J=6.2 Hz, 3H).
Intermediate I-76B: (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane
2,2-dioxide
##STR00221##
[1478] A solution of Intermediate I-76A in CCl.sub.4 (73.4 ml),
acetonitrile (73.4 ml) and H.sub.2O (147 ml) was cooled to
0.degree. C. Sodium periodate (18.85 g, 88 mmol) was added to the
mixture followed by ruthenium(III) chloride (0.244 g, 1.175 mmol).
The resulting mixture was stirred at 0.degree. C. for 1 h, over
which time it took on a reddish-brown hue. The reaction mixture was
then diluted with 200 mL DI H.sub.2O and extracted with 500 mL
EtOAc. The organic phase was washed with brine, dried over
MgSO.sub.4, and filtered over a pad of silica gel. This organic
solution was concentrated down to a black oil and retaken in DCM.
This DCM solution was filtered over a second pad of silica gel
which removed more of the ruthenium impurities. The resulting
solution was concentrated to afford Intermediate I-76B (7.6 g, 49.9
mmol, 85% yield) as a brown tinged oil. [Note: This material can be
stored as a frozen solid at -20.degree. C.]. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 4.75-4.63 (m, 2H), 1.58-1.52 (m, 6H).
Intermediate I-76
[1479] To a solution of Intermediate I-60 (2.65 g, 10.68 mmol) in
THF (42.7 ml) was added Intermediate I-76B followed by potassium
carbonate (2.215 g, 16.02 mmol). A reflux condenser was attached,
and the reaction mixture was heated to reflux (65.degree. C.)
overnight. After 15 h of refluxing, the solution was cooled to
0.degree. C. Cleavage of the resulting sulfate intermediate was
affected by the addition of concentrated sulfuric acid (1.708 ml,
32.0 mmol) followed by water (0.962 ml, 53.4 mmol) [Note: vigorous
bubbling observed]. The reaction mixture was allowed to thaw to
room temperature and stirred vigorously for 1 h. The reaction
mixture was then quenched with 100 mL of a 1.5 M K.sub.2HPO.sub.4
solution, extracted with 300 mL EtOAc, washed with brine, dried
over MgSO.sub.4, filtered and concentrated to afford a beige solid.
This solid was dry loaded onto Celite and purified by ISCO (220 g,
0-50% EtOAc/DCM, 36 min. Product at 15%) to afford Intermediate
I-76 (3.1 g, 9.68 mmol, 91% yield, 99% ee) as an off-white solid.
LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: 399.9, 401.9
(M+H).sup.+-Sulfate Intermediate. LC-MS: Method H, RT=0.93 min, MS
(ESI) m/z: 320.0, 322.0 (M+H).sup.+-Desired Alcohol. Chiral HPLC:
Chiral AD 10 micron 4.6.times.250 mm, Solvent A (heptane), Solvent
B (1:1 MeOH/EtOH). Isocratic gradient at 16% B, product retention
time 6.0 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.98 (d,
J=8.4 Hz, 1H), 7.91 (d, J=11.7 Hz, 1H), 4.90 (d, J=5.3 Hz, 1H),
4.35-4.26 (m, 1H), 3.85-3.73 (m, 1H), 1.27 (d, J=6.2 Hz, 3H), 1.16
(d, J=6.4 Hz, 3H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-132.96 (s, 1F).
Intermediate I-77
(2R,3S)-3-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
##STR00222##
[1481] This intermediate was prepared in a manner analogous to
Intermediate I-76. Thus, Intermediate I-44 was reacted with
Intermediate I-76A to afford Intermediate I-77 (58% yield) as an
off-white solid. LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 353.9,
355.9, 358.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.34 (d, J=7.0 Hz, 1H), 4.38 (dd, J=6.3, 3.4 Hz, 1H), 4.16-4.03 (m,
1H), 2.01 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.6
Hz, 3H).
Intermediate I-78
(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[-
d]thiazol-6-yl)oxy)butan-2-ol
##STR00223##
[1483] To a flask charged with Intermediate I-1 (254 mg, 0.756
mmol) and Intermediate I-76 (220 mg, 0.687 mmol) was added toluene
(2577 .mu.l) and EtOH (859 .mu.l) followed by a 2 M aqueous
solution of sodium carbonate (515 .mu.l, 1.031 mmol). The mixture
was stirred vigorously and sparged with argon for 10 minutes.
[1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (56.1 mg, 0.069 mmol) was then
added and the mixture was sparged with argon for an additional 5
min. The flask was then heated to reflux under an atmosphere of
argon. After 2 h of refluxing, the reaction mixture was diluted
with EtOAc, filtered over Celite and concentrated. The crude
residue was dry-loaded onto Celite and purified by ISCO (80 g,
0-70% DCM/EtOAc, product at 20%) to afford Intermediate I-78 (260
mg, 0.578 mmol, 84% yield) as a bright yellow foaming solid. LC-MS:
Method H, RT=1.14 min, MS (ESI) m/z: 450.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.76 (d, J=2.0 Hz, 1H), 8.69 (s, 1H),
7.83 (d, J=11.4 Hz, 1H), 7.80 (dd, J=1.9, 1.0 Hz, 1H), 7.66 (t,
J=71.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 4.40 (qd, J=6.3, 3.3 Hz,
1H), 4.18-4.06 (m, 1H), 2.69 (s, 3H), 2.14 (d, J=4.8 Hz, 1H), 1.38
(d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H). .sup.19F NMR (376 MHz,
CDCl.sub.3) .delta. -89.77 (s, 2F), -132.68 (s, 1F).
Intermediate I-79
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy) butan-2-ol
##STR00224##
[1485] The starting material Intermediate I-78 (0.91 g, 2.025 mmol)
was co-evaporated with toluene to remove any adventitious water.
The dried solid was retaken in THF (40.5 ml) and a 0.5 M solution
of sodium methoxide in methanol (40.5 ml, 20.25 mmol) was added.
After 1 h of stirring, the reaction mixture was quenched with 1.0 N
HCl (41 mL). The mixture was then diluted with 500 mL EtOAc and
washed with 150 mL Brine. The organic phase was dried over
MgSO.sub.4, filtered, and concentrated onto Celite for dry-load
purification by ISCO (80 g, 0-100% DCM/EtOAc) to give Intermediate
I-79 (0.73 g, 1.766 mmol, 87% yield) as a yellow foamy solid.
LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 414.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.58 (d,
J=1.8 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.95 (d, J=11.7 Hz, 1H),
7.83 (d, J=0.7 Hz, 1H), 4.91 (d, J=5.1 Hz, 1H), 4.38 (quin, J=5.8
Hz, 1H), 4.09 (s, 3H), 3.87-3.77 (m, 1H), 2.63 (s, 3H), 1.31 (d,
J=6.2 Hz, 3H), 1.19 (d, J=6.2 Hz, 3H)
Intermediate I-80
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy) butan-2-ol
##STR00225##
[1487] To a solution of Intermediate I-78 (370 mg, 0.823 mmol) in
THF (6174 .mu.l) was added ethanol (2058 .mu.l) followed by the
portion-wise addition of sodium hydride (329 mg, 8.23 mmol). After
10 minutes of stirring, the reaction mixture was quenched with
saturated NH.sub.4Cl (.about.2 mL), and the resulting mixture was
concentrated onto Celite for dry loading and purified by ISCO (80
g, 0-70% DCM/EtOAc, 33 min, product at 20%) to afford Intermediate
I-80 (320 mg, 0.749 mmol, 91% yield) as a bright yellow solid.
LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 428.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.58 (d,
J=2.0 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.95 (d, J=11.7 Hz, 1H),
7.81 (s, 1H), 4.91 (d, J=5.3 Hz, 1H), 4.54 (q, J=7.0 Hz, 2H), 4.37
(quin, J=5.8 Hz, 1H), 3.87-3.78 (m, 1H), 2.63 (s, 3H), 1.45 (t,
J=7.0 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.4 Hz, 3H).
Intermediate I-81
(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)butan-2-ol
##STR00226##
[1489] This intermediate was prepared in a manner analogous to
Intermediate I-78. Thus, Intermediate I-9 was reacted with
Intermediate I-77 to afford Intermediate I-81 (25% yield) as a
yellow solid. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 447.9,
449.8 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.71
(d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.41 (d,
J=7.0 Hz, 1H), 4.43-4.33 (m, 1H), 4.15-4.06 (m, 4H), 2.65 (s, 3H),
2.15 (d, J=4.2 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz,
3H).
Intermediate I-82
(R)-methyl 5-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate
##STR00227##
[1491] To a solution Intermediate I-67 (194 mg, 0.486 mmol) in THF
(9714 .mu.l) was added a 15% phosgene solution in toluene (3425
.mu.l, 4.86 mmol). The resulting slurry was allowed to stir
overnight before being concentrated down to a crude yellow residue.
This intermediate chloroformate was retaken in THF (9714 .mu.l) and
added dropwise to a premixed solution of methyl 5-aminopicolinate
(217 mg, 1.429 mmol) and pyridine (385 .mu.l, 4.76 mmol) in THF
(9526 .mu.l). After 10 min of stirring, the reaction mixture was
concentrated and loaded directly onto an ISCO cartridge for
purification (40 g, 0-100% EtOAc/DCM, product at 35%) to afford
Intermediate I-82 (250 mg, 0.433 mmol, 91% yield) as a yellow
solid. LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 578.2
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.40 (s,
1H), 8.78-8.72 (m, 2H), 8.58 (d, J=1.8 Hz, 1H), 8.12-7.94 (m, 4H),
7.84 (s, 1H), 5.30 (td, J=6.2, 3.2 Hz, 1H), 4.47-4.36 (m, 1H),
4.35-4.24 (m, 1H), 4.09 (s, 3H), 3.84 (s, 3H), 2.64 (s, 3H), 1.45
(d, J=6.6 Hz, 3H).
Intermediate I-83
(R)-methyl
4-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate
##STR00228##
[1493] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-67 was reacted with methyl
4-aminopicolinate to afford Intermediate I-83 (59% yield) as a
yellow solid. LC-MS: Method H, RT=1.33 min, MS (ESI) m/z: 578.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.63-8.57
(m, 2H), 8.53 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.81 (d, J=11.4 Hz,
1H), 7.78-7.70 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.14 (s, 1H),
5.43-5.33 (m, 1H), 4.30-4.17 (m, 2H), 4.12 (s, 3H), 3.98 (s, 3H),
2.64 (s, 3H), 1.51 (d, J=6.4 Hz, 3H).
Intermediate I-84
(R)-methyl
5-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
##STR00229##
[1495] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-67 was reacted with
Intermediate I-107 to afford Intermediate I-84 (66% yield) as a
yellow solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 579.0
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.57 (br.
s., 1H), 9.01 (s, 2H), 8.76 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.03
(d, J=8.4 Hz, 1H), 7.99 (d, J=11.7 Hz, 1H), 7.85 (dd, 1.0 Hz, 1H),
5.31 (td, J=6.2, 3.2 Hz, 1H), 4.45-4.38 (m, 1H), 4.35-4.27 (m, 1H),
4.10 (s, 3H), 3.87 (s, 3H), 2.64 (s, 3H), 1.45 (d, J=6.6 Hz,
3H)
Intermediate I-85
Methyl
4-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
##STR00230##
[1497] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-79 was reacted with methyl
4-aminopicolinate to afford Intermediate I-85 (46% yield) as a
yellow solid. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 592.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=1.8 Hz, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.51 (s, 1H), 7.99 (d, J=2.0
Hz, 1H), 7.80 (d, J=11.4 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.69 (dd,
J=5.6, 2.1 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.12 (s, 1H), 5.16 (qd,
J=6.5, 3.0 Hz, 1H), 4.67-4.56 (m, 1H), 4.12 (s, 3H), 3.95 (s, 3H),
2.64 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H).
Intermediate I-86
Methyl
5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carbo-
xylate
##STR00231##
[1499] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-67 was reacted with
Intermediate I-107 to afford Intermediate I-86 (66% yield) as a
yellow solid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 593.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.03 (s,
2H), 8.62 (br. s., 1H), 8.57 (d, J=1.8 Hz, 1H), 8.51 (s, 1H), 7.78
(d, J=11.4 Hz, 1H), 7.76-7.73 (m, 1H), 7.49 (d, J=7.7 Hz, 1H), 5.17
(qd, J=6.5, 3.1 Hz, 1H), 4.62 (qd, J=6.4, 2.9 Hz, 1H), 4.12 (s,
3H), 4.02 (s, 3H), 2.64 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.41 (d,
J=6.4 Hz, 3H).
Intermediate I-87
(R)-methyl
4-((((1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-y-
l)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate
##STR00232##
[1501] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-69 was reacted with methyl
4-aminopicolinate to afford Intermediate I-87 (58% yield) as a
yellow solid. LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 612.2,
614.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76
(d, J=1.5 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.55 (s, 1H), 8.04 (d,
J=2.0 Hz, 1H), 7.80 (dd, J=2.0, 0.9 Hz, 1H), 7.75 (dd, 2.2 Hz, 1H),
7.43 (d, J=7.3 Hz, 1H), 7.01 (s, 1H), 5.46-5.35 (m, 1H), 4.35-4.20
(m, 2H), 4.16 (s, 3H), 4.02 (s, 3H), 2.69 (s, 3H), 1.55 (d, J=6.6
Hz, 3H).
Intermediate I-88
(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
##STR00233##
[1502] Intermediate I-88A:
(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl
carbonochloridate
##STR00234##
[1504] To a solution Intermediate I-72A (780 mg, 2.436 mmol) in THF
(24.4 mL, 0.1 M) was added 15% phosgene in toluene (8.59 mL, 12.18
mmol). The resulting slurry was allowed to stir at room
temperature. After t=5 h, the resulting mixture was concentrated to
remove the excess phosgene and afford Intermediate I-88A (824 mg,
2.436 mmol) as a yellow solid. Quantitative yield was assumed, and
this material was telescope into the next reaction without
purification. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 338.0,
339.9 (M+H).sup.+.
Intermediate I-88B:
(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-yl)carbamate
##STR00235##
[1506] To a solution of Intermediate I-97 (784 mg, 2.91 mmol) and
pyridine (1.961 mL, 24.25 mmol) in DCM (48.5 mL, 0.05 M) was added
crude Intermediate I-88A (820 mg, 2.425 mmol) dropwise from its own
solution of DCM (48.500 mL). [Note: Addition funnel was used to add
solution over 10 min]. Following the reagent addition, the reaction
mixture was concentrated down to remove excess pyridine and
purified by ISCO (0-100% EtOAc/Hex, product at 35%) to afford
Intermediate I-88B (1.10 g, 1.63 mmol, 67% yield) as an off-white
solid. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 571.0, 573.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.67-8.49
(m, 2H), 7.66 (dd, J=11.0, 3.5 Hz, 1H), 7.41-7.34 (m, 1H), 5.12
(dd, J=6.5, 3.0 Hz, 1H), 4.55 (dd, J=6.3, 3.0 Hz, 1H), 4.45-4.39
(m, 2H), 3.98 (t, J=5.5 Hz, 2H), 1.34 (d, J=6.4 Hz, 3H), 1.28 (d,
J=6.6 Hz, 3H), 0.92-0.86 (m, 9H), 0.08 (s, 6H).
Intermediate I-88
[1507] To a solution of Intermediate I-88B (95 mg, 0.166 mmol) in
THF (3327 .mu.l) was added 1 M HCl (832 .mu.l, 0.832 mmol) at room
temperature (12 pm). After 1.5 h, the reaction was quenched with
saturated NaHCO.sub.3, diluted with EtOAc, extracted, dried over
MgSO.sub.4, filtered, concentrated, and purified by ISCO (12 g,
0-100% EtOAc/DCM, product at 85%) to afford Intermediate I-88 (50
mg, 0.109 mmol, 65.8% yield) as a colorless oil. LC-MS: Method H,
RT=0.91 min, MS (ESI) m/z: 456.9, 458.9 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.61 (br. s., 2H), 7.64 (d, J=11.0
Hz, 1H), 7.43-7.32 (m, 1H), 7.00 (br. s., 1H), 5.12 (qd, J=6.5, 3.0
Hz, 1H), 4.56 (qd, J=6.4, 3.1 Hz, 1H), 4.51-4.44 (m, 2H), 4.23 (t,
J=6.3 Hz, 1H), 3.98 (m, 2H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4
Hz, 3H).
Intermediate I-89
methyl
5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenz-
o[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
##STR00236##
[1509] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-80 was reacted with methyl
5-aminopicolinate and purified by ISCO (0-100% EtOAc/DCM, product
at 35%) to afford Intermediate I-89 (76% yield) as a yellow solid.
LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 606.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (s, 2H), 8.47 (s,
1H), 8.20-8.11 (m, 1H), 8.10-8.05 (m, 1H), 7.78 (d, J=11.4 Hz, 1H),
7.70 (dd, J=2.0, 0.9 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.24 (s, 1H),
5.16 (qd, J=6.5, 3.0 Hz, 1H), 4.65-4.58 (m, 1H), 4.55 (q, J=7.0 Hz,
2H), 3.95 (s, 3H), 2.62 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.46 (d,
J=6.6 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H).
Intermediate I-90
methyl
5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenz-
o[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylat-
e
##STR00237##
[1511] This intermediate was prepared in a manner analogous to
Intermediate I-82. Thus, Intermediate I-80 was reacted with
Intermediate I-107 and purified by ISCO (0-80% EtOAc/DCM, product
at 40%) to afford Intermediate I-90 (81% yield) as a yellow solid.
LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 607.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.04 (s, 2H), 8.53 (d,
J=2.0 Hz, 1H), 8.47 (s, 1H), 7.77 (d, J=11.2 Hz, 1H), 7.70 (dd,
J=1.8, 0.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.45 (s, 1H), 5.17 (qd,
J=6.5, 2.9 Hz, 1H), 4.65-4.58 (m, 1H), 4.58-4.51 (m, 2H), 4.02 (s,
3H), 2.62 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H),
1.40 (d, J=6.6 Hz, 3H). .sup.19F NMR (376 MHz, CDCl.sub.3) .delta.
-132.68 (s, 1F).
Intermediate I-91
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan
##STR00238##
[1513] This intermediate was prepared in a manner analogous to
Intermediate I-78. Thus, Intermediate I-72A was reacted with
Intermediate I-121 and purified by ISCO (0-70% EtOAc/DCM, product
at 30%) to afford I-91 (55% yield) as a yellow solid. LC-MS: Method
H, RT=1.16 min, MS (ESI) m/z: 433.0, 435.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.90 (d, J=3.1 Hz, 1H), 8.65 (d,
J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.03-7.94 (m, 3H), 4.89 (d,
J=5.1 Hz, 1H), 4.43-4.34 (m, 1H), 4.01 (s, 3H), 3.88-3.77 (m, 1H),
1.32 (d, J=6.2 Hz, 3H), 1.20 (d, J=6.2 Hz, 3H).sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. -133.13 (s, 1F).
Intermediate I-92
1-(5-aminopyridin-2-yl)-2-methylpropan-2-ol
##STR00239##
[1514] Intermediate I-92A:
1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol
##STR00240##
[1516] 5-bromo-2-methylpyridine (0.7 g, 4.07 mmol) was dissolved in
anhydrous THF (20 mL). The solution was cooled to -78.degree. C.
and 2M LDA in THF (2.442 mL, 4.88 mmol) was added dropwise. The
reaction mixture was stirred for 20 minutes at -78.degree. C. then
freshly distilled acetone (1.046 mL, 14.24 mmol) was added and the
reaction mixture continued to stir for 20 minutes at -78.degree. C.
The reaction mixture was then quenched with saturated ammonium
chloride and extracted with EtOAc (3.times.). The combined organic
layer was washed with brine (1.times.), dried with sodium sulfate,
filtered and concentrated. The resulting residue was dissolved in a
small amount of methylene chloride before being charged to a 24 g
silica gel cartridge which was eluted with a 15 min gradient from
0-100% EtOAc in hexane, The desired fractions were collected and
concentrated to yield Intermediate I-92A (0.432 g, 1.877 mmol,
46.1% yield). LC-MS: Method H, MS (ESI) m/z: 232.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.61 (d, J=2.2 Hz, 1H),
7.79 (dd, J=8.1, 2.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.91 (s, 2H),
1.28-1.17 (m, 6H).
Intermediate I-92
[1517] To a solution of Intermediate I-92A (432 mg, 1.877 mmol)
dissolved in DMSO (5 mL) was added L-proline (86 mg, 0.751 mmol),
ammonium hydroxide (0.146 mL, 3.75 mmol), potassium carbonate (519
mg, 3.75 mmol) and copper(I) iodide (71.5 mg, 0.375 mmol). The
reaction vessel was evacuated and backfilled with Ar 3.times. then
stirred at 90.degree. C. for 18 h. The reaction mixture was then
diluted with water and extracted with EtOAc (3.times.). The
combined organic layer was washed with brine, dried with sodium
sulfate, filtered and concentrated. The resulting residue was
dissolved in methylene chloride before being charged to a 24 g
silica gel cartridge which was eluted with a 15 min gradient from
0-30% MeOH in methylene chloride. The desired fractions were
collected and concentrated to yield Intermediate I-92 (47 mg, 0.283
mmol, 15% yield), as a white solid. LC-MS: Method H, MS (ESI) m/z:
167.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04
(d, J=2.6 Hz, 1H), 7.00-6.96 (m, 1H), 6.95-6.90 (m, 1H), 2.81 (s,
2H), 1.22 (s, 6H).
Intermediate I-93
6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine
##STR00241##
[1518] Intermediate I-93A: 2-((5-nitropyridin-2-yl)oxy)ethanol
##STR00242##
[1520] Ethylene glycol (0.883 mL, 15.84 mmol) was dissolved in DMF
(10 mL) at 0.degree. C. Sodium hydride (253 mg, 6.33 mmol, 60% in
mineral oil) was added to the reaction mixture portion wise and the
reaction mixture was stirred for 10 minutes at 0.degree. C.
2-fluoro-5-nitropyridine (450 mg, 3.17 mmol) dissolved in 1 mL of
DMF was then added to the reaction mixture which was allowed to
stir for 15 minutes at room temperature. The mixture was then
quenched with saturated ammonium chloride and extracted with EtOAc
(1.times.). The organic layer was then washed with 10% aqueous LiCl
(3.times.), brine (1.times.), dried with sodium sulfate, filtered
and concentrated to yield Intermediate I-93A, (530 mg, 2.88 mmol,
91% yield), as a clear oil which was brought forward without
further purification. LC-MS: Method H, MS (ESI) m/z: 185.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.09 (d,
J=2.9 Hz, 1H), 8.41 (dd, J=9.0, 2.9 Hz, 1H), 6.92 (dd, J=9.2, 0.4
Hz, 1H), 4.65-4.54 (m, 2H), 4.09-3.96 (m, 2H), 2.32 (t, J=5.9 Hz,
1H).
Intermediate I-93B:
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine
##STR00243##
[1522] Intermediate I-93A (530 mg, 2.88 mmol) was dissolved in
dichloromethane (20 mL) along with TEA (0.521 mL, 3.74 mmol) and
DMAP (70.3 mg, 0.576 mmol). TBS-Cl (521 mg, 3.45 mmol) was added to
the reaction mixture which was allowed to stir at room temperature
for 18 h. The reaction mixture was then quenched with saturated
aqueous sodium bicarbonate and extracted with DCM (2.times.). The
organic layer was washed with brine (1.times.), dried with sodium
sulfate, filtered and concentrated. The resulting residue was
dissolved in methylene chloride before being charged to a 40 g
silica gel cartridge which was eluted with a 15 min gradient from
0-100% EtOAc in hexane. The desired fractions were collected and
concentrated to yield Intermediate I-93B, (700 mg, 2.346 mmol, 82%
yield), as a clear oil. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z:
299.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.98
(d, J=2.4 Hz, 1H), 8.27 (dd, J=9.0, 2.9 Hz, 1H), 6.80-6.72 (m, 1H),
4.47-4.35 (m, 2H), 3.90 (dd, 4.5 Hz, 2H), 0.84-0.73 (m, 9H),
0.03-0.01 (m, 6H).
Intermediate I-93
[1523] Intermediate I-93B (700 mg, 2.346 mmol) was dissolved in
ethyl acetate (10 mL). Pd--C (125 mg, 0.117 mmol, 10% by wt.) was
added to the reaction mixture which was evacuated and backfilled
with 1 atm of hydrogen 3.times. and stirred under 1 atm of hydrogen
at room temperature for 3 h. The reaction mixture was then filtered
through a pad of celite and the filtrate was concentrated to yield
Intermediate I-93, (561 mg, 2.090 mmol, 89% yield), as a yellow
oil. The product was brought forward without further purification.
LC-MS: Method H, MS (ESI) m/z: 289.2 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.59-7.53 (m, 1H), 7.01-6.86 (m, 1H),
6.58-6.47 (m, 1H), 4.27-4.14 (m, 2H), 3.96-3.80 (m, 2H), 3.37-3.11
(m, 2H), 0.86-0.77 (m, 10H), 0.00 (s, 6H).
Intermediate I-94
2-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-4-amine
##STR00244##
[1524] Intermediate I-94A: 2-(4-bromopyridin-2-yl)ethanol
##STR00245##
[1526] 4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) was dissolved
in anhydrous THF (50 mL) at -78.degree. C. LDA (25.4 mL, 50.9 mmol)
was added to the reaction mixture which was allowed to stir at
-78.degree. C. for 30 minutes. Anhydrous DMF (3.38 mL, 43.6 mmol)
was then added to the reaction mixture which continued to stir at
-78.degree. C. for an additional 45 minutes. A mixture of acetic
acid (3.33 mL, 58.1 mmol)/MeOH (10 mL) was then added to the
mixture at -78.degree. C. followed by sodium borohydride (0.550 g,
14.53 mmol). The reaction mixture was then allowed to warm to room
temperature and was stirred for 1 h then quenched with 10% aqueous
citric acid solution at room temperature and stirred for an
additional 10 minutes. The reaction mixture was extracted with
EtOAc (3.times.). The organic layer was washed with brine
(1.times.), dried with sodium sulfate, filtered and concentrated to
yield Intermediate I-94A which was brought forward without further
purification. LC-MS: Method H, MS (ESI) m/z: 201.9 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.37 (d, J=5.3 Hz, 1H),
7.58 (d, J=1.8 Hz, 1H), 7.49 (dd, J=5.4, 1.9 Hz, 1H), 3.78-3.70 (m,
1H), 2.89-2.86 (m, 2H), 2.28 (d, J=5.5 Hz, 1H).
Intermediate I-94B: 2-(4-bromopyridin-2-yl)ethyl acetate
##STR00246##
[1528] Intermediate I-94A (2.9 g, 14.35 mmol) was dissolved in THF
(50 mL). Acetic anhydride (4.06 mL, 43.1 mmol) was added to the
reaction mixture followed by DMAP (0.351 g, 2.87 mmol) and pyridine
(3.48 mL, 43.1 mmol). The mixture was stirred at room temperature
for 2 hours then diluted with EtOAc and 1.5M potassium diphosphate
solution and extracted with EtOAc (3.times.). The organic layer was
washed with brine (1.times.), dried with sodium sulfate, filtered
and concentrated. The resulting residue was dissolved in methylene
chloride before being charged to an 80 g silica gel cartridge which
was eluted with a 30 min gradient from 0-80% EtOAc in hexane. The
desired fractions were collected and concentrated to yield
Intermediate I-94B (0.98 g, 4.01 mmol, 28.0% yield) as a yellow
oil. LC-MS: Method H, MS (ESI) m/z: 246.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.40 (d, J=5.5 Hz, 1H), 7.41 (d,
J=1.8 Hz, 1H), 7.36 (dd, J=5.3, 1.8 Hz, 1H), 4.48 (t, J=6.6 Hz,
2H), 3.11 (t, J=6.6 Hz, 2H), 2.08-1.99 (m, 3H).
Intermediate I-94
[1529] Intermediate I-94B (282 mg, 3.20 mmol),
2,2,2-trifluoroacetamide (722 mg, 6.39 mmol),
2-(4-bromopyridin-2-yl)ethyl acetate (780 mg, 3.20 mmol), 3 .ANG.
molecular sieves (250 mg, 3.20 mmol), copper(I) iodide (122 mg,
0.639 mmol) and potassium carbonate (883 mg, 6.39 mmol) were
dissolved in dioxane (1 mL). The reaction vessel was evacuated and
backfilled with Ar 3.times. then heated to 75.degree. C. for 4 h. 5
mL of MeOH was then added to the reaction mixture which was allowed
to stir for 30 minutes at room temperature. The reaction mixture
was then filtered through celite and the filtrate was concentrated.
The resulting residue was dissolved in THF (30 mL). 1M aqueous LiOH
(12.05 mL, 12.05 mmol) was added to the mixture which was allowed
to stir at room temperature for 18 h. The reaction mixture was then
concentrated to dryness, redissolved in THF (30 mL) and filtered
through a pad of celite. The celite pad was washed with excess THF.
To the THF solution (.about.50 mL) was added TBS-Cl (3028 mg, 20.09
mmol) and imidazole (1368 mg, 20.09 mmol). The reaction mixture was
stirred at room temperature for 1 hour then filtered through a pad
of celite and the filtrate was concentrated. The resulting residue
was dissolved in methylene chloride before being charged to an 80 g
silica gel cartridge which was eluted with a 30 min gradient from
0-25% MeOH in methylene chloride. The fractions containing desired
product were concentrated and the resulting isolate was repurified
on an 80 g column using 1M NH.sub.3 MeOH/DCM (0-20%, 30 min
gradient). Fractions containing the desired product were
concentrated to yield Intermediate I-94 (293 mg, 1.16 mmol, 29%
yield). LC-MS: Method H, MS (ESI) m/z: 253.2 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.20 (d, J=5.7 Hz, 1H), 6.51 (d,
J=2.2 Hz, 1H), 6.44 (dd, J=5.6, 2.3 Hz, 1H), 4.35-4.11 (m, 2H),
3.97 (t, J=6.6 Hz, 2H), 2.91 (t, J=6.5 Hz, 2H), 0.88 (s, 9H), 0.00
(s, 6H).
Intermediate I-95
1-(4-aminopyridin-2-yl)-2-methylpropan-2-ol
##STR00247##
[1530] Intermediate I-95A:
1-(4-bromopyridin-2-yl)-2-methylpropan-2-ol
##STR00248##
[1532] To a stirred solution of 4-bromo-2-methylpyridine (0.7 g,
4.07 mmol) in anhydrous THF (20 mL) at -78.degree. C. was added 2M
LDA in THF (2.442 mL, 4.88 mmol) dropwise. The reaction mixture was
stirred for 20 minutes at -78.degree. C. Freshly distilled acetone
(1.046 mL, 14.24 mmol) was then added to the reaction mixture which
stirred for an additional 20 minutes at -78.degree. C. The reaction
mixture was then quenched with saturated ammonium chloride and was
allowed to warm to room temperature. The reaction mixture was then
diluted with water and extracted with EtOAc (3.times.). The organic
layer was washed with brine (1.times.), dried with sodium sulfate,
filtered and concentrated. The resulting residue was dissolved in
methylene chloride before being charged to a 24 g silica gel
cartridge which was eluted with a 15 min gradient from 0-100% EtOAc
in hexane. The desired fractions were collected and concentrated to
yield Intermediate I-95A (0.588 g, 2.56 mmol, 62.8% yield). LC-MS:
Method H, MS (ESI) m/z: 232.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.36 (d, J=5.3 Hz, 1H), 7.42-7.34 (m, 2H),
5.35-5.01 (m, 1H), 2.92 (s, 2H), 1.25 (s, 6H).
Intermediate I-95
[1533] Intermediate I-95A (588 mg, 2.56 mmol) was dissolved in DMSO
(5 mL) along with L-proline (118 mg, 1.022 mmol), ammonium
hydroxide (0.199 mL, 5.11 mmol), potassium carbonate (706 mg, 5.11
mmol) and copper(I) iodide (97 mg, 0.511 mmol). The reaction
mixture was evacuated and backfilled with argon three times before
being sealed and heated to 90.degree. C. for 5 hours. The reaction
mixture was then filtered through celite, washed with MeOH and the
filtrate was concentrated. The resulting residue was dissolved in
methylene chloride before being charged to a 24 g silica gel
cartridge which was eluted with a 15 min gradient from 0-30% MeOH
in methylene chloride. Fractions containing desired product were
concentrated and repurified by Prep HPLC using Method A to yield
Intermediate I-95 (28 mg, 0.168 mmol, 7% yield). LC-MS: Method H,
MS (ESI) m/z: 167.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 7.94 (d, J=7.0 Hz, 1H), 6.76 (dd, J=6.9, 2.3
Hz, 1H), 6.74-6.68 (m, 1H), 2.84 (s, 2H), 1.28 (s, 6H).
Intermediate I-96
1-((4-aminopyridin-2-yl)oxy)-2-methylpropan-2-ol
##STR00249##
[1534] Intermediate I-96A:
1-((4-bromopyridin-2-yl)oxy)-2-methylpropan-2-ol
##STR00250##
[1536] This intermediate was prepared according to Procedure D from
2-methylpropane-1,2-diol. Intermediate I-96A was afforded in 52%
yield after column chromatography. LC-MS: Method H, MS (ESI) m/z:
247.9 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98
(d, J=5.5 Hz, 1H), 7.08 (dd, J=5.5, 1.5 Hz, 1H), 7.05 (d, J=1.3 Hz,
1H), 4.23 (s, 2H), 3.01 (s, 1H), 1.34 (s, 6H).
Intermediate I-96
[1537] This intermediate was prepared from Intermediate I-96A
according to Procedure E. Intermediate I-96 was afforded in 66%
yield. LC-MS: Method H, MS (ESI) m/z: 183.1 (M+H).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.72-7.38 (m, 1H), 6.24-6.15
(m, 1H), 6.14-5.95 (m, 2H), 5.91-5.80 (m, 1H), 3.91 (s, 2H), 1.15
(s, 6H).
Intermediate I-97
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-amine
##STR00251##
[1538] Intermediate I-97A:
2-((5-nitropyrimidin-2-yl)oxy)ethanol
##STR00252##
[1540] 2-chloro-5-nitropyrimidine (1 g, 6.27 mmol) was mixed with
ethylene glycol (8 ml, 143 mmol) and DIEA (3.28 ml, 18.81 mmol) was
added. The mixture was stirred at 80.degree. C. for 20 minutes and
was then poured into 30 mL of ice water. 40 mL of EtOAc was added
to the mixture followed by 20 mL of 1N aqueous HCl. EtOAc (30
mL.times.3) was used to extract the aqueous layer. The combined
organic layer was washed with brine, dried with sodium sulfate,
filtered and concentrated to give Intermediate I-97A in
quantitative yield as a yellow oil. The product was brought forward
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.33 (s, 2H), 4.73-4.51 (m, 2H), 4.08-3.96 (m, 2H), 2.41
(br. s., 1H).
Intermediate I-97B:
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyrimidine
##STR00253##
[1542] Intermediate I-97A, (1.23 g, 6.64 mmol), was mixed with
tert-butylchlorodimethylsilane (2.003 g, 13.29 mmol) in DCM (20
ml). Imidazole (0.905 g, 13.29 mmol) was added to the reaction
mixture and the reaction mixture stirred at room temperature for 30
minutes. The solid was filtered off and the filter cake was washed
with a small amount of DCM. The filtrate was mixed with 30 g of
silica gel, evaporated to dryness and loaded on CombiFlash (80 g
column, 0-50% EtOAc/Hexane) for purification. The fractions
containing desired product were collected and concentrated to give
Intermediate I-97B, (1.73 g, 5.78 mmol, 87% yield), as a light
yellow solid. LC-MS: Method H, MS (ESI) m/z: 300.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 9.30 (2H, s), 4.61
(2H, dd, J=5.50, 4.62 Hz), 4.02 (2H, dd, J=5.61, 4.73 Hz), 0.88
(9H, s), 0.09 (6H, s).
Intermediate I-97
[1543] Intermediate I-97B, (1.73 g, 5.78 mmol), was dissolved in
THF (40 ml). Wet Pd--C (0.307 g, 0.289 mmol, 10% by wt.) was then
added to the solution. The mixture was then evacuated and
backfilled with hydrogen 3.times., and the mixture was stirred
under 1 atm H.sub.2 for 7 hours at room temperature. The catalyst
was filtered off over a pad of celite which was washed with a small
amount of EtOAc. The filtrate was concentrated to yield
Intermediate I-97, (1.53 g, 5.68 mmol, 98% yield), as a gray solid.
LC-MS: Method H, MS (ESI) m/z: 270.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.05 (2H, s), 4.35 (2H, t, J=5.50 Hz),
3.97 (2H, t, J=5.61 Hz), 1.69 (2H, d, J=5.06 Hz), 0.89 (9H, s),
0.08 (6H, s).
Intermediate I-98
2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidin-5-amine
##STR00254##
[1544] Intermediate I-98A: 3-hydroxypropanimidamide, HCl
##STR00255##
[1546] To a mixture of MeOH (5 mL, 124 mmol)/toluene (30.1 mL) at
0.degree. C. was added acetyl chloride (3.00 mL, 42.2 mmol) slowly
over 10 minutes. The reaction mixture was allowed to stir at
0.degree. C. for 10 minutes then at room temperature for 10
minutes. The reaction mixture was cooled to 0.degree. C. and
3-hydroxypropanenitrile (1.5 g, 21.10 mmol) dissolved in 5 mL of
toluene added and the reaction mixture was allowed to stir at room
temperature for 18 h. The reaction mixture was cooled to 0.degree.
C. and 7N ammonia in MeOH (15.07 mL, 106 mmol) was added carefully
over 5 minutes. The reaction mixture was then allowed to warm to
room temperature and stirred for 18 h at room temperature. The
mixture was then filtered through celite and the filter cake washed
with 2:1 toluene/MeOH. The filtrate was concentrated to yield
Intermediate I-98A in quantitative yield. The product was brought
forward without further purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 3.70 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz,
2H).
Intermediate I-98B: methyl
2-(2-hydroxyethyl)pyrimidine-5-carboxylate
##STR00256##
[1548] Intermediate I-98A (8.9 g, 71.4 mmol) was dissolved in DMF
(200 ml). While the solution stirred at room temperature, sodium
(Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (16.5 g,
83 mmol) was added in portion-wise and the reaction mixture was
stirred at room temperature for 18 h. The reaction mixture was then
concentrated under reduced pressure and heat. The resulting residue
was then suspended in 10:1 DCM:MeOH mixture and run through a pad
of silica gel/celite which was washed with 500 mL of additional
10:1 DCM/MeOH solution. The filtrate was concentrated to yield
Intermediate I-98B (10.5 g, 57.6 mmol, 81% yield), as a red oil.
The product was brought forward without further purification.
LC-MS: Method H, MS (ESI) m/z: 183.0 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.16 (s, 2H), 4.69 (t, J=5.4 Hz, 1H),
4.03-3.79 (m, 5H), 3.12 (t, J=6.6 Hz, 2H).
Intermediate I-98C: methyl
2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidine-5-carboxylate
##STR00257##
[1550] To the solution of Intermediate I-98B (4 g, 21.96 mmol) in
THF (80 mL) was added DMAP (0.134 g, 1.098 mmol), TEA (7.65 mL,
54.9 mmol) and TBDPS-Cl (8.46 mL, 32.9 mmol). The reaction mixture
was stirred for 18 h at room temperature. 5 mL of methanol was then
added and the reaction mixture stirred for 10 minutes at room
temperature followed by evaporation under reduced pressure. The
crude product was purified by silica gel chromatography on a 120 g
silica column using petroleum ether, chloroform and EtOAc as
eluent. First an eluent of 0-100% chloroform in petroleum ether was
used followed by an eluent of 0-100% EtOAc in chloroform. Fractions
containing desired product were collected and concentrated to yield
Intermediate I-98C (7.5 g, 17.9 mmol, 82% yield), as a colorless
oil. LC-MS: Method H, MS (ESI) m/z: 421.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.16 (s, 2H), 7.73-7.28 (m, 10H),
4.22 (t, J=6.4 Hz, 2H), 3.97 (s, 4H), 3.30 (t, J=6.4 Hz, 2H),
0.98-0.94 (m, 9H).
Intermediate I-98D:
2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidine-5-carboxylic
acid
##STR00258##
[1552] Intermediate I-98C (2.14 g, 5.09 mmol) was dissolved in THF
(60 mL). 1M aqueous LiOH (15.26 mL, 15.26 mmol) was added and the
reaction mixture was allowed to stir at room temperature for 1
hour. The majority of the THF was concentrated under reduced
pressure and the reaction mixture was acidified with 10% citric
acid to pH 4-5 then extracted 3.times. with EtOAc. The combined
organic layer was washed with brine, dried with sodium sulfate,
filtered and concentrated to yield Intermediate I-98D, (2.07 g,
5.09 mmol, 100% yield), as a clear glass. LC-MS: Method H, MS (ESI)
m/z: 407.2 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.13 (s, 2H), 7.76-7.23 (m, 10H), 4.19 (t, J=6.3 Hz, 2H), 3.25 (t,
J=6.3 Hz, 2H), 0.90 (s, 9H).
Intermediate I-98
[1553] Intermediate I-98D (5.5 g, 13.53 mmol) was dissolved in THF
(350 mL). TEA (9.43 mL, 67.6 mmol) was added to the mixture
followed by diphenyl phosphorazidate (9.31 g, 33.8 mmol) at room
temperature. The reaction mixture was heated to 65.degree. C. under
a reflux condenser for 22 hours. The reaction mixture was then
allowed to cool to room temperature and water (175 mL) was added.
The mixture was stirred at room temperature for 2 hours and 15
minutes. The majority of THF was evaporated off under reduced
pressure and the mixture was then diluted with water and a small
amount of brine and extracted 3.times. with a total of .about.500
mL of EtOAc. The organic layer was washed with brine, dried with
sodium sulfate, filtered and concentrated. The resulting residue
was dissolved in methylene chloride before being charged to a 330 g
column which was eluted with a gradient from 0-20% MeOH/DCM.
Fractions containing desired product were collected and
concentrated to yield Intermediate I-98, (1.135 g, 3.01 mmol, 22%
yield), as an orange oil. LC-MS: Method H, MS (ESI) m/z: 378.2.
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.04 (s,
2H), 7.59-7.53 (m, 4H), 7.47-7.31 (m, 6H), 5.76 (s, 2H), 4.02 (t,
J=6.7 Hz, 2H), 2.97 (t, J=6.7 Hz, 2H), 0.92 (s, 9H).
Intermediate I-99
6-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)pyridin-3-amine
##STR00259##
[1554] Intermediate I-99A:
2,2-difluoro-3-((5-nitropyridin-2-yl)oxy)propan-1-ol
##STR00260##
[1556] 2,2-difluoropropane-1,3-diol (394 mg, 3.52 mmol) was
dissolved in DMF (10 mL). Sodium hydride (77 mg, 1.934 mmol, 60% by
wt.) was added to the mixture at 0.degree. C. and the reaction
mixture was stirred at 0.degree. C. for 10 minutes.
2-fluoro-5-nitropyridine (250 mg, 1.758 mmol) dissolved in 1 mL of
DMF was then added to the reaction mixture which was allowed to
stir at room temperature for 1 hour. The mixture was then quenched
with saturated ammonium chloride and diluted with EtOAc. The
organic layer was washed with 10% aqueous LiCl (3.times.), and
brine (1.times.), dried with sodium sulfate, filtered and
concentrated to yield
2,2-difluoro-3-((5-nitropyridin-2-yl)oxy)propane as a yellow oil.
To the crude intermediate dissolved in DCM (9 mL) was added TEA
(1137 .mu.l, 8.16 mmol) and DMAP (39.9 mg, 0.326 mmol) followed by
TBS-Cl (738 mg, 4.89 mmol). The reaction mixture stirred for 18 h
at room temperature. 5 mL of MeOH was then added to the reaction
mixture which was allowed to stir for 10 minutes at room
temperature. The reaction mixture was then quenched with saturated
sodium bicarbonate and extracted DCM (3.times.). The organic layer
was washed with brine (1.times.), dried with sodium sulfate,
filtered and concentrated. The resulting residue was dissolved in a
small amount of methylene chloride and charged to a 40 g silica gel
cartridge which was eluted with a 15 min gradient from 0-100% EtOAc
in hexane. Fractions containing desired product were concentrated
to yield Intermediate I-99A (204 mg, 0.586 mmol, 36% yield) as a
clear oil. LC-MS: Method H, MS (ESI) m/z: 349.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.01 (dd, J=2.9, 0.4 Hz,
1H), 8.34 (dd, J=9.1, 2.8 Hz, 1H), 6.86 (dd, J=9.0, 0.4 Hz, 1H),
4.66 (t, J=12.4 Hz, 2H), 3.85 (t, J=12.2 Hz, 2H), 0.81-0.78 (m,
9H), 0.00 (s, 6H).
Intermediate I-99
[1557] Intermediate I-99A (204 mg, 0.586 mmol) was dissolved in
EtOAc (10 mL). Pd--C (18.69 mg, 0.176 mmol, 10% by wt.) was added
to the solution and the flask was evacuated and backfilled with 1
atm of hydrogen 3.times.. The reaction mixture was stirred under 1
atm of hydrogen for 18 h and then filtered through celite and the
celite pad washed with excess EtOAc. The filtrate was concentrated
to yield Intermediate I-99 in quantitative yield as a green oil.
The product was brought forward without further purification.
LC-MS: Method H, MS (ESI) m/z: 319. (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.60-7.54 (m, 1H), 7.02-6.95 (m, 1H),
6.63-6.50 (m, 1H), 4.45 (t, J=12.5 Hz, 2H), 3.86 (t, J=12.4 Hz,
2H), 0.81 (s, 9H), 0.00 (s, 6H).
Intermediate I-100
4-((5-aminopyrimidin-2-yl)oxy)-2-methylbutan-2-ol, HCl
##STR00261##
[1558] Intermediate I-100A:
4-((5-bromopyrimidin-2-yl)oxy)-2-methylbutan-2-ol
##STR00262##
[1560] This intermediate was prepared according to Procedure A from
3-methylbutane-1,3-diol. Intermediate I-100A was afforded in 68%
yield after silica gel chromatography. LC-MS: Method H, MS (ESI)
m/z: 263.0. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (s, 2H),
4.56 (t, J=6.8 Hz, 2H), 2.05 (t, J=6.8 Hz, 2H), 1.34 (s, 6H).
Intermediate I-100B:
4-((5-((diphenylmethylene)amino)pyrimidin-2-yl)oxy)-2-methylbutan-2-ol
##STR00263##
[1562] This intermediate was prepared according to Procedure B from
Intermediate I-100A. Intermediate I-100B was afforded in 81% yield
after silica gel chromatography. LC-MS: Method H, MS (ESI) m/z:
362.1.
Intermediate I-100
[1563] Intermediate I-100 was afforded from Intermediate I-100B in
77% yield according to Procedure C. LC-MS: Method H, MS (ESI) m/z:
198.1.
Intermediate I-101
2-(2-methyl-2-((triethylsilyl)oxy)propoxy)pyrimidin-5-amine
##STR00264##
[1564] Intermediate I-101A:
1-((5-bromopyrimidin-2-yl)oxy)-2-methylpropan-2-ol
##STR00265##
[1566] This intermediate was prepared according to Procedure A from
2-methylpropane-1,2-diol. Intermediate I-101A was afforded in 29%
yield after silica gel chromatography. LC-MS: Method H, MS (ESI)
m/z: 249.0. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.57 (s, 2H),
4.25 (s, 2H), 1.38 (s, 6H).
Intermediate I-101B:
1-((5-((diphenylmethylene)amino)pyrimidin-2-yl)oxy)-2-methylpropan-2-ol
##STR00266##
[1568] This intermediate was prepared according to Procedure B from
Intermediate I-101A. Intermediate I-101B was afforded in 58% yield
after silica gel chromatography. LC-MS: Method H, MS (ESI) m/z:
348.2. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.99 (s, 2H),
7.81-7.67 (m, 2H), 7.58-7.35 (m, 6H), 7.19-7.02 (m, 2H), 4.17 (s,
2H), 1.34 (s, 6H).
Intermediate I-101
[1569] Intermediate I-101B (152 mg, 0.438 mmol) was dissolved in
MeOH (5 mL)/THF (5.00 mL). 1M HCl (1.0 mL, 1.0 mmol) was added to
the reaction mixture and the reaction mixture was stirred for 30
minutes at room temperature. The mixture was then concentrated
under reduced pressure and azeotroped with toluene 3.times.. The
resulting residue was dissolved in anhydrous DCM (5 mL) along with
Hunig's Base (0.534 mL, 3.06 mmol). The reaction mixture was then
cooled to 0.degree. C. and triethylsilyl trifluoromethanesulfonate
(347 mg, 1.311 mmol) was added dropwise and the reaction mixture
was allowed to stir at 0.degree. C. for 30 minutes and then at room
temperature for 30 minutes. The mixture was then quenched with
saturated sodium bicarbonate and extracted with DCM (3.times.). The
organic layer was washed with brine (1.times.), dried with sodium
sulfate, filtered and concentrated. The resulting residue was
dissolved in methylene chloride before being charged to a 24 g
silica gel cartridge which was eluted with a 15 min gradient from
0-25% MeOH in methylene chloride. The desired fractions were
collected and concentrated to yield Intermediate I-101 (42 mg,
0.141 mmol, 32.3% yield). LC-MS: Method H, MS (ESI) m/z: 298.2.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (s, 2H), 4.08 (s,
2H), 1.38 (s, 6H), 0.98-0.93 (m, 6H), 0.67-0.57 (m, 9H).
Intermediate I-102
1-(5-aminopyrimidin-2-yl)-2-methylpropan-2-ol
##STR00267##
[1570] Intermediate I-102A: 3-hydroxy-3-methylbutanimidamide,
HCl
##STR00268##
[1572] This intermediate was synthesized from
3-hydroxy-3-methylbutanenitrile using the method described to
synthesize Intermediate I-98A. Intermediate I-102A was afforded in
quantitative yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
2.54 (s, 2H), 1.36-1.00 (m, 6H).
Intermediate I-102B: methyl
2-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxylate
##STR00269##
[1574] This intermediate was synthesized from I-102A using the
procedure described for Intermediate I-98B. Intermediate I-102B was
afforded in 58% yield after chromatography. LC-MS: Method H, MS
(ESI) m/z: 211.0 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.18 (s, 2H), 4.70 (s, 1H), 3.91 (s, 3H), 3.09 (s, 2H),
1.17 (s, 6H).
Intermediate I-102C: methyl
2-(2-methyl-2-((triethylsilyl)oxy)propyl)pyrimidine-5-carboxylate
##STR00270##
[1576] To a solution of Intermediate I-102B (0.7 g, 3.33 mmol) and
2,6-lutidine (0.776 ml, 6.66 mmol) in DCM (16.65 ml) was added
triethylsilyl trifluoromethanesulfonate (1.408 g, 5.33 mmol)
dropwise at 0.degree. C. The reaction mixture was allowed to stir
at 0.degree. C. for 30 minutes. The reaction mixture was quenched
with saturated sodium bicarbonate and extracted with DCM
(3.times.). The combined organic layer was washed with brine, dried
with sodium sulfate, filtered and concentrated. The resulting
residue was dissolved in a small amount of methylene chloride and
charged to a 40 g silica gel cartridge which was eluted with a 15
min gradient from 0-100% EtOAc in hexane. Fractions containing the
desired product were concentrated to yield Intermediate I-102C
(0.629 g, 1.938 mmol, 58% yield) as a clear oil. LC-MS: Method H,
MS (ESI) m/z: 325.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.22 (s, 2H), 4.00 (s, 3H), 3.24 (s, 2H), 1.37 (s, 6H),
0.94-0.81 (m, 9H), 0.56 (q, J=8.1 Hz, 7H).
Intermediate I-102D:
2-(2-methyl-2-((triethylsilyl)oxy)propyl)pyrimidine-5-carboxylic
acid
##STR00271##
[1578] Intermediate I-102C (0.629 g, 1.938 mmol) was dissolved in
THF (20 mL). 1M aqueous LiOH (5.82 mL, 5.82 mmol) was added to the
reaction mixture which was allowed to stir at room temperature for
1 hour. Most of the THF was evaporated off and the reaction mixture
was acidified to pH 4-5 with 10% citric acid and extracted with
EtOAc (3.times.). The combined organic layer was washed with brine,
filtered and concentrated to yield Intermediate I-102D (0.6 g,
1.623 mmol, 84% yield) as a clear glass. LC-MS: Method H, MS (ESI)
m/z: 311.2 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.14 (s, 2H), 3.13 (s, 2H), 1.31 (s, 6H), 0.84 (t, J=7.9 Hz, 9H),
0.53-0.40 (m, 6H).
Intermediate I-102
[1579] This intermediate was synthesized from I-102D according to
the procedure described for conversion of Intermediate I-98D to
Intermediate I-98. Intermediate I-102 was afforded in 78% yield
after chromatography. LC-MS: Method H, MS (ESI) m/z: 168.1
(M+H).sup.+. .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 8.16 (s,
2H), 2.94 (s, 2H), 1.22 (s, 6H).
Intermediate I-103
(R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-amine
##STR00272##
[1581] This intermediate was prepared from (R)-ethyl
2-hydroxypropanoate in the same manner as described for
Intermediate I-104 below. LC-MS: Method H, MS (ESI) m/z: 284.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97 (s,
2H), 4.20-4.06 (m, 2H), 4.01-3.93 (m, 1H), 3.29 (br. s., 2H), 1.17
(d, J=6.2 Hz, 3H), 0.81 (s, 9H), 0.01 (d, J=6.2 Hz, 6H). MS (ESI)
m/z: 284.2 (M+H).sup.+.
Intermediate I-104
(S)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-amine
##STR00273##
[1582] Intermediate I-104A: (S)-ethyl
2-((tert-butyldimethylsilyl)oxy)propanoate
##STR00274##
[1584] (S)-ethyl 2-hydroxypropanoate (1.50 g, 12.70 mmol) was
reacted according to Procedure I using DCM as a solvent to afford
Intermediate I-104A (2.3 g, 9.90 mmol, 78% yield) as a clear oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.35-4.28 (m, 1H), 4.18
(t, J=7.5 Hz, 2H), 1.40 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H),
0.91 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H).
Intermediate I-104B:
(S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol
##STR00275##
[1586] Intermediate I-104A (2.2 g, 9.47 mmol) was dissolved in THF
(100 ml) and the solution was cooled to -78.degree. C. To the
reaction mixture was added DIBAL-H (23.67 ml, 23.67 mmol) and the
reaction mixture was allowed to warm to room temperature and
stirred for 3 h at room temperature before being quenched with
saturated Rochelle's salt. The quenched reaction mixture was
stirred for 18 h at room temperature and then extracted with EtOAc
(3.times.). The combined organic layer was washed with brine, dried
with sodium sulfate, filtered and concentrated under reduced
pressure to yield Intermediate I-104B in quantitative yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.87-3.77 (m, J=2.6 Hz,
1H), 3.46-3.37 (m, 1H), 3.32-3.21 (m, 1H), 1.03 (d, J=6.4 Hz, 3H),
0.82 (s, 9H), 0.00 (s, 6H).
Intermediate I-104C:
(S)-5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidine
##STR00276##
[1588] Triphenylphosphine (2.88 g, 10.98 mmol) was dissolved in THF
(143 ml) and the solution was cooled to 0.degree. C. DIAD (1.941
ml, 9.98 mmol) was added and reaction mixture was allowed to stir
for 5 minutes at 0.degree. C. Intermediate I-104B (1.9 g, 9.98
mmol) was added to the reaction mixture and the reaction mixture
was allowed to stir for 10 minutes at 0.degree. C.
5-bromopyrimidin-2-ol (1.5 g, 8.57 mmol) was then added to the
reaction mixture which was allowed to warm to room temperature
slowly and stirred for 72 hours at room temperature. The reaction
mixture was then diluted with water and extracted with EtOAc
(3.times.). The combined organic layer was washed with brine
(1.times.), dried with sodium sulfate, filtered and concentrated.
The resulting residue was dissolved in a small amount of methylene
chloride before being charged to an 80 g silica gel cartridge which
was eluted with a 30 min gradient from 0-100% EtOAc in hexane.
Fractions containing desired product were collected and
concentrated to yield Intermediate I-104C (1.9 g, 5.47 mmol, 55%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.52 (s, 2H),
4.34-4.26 (m, 1H), 4.18 (s, 1H), 4.15-4.05 (m, 1H), 1.24 (d, J=6.2
Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=8.1 Hz, 5H). LC-MS: Method H, MS
(ESI) m/z: 349.1 (M+H).sup.+.
Intermediate I-104D
(S)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)-N-(diphenylmethylene)pyrim-
idin-5-amine
##STR00277##
[1590] This intermediate was synthesized from Intermediate I-104C
using Procedure B. Intermediate I-104D was afforded in 78% yield
after chromatography. LC-MS: Method H, MS (ESI) m/z: 448.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95 (s,
2H), 7.78-7.71 (m, 2H), 7.53-7.30 (m, 6H), 7.16-7.06 (m, 2H),
4.31-4.11 (m, 2H), 4.08-4.01 (m, 1H), 1.22 (d, J=5.9 Hz, 3H), 0.87
(s, 9H), 0.05 (d, J=9.9 Hz, 6H).
Intermediate I-104
[1591] Intermediate I-104D (1.9 g, 4.24 mmol) was dissolved in
90:10:0.1 MeOH/water/TFA (14 ml) and the solution stirred for 15
minutes at room temperature then basified with 1.5 M dipotassium
phosphate solution and extracted with EtOAc (3.times.). The
combined organic layer was washed with brine (1.times.), dried with
sodium sulfate, filtered and concentrated. The resulting residue
was dissolved in methylene chloride and charged to an 80 g silica
gel cartridge which was eluted with a 30 min gradient from 0-15%
MeOH in methylene chloride. Fractions containing the desired
product were concentrated to yield Intermediate I-104 (210 mg,
0.741 mmol, 17% yield). LC-MS: RT=1.01 min, LC-MS: Method H, MS
(ESI) m/z: 284.2 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.92 (s, 2H), 4.93 (s, 2H), 4.16-3.83 (m, J=7.4, 5.6 Hz,
3H), 1.12 (d, J=6.2 Hz, 3H).
Intermediate I-105
(S)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyrimidin-5-amine
##STR00278##
[1593] This intermediate was prepared from (S)-propane-1,2-diol
using the same reaction sequence as described for Intermediate
I-106 below. LC-MS: Method H, MS (ESI) m/z: 284.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97 (s, 2H), 5.04 (d,
J=6.2 Hz, 1H), 3.78 (dd, J=10.3, 5.5 Hz, 1H), 3.60 (dd, J=10.3, 5.7
Hz, 1H), 1.28 (d, J=6.4 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 3H), -0.03
(s, 3H).
Intermediate I-106
(R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyrimidin-5-amine
##STR00279##
[1594] Intermediate I-106A:
(R)-2-((5-nitropyrimidin-2-yl)oxy)propan-1-ol,
(R)-1-((5-nitropyrimidin-2-yl)oxy)propan-2-ol
##STR00280##
[1596] To a vial containing 2-chloro-5-nitropyrimidine (300 mg, 1.9
mmol) was added DMF (3 mL) followed by (R)-propane-1,2-diol (0.5
mL, 6.81 mmol). Potassium carbonate (520 mg, 3.76 mmol) was then
added to the reaction mixture which was allowed to stir vigorously
at 65.degree. C. for 1 h. The reaction mixture was then quenched
with acetic acid (0.323 mL, 5.64 mmol), diluted with EtOAc and
filtered over a pad of silica gel. The filtrate was concentrated
before being purified by ISCO (40 g Gold Column, 0-100% EtOAc/Hex)
to afford Intermediate I-106A as a mixture of regioisomers (64 mg,
0.32 mmol, 17% yield). LC-MS: Method H, MS (ESI) m/z: 199.6
(M+H).sup.+.
Intermediate I-106B:
(R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-nitropyrimidin-
e
##STR00281##
[1598] Intermediate I-106A (64.0 mg, 0.321 mmol) was dissolved in
THF (5 mL) along with TEA (0.224 mL, 1.607 mmol) and DMAP (7.85 mg,
0.064 mmol). TBS-Cl (242 mg, 1.607 mmol) was added to the reaction
mixture which was allowed to stir for 18 h at room temperature. The
reaction mixture was then concentrated and the resulting residue
was dissolved in a small amount of methylene chloride and charged
to a 24 g silica gel cartridge which was eluted with a 15 min
gradient from 0-100% EtOAc in hexane. Fractions containing the
desired product concentrated to yield Intermediate I-106B (67 mg,
0.214 mmol, 66.5% yield). LC-MS: Method H, MS (ESI) m/z: 314.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.22 (s,
2H), 5.38 (d, J=4.8 Hz, 1H), 3.83-3.64 (m, 2H), 0.80-0.77 (m, 9H),
0.00 (s, 3H), -0.03 (s, 3H). MS (ESI) m/z 314.1 (M+H).
Intermediate I-106
[1599] Intermediate I-106B (67 mg, 0.214 mmol) was dissolved in
EtOAc (10 mL). Wet Pd--C (22.75 mg, 0.021 mmol, 10% by wt.) was
added to the reaction mixture which was allowed to stir under 1 atm
of hydrogen for 6 hours at room temperature. The reaction mixture
was then filtered through celite. The filtrate was concentrated to
yield Intermediate I-106 (55 mg, 0.194 mmol, 91% yield). The
product was brought forward without further purification. LC-MS:
Method H, MS (ESI) m/z: 284.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.97 (s, 2H), 5.11-4.82 (m, 1H), 3.80-3.73 (m,
1H), 3.64-3.52 (m, 1H), 3.28 (br. s., 2H), 1.28 (d, J=6.2 Hz, 3H),
0.83-0.77 (m, 9H), 0.00 (s, 3H), -0.03 (s, 3H).
Intermediate I-107
Methyl 5-aminopyrimidine-2-carboxylate
##STR00282##
[1600] Intermediate I-107A: methyl
5-((diphenylmethylene)amino)pyrimidine-2-carboxylate
##STR00283##
[1602] 5-bromopyrimidine-2-carboxylate was reacted according to
Procedure B to afford Intermediate I-107A (3.1 g, 9.77 mmol, 70.7%
yield) as a yellow solid. LC-MS: Method H, MS (ESI) m/z: 318.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.33 (s,
2H), 7.82 (d, J=6.3 Hz, 2H), 7.72-7.32 (m, 6H), 7.13 (br. s., 2H),
4.04 (s, 3H).
Intermediate I-107
[1603] Intermediate I-107A (0.2 g, 0.630 mmol) was solvated in a
mixture of THF (5 ml) and MeOH (5.00 ml). To this solution was
added 1M aqueous HCl (1.576 ml, 1.576 mmol). After 30 minutes of
stirring at room temperature the reaction mixture was diluted with
water and the aqueous phase was washed with 4:1 EtOAc/Hexanes
(3.times.) then concentrated to afford the aminopyrimidine HCl salt
intermediate. This crude intermediate was dissolved in MeOH and run
through solid supported HCO.sub.3.sup.- cartridge (PL-HCO3 MP SCE)
to form the free base. The cartridge was washed with MeOH and the
resulting solution was concentrated to yield Intermediate I-107
(0.065 g, 0.42 mmol, 67% yield). LC-MS: Method H, MS (ESI) m/z:
154.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16
(s, 2H), 6.38 (s, 2H), 3.80 (s, 3H).
Intermediate I-108
4-((4-aminopyridin-2-yl)oxy)-2-methylbutan-2-ol
##STR00284##
[1604] Intermediate I-108A:
4-((4-bromopyridin-2-yl)oxy)-2-methylbutan-2-ol
##STR00285##
[1606] This intermediate was prepared according to Procedure D from
3-methylbutane-1,3-diol. Intermediate I-108A was afforded in 80%
yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 261.9.
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (d,
J=5.5 Hz, 1H), 7.05 (dd, J=5.5, 1.8 Hz, 1H), 6.96 (d, J=1.5 Hz,
1H), 4.52 (t, J=6.5 Hz, 2H), 2.00 (t, J=6.5 Hz, 2H), 1.32 (s,
6H).
Intermediate I-108
[1607] Intermediate I-108 was prepared from Intermediate I-108A
according to Procedure E. Intermediate I-108 was afforded in 61%
yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 197.0.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (d, J=5.7 Hz, 1H),
6.14 (dd, J=5.7, 2.0 Hz, 1H), 5.89 (s, 2H), 5.77 (d, J=1.8 Hz, 1H),
4.33 (s, 1H), 4.21 (t, J=7.4 Hz, 2H), 1.76 (t, J=7.4 Hz, 2H), 1.13
(s, 6H).
Intermediate I-109
6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine
##STR00286##
[1608] Intermediate I-109A: methyl
2-(5-nitropyridin-2-yl)acetate
##STR00287##
[1610] Tert-butyl methyl malonate (2.64 g, 15.14 mmol) was
dissolved in THF (50 mL). Sodium hydride (0.605 g, 15.14 mmol) was
added portion-wise at 0.degree. C. and the reaction mixture was
allowed to stir for 15 min at room temperature.
2-chloro-5-nitropyridine (2.0 g, 12.61 mmol) dissolved in 10 mL of
THF was then added to the mixture and the mixture was allowed to
stir for 4 hours at room temperature before being quenched with
saturated aqueous ammonium chloride and extracted with EtOAc
(3.times.). The combined organic layer was washed with brine, dried
with sodium sulfate, filtered and concentrated. The resulting
residue was dissolved in 30 mL of 2:1 DCM/TFA and stirred for 1.5
hours. The reaction mixture was then diluted with 1.5 M potassium
phosphate solution and extracted with EtOAc (3.times.). The
combined organic layer was washed with brine, dried with sodium
sulfate, filtered and concentrated. The resulting residue was
dissolved in methylene chloride before being charged to an 80 g
silica gel cartridge which was eluted with a 30 min gradient from
0-100% EtOAc in hexane. Fractions containing the desired product
were concentrated to yield Intermediate I-109A (1.06 g, 5.40 mmol,
42.8% yield), as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 197.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.41 (d,
J=2.6 Hz, 1H), 8.49 (dd, J=8.6, 2.6 Hz, 1H), 7.56 (d, J=8.6 Hz,
1H), 4.02 (s, 2H), 3.78 (s, 3H).
Intermediate I-109B: 2-(5-nitropyridin-2-yl)ethanol
##STR00288##
[1612] This intermediate was prepared from Intermediate I-109A
using Procedure F. Intermediate I-109B was afforded in quantitative
yield and was brought forward without purification. LC-MS: Method
H, MS (ESI) m/z: 169.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 9.30 (d, J=2.6 Hz, 1H), 8.51 (dd, J=8.6, 2.6
Hz, 1H), 7.64-7.49 (m, 1H), 3.96 (t, J=6.3 Hz, 2H), 3.12 (t, J=6.4
Hz, 2H).
Intermediate I-109C:
2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitropyridine
##STR00289##
[1614] Intermediate I-109B was reacted according to Procedure I
using THF as a solvent to afford Intermediate I-109C (0.150 g,
0.531 mmol, 89% yield) as a yellow oil. LC-MS: Method H, MS (ESI)
m/z: 283.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.27 (d, J=2.6 Hz, 1H), 8.28 (dd, J=8.6, 2.6 Hz, 1H), 7.32 (d,
J=8.6 Hz, 1H), 3.92 (t, J=6.2 Hz, 2H), 3.01 (t, J=6.2 Hz, 2H), 0.81
(s, 9H), 0.00 (s, 6H).
Intermediate I-109
[1615] Intermediate I-109C (0.150 g, 0.531 mmol) was dissolved in
ethanol (5.3 ml) and Pd--C (0.113 g, 0.106 mmol, 10% by wt.) was
added to the solution followed by ammonium formate (0.167 g, 2.66
mmol). The reaction mixture was allowed to stir at reflux for 3
hours and was then filtered over celite and concentrated under
reduced pressure to yield Intermediate I-109 (0.075 g, 0.297 mmol,
56% yield). LC-MS: Method H, MS (ESI) m/z: 253.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, J=2.6 Hz, 1H),
7.02 (s, 1H), 6.99-6.94 (m, 1H), 3.94 (t, J=6.7 Hz, 2H), 3.69-3.54
(m, 2H), 2.92 (s, 2H), 0.89 (s, 9H), 0.00 (s, 6H).
Intermediate I-110
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-4-amine
##STR00290##
[1616] Intermediate I-110A: 2-((4-bromopyridin-2-yl)oxy)ethanol
##STR00291##
[1618] This intermediate was prepared according to Procedure D from
ethane-1,2-diol. Intermediate I-110A was afforded in 78% yield
after chromatography. LC-MS: Method H, MS (ESI) m/z: 219.9
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98 (d,
J=5.5 Hz, 1H), 7.09 (dd, 1.5 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H),
4.51-4.47 (m, 2H), 4.01-3.87 (m, 2H), 3.16 (s, 1H).
Intermediate I-110
[1619] Intermediate I-110A was reacted according to Procedure E to
afford the 4-aminopyridine intermediate which was brought forward
without further purification. To a solution of the crude
4-aminopyridine intermediate (205 mg, 1.330 mmol) dissolved in THF
(5 mL) was added DMAP (32.5 mg, 0.266 mmol) and TEA (0.927 mL, 6.65
mmol) followed by TBS-Cl (1002 mg, 6.65 mmol) and the mixture was
allowed to stir for 18 h at room temperature. The mixture was then
filtered through celite and the filtrate was concentrated. The
resulting residue was dissolved in methylene chloride before being
charged to a 24 g silica gel cartridge which was eluted with a 15
min gradient from 0-25% 2M NH.sub.3/MeOH in methylene chloride. The
fractions containing desired product were extracted with saturated
sodium bicarbonate (3.times.) to remove triethyl amine
hydrochloride, washed with brine (1.times.), dried with sodium
sulfate, filtered and concentrated to yield Intermediate I-110 (70
mg, 0.261 mmol, 20% yield), as a clear oil. LC-MS: Method H, MS
(ESI) m/z: 269.4 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.89-7.58 (m, 1H), 6.27-6.08 (m, 1H), 6.02-5.63 (m, 1H),
4.28-4.18 (m, 2H), 3.91-3.80 (m, 2H), 0.82 (s, 9H), 0.00 (s,
6H).
Intermediate I-111
(R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-4-amine,
(R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyridin-4-amine
(regioisomeric mixture)
##STR00292##
[1620] Intermediate I-111A:
(R)-1-((4-bromopyridin-2-yl)oxy)propan-2-ol,
(R)-2-((4-bromopyridin-2-yl)oxy)propan-1-ol (mixture of
regioisomer)
##STR00293##
[1622] This intermediate was prepared from (R)-propane-1,2-diol
using Procedure D. Intermediate I-111A was afforded as mixture of
regioisomers in quantitative yield. LC-MS: Method H, MS (ESI) m/z:
233.9 (M+H).sup.+.
Intermediate I-111
[1623] Intermediate I-111A was reacted according to Procedure E to
afford the 4-aminopyridine intermediates as a mixture of
regioisomers. To the crude mixture of 4-aminopyridine regioisomers
(302 mg, 1.8 mmol) dissolved in THF (5 mL) was added DMAP (43.9 mg,
0.359 mmol) and TEA (1.251 mL, 8.98 mmol) followed by TBS-Cl (1353
mg, 8.98 mmol) and the reaction mixture was allowed to stir at room
temperature for 18 h. The reaction mixture was then filtered
through celite and the filtrate was concentrated. The resulting
residue was dissolved in methylene chloride before being charged to
a 24 g silica gel cartridge which was eluted with a 15 min gradient
from 0-25% 2M NH.sub.3/MeOH in methylene chloride. Fractions
containing the desired product were concentrated to yield
Intermediate I-111 as a mixture (327 mg, 1.2 mmol, 65% yield).
LC-MS: Method H, MS (ESI) m/z: 283.0 (M+H).sup.+.
Intermediate I-112
5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-amine
##STR00294##
[1624] Intermediate I-112A: ethyl
5-((tert-butoxycarbonyl)amino)-2-methylnicotinate
##STR00295##
[1626] Tert-butyl carbamate (605 mg, 5.16 mmol), ethyl
5-bromo-2-methylnicotinate (420 mg, 1.72 mmol), xanthphos (100 mg,
0.172 mmol), Pd.sub.2(dba).sub.3 (158 mg, 0.172 mmol), cesium
carbonate (1121 mg, 3.44 mmol) and tert-butyl carbamate (605 mg,
5.16 mmol) were dissolved in dioxane (10 mL) in a pressure rated
vial and evacuated and backfilled with Ar 3.times.. The reaction
mixture was then heated at 85.degree. C. for 18 h. The reaction
mixture was then filtered through celite and the filtrate was
concentrated. The resulting residue was dissolved in a small amount
of methylene chloride before being charged to a 4 g silica gel
cartridge which was eluted with a 15 min gradient from 0-100% EtOAc
in hexane. Fractions containing the desired product were
concentrated to yield Intermediate I-112A in quantitative yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.44 (d, J=2.6 Hz, 1H),
8.32-8.24 (m, 1H), 6.49-6.31 (m, 1H), 4.31 (q, J=7.3 Hz, 2H), 1.46
(s, 9H), 1.33 (t, J=7.2 Hz, 3H).
Intermediate I-112
[1627] Intermediate I-112A (555 mg, 1.4 mmol) was dissolved in DCM
(10 mL)/TFA (2.5 mL) and the solution was stirred for 30 minutes at
room temperature. The reaction mixture was then concentrated to
yield the deprotected aminopyridine intermediate. This crude
intermediate was dissolved in THF (20 mL) at 0.degree. C. under Ar.
1M LAH in THF (12.94 mL, 12.94 mmol) was added dropwise to the
reaction mixture and the reaction mixture was allowed to stir at
room temperature for 1.5 hours. The reaction mixture was then
cooled to 0.degree. C. and quenched with 0.5 mL of water, 1 mL of
3N NaOH and then 5 mL of water. Magnesium sulfate was added to the
quenched mixture, which stirred for 10 minutes before being
filtered through celite and concentrated to yield the alcohol
intermediate. To the crude alcohol dissolved in DCM (10 mL) was
added imidazole (308 mg, 4.53 mmol) followed by TBS-Cl (634 mg,
4.21 mmol). The reaction mixture was stirred at room temperature
for 1 hour and was then concentrated to dryness. The resulting
residue was dissolved in a small amount of methylene chloride
before being charged to a 12 g silica gel cartridge which was
eluted with a 15 min gradient from 0-100% EtOAc in hexane.
Fractions containing desired product were concentrated to yield
Intermediate I-112 (22 mg, 0.087 mmol, 3% yield). LC-MS: Method H,
MS (ESI) m/z: 253.2 (M+H).sup.+.
Intermediate I-113
(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-amine
##STR00296##
[1628] Intermediate I-113A:
(R)-5-bromo-2((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)
pyrimidine
##STR00297##
[1630] (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (189 mg, 1.429
mmol) was reacted with 5-bromopyrimidin-2-ol (250 mg, 1.429 mmol)
according to the procedure described for Intermediate I-104C. After
silica gel chromatography, Intermediate I-113A (315 mg, 1.089 mmol,
76% yield) was yielded as a colorless oil. LC-MS: Method H, MS
(ESI) m/z: 290.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.53 (s, 1H), 4.54-4.46 (m, 1H), 4.46-4.40 (m, 1H),
4.38-4.31 (m, 1H), 4.15 (dd, J=8.6, 6.4 Hz, 1H), 3.93 (dd, J=8.5,
5.6 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).
Intermediate I-113B:
(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(diphenylmethylene)pyri-
midin-5-amine
##STR00298##
[1632] Intermediate I-113A ((315 mg, 1.089 mmol) was reacted
according to Procedure B to afford Intermediate I-113B, (300 mg,
1.089 mmol, 71% yield). LC-MS: Method H, MS (ESI) m/z: 390.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95 (s,
1H), 7.79-7.72 (m, 1H), 7.53-7.47 (m, 1H), 7.45-7.39 (m, 2H),
7.38-7.31 (m, 3H), 7.16-7.09 (m, 2H), 4.50-4.42 (m, 1H), 4.38-4.31
(m, 1H), 4.29-4.23 (m, 1H), 4.15-4.08 (m, 1H), 3.91 (dd, J=8.6, 5.7
Hz, 1H), 1.45-1.41 (m, 3H), 1.39-1.35 (m, 3H).
Intermediate I-113
[1633] Intermediate I-113B (300 mg, 0.770 mmol) was solvated in
MeOH with 0.1% TFA (8 mL) and the solution was stirred vigorously.
After 30 min of stirring, the reaction mixture was passed through a
PL-HCO.sub.3 ion exchange cartridge and washed with MeOH to remove
the TFA. The resulting solution was concentrated and azeotroped
with toluene to afford a 1:1 mixture of Intermediate I-113 and
benzophenone (115 mg, 0.631 mmol, 82% yield). The intermediate was
brought forward without further purification. LC-MS: Method H, MS
(ESI) m/z: 226.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.03 (s, 1H), 4.55-4.44 (m, 1H), 4.41-4.33 (m, 1H),
4.30-4.21 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.93 (dd, J=8.5,
5.8 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).
Intermediate I-114
(S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-amine
##STR00299##
[1635] Intermediate I-114 was prepared using the same reaction
sequence as described for I-113. LC-MS: Method H, MS (ESI) m/z:
226.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.03
(s, 1H), 4.55-4.44 (m, 1H), 4.41-4.33 (m, 1H), 4.30-4.21 (m, 1H),
4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.93 (dd, J=8.5, 5.8 Hz, 1H), 1.45
(s, 3H), 1.38 (s, 3H).
Intermediate I-115
N2,N2-dimethylpyrimidine-2,5-diamine, 2 HCl
##STR00300##
[1636] Intermediate I-115A:
N5-(diphenylmethylene)-N2,N2-dimethylpyrimidine-2,5-diamine
##STR00301##
[1638] 5-bromo-N,N-dimethylpyrimidin-2-amine (200 mg, 1.0 mmol) was
reacted according to Procedure B to afford Intermediate I-115A, (70
mg, 0.23 mmol, 24% yield) after chromatography. LC-MS: Method H, MS
(ESI) m/z: 303.2 (M+H).sup.+.
Intermediate I-115
[1639] Intermediate I-115A was reacted according to Procedure C to
afford Intermediate I-115 in quantitative yield. This intermediate
was brought forward without further purification. LC-MS: Method H,
MS (ESI) m/z: 138.9 (M+H).sup.+.
Intermediate I-116
N-(5-aminopyrimidin-2-yl)-N-methylmethanesulfonamide
##STR00302##
[1640] Intermediate I-116A:
N-(5-bromopyrimidin-2-yl)-N-methylmethanesulfonamide
##STR00303##
[1642] To a solution of 5-bromo-N-methylpyrimidin-2-amine (2.55 g,
13.56 mmol) in DMF (30 mL) at 0.degree. C. was added NaH (0.705 g,
17.63 mmol) portion-wise. The mixture was stirred for 30 min at
0.degree. C. Methanesulfonyl chloride (1.864 g, 16.27 mmol) was
then added dropwise. The mixture was warmed to room temperature and
stirred for an additional 2 h at room temperature. The reaction
mixture was then quenched with water (10 mL) at 0.degree. C. and
then extracted with EtOAc (3.times.30 mL). The combined organic
layer was washed with brine (30 mL), dried over MgSO.sub.4,
filtered, and concentrated. This resulting residue was dissolved in
a small amount of methylene chloride before being charged to an 80
g column which was eluted with 1% MeOH in DCM. Fractions containing
the desired product were concentrated to yield Intermediate I-116A
(1.26 g, 35% yield). LC-MS: Method H, MS (ESI) m/z: 268.0
(M+H).sup.+.
Intermediate I-116
[1643] Intermediate I-116A was reacted according to Procedure B to
provide to the desired imine intermediate after silica gel
chromatography. This imine intermediate was reacted according to
Procedure C to afford the desired product which was brought forward
without further purification. LC-MS: Method H, MS (ESI) m/z: 203.0
(M+H).sup.+.
Intermediate I-117
methyl 3-(5-aminopyrimidin-2-yl)propanoate
##STR00304##
[1644] Intermediate I-117A:
5-((diphenylmethylene)amino)pyrimidine-2-carbaldehyde
##STR00305##
[1646] Intermediate I-107A (1.1 g, 3.47 mmol) was dissolved in THF
(50 ml) and the mixture was cooled to -78.degree. C. DIBAL-H (10.40
ml, 10.40 mmol) was added to the mixture which was allowed to stir
for 1 hour at -78.degree. C. The reaction mixture was then quenched
with saturated Rochelle's salt at -78.degree. C. and the resulting
slurry was allowed to stir overnight under a stream of Ar. The
mixture was then extracted with EtOAc (3.times.) and the combined
organic layer was washed with brine, dried with sodium sulfate,
filtered through celite and concentrated to yield Intermediate
I-117A in quantitative yield. LC-MS: Method H, MS (ESI) m/z: 154.1
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.17 (s,
2H), 3.80 (s, 3H).
Intermediate I-117B: (E)-methyl
3-(5-((diphenylmethylene)amino)pyrimidin-2-yl)acrylate
##STR00306##
[1648] Methyl 2-(dimethoxyphosphoryl)acetate (0.190 g, 1.044 mmol)
was dissolved in THF (10 mL). 60% sodium hydride in mineral oil
(0.042 g, 1.044 mmol) was added to the solution at 0.degree. C. and
the solution was allowed to stir at 0.degree. C. for 20 minutes.
Intermediate I-117A (0.25 g, 0.870 mmol) dissolved in 2 mL of THF
was then added to the reaction mixture at 0.degree. C. which was
then allowed to warm to room temperature and stir for 5 minutes.
The reaction mixture was then quenched with saturated ammonium
chloride and extracted with EtOAc (3.times.). The combined organic
layer was washed with brine, dried with sodium sulfate, filtered
and concentrated. The resulting residue was dissolved in a small
amount of methylene chloride and charged to a 24 g silica gel
cartridge which was eluted with a 15 min gradient from 0-100% EtOAc
in hexane. Fractions containing desired product were collected and
concentrated to yield Intermediate I-117B (250 mg, 0.728 mmol, 84%
yield) as a yellow solid. LC-MS: Method H, MS (ESI) m/z: 344.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.18 (s,
2H), 7.84-7.71 (m, 3H), 7.60 (d, J=15.8 Hz, 1H), 7.55-7.29 (m, 8H),
7.17-7.09 (m, 3H), 7.02 (d, J=15.6 Hz, 1H), 3.80 (s, 3H).
Intermediate I-117
[1649] Intermediate I-117B (170 mg, 0.495 mmol) was dissolved in
MeOH (10 mL)/water (0.5 mL). TFA (0.038 mL, 0.495 mmol) was added
to the solution which was allowed to stir at room temperature for
2.5 h. The reaction mixture was concentrated. The resulting free
aniline intermediate was then dissolved in ethanol (10 mL)/ethyl
acetate (10 mL) and Hunig's Base (0.432 mL, 2.473 mmol) was added
to the solution. Wet Pd--C (25 mg, 0.235 mmol, 10% by wt.) was then
added to the reaction mixture which was evacuated and backfilled
with 1 atm of hydrogen 3.times.. The reaction mixture was allowed
to stir for 1 h under 1 atm of hydrogen at room temperature. The
mixture was then filtered through a pad of celite, concentrated and
the resulting residue was dissolved in methylene chloride and
charged to a 12 g silica gel cartridge which was eluted with a 15
min gradient from 0-20% MeOH in methylene chloride. Fractions
containing the desired product were collected and concentrated to
yield Intermediate I-117 (30 mg, 0.166 mmol, 34% yield). LC-MS:
Method H, MS (ESI) m/z: 182.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.17 (s, 2H), 3.70 (s, 3H), 3.60 (br. s., 2H),
3.22 (t, J=7.4 Hz, 2H), 2.86 (t, J=7.4 Hz, 2H).
Intermediate I-118
methyl
5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)ben-
zo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)nicotinate
##STR00307##
[1651] Intermediate I-118 was prepared from Intermediate I-72 and
methyl 5-aminonicotinate according to the procedure described in
the table of carbamate examples below. LC-MS: Method H, MS (ESI)
m/z: 593.0 (M+H).sup.+.
Intermediate I-119
5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine
##STR00308##
[1653] Methyl 5-aminonicotinate (250 mg, 1.643 mmol) was dissolved
in THF (20 mL) at 0.degree. C. LAH (6.57 mL, 6.57 mmol, 1 M in THF)
was added dropwise to the solution over 2 minutes. The reaction
mixture was then allowed to warm to room temperature and stirred at
room temperature for 1.5 hours. The reaction mixture was then
quenched water at 0.degree. C. (1 mL), followed by addition of 1M
NaOH (2 mL) and an additional 4 mL of water. The quenched reaction
mixture was stirred for 10 minutes at room temperature then
magnesium sulfate was added. The mixture was filtered through
celite and the filtrate was concentrated to yield the intermediate
alcohol. This crude alcohol intermediate was reacted according to
Procedure I to yield Intermediate I-119 (251 mg, 1.05 mmol, 65%
yield) after silica chromatography. LC-MS: Method H, MS (ESI) m/z:
239.2 (M+H).sup.+.
Intermediate I-120
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-formylpyrimidin-5-yl)carbamate
##STR00309##
[1655] Intermediate I-86 (16 mg, 0.027 mmol) was dissolved in THF
(5 mL) and cooled -78.degree. C. DIBAL-H (0.135 mL, 0.135 mmol) was
added to the reaction mixture dropwise which was then allowed to
stir at -78.degree. C. for 1 hour. The mixture was then quenched
with saturated Rochelle's salt and stirred for 30 min. at room
temperature. The resulting mixture was extracted with EtOAc
(3.times.) and the combined organic layer was washed with brine,
dried with sodium sulfate, filtered and concentrated to yield
Intermediate I-120 (5 mg, 8.89 .mu.mol, 32.9% yield). The product
was brought forward without further purification. LC-MS: Method H,
MS (ESI) m/z: 562.9 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.92 (s, 1H), 8.99 (s, 2H), 8.53-8.28 (m, 2H), 7.77-7.60
(m, 2H), 7.42 (d, J=7.7 Hz, 1H), 6.91 (s, 1H), 5.17-5.05 (m, 1H),
4.66-4.46 (m, 1H), 4.13-3.83 (m, 3H), 2.56 (s, 3H), 1.47-1.39 (m,
3H), 1.35-1.33 (m, 3H).
Intermediate I-121
6-chloro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-
e
##STR00310##
[1656] Intermediate I-121A: 8-bromo-6-chloro-3-methoxyquinoline
##STR00311##
[1658] Intermediate I-122 (2 g, 6.78 mmol), potassium carbonate
(2.81 g, 20.3 mmol), and methyl iodide (0.848 mL, 13.6 mmol) were
dissolved in acetone (67.8 mL) and heated to 50.degree. C. in a
sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
I-121A (2.04 g, 7.48 mmol) as a yellow solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.76 (d, J=2.6 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H),
7.70 (d, J=2.2 Hz, 1H), 7.29 (d, J=2.9 Hz, 1H), 3.97 (s, 3H);
LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 272/274
(M+H).sup.+.
Intermediate I-121
[1659] Intermediate I-121A (1 g, 3.67 mmol), bispinacolatodiboron
(1.86 g, 7.34 mmol), potassium acetate (0.900 g, 9.17 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.240 g, 0.294 mmol) were
stored on HIVAC for 15 minutes then were dissolved in dry
1,4-dioxane (18.4 mL) and degassed for 15 minutes by bubbling with
argon. The reaction mixture was heated to 130.degree. C. in the
microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 80 g silica gel column, 29
minute gradient from 0 to 100% EtOAc in DCM, followed by 0 to 20%
MeOH in DCM) to give Intermediate I-121 (368 mg, 1.15 mmol, 31.4%)
as a brown solid: LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 237.9
(boronic acid mass observed, M+H).sup.+.
Intermediate I-122
8-bromo-6-chloroquinolin-3-ol, HCl
##STR00312##
[1660] Intermediate I-122A:
3-(benzyloxy)-8-bromo-6-chloroquinoline
##STR00313##
[1662] Intermediate I-123 (5 g, 21.32 mmol),
2-(benzyloxy)acetaldehyde (3.20 g, 21.3 mmol), and sodium methoxide
solution (0.5 M in MeOH, 46.9 mL, 23.5 mmol) were dissolved in MeOH
(42.6 mL) and heated to reflux. After heating overnight, the
reaction mixture was diluted with saturated NH.sub.4Cl, partially
concentrated in vacuo and diluted with EtOAc. The layers were
separated and the organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 330 g silica
gel column, 30 minute gradient from 0 to 17% EtOAc in hexanes) to
give Intermediate I-122A (4.97 g, 14.3 mmol, 67%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.85 (d, J=2.8 Hz,
1H), 7.89 (d, J=1.9 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.52-7.48 (m,
2H), 7.48-7.43 (m, 2H), 7.43-7.38 (m, 1H), 7.37 (d, J=2.8 Hz, 1H),
5.24 (s, 2H); LC-MS: Method H, RT=1.46 min, MS (ESI) m/z: 348/350
(M+H).sup.+.
Intermediate I-122
[1663] Intermediate I-122A (4.87 g, 14 mmol) and pentamethylbenzene
(14.5 g, 98 mmol) were dissolved in DCM (279 mL) and cooled to
-78.degree. C. Boron trichloride (1 M in heptane, 36.3 mL, 36.3
mmol) was then added and the reaction mixture was allowed to slowly
warm to ambient temperature. After stirring overnight, the reaction
mixture was diluted with hexanes and 1 N HCl and allowed to stir
for 1 hour. The resulting solid was collected by suction
filtration, rinsing with water and hexanes to give Intermediate
I-122 (3.39 g, 11.5 mmol, 82%) as an off-white solid: .sup.1H NMR
(400 MHz, MeOH.sub.4) .delta. 8.59 (d, J=2.6 Hz, 1H), 7.84 (d,
J=2.2 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H);
LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 258/260
(M+H).sup.+.
Intermediate I-123
2-amino-3-bromo-5-chlorobenzaldehyde
##STR00314##
[1664] Intermediate I-123A: methyl
2-amino-3-bromo-5-chlorobenzoate
##STR00315##
[1666] Methyl 2-amino-5-chlorobenzoate (18.1 g, 97 mmol) and NBS
(17.3 g, 97 mmol) were dissolved in AcOH (195 mL) and heated to
120.degree. C. After 1.5 hours, the reaction mixture was cooled to
ambient temperature and diluted with EtOAc. The reaction was then
quenched with vigorous stirring with saturated NaHCO.sub.3. The
layers were separated and the organic layer further washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate I-123A (25.7 g, 97 mmol, 100%) as a
yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.87 (d,
J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 6.36 (br. s., 2H), 3.92 (s,
3H); LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 264/266
(M+H).sup.+.
Intermediate I-123B: (2-amino-3-bromo-5-chlorophenyl)methanol
##STR00316##
[1668] Intermediate I-123A (25.7 g, 97 mmol) was dissolved in THF
(324 mL). Lithium borohydride (4.23 g, 194 mmol) was added and the
reaction mixture was heated to 50.degree. C. After 2 hours, the
reaction mixture was diluted with water and stirred for 30 minutes.
All of the lithium borohydride had not dissolved, so concentrated
HCl was added carefully to speed up the quenching process. The
reaction mixture was then extracted thrice with EtOAc. The combined
organic layers were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate I-123B
(23.9 g, 101 mmol, 100%) as a white solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.43 (d, J=2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H),
4.72 (br. s., 2H), 4.68 (d, J=5.9 Hz, 2H), 1.63 (t, J=5.8 Hz, 1H);
LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 236/238
(M+H).sup.+.
Intermediate I-123
[1669] Intermediate I-123B (23.9 g, 101 mmol) was dissolved in
CHCl.sub.3 (674 mL). Manganese dioxide (17.6 g, 202 mmol) was added
and the reaction mixture was heated to 40.degree. C. After heating
for 2 days, more manganese dioxide (17.6 g, 202 mmol) was added and
heating was continued. After heating overnight, the reaction
mixture was filtered through celite and concentrated in vacuo to
give Intermediate I-123 (22 g, 94 mmol, 93%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.79 (s, 1H), 7.64 (d,
J=2.4 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 6.70 (br. s., 2H); LC-MS:
Method H, RT=1.27 min, compound did not ionize.
Intermediate I-124
3-methoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-
e
##STR00317##
[1671] Intermediate I-125 (183 mg, 0.726 mmol),
bispinacolatodiboron (369 mg, 1.45 mmol), potassium acetate (178
mg, 1.82 mmol), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (47.4
mg, 0.058 mmol) were stored on HIVAC for 15 minutes then were
dissolved in dry 1,4-dioxane (7.26 mL) and degassed for 15 minutes
by bubbling with argon. The reaction mixture was heated to
130.degree. C. in the microwave for 40 minutes. The reaction
mixture was diluted with EtOAc and washed with water then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 24 g
silica gel column, 19 minute gradient from 0 to 100% EtOAc in DCM
then 0 to 20% MeOH in DCM) to give Intermediate I-124 (108 mg, 0.36
mmol, 50%) as a brown solid: LC-MS: Method H, RT=0.80 min, MS (ESI)
m/z: 218.0 (boronic acid observed, M+H).sup.+.
Intermediate I-125
8-bromo-3-methoxy-6-methylquinoline
##STR00318##
[1672] Intermediate I-125A: methyl
2-amino-3-bromo-5-methylbenzoate
##STR00319##
[1674] 2-Amino-3-bromo-5-methylbenzoic acid (3.8 g, 16.5 mmol) was
dissolved in MeOH (33.0 mL). Thionyl chloride (3.62 mL, 49.6 mmol)
was added carefully dropwise and the reaction mixture was heated to
65.degree. C. After stirring for 8 days, the reaction mixture was
concentrated in vacuo. The crude material was redissolved in EtOAc,
washed with 1 N NaOH, water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate I-125A
(3.38 g, 13.9 mmol, 84%) as an orange oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.66 (d, J=1.1 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H),
6.14 (br. s., 2H), 3.88 (s, 3H), 2.22 (s, 3H); LC-MS: Method H,
RT=1.18 min, MS (ESI) m/z: 244/246 (M+H).sup.+.
Intermediate I-125B: (2-amino-3-bromo-5-methylphenyl)methanol
##STR00320##
[1676] Intermediate I-125A (3.38 g, 13.8 mmol) was dissolved in THF
(46.2 mL). Lithium borohydride (0.603 g, 27.7 mmol) was added and
the reaction mixture was heated to 50.degree. C. After 1 hour, the
reaction mixture was diluted with water and stirred for 30 minutes.
All of the lithium borohydride had not dissolved, so concentrated
HCl was added carefully to speed up the quenching process. The
reaction mixture was then extracted thrice with EtOAc. The combined
organic layers were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate I-125B
(2.85 g, 13.2 mmol, 95%) as a white solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.23 (d, J=1.1 Hz, 1H), 6.84 (d, J=1.3 Hz, 1H),
4.65 (s, 2H), 4.53 (br. s., 2H), 2.22 (s, 3H); LC-MS: Method H,
RT=1.00 min, MS (ESI) m/z: 216/218 (M+H).sup.+.
Intermediate I-125C: 2-amino-3-bromo-5-methylbenzaldehyde
##STR00321##
[1678] Intermediate I-125B (2.85 g, 13.2 mmol) was dissolved in
CHCl.sub.3 (88 mL). Manganese dioxide (6.88 g, 79 mmol) was added
and the reaction mixture was heated to 40.degree. C. After heating
overnight, the reaction mixture was filtered through celite and
concentrated in vacuo to give Intermediate I-125C (2.72 g, 12.7
mmol, 96%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.78 (s, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.28-7.26 (m, 1H),
6.49 (br. s., 2H), 2.28 (s, 3H); LC-MS: Method H, RT=1.26 min, MS
(ESI) m/z: 214/216 (M+H).sup.+.
Intermediate I-125D: 3-(benzyloxy)-8-bromo-6-methylquinoline
##STR00322##
[1680] Intermediate I-125C (2.72 g, 12.7 mmol),
2-(benzyloxy)acetaldehyde (1.91 g, 12.7 mmol), and sodium methoxide
(0.5 M in MeOH, 28.0 mL, 13.98 mmol) were dissolved in MeOH (50.8
mL) and heated to reflux. After heating overnight, the reaction
mixture was diluted with saturated NH.sub.4Cl, partially
concentrated in vacuo and diluted with EtOAc. The layers were
separated and the organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 220 g silica
gel column, 41 minute gradient from 0 to 40% EtOAc in hexanes) to
give Intermediate I-125D (1.86 g, 5.67 mmol, 45%) as a yellow
solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.79 (d, J=2.9 Hz,
1H), 7.74 (d, J=1.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.45-7.40 (m, 3H),
7.39-7.33 (m, 2H), 5.20 (s, 2H), 2.49 (s, 3H); LC-MS: Method H,
RT=1.22 min, MS (ESI) m/z: 328/330 (M+H).sup.+.
Intermediate I-125E: 8-bromo-6-methylquinolin-3-ol
##STR00323##
[1682] Intermediate I-125D (1.86 g, 5.67 mmol) and
pentamethylbenzene (5.88 g, 39.7 mmol) were dissolved in DCM (113
mL) and cooled to -78.degree. C. Boron trichloride (1 M in heptane,
14.7 mL, 14.7 mmol) was added and the reaction mixture was allowed
to warm slowly to ambient temperature. After stirring overnight,
the reaction mixture was diluted with hexanes and 1 N HCl and
allowed to stir for 1 hour. The aqueous layer still contained
product by LCMS. The aqueous layer was neutralized with NaOH until
approximately pH 7 and copious amounts of precipitates were formed.
The precipitate was collected by suction filtration to give I-125E
(829 mg, 3.48 mmol, 62%) as an off-white solid: .sup.1H NMR (400
MHz, MeOH.sub.4) .delta. 8.50 (d, J=2.6 Hz, 1H), 7.72 (s, 1H), 7.51
(s, 1H), 7.43 (d, J=1.8 Hz, 1H), 2.47 (s, 3H); LC-MS: Method H,
RT=0.82 min, MS (ESI) m/z: 238/240 (M+H).sup.+.
Intermediate I-125
[1683] Intermediate I-125E (200 mg, 0.728 mmol), K.sub.2CO.sub.3
(302 mg, 2.18 mmol), and methyl iodide (91 .mu.l, 1.46 mmol) were
dissolved in acetone (7.29 mL) and heated to 50.degree. C. in a
sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate I-125 (207 mg, 0.82 mmol, 100%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.71 (d, J=2.9 Hz, 1H),
7.74 (d, J=1.8 Hz, 1H), 7.46 (s, 1H), 7.29 (d, J=2.9 Hz, 1H), 3.95
(s, 3H), 2.50 (s, 3H); LC-MS: Method H, RT=1.06 min, MS (ESI) m/z:
252/254 (M+H).sup.+.
Intermediate I-126
6-chloro-3-ethoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
##STR00324##
[1684] Intermediate I-126A: 8-bromo-6-chloro-3-ethoxyquinoline
##STR00325##
[1686] Intermediate I-122 (300 mg, 1.02 mmol), K.sub.2CO.sub.3 (422
mg, 3.05 mmol), and iodoethane (163 .mu.L, 2.03 mmol) were
dissolved in Acetone (10 mL) and heated to 50.degree. C. in a
sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate I-126A (319 mg, 1.11 mmol, 100%) as a light yellow
solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.74 (d, J=2.6 Hz,
1H), 7.85 (d, J=2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.28-7.24 (m,
1H), 4.17 (q, J=6.9 Hz, 2H), 1.52 (t, J=7.0 Hz, 3H); LC-MS: Method
H, RT=1.22 min, MS (ESI) m/z: 286/288 (M+H).sup.+.
Intermediate I-126
[1687] Intermediate I-126A (319 mg, 1.11 mmol),
bispinacolatodiboron (565 mg, 2.23 mmol), potassium acetate (273
mg, 2.78 mmol), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (72.7
mg, 0.089 mmol) were stored on HIVAC for 15 minutes then were
dissolved in dry 1,4-dioxane (5.67 mL) and degassed for 15 minutes
by bubbling with argon. The reaction mixture was heated to
130.degree. C. in the microwave for 40 minutes. The reaction
mixture was diluted with EtOAc and washed with water then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 80 g
silica gel column, 29 minute gradient from 0 to 100% EtOAc in DCM,
followed by 0 to 20% MeOH in DCM) to give Intermediate I-126 (114
mg, 0.343 mmol, 31%) as a brown solid: LC-MS: Method H, RT=0.88
min, MS (ESI) m/z: 251.9 (boronic acid mass observed,
M+H).sup.+.
Intermediate I-127
6-chloro-3-(difluoromethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)quinoline
##STR00326##
[1688] Intermediate I-127A:
8-bromo-6-chloro-3-(difluoromethoxy)quinoline
##STR00327##
[1690] Intermediate I-122 (0.5 g, 1.7 mmol) and K.sub.2CO.sub.3
(1.17 g, 8.48 mmol) were suspended in DMF (17 mL) and heated to
100.degree. C. Sodium 2-chloro-2,2-difluoroacetate (1.03 g, 6.78
mmol) was then added. After heating for 1 hour, the reaction
mixture was cooled to ambient temperature, diluted with water, and
extracted thrice with EtOAc. The combined organic extracts were
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 12 g silica gel column, 17 minute gradient
from 0 to 50% EtOAc in hexanes) to give Intermediate I-127A (342
mg, 1.11 mmol, 66%) as a light yellow solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.87 (d, J=2.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H),
7.80 (d, J=2.4 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 6.88-6.49 (m, 1H);
LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 308/310
(M+H).sup.+.
Intermediate I-127
[1691] Intermediate I-127A (340 mg, 1.1 mmol), bispinacolatodiboron
(560 mg, 2.2 mmol), potassium acetate (270 mg, 2.76 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (72.0 mg, 0.088 mmol) were
stored on HIVAC for 15 minutes then were dissolved in dry
1,4-dioxane (5.51 mL) and degassed for 15 minutes by bubbling with
argon. The reaction mixture was heated to 130.degree. C. in the
microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 80 g silica gel column, 29
minute gradient from 0 to 100% EtOAc in DCM, followed by 0 to 20%
MeOH in DCM) to give Intermediate I-127 (175 mg, 0.492 mmol, 45%)
as a brown solid: LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 274.1
(boronic acid mass observed, M+H).sup.+.
Intermediate I-128
6-(difluoromethyl)-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)quinoline
##STR00328##
[1692] Intermediate I-128A:
8-bromo-3-methoxyquinoline-6-carbaldehyde
##STR00329##
[1694] Intermediate I-125 (152 mg, 0.602 mmol) and selenium dioxide
(401 mg, 3.61 mmol) were suspended in 1,4-dioxane (3.01 mL) and
heated to 180.degree. C. in the microwave for 8 hours. The reaction
mixture was filtered and concentrated in vacuo. The solids were
then suspended in DCM and the insoluble material removed by suction
filtration to give Intermediate I-128A (170 mg, 0.639 mmol, 100%)
as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.15
(s, 1H), 8.93 (d, J=2.9 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.25 (d,
J=1.5 Hz, 1H), 7.56 (d, J=2.9 Hz, 1H), 4.04 (s, 3H); LC-MS: Method
H, RT=0.89 min, MS (ESI) m/z: 266/268 (M+H).sup.+.
Intermediate I-128B:
8-bromo-6-(difluoromethyl)-3-methoxyquinoline
##STR00330##
[1696] Intermediate I-128A (50 mg, 0.188 mmol) and deoxofluor (104
.mu.l, 0.564 mmol) were dissolved in DCM (940 .mu.L). After
stirring overnight, the reaction mixture was diluted carefully with
water then extracted thrice with DCM. The combined organic layers
were washed with saturated NaHCO.sub.3 then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate I-128B (37 mg, 0.129 mmol, 68%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.88 (d, J=2.9 Hz, 1H),
8.03 (d, J=1.5 Hz, 1H), 7.89 (d, J=1.3 Hz, 1H), 7.46 (d, J=2.9 Hz,
1H), 6.96-6.64 (t, J=56 Hz, 1H), 4.02 (s, 1H); LC-MS: Method H,
RT=0.98 min, MS (ESI) m/z: 288/290 (M+H).sup.+.
Intermediate I-128
[1697] Intermediate I-128B (37 mg, 0.128 mmol),
bispinacolatodiboron (65.2 mg, 0.257 mmol), potassium acetate (31.5
mg, 0.321 mmol), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (8.39
mg, 10.3 .mu.mol) were stored on HIVAC for 15 minutes then were
dissolved in dry 1,4-dioxane (642 .mu.L) and degassed for 15
minutes by bubbling with argon. The reaction mixture was heated to
130.degree. C. in the microwave for 40 minutes. The reaction
mixture was diluted with EtOAc and washed with water then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate I-128. The crude material was used directly in
the subsequent step: LC-MS: Method H, RT=0.80 min, MS (ESI) m/z:
254.1 (boronic acid mass observed, M+H).sup.+.
Intermediate I-129
6-(fluoromethyl)-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
quinoline
##STR00331##
[1698] Intermediate I-129A:
(8-bromo-3-methoxyquinolin-6-yl)methanol
##STR00332##
[1700] Intermediate I-128A (50 mg, 0.188 mmol) was dissolved in
MeOH (1.88 mL) and cooled to 0.degree. C. Sodium borohydride (14.2
mg, 0.376 mmol) was then added. After 1 hour, the reaction mixture
was diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate I-129A (38.6 mg, 0.144 mmol, 77%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.79 (d, J=2.9 Hz, 1H),
7.92 (d, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=2.9 Hz, 1H), 4.89
(d, J=5.1 Hz, 2H), 4.00 (s, 3H), 1.89 (t, J=5.6 Hz, 1H); LC-MS:
Method H, RT=0.73 min, MS (ESI) m/z: 268/270 (M+H).sup.+.
Intermediate I-129B:
8-bromo-6-(fluoromethyl)-3-methoxyquinoline
##STR00333##
[1702] Intermediate I-129A (38 mg, 0.142 mmol) and Deoxofluor (78
.mu.L, 0.425 mmol) were dissolved in DCM (709 .mu.L). After
stirring overnight, the reaction mixture was diluted carefully with
water then extracted thrice with DCM. The combined organic layers
were washed with saturated NaHCO.sub.3 then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate I-129B (29 mg, 0.109 mmol, 77%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.83 (d, J=2.9 Hz, 1H),
7.91 (s, 1H), 7.73 (s, 1H), 7.41 (d, J=2.6 Hz, 1H), 5.62-5.48 (t,
J=48 Hz, 2H), 4.00 (s, 3H); LC-MS: Method H, RT=0.94 min, MS (ESI)
m/z: 270/272 (M+H).sup.+.
Intermediate I-129
[1703] Intermediate I-129B (29 mg, 0.107 mmol),
bispinacolatodiboron (54.5 mg, 0.215 mmol), potassium acetate (26.3
mg, 0.268 mmol), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (7.01
mg, 8.59 .mu.mol) were stored on HIVAC for 15 minutes then were
dissolved in dry 1,4-dioxane (537 .mu.L) and degassed for 15
minutes by bubbling with argon. The reaction mixture was heated to
130.degree. C. in the microwave for 40 minutes. The reaction
mixture was diluted with EtOAc and washed with water then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate I-129, which was used directly for the subsequent
step: LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 236.1 (boronic
acid mass observed, M+H).sup.+
Intermediate I-130
(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR00334##
[1705] Intermediate I-72A (300 mg, 0.937 mmol) was dissolved in THF
(18.7 mL). Phosgene solution (15% in toluene, 7.14 mL, 9.37 mmol)
was then added. After stirring overnight, the reaction mixture was
concentrated in vacuo and stored on HIVAC for 3 hours. The reaction
mixture was dissolved in THF (18.7 mL). 2-Methylpyrimidin-5-amine
(123 mg, 1.12 mmol) and pyridine (758 .mu.L, 9.37 mmol) were added.
After 1 hour, the reaction mixture was concentrated in vacuo and
purified by column chromatography (ISCO, 24 g silica gel column, 19
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate I-130 (327 mg, 0.796 mmol, 85%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.72 (br. s., 2H), 7.66
(d, J=11.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 6.55 (br. s., 1H), 5.14
(dd, J=6.5, 3.0 Hz, 1H), 4.60-4.49 (m, 1H), 2.71 (s, 3H), 1.44 (d,
J=6.6 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H); LC-MS: Method H, RT=0.95
min, MS (ESI) m/z: 411.0 (M+H).sup.+.
Intermediate I-131
(R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
##STR00335##
[1706] Intermediate I-131A:
6-fluoro-5-methoxythiazolo[5,4-b]pyridin-2-amine
##STR00336##
[1708] Potassium thiocyanate (0.738 g, 7.59 mmol) was dissolved in
acetic acid (5 mL) and cooled to 0.degree. C.
5-fluoro-6-methoxypyridin-3-amine (1.079 g, 7.59 mmol) was
dissolved in acetic acid (1.667 mL) and added dropwise. Bromine
(0.782 mL, 15.18 mmol) was dissolved in acetic acid (1.667 mL) and
added dropwise to the reaction. The reaction mixture was allowed to
warm to room temperature and stir overnight. The reaction mixture
was concentrated under reduced pressure. The resultant residue was
diluted with water and neutralized with 1 N NaOH. The aqueous
solution was extracted with EtOAc.times.3. The combined organic
layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate I-131A
(1.496 g, 7.51 mmol, 99% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.49 (d, J=10.6 Hz, 1H), 5.14 (br. s., 2H), 4.03 (s, 3H).
LC-MS: method H, RT=0.65 min, MS (ESI) m/z: 200.0 (M+H).sup.+.
Intermediate I-131B: 2-amino-6-fluorothiazolo[5,4-b]pyridin-5-ol,
2hydrobromide
##STR00337##
[1710] Intermediate I-131A (0.500 g, 2.510 mmol) was dissolved in a
solution of HBr in acetic acid (1.704 mL, 15.06 mmol, 33% by wt.)
and the reaction mixture was stirred at 130.degree. C. for 3h. The
reaction mixture was concentrated under reduced pressure to yield
Intermediate I-131B (0.88 g, 2.54 mmol, 101% yield) as a tan solid.
.sup.1H NMR (400 MHz, MeOH.sub.4) .delta. 7.66 (d, J=9.7 Hz, 1H)
LC-MS: method H, RT=0.45 min, MS (ESI) m/z: 186.1 (M+H).sup.+.
Intermediate I-131C
(R)-1-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
##STR00338##
[1712] To a solution of Intermediate I-131B (1.00 g, 2.88 mmol) in
tetrahydrofuran (23.05 ml) was added
(R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (0.478 g, 3.46 mmol)
followed by potassium carbonate (1.195 g, 8.65 mmol). The reaction
mixture was stirred vigorously at 60.degree. C. for 3h then at room
temperature for 48 hours. Sulfuric acid (0.768 ml, 14.41 mmol)
followed by water (0.156 ml, 8.65 mmol) were added slowly to the
reaction. The reaction mixture was allowed to stir at room
temperature for 1 h. The reaction mixture was diluted with 1 N NaOH
and EtOAc. The layers were separated and the organic layer was
washed with brine, dried with sodium sulfate, and concentrated
under reduced pressure to yield Intermediate I-131C (0.284 g, 1.167
mmol, 40.5% yield) as a yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51 (d, J=10.6 Hz, 1H), 5.09 (br. s., 2H),
4.40 (d, J=7.9 Hz, 1H), 4.23 (d, J=6.6 Hz, 2H), 2.58 (d, J=2.9 Hz,
1H), 1.30 (d, J=5.9 Hz, 3H). LC-MS: method H, RT=0.59 min, MS (ESI)
m/z: 244.1 (M+H).sup.+.
Intermediate I-131
[1713] Copper(II) chloride (0.658 g, 4.89 mmol) and t-butyl nitrite
(0.582 ml, 4.89 mmol) were dissolved in MeCN (11.51 ml) and allowed
to stir 10 minutes. Intermediate I-131C (0.700 g, 2.88 mmol) was
dissolved in MeCN (17.27 ml) and the copper solution was added. The
reaction mixture was stirred for 2.5 hours at 60.degree. C. The
reaction mixture was diluted with EtOAc, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Purified
on ISCO using a 12 g column with 0-100% gradient of EtOAc in
hexanes to Intermediate I-131 (0.698 g, 2.66 mmol, 92% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=9.9 Hz, 1H),
4.45-4.34 (m, 1H), 4.26-4.19 (m, 2H), 3.86-3.71 (m, 1H), 2.25 (d,
J=3.5 Hz, 1H), 1.39-1.24 (m, 3H). LC-MS: method H, RT=0.88 min, MS
(ESI) m/z: 263.0 (M+H).sup.+.
Intermediate I-132
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyrid-
in-5-yl)oxy) propan-2-yl carbonochloridate
##STR00339##
[1715] Intermediate I-132A:
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
##STR00340##
[1716] Intermediate I-9 (0.343 g, 1.142 mmol) and Intermediate
I-131 (0.300 g, 1.142 mmol) were dissolved in DMF (11.42 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.056 g, 0.069 mmol) was
added, and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.381 ml, 1.142
mmol) was added and the reaction degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
The reaction mixture was purified on ISCO using a 24 g column
eluting with 0-100% EtOAc in hexanes to yield Intermediate I-132A
(0.223 g, 0.557 mmol, 48.8% yield) as a yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.56 (d, J=12.5 Hz, 1H), 8.01 (d,
J=10.1 Hz, 1H), 7.78 (br. s., 1H), 7.33-7.28 (m, 1H), 4.55 (d,
J=11.2 Hz, 1H), 4.38 (br. s., 2H), 4.13 (s, 4H), 2.65 (br. s., 3H),
1.35 (d, J=5.9 Hz, 3H). LC-MS: method H, RT=1.25 min, MS (ESI) m/z:
401.1 (M+H).sup.+.
Intermediate I-132
[1717] To a solution of
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyri-
din-5-yl)oxy)propan-2-ol (0.098 g, 0.245 mmol) in THF (3 mL) at
room temperature was added 15% phosgene in toluene (0.863 mL, 1.224
mmol) and the mixture was stirred at room temperature for 1 h.
Solvent was completely removed and the sample was under vacuum
overnight to give Intermediate I-132 (0.113 g, 0.244 mmol, 100%
yield) as a yellow solid. This intermediate was used without
further purification in the next step. LC-MS: method H, RT=1.37
min, MS (ESI) m/z: 463.0 (M+H).sup.+.
Intermediate I-133
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
##STR00341##
[1718] Intermediate I-133A:
(2R,3S)-3-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)
butan-2-ol
##STR00342##
[1720] To a solution of Intermediate I-131B (150 mg, 0.432 mmol) in
DMF (1729 .mu.l) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane
2,2-dioxide (79 mg, 0.519 mmol) followed by potassium carbonate
(179 mg, 1.297 mmol). The reaction mixture was stirred vigorously
at 60.degree. C. for 3h and then allowed to stir at room
temperature for 48 h. The reaction mixture was then diluted with
EtOAc and filtered. The resulting solution was concentrated under
reduced pressure to yield a dark oil. This residue was dissolved in
THF (1729 .mu.l) and sulfuric acid (69.1 .mu.l, 1.297 mmol)
followed by water (23.36 .mu.l, 1.297 mmol). This reaction mixture
was allowed to stir at room temperature for 1 hour before being
diluted with 1 N NaOH and EtOAc. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate I-133A
(0.11 g, 0.428 mmol, 99% yield) as a yellow solid. .sup.1H NMR (400
MHz, MeOH.sub.4) .delta. 7.42 (d, J=11.0 Hz, 1H), 5.12-5.02 (m,
1H), 3.96-3.88 (m, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.24 (d, J=6.6 Hz,
3H). LC-MS: method H, RT=0.63 min, MS (ESI) m/z: 258.0
(M+H).sup.+.
Intermediate I-133
[1721] Copper(II) chloride (0.588 g, 4.37 mmol) and t-butyl nitrite
(0.589 ml, 4.96 mmol) were dissolved in MeCN (11.66 ml) and allowed
to stir 10 minutes. Intermediate I-133A (0.750 g, 2.92 mmol) was
dissolved in MeCN (17.49 ml) and the copper solution was added. The
reaction mixture was stirred for 1.5h at 60.degree. C. The reaction
mixture was diluted with EtOAc, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Purified
on ISCO using a 40 g column with 0-100% gradient of EtOAc in
hexanes to yield Intermediate I-133 (0.722 g, 2.61 mmol, 90%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.87 (d, J=9.9
Hz, 1H), 5.31 (dd, J=6.4, 3.1 Hz, 1H), 4.12 (ddd, J=6.4, 4.7, 3.2
Hz, 1H), 2.14 (d, J=4.6 Hz, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.31 (d,
J=6.4 Hz, 3H). LC-MS: method H, RT=0.95, MS (ESI) m/z: 277.1
(M+H).sup.+.
Intermediate I-134
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl carbonochloridate
##STR00343##
[1722] Intermediate I-134A:
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
##STR00344##
[1724] Intermediate I-9 (0.067 g, 0.224 mmol) and Intermediate
I-133 (0.062 g, 0.224 mmol) were dissolved in DMF (2.241 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (10.98 mg, 0.013 mmol) was
added and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.075 ml, 0.224
mmol) was added and the reaction degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
Purified on ISCO using a 40 g column eluting with 0-100% EtOAc in
hexanes to yield Intermediate I-134A (0.090 g, 0.219 mmol, 95%) as
a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.57 (d,
J=1.8 Hz, 1H), 8.54 (s, 1H), 7.99 (d, J=10.1 Hz, 1H), 7.77 (s, 1H),
5.37 (dd, J=6.4, 2.9 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 2.46 (d,
J=4.8 Hz, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4 Hz, 1H), 1.30
(d, J=6.6 Hz, 5H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z:
415.1 (M+H).sup.+.
Intermediate I-134
[1725] To a solution of Intermediate I-134A (0.045 g, 0.109 mmol)
in THF (3 mL) at room temperature was added 15% phosgene solution
in toluene (0.383 mL, 0.543 mmol) and the mixture was stirred room
temperature overnight. Solvent was completely removed to yield
Intermediate I-134 (0.052 g, 0.098 mmol, 90% yield) as a yellow
solid. Used without further purification in the next step. LC-MS:
method H, RT=1.46 min, MS (ESI) m/z: 477.0 (M+H).sup.+.
Intermediate I-135
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR00345##
[1726] Intermediate I-135A:
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)
butan-2-yl carbonochloridate
##STR00346##
[1728] To a solution of Intermediate I-133 (0.030 g, 0.108 mmol) in
THF (3 mL) at room temperature was added 15% phosgene solution in
toluene (0.382 mL, 0.542 mmol), and the mixture was stirred at room
temperature overnight. Solvent was completely removed to give
Intermediate I-135A (0.035 g, 0.103 mmol, 95% yield) as a yellow
solid. Used without further purification in the next step. LC-MS:
method H, RT=1.46 min, MS (ESI) m/z: 340.0 (M+H).sup.+.
Intermediate I-135
[1729] 2-Methylpyrimidin-5-amine (0.023 g, 0.206 mmol) and pyridine
(0.083 mL, 1.032 mmol) were dissolved in DCM (2 mL) To this
solution was added Intermediate I-135A (0.035 g, 0.103 mmol) as a
solution in DCM (1 mL). The reaction mixture was allowed to stir
for 1h. The reaction mixture was concentrated under reduced
pressure to yield Intermediate I-135 (0.040 g, 0.097 mmol, 94%).
LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 412.0 (M+H).sup.+.
Intermediate I-136
6-fluoro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-
e
##STR00347##
[1730] Intermediate I-136A:
(2-amino-3-bromo-5-fluorophenyl)methanol
##STR00348##
[1732] Methyl 2-amino-3-bromo-5-fluorobenzoate (0.910 g, 3.67 mmol)
was dissolved in THF (12.23 ml). LiBH.sub.4 (0.160 g, 7.34 mmol)
was added and the reaction mixture was heated to 50.degree. C. for
2 hours. The reaction mixture was diluted with water and stirred
for 30 minutes. The reaction mixture was then extracted thrice with
EtOAc. The combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to yield
Intermediate I-136A (0.799 g, 3.63 mmol, 99% yield) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.20 (dd, J=7.7,
2.9 Hz, 1H), 6.86 (dd, J=8.4, 2.9 Hz, 1H), 4.68 (s, 2H), 4.52 (d,
J=12.8 Hz, 2H), 1.89-1.69 (m, 1H). LC-MS: method H, RT=0.94 min, MS
(ESI) m/z: 219.9 (M+H).sup.+.
Intermediate I-136B: 2-amino-3-bromo-5-fluorobenzaldehyde
##STR00349##
[1734] Intermediate I-136A (0.799 g, 3.63 mmol) was dissolved in
CHCl.sub.3 (24.21 ml). Manganese dioxide (1.263 g, 14.52 mmol) was
added and the reaction mixture was heated to 40.degree. C.
overnight. The reaction mixture was filtered through celite and
concentrated in vacuo to yield Intermediate I-136B (0.750 g, 3.44
mmol, 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.80 (s, 1H),
7.48 (dd, J=7.5, 2.9 Hz, 1H), 7.25 (dd, J=7.9, 2.9 Hz, 1H), 6.55
(br. s., 2H).
Intermediate I-136C: 3-(benzyloxy)-8-bromo-6-fluoroquinoline
##STR00350##
[1736] Intermediate I-136B (0.800 g, 3.67 mmol),
2-(benzyloxy)acetaldehyde (0.551 g, 3.67 mmol), and sodium
methoxide (8.07 ml, 4.04 mmol) were dissolved in MeOH (7.34 ml) and
heated to reflux overnight. The reaction mixture was diluted with
saturated NH.sub.4Cl, partially concentrated in vacuo and diluted
with EtOAc. The layers were separated and the organic layer was
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. Purified on ISCO using 80 g column eluting
with 0-60% gradient of EtOAc in hexanes to yield Intermediate
I-136C (0.363 g, 1.093 mmol, 30%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.83 (d, J=2.5 Hz, 1H), 7.72 (dd, J=8.1, 2.6
Hz, 1H), 7.52-7.49 (m, 2H), 7.45 (t, J=7.3 Hz, 2H), 7.41 (d, J=2.8
Hz, 2H), 7.34 (dd, J=8.7, 2.6 Hz, 1H), 5.24 (s, 2H). LC-MS: method
H, RT=1.38 min, MS (ESI) m/z: 331.9 (M+H).sup.+.
Intermediate I-136D: 8-bromo-6-fluoroquinolin-3-ol
##STR00351##
[1738] Intermediate I-136C (0.363 g, 1.093 mmol) and
pentamethylbenzene (1.134 g, 7.65 mmol) were dissolved in DCM
(21.86 ml) and cooled to -78.degree. C. Boron trichloride (1 M in
heptane) (2.84 ml, 2.84 mmol) was added and the reaction mixture
was allowed to warm to room temperature overnight. The reaction
mixture was diluted with hexanes and 1 N HCl and allowed to stir
for 1 hour. The resulting solid was collected by suction
filtration, washing with water and hexanes to yield Intermediate
I-136D (0.176 g, 0.727 mmol, 66.5% yield): .sup.1H NMR (400 MHz,
MeOH.sub.4) .delta. 8.53 (d, J=2.9 Hz, 1H), 7.68 (dd, J=8.4, 2.6
Hz, 1H), 7.49-7.37 (m, 2H). LC-MS: method H, RT=1.12 min, MS (ESI)
m/z: 241.9 (M+H).sup.+.
Intermediate I-136E: 8-bromo-6-fluoro-3-methoxyquinoline
##STR00352##
[1740] Intermediate I-136D (0.095 g, 0.341 mmol), K.sub.2CO.sub.3
(0.141 g, 1.023 mmol), and methyl iodide (0.043 ml, 0.682 mmol)
were dissolved in acetone (3.41 ml) and heated to 50.degree. C. in
a sealed tube overnight. The reaction mixture was diluted with
EtOAc, washed with water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to yield Intermediate I-136E
(0.060 g, 0.234 mmol, 68.7% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.76 (dd, J=2.8, 0.6 Hz, 1H), 7.72 (dd, J=8.0,
2.8 Hz, 1H), 7.37 (dd, J=8.8, 2.6 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H),
4.00 (s, 3H). LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 255.8
(M+H).sup.+.
Intermediate I-136
[1741] Intermediate I-136E (0.087 g, 0.340 mmol), BISPIN (0.173 g,
0.679 mmol), potassium acetate (0.083 g, 0.849 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.022 g, 0.027 mmol) were
stored on HIVAC for 15 minutes then were dissolved in 1,4-dioxane
(3 ml) and degassed for 15 minutes by bubbling with argon. The
reaction mixture was heated to 130.degree. C. in the microwave for
40 minutes. The reaction mixture was diluted with EtOAc and washed
with water then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to yield Intermediate I-136 (0.103 g, 0.170
mmol, 50%). This material was dissolved in DMF to make a stock
solution of 10 mg per mL and used without further purification.
LC-MS: method H, RT=1.10 min, MS (ESI) m/z: 221.9 (M+H).sup.+. See
the mass of the boronic acid in the LC/MS.
Intermediate I-137
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-yl)carbamate
##STR00353##
[1742] Intermediate I-137A:
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)
butan-2-yl carbonochloridate
##STR00354##
[1744] To a solution of Intermediate I-133 (0.100 g, 0.361 mmol) in
THF (5 mL) at room temperature was added 15% phosgene solution in
toluene (1.274 mL, 1.807 mmol) and the mixture was stirred at room
temperature overnight. Solvent was completely removed to give
Intermediate I-137A (0.125 g, 0.369 mmol, 102% yield) as a yellow
solid. LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 338.9
(M+H).sup.+.
Intermediate I-137
[1745] 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-amine
(0.199 g, 0.737 mmol) and pyridine (0.298 mL, 3.69 mmol) were
dissolved in DCM (2 mL) To this solution was added Intermediate
I-137A (0.125 g, 0.369 mmol) as a solution in DCM (1 mL). The
reaction mixture was allowed to stir for 1 h. The reaction mixture
was concentrated under reduced pressure to yield Intermediate I-137
(0.130 g, 0.227 mmol, 62%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.48 (br. s., 2H), 7.76 (d, J=9.7 Hz, 1H), 5.45 (dd, J=6.6,
2.9 Hz, 1H), 5.12 (dd, J=6.6, 2.9 Hz, 1H), 4.33 (t, J=5.5 Hz, 2H),
3.90 (t, J=5.4 Hz, 2H), 1.34 (d, J=6.6 Hz, 6H), 0.81 (s, 9H), 0.00
(s, 6H). LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 572.1
(M+H).sup.+.
Intermediate I-138
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl carbonochloridate
##STR00355##
[1746] Intermediate I-138A:
2-amino-7-methylthiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
##STR00356##
[1748] Intermediate I-16B (0.500 g, 2.56 mmol) was dissolved in HBr
in acetic acid (1.738 mL, 15.37 mmol, 33% by wt.), and the reaction
mixture was stirred at 130.degree. C. for 3h. The reaction mixture
was concentrated under reduced pressure to yield Intermediate
I-138A (0.636, 1.854 mmol, 72.4% yield) as a tan solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 6.66 (d, J=0.9 Hz, 1H), 2.48 (d,
J=0.7 Hz, 3H). LC-MS: method H, RT=0.46 min, MS (ESI) m/z: 182.1
(M+H).sup.+.
Intermediate I-138B:
(R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-7-methylthiazolo[5,4-b]py-
ridin-2-amine
##STR00357##
[1750] Intermediate I-138A (0.500 g, 1.458 mmol) was dissolved in
DMF (14.58 ml) and Cs.sub.2CO.sub.3 (2.85 g, 8.75 mmol) was added
followed by (R)-tert-Butyl((1-iodopropan-2-yl)oxy)diphenylsilane
(0.619 g, 1.458 mmol). The reaction mixture was stirred at room
temperature for 3 h. The reaction mixture was then heated to
40.degree. C. and allow to stir overnight. The reaction mixture was
diluted with water and EtOAc. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure. The resulting residue was
purified on ISCO using 40 g column eluting with 0-100% EtOAc in
hexanes to yield Intermediate I-138B (0.324 g, 0.678 mmol, 46.5%
yield) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.69 (ddd, J=8.0, 4.1, 1.5 Hz, 4H), 7.42-7.28 (m, 6H), 6.32 (d,
J=0.7 Hz, 1H), 4.97 (s, 2H), 4.26-4.18 (m, 2H), 4.16-4.09 (m, 5H),
2.45 (d, J=0.7 Hz, 3H), 1.15 (d, J=6.2 Hz, 3H), 1.06 (s, 9H).
LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 478.3 (M+H).sup.+.
Intermediate I-138C
(R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-2-chloro-7-methylthiazolo[-
5,4-b]pyridine
##STR00358##
[1752] Copper(II) chloride (0.155 g, 1.153 mmol) and t-butyl
nitrite (0.137 ml, 1.153 mmol) were dissolved in MeCN (2.71 ml) and
allowed to stir 10 minutes. Intermediate I-138B (0.324 g, 0.678
mmol) was dissolved in MeCN (4.07 ml) and the copper solution was
added. The reaction mixture was stirred for 2.5h at 60.degree. C.
The reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. Purified on ISCO using a 24 g
column with 0-100% gradient of EtOAc in hexanes to yield
Intermediate I-138C (0.222 g, 0.447 mmol, 65.8% yield) as a yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71-7.64 (m, 4H),
7.44-7.28 (m, 6H), 6.42 (s, 1H), 4.34-4.09 (m, 3H), 2.56 (d, J=0.7
Hz, 3H), 1.18 (d, J=5.9 Hz, 3H), 1.06 (s, 9H). LC-MS: method H,
RT=1.71 min, MS (ESI) m/z: 497.2 (M+H).sup.+.
Intermediate I-138D
(R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-2-(2-methoxy-7-methylquino-
xalin-5-yl)-7-methylthiazolo[5,4-b]pyridine
##STR00359##
[1754] Intermediate I-9 (0.052 g, 0.173 mmol) and Intermediate
I-138C (0.086 g, 0.173 mmol) were dissolved in DMF (1.730 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (8.48 mg, 10.38 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 ml, 0.300
mmol) was added and the reaction degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
The reaction mixture was filtered and purified on ISCO using 0-100%
EtOAc in hexanes on a 24 g column to yield Intermediate I-138D
(0.055 g, 0.087 mmol, 50.1% yield) as a yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.59 (d, J=2.0 Hz, 1H), 8.54 (s, 1H),
7.71-7.69 (m, 4H), 7.41-7.30 (m, 7H), 6.47 (d, J=0.9 Hz, 1H),
4.40-4.24 (m, 4H), 4.12 (s, 3H), 2.74 (d, J=0.9 Hz, 3H), 2.66 (s,
3H), 1.19 (d, J=5.9 Hz, 3H), 1.08 (s, 9H). LC-MS: method H, RT=1.15
min, Compound does not ionize.
Intermediate I-138E
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyrid-
in-5-yl)oxy) propan-2-ol
##STR00360##
[1756] Intermediate I-138D (0.055 g, 0.087 mmol) was dissolved in
THF (0.866 ml) and TBAF (0.104 ml, 0.104 mmol) was added. The
reaction mixture was allowed to stir at room temperature for 1h and
concentrated under reduced pressure. Purified on ISCO using 0-100%
EtOAc in hexanes gradient on a 12 g column to yield Intermediate
I-138E (0.027 g, 0.068 mmol, 79% yield) as a yellow solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (d, J=1.8 Hz, 1H), 8.54 (s,
1H), 7.75 (s, 1H), 6.75 (d, J=0.9 Hz, 1H), 4.56-4.19 (m, 4H), 4.12
(s, 3H), 3.49 (d, J=5.5 Hz, 1H), 2.95 (s, 1H), 2.80 (d, J=0.9 Hz,
3H), 2.66 (s, 3H), 1.31 (d, J=6.2 Hz, 3H). LC-MS: method H, RT=1.26
min, MS (ESI) m/z: 397.2 (M+H).sup.+.
Intermediate I-138
[1757] To a solution of Intermediate I-138E (0.027 g, 0.068 mmol)
in THF (3 mL) at room temperature was added 15% phosgene solution
in toluene (0.240 mL, 0.341 mmol) and the mixture was stirred at
room temperature for 1 h. Solvent was completely removed and the
sample was under vacuum overnight to give Intermediate I-138 (0.030
g, 0.065 mmol, 96% yield) as a yellow solid. Used without any
purification. LC-MS: method H, RT=1.43 min, MS (ESI) m/z: 459.1
(M+H).sup.+.
Intermediate I-139
(R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR00361##
[1758] Intermediate I-139A
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl
carbonochloridate
##STR00362##
[1760] To a solution of Intermediate I-131 (0.030 g, 0.114 mmol) in
THF (3 mL) at room temperature was added 15% phosgene solution in
toluene (0.403 mL, 0.571 mmol), and the mixture was stirred at room
temperature overnight. Solvent was completely removed to give
Intermediate I-139A (0.035 g, 0.108 mmol, 95% yield) as a yellow
solid. Used without further purification in the next step. LC-MS:
method H, RT=1.22 min, MS (ESI) m/z: 325.0 (M+H).sup.+.
Intermediate I-139
[1761] 2-Methylpyrimidin-5-amine (0.023 g, 0.215 mmol) and pyridine
(0.083 mL, 1.032 mmol) were dissolved in DCM (2 mL) To this
solution was added Intermediate I-139A (0.035 g, 0.108 mmol) as a
solution in DCM (1 mL). The reaction mixture was allowed to stir
for 1h. The reaction mixture was concentrated under reduced
pressure to yield Intermediate I-139 (0.038 g, 0.096 mmol, 89%).
LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 398.0 (M+H).sup.+.
Intermediate I-140
(3-Methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-6-yl)me-
thanol
##STR00363##
[1762] Intermediate I-140A:
8-Bromo-3-methoxyquinoline-6-carbaldehyde
##STR00364##
[1764] A mixture of Intermediate I-125 (0.050 g, 0.198 mmol) and
selenium dioxide (0.132 g, 1.190 mmol) in dioxane (3.0 mL) was
heated in a microwave at 180.degree. C. for 9 hours. The insoluble
material was removed by filtration and washed with EtOAc. The crude
product was purified by flash chromatography (loading in
chloroform, 0% to 100% EtOAc in hexane using a 12 g silica gel
cartridge). The desired fractions were combined and concentrated to
yield Intermediate I-140A (0.051 g, 0.163 mmol, 82% yield) as a
white solid. Contains 15% starting material. Will be used without
further purification. LC-MS: method H, RT=0.83 min, MS (ESI) m/z:
267.9 (M+H).sup.+.
Intermediate I-140B: (8-Bromo-3-methoxyquinolin-6-yl)methanol
##STR00365##
[1766] Intermediate I-140A (0.0502 g, 0.189 mmol) was dissolved in
THF (1.887 ml) and sodium borohydride (7.14 mg, 0.189 mmol) was
added in one portion. The reaction mixture was allowed to stir at
room temperature for 3h. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with water, washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure to yield
Intermediate I-140B (0.048 g, 0.179 mmol, 95% yield) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.79 (d, J=2.9 Hz,
1H), 7.92 (d, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=2.9 Hz, 1H),
4.89 (d, J=5.1 Hz, 2H), 4.00 (s, 3H), 1.91 (s, 1H). LC-MS: method
H, RT=0.69 min, MS (ESI) m/z: 269.9 (M+H).sup.+.
Intermediate I-140
[1767] Intermediate I-140B (0.0524 g, 0.195 mmol), BISPIN (0.099 g,
0.391 mmol), potassium acetate (0.048 g, 0.489 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.013 g, 0.016 mmol) were
stored on HIVAC for 15 minutes then were dissolved in 1,4-dioxane
(3 ml) (sure sealed bottle) and degassed for 15 minutes by bubbling
with argon. The reaction mixture was heated to 130.degree. C. in
the microwave for 40 minutes (fixed hold time off). The reaction
mixture was diluted with EtOAc and washed with water then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue was dissolved in dioxanes to provide a 10 mg/mL stock
solution of the above boronic ester. Used without further
purification. See mass of boronic acid in the LC/MS LC-MS: method
H, RT=0.50 min, MS (ESI) m/z: 234.0 (M+H).sup.+.
Intermediate I-141
Methyl
5-(((((2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)-
butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
##STR00366##
[1768] Intermediate I-141A:
(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)
butan-2-yl carbonochloridate
##STR00367##
[1770] To a solution of Intermediate I-133 (0.058 g, 0.210 mmol) in
THF (5 mL) at room temperature was added 15% phosgene in toluene
(0.739 mL, 1.048 mmol) and the mixture was stirred at room
temperature overnight. The solvent was completely removed to give
Intermediate I-141A (0.071 g, 0.209 mmol, 100% yield) as a yellow
solid. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 339.1
(M+H).sup.+.
Intermediate I-141
[1771] Methyl 5-aminopyrimidine-2-carboxylate (0.065 g, 0.425 mmol)
and pyridine (0.172 mL, 2.123 mmol) were dissolved in DCM (2 mL).
To this solution was added Intermediate I-141A (0.072 g, 0.212
mmol) as a solution in DCM (1 mL). The reaction mixture was allowed
to stir for 1h. The reaction mixture was concentrated under reduced
pressure. Purified on ISCO using 0-100% EtOAc in hexanes to yield
Intermediate I-141 (0.066 g, 0.145 mmol, 68.2% yield) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.04 (s, 2H), 7.87
(d, J=9.7 Hz, 1H), 6.94 (s, 1H), 5.56 (dd, J=6.5, 2.8 Hz, 1H),
5.38-5.17 (m, 1H), 4.09 (s, 3H), 1.47 (d, J=6.4 Hz, 6H). LC-MS:
method H, RT=0.93 min, MS (ESI) m/z: 456.0 (M+H).sup.+.
Intermediate I-142
(R)-methyl
5-((((1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)prop-
an-2-yl)oxy) carbonyl)amino)pyrimidine-2-carboxylate
##STR00368##
[1772] Intermediate I-142A:
(R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)
propan-2-yl carbonochloridate
##STR00369##
[1774] To a solution of Intermediate I-131 (0.058 g, 0.210 mmol) in
THF (5 mL) at room temperature was added 15% phosgene in toluene
(0.739 mL, 1.048 mmol) and the mixture was stirred at room
temperature overnight. The solvent was completely removed to give
Intermediate I-142A (0.072 g, 0.221 mmol, 100% yield) as a yellow
solid. LC-MS: method H, RT=1.17 min, MS (ESI) m/z: 325.1
(M+H).sup.+.
Intermediate I-142
[1775] Methyl 5-aminopyrimidine-2-carboxylate (0.068 g, 0.443 mmol)
and pyridine (0.179 mL, 2.214 mmol) were dissolved in DCM (2 mL).
To this solution was added Intermediate I-142A (0.072 g, 0.221
mmol) as a solution in DCM (1 mL). The reaction mixture was allowed
to stir for 1 h. The reaction mixture was concentrated under
reduced pressure. Purified on ISCO using 0-100% EtOAc in hexanes to
yield I-142 (0.87 g, 0.197 mmol, 89% yield) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.06 (s, 2H), 7.89 (d,
J=9.9 Hz, 1H), 6.98 (s, 1H), 5.42 (d, J=3.3 Hz, 1H), 4.72 (dd,
J=11.9, 3.1 Hz, 1H), 4.48 (dd, J=11.9, 6.6 Hz, 1H), 4.09 (s, 3H),
1.51 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.88 min, MS (ESI) m/z:
442.0 (M+H).sup.+.
Intermediate I-143
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl carbonochloridate
##STR00370##
[1776] Intermediate I-143A:
(2R,3S)-3-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)
butan-2-ol
##STR00371##
[1778] To a solution of Intermediate I-44 (0.200 g, 0.708 mmol) in
THF (2.83 ml) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane
2,2-dioxide (0.140 g, 0.920 mmol) followed by potassium carbonate
(0.147 g, 1.062 mmol). The reaction vial was sealed and heated to
65.degree. C. overnight. The crude mixture was cooled to 0.degree.
C. and concentrated sulfuric acid (0.113 ml, 2.124 mmol) was added
followed by water (0.064 ml, 3.54 mmol). The reaction mixture was
allowed to thaw to room temperature, and stirred for 20 min. The
reaction mixture was quenched with 20 mL 1.5 M K.sub.2HPO.sub.4,
extracted with 100 mL EtOAc, washed with brine, dried over
MgSO.sub.4, filtered and concentrated to afford a beige solid that
was dry loaded onto celite and purified by ISCO (40 g, 0-50%
DCM/EtOAc) to afford Intermediate I-143A (0.145 g, 0.409 mmol,
57.8% yield) as an off white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.34 (d, J=7.0 Hz, 1H), 4.38 (dd, J=6.3, 3.4
Hz, 1H), 4.16-4.03 (m, 1H), 2.01 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.4
Hz, 3H), 1.31 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.82 min, MS
(ESI) m/z: 353.9 (M+H).sup.+.
Intermediate I-143B:
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-ol
##STR00372##
[1780] Intermediate I-121 (149 mg, 0.467 mmol), Intermediate I-143A
(145 mg, 0.467 mmol) and PdCl.sub.2(dppf) (20.52 mg, 0.028 mmol)
were dissolved in dioxane (8.523 mL) and Na.sub.2CO.sub.3 (2.104
mL, 4.21 mmol, 2 M) and heated to 100.degree. C. in an oil bath for
1 hour. The reaction mixture was cooled to ambient temperature,
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Purified
on ISCO using 0-100% EtOAc in DCM on a 24 g column to yield
Intermediate I-143B (0.022 g, 0.047 mmol, 10.07% yield): LC-MS:
method H, RT=1.40 min, MS (ESI) m/z: 466.8 (M+H).sup.+.
Intermediate I-143
[1781] To a solution of Intermediate I-143B (0.022 g, 0.047 mmol)
in THF (5 mL) at room temperature was added 15% phosgene in toluene
(0.166 mL, 0.235 mmol) and the mixture was stirred at room
temperature overnight. Solvent was completely removed to give
Intermediate I-143 (0.025 g, 0.047 mmol, 100% yield) as a yellow
solid. LC-MS: method H, RT=1.41 min, MS (ESI) m/z: 530.8
(M+H).sup.+.
Intermediate I-144
2-ethoxy-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxali-
ne
##STR00373##
[1782] Intermediate I-144A:
5-bromo-2-ethoxy-7-methylquinoxaline
##STR00374##
[1784] Intermediate I-1G (372 mg, 1.287 mmol) was suspended in EtOH
(10 mL) and was mixed with 21% sodium ethoxide in ethanol (2 mL,
5.36 mmol). Mixture was stirred at 40.degree. C. for 1 hour. The
solvent was removed on rotavapor and residue was dissolved in 20 mL
of EtOAc and 15 mL of water. The layers were separated and the
aqueous layer was extracted with EtOAc (10 mL.times.2). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. Crude product was
loaded on ISCO (24 g column, 0-50% EtOAC/Hexane gradient) to yield
Intermediate I-144A (292 mg, 1.093 mmol, 85% yield) as white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.58 (s, 1H), 7.85 (d,
J=1.5 Hz, 1H), 7.65 (s, 1H), 4.50 (q, J=7.0 Hz, 2H), 2.50 (s, 3H),
1.42 (t, J=7.0 Hz, 3H) LC-MS: method H, RT=1.14 min, MS (ESI) m/z:
269.1 (M+H).sup.+.
Intermediate I-144
[1785] In a sealed tube, Intermediate I-144A (290 mg, 1.086 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (551
mg, 2.171 mmol), potassium acetate (213 mg, 2.171 mmol) were mixed
in 1,4-dioxane (5 mL). After degassing with bubbling N.sub.2 for 10
minutes, Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 adduct (44.3 mg, 0.054
mmol) was added. The vial was sealed and was heated at 120.degree.
C. for 60 minutes. The reaction mixture was cooled room temperature
and loaded on celite. Purified on ISCO (40 g column, 0-50%
EtOAc/Hexane in 18 minutes) to yield I-144 (0.311 g, 0.990 mmol,
91% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.53 (s,
1H), 7.91 (s, 1H), 7.68 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.26 (br.
s., 3H), 1.41 (t, J=7.0 Hz, 3H), 1.34 (s, 12H). LC-MS: method H,
RT=0.94 min, MS (ESI) m/z: 233.0 (M+H).sup.+. See mass of boronic
acid.
Example 1
5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
##STR00375##
[1787] A mixture of Intermediate I-1G (40 mg, 0.138 mmol),
benzofuran-2-ylboronic acid (28.0 mg, 0.173 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.78 mg, 8.30 .mu.mol) in
toluene (1.8 mL) and EtOH (0.600 mL) was degassed with argon for
2.0 min. To this solution was added sodium carbonate (2M, 0.121 mL,
0.242 mmol). The mixture was heated in a microwave reactor at
100.degree. C. for 30 min. The reaction mixture was diluted with
EtOAc/water. The organic layer was collected, dried over sodium
sulfate. The crude residue was dissolved in DMSO/acetonitrile (6
mL/6 mL), purified using a preparative HPLC (method A, 70-100% B in
10 min, flow rate of 40 mL/min). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 1 (28 mg, 0.085 mmol, 61.4% yield) as yellow lyophilate.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.87 (s, 1H), 8.27 (d,
J=1.9 Hz, 1H), 8.13 (d, J=0.8 Hz, 1H), 7.85 (t, J.sub.HF=71.85 Hz,
1H), 7.79 (dd, J=7.7, 0.6 Hz, 1H), 7.75 (dd, J=1.8, 1.0 Hz, 1H),
7.68 (dd, J=8.3, 0.8 Hz, 1H), 7.41 (ddd, J=8.3, 7.2, 1.1 Hz, 1H),
7.34-7.30 (m, 1H), 2.66 (s, 3H); .sup.19F NMR (471 MHz,
DMSO-d.sub.6) .delta. -88.42 (s, 2F); LC-MS: Method A, 50 to 100%
B. RT=2.32 min, MS (ESI) m/z: 327.1 (M+H).sup.+. Analytical HPLC
(low pH, 254 nM): Sunfire, RT=12.62 min, 100% purity; XBridge,
RT=8.29 min, 99% purity.
Example 2
2-(difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline
##STR00376##
[1788] Intermediate 2A: (5-methoxybenzofuran-2-yl)boronic acid
##STR00377##
[1790] To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL)
at -78.degree. C. was added 1.6 N n-BuLi in hexanes (1.190 mL,
1.903 mmol) dropwise. The solution became slightly yellow. The
reaction mixture was stirred at -78.degree. C. for 20 min, followed
by addition of triisopropyl borate (0.737 mL, 3.17 mmol). After 30
min stirring at -78.degree. C., the cooling bath was removed and
the stirring was continued at room temperature for 1.5 h. The
reaction mixture was diluted with EtOAc, quenched with 3.0 mL of
1.0 N HCl. After stirring at room temperature for 25 min, the
organic layer was collected, washed with brine and dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform/a drop of MeOH and
charged to a 4 g silica gel cartridge which was eluted with hexanes
for 2 min., then a 10 min gradient from 0% to 60%. The desired
fractions were combined, concentrated and lyophilized to give
Intermediate 2A (170 mg, 0.886 mmol, 69.8% yield) as a white solid.
.sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.41 (d, J=9.1 Hz,
1H), 7.30 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz,
1H), 3.84 (s, 3H); LC-MS: method A, RT=1.45 min, MS (ESI) m/z:
149.0 (M-B(OH).sub.2).sup.+.
Example 2
[1791] A mixture of Intermediate I-1G (22 mg, 0.076 mmol),
Intermediate 2A (18.26 mg, 0.095 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (4.97 mg, 6.09 .mu.mol) in
toluene (1.5 mL) and EtOH (0.5 mL) was degassed with argon for 2.0
min. To this solution was added sodium carbonate (2M, 0.067 mL,
0.133 mmol). The reaction mixture was heated in a microwave reactor
at 100.degree. C. for 30 min, then diluted with EtOAc/water. The
organic layer was collected, dried over sodium sulfate. After
evaporation of solvent, the crude residue was dissolved in
DMSO/MeOH (6 mL/4 mL), purified using a preparative HPLC (method A,
70-100% B in 10 min, flow rate of 40 mL/min). The desired fractions
were placed in a SpeedVac overnight to remove solvent, then
lyophilized to give Example 2 (15 mg, 0.042 mmol, 54.8% yield) as
yellow lyophilate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.90
(s, 1H), 8.21 (d, J=1.4 Hz, 1H), 8.05 (s, 1H), 7.88 (t,
J.sub.HF=71.53 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.30
(d, J=2.8 Hz, 1H), 6.98 (dd, J=8.9, 2.6 Hz, 1H), 3.82 (s, 3H), 2.63
(s, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta. -87.80 (s,
2F); LC-MS: Method A, 50 to 100% B. RT=2.27 min, MS (ESI) m/z:
357.0 (M+H).sup.+. Analytical HPLC (low pH, 254 nM): Sunfire,
RT=12.92 min, 99% purity; XBridge, RT=9.70 min, 99% purity.
Example 3
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]oxazole
##STR00378##
[1792] Intermediate 3A: 2-iodobenzo[d]oxazole
##STR00379##
[1794] To magnesium bromide (52 mg, 0.282 mmol) in THF (0.5 mL)
cooled at -10.degree. C. was added 1.6 N n-BuLi in hexanes (0.530
mL, 0.847 mmol) dropwise. The reaction mixture was stirred between
-10.degree. C. and 0.degree. C. for 1.0 h. Benzo[d]oxazole (101 mg,
0.847 mmol) in THF (0.5 mL) was added, and the brown mixture was
stirred at room temperature for 2.0 h. Iodine (79 mg, 0.311 mmol)
in THF (0.5 mL) was added, and the reaction mixture was stirred at
room temperature for 18 h. The mixture was diluted with EtOAc,
quenched with 10% Na.sub.2S.sub.2O.sub.3. The organic layer was
washed with water, brine and dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform and charged to a 12 g silica gel cartridge
which was eluted with hexanes for 3 min., then a 15 min gradient
from 0% to 30%. The desired fractions were combined and
concentrated to give Intermediate 3A (47 mg, 0.192 mmol, 67.9%
yield) as a solid. .sup.1H NMR (400 MHz, chloroform-d) .delta.
7.67-7.60 (m, 1H), 7.50-7.44 (m, 1H), 7.28-7.20 (m, 2H); LC-MS:
method A, RT=1.73 min, MS (ESI) m/z: 246.0 (M+H).sup.+.
Example 3
[1795] To Intermediate I-1 (31 mg, 0.092 mmol), Intermediate 3A
(29.4 mg, 0.120 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.03 mg, 7.38 .mu.mol) was
added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.101 mL, 0.203 mmol). The reaction mixture was
heated in a microwave reactor at 110.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate. After evaporation of solvent, the crude
residue was purified using a preparative HPLC (method A, 40-100% B
in 10 min, flow rate of 40 mL/min). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Example 3 (27 mg, 0.082 mmol, 89% yield) as a white
lyophilate. .sup.1H NMR (500 MHz, acetonitrile-d.sub.3) 8.74 (br.
s., 1H), 8.32 (d, J=1.9 Hz, 1H), 7.93 (br. s., 1H), 7.89-7.85 (m,
1H), 7.76 (d, J=7.2 Hz, 1H), 7.71 (t, J.sub.HF=71.53 Hz, 1H),
7.53-7.45 (m, 2H), 2.69 (s, 3H); .sup.19F NMR (471 MHz,
acetonitrile-d.sub.3) .delta. -90.12 (s, 2F); LC-MS: Method A, 40
to 100% B. RT=1.81 min, MS (ESI) m/z: 328.0 (M+H).sup.+. Analytical
HPLC (low pH, 254 nM): Sunfire, RT=9.41 min, 99% purity; XBridge,
RT=7.19 min, 99% purity.
Example 4
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR00380##
[1797] To a microwave reaction tube was charged
dichlorobis(chloro-di-tert-butylphosphine)palladium (1.118 mg,
2.076 .mu.mol), Cu(Xantphos)I (6.39 mg, 8.30 .mu.mol), cesium
carbonate (85 mg, 0.259 mmol), benzo[d]thiazole (0.017 mL, 0.156
mmol) and Intermediate I-1G (30 mg, 0.104 mmol). Toluene (1.0 mL)
was added and the reaction mixture was sealed and heated at
100.degree. C. The mixture was diluted with EtOAc/water, the
organic layer was collected, dried over sodium sulfate. The crude
residue was purified using a preparative HPLC (method A, 60-100% B
in 10 min, flow rate of 40 mL/min). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Example 4 (2.2 mg, 6.34 .mu.mol, 6.11% yield) as a white
lyophilate. .sup.1H NMR (500 MHz, acetonitrile-d.sub.3) .delta.
8.84 (d, J=1.7 Hz, 1H), 8.78 (s, 1H), 8.15-8.11 (m, 2H), 7.87 (dd,
J=1.8, 1.0 Hz, 1H), 7.72 (t, J.sub.HF=71.82 Hz, 1H), 7.59 (ddd,
J=8.2, 7.1, 1.2 Hz, 1H), 7.50 (td, J=7.6, 1.1 Hz, 1H), 2.72 (s,
3H); .sup.19F NMR (471 MHz, acetonitrile-d.sub.3) .delta. -90.06
(s, 2F); LC-MS: Method H, 50 to 100% B. RT=1.93 min, MS (ESI) m/z:
344.2 (M+H).sup.+. Analytical HPLC (low pH, 254 nM): Sunfire,
RT=12.49 min, 100% purity; XBridge, RT=9.38 min, 99% purity.
Example 5
2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline
##STR00381##
[1798] Intermediate 5A: tert-butyl
2-(tributylstannyl)-1H-indole-1-carboxylate
##STR00382##
[1800] To diisopropylamine (0.984 mL, 6.90 mmol) in THF (12 mL) at
-78.degree. C. was added 1.6 N n-BuLi in hexanes (4.32 mL, 6.90
mmol). The reaction mixture was stirred at -78.degree. C. for 0.5
h. Next, tert-butyl 1H-indole-1-carboxylate (0.935 mL, 4.60 mmol)
was added, and the reaction mixture was stirred at -78.degree. C.
for 0.5 h. Tributyltin chloride (1.489 mL, 5.52 mmol) was added,
and the reaction mixture was stirred at -78.degree. C. for 0.5 h,
then at room temperature for 1.5 h. The reaction mixture was
diluted with EtOAc, quenched with saturated ammonium chloride. The
organic layer was washed with brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform and charged to a 40 g silica gel
cartridge which was eluted with hexanes for 3 min., then a 18 min
gradient from 0% to 30%. The desired fractions were combined and
concentrated to give Intermediate 5A (2.1 g, 4.15 mmol, 90% yield)
as clear oil. .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.98-7.94
(m, 1H), 7.54-7.50 (m, 1H), 7.26-7.15 (m, 2H), 6.74-6.69 (m, 1H),
1.71 (s, 9H), 1.58-1.49 (m, 7H), 1.33 (sxt, J=7.3 Hz, 6H),
1.11-1.06 (m, 5H), 0.89 (t, J=7.4 Hz, 9H); LC-MS: Method A, 60 to
100% B. RT=1.86 min, MS (ESI) m/z: not observed.
Example 5
[1801] A solution of Intermediate 5A (65.7 mg, 0.130 mmol) and
Intermediate I-1G (30 mg, 0.104 mmol) in toluene (1.2 mL) was
degassed with argon for 3 min.
Tetrakis(triphenylphosphine)palladium(O) (6.00 mg, 5.19 .mu.mol)
was added. The reaction mixture was sealed and heated in a
microwave reactor at 125.degree. C. for 30 min. HPLC and LCMS
indicated only 15% conversion. Then another portion of Intermediate
5A (65.7 mg, 0.130 mmol) and
tetrakis(triphenylphosphine)palladium(O) (6.00 mg, 5.19 .mu.mol)
were added, and the reaction mixture was heated at 125.degree. C.
for another 1.0 h. Toluene was removed under vacuum. 4.0 N HCl in
dioxane (2.076 mL, 8.30 mmol) was added and the reaction mixture
was stirred at room temperature overnight. Solvent was removed in
vacuum. The crude residue was purified using a preparative HPLC
(method A, 50-100% B in 10 min, flow rate of 40 mL/min). The
desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 5 (5.0 mg, 0.014 mmol,
13.92% yield) as yellow lyophilate. .sup.1H NMR (500 MHz,
acetonitrile-d.sub.3) .delta. 8.72 (s, 1H), 8.26 (d, J=1.7 Hz, 1H),
7.71 (t, J.sub.HF=71.82 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.65 (d,
J=0.8 Hz, 1H), 7.61 (dd, J=8.3, 0.8 Hz, 1H), 7.30-7.28 (m, 1H),
7.23 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.12 (td, J=7.5, 1.0 Hz, 1H),
2.65 (s, 3H); .sup.19F NMR (471 MHz, acetonitrile-d.sub.3) .delta.
-90.04 (s, 2F); LC-MS: Method H, 0 to 100% B. RT=1.88 min, MS (ESI)
m/z: 326.3 (M+H).sup.+. Analytical HPLC (method A): Sunfire,
RT=11.54 min, 99% purity; XBridge, RT=9.21 min, 90% purity.
Example 6
2-(difluoromethoxy)-5-(4,5-dimethoxybenzofuran-2-yl)-7-methylquinoxaline
##STR00383##
[1802] Intermediate 6A:
5-(hydroxymethylene)-6,7-dihydrobenzofuran-4(5H)-one
##STR00384##
[1804] To sodium hydride (1.175 g, 29.4 mmol) and potassium hydride
(0.098 g, 0.734 mmol) in THF (25 mL) at 0.degree. C. was added
ethyl formate (2.99 mL, 36.7 mmol), followed by addition of
6,7-dihydrobenzofuran-4(5H)-one (1.0 g, 7.34 mmol) in THF (5.0 mL)
dropwise. The reaction mixture was stirred at room temperature for
1.0 h and heated at 50.degree. C. for 1.5 h. HPLC and LCMS
indicated a completion of reaction. The mixture was diluted with
EtOAc, cooled to 0.degree. C., quenched with 3.0 mL MeOH/water, pH
was adjusted to 7 with 1.0 N HCl. The organic layer was collected,
washed with brine, dried over sodium sulfate. After evaporation of
solvent, Intermediate 6A (1.36 g, 8.28 mmol, 113% yield) was
obtained as yellow liquid. It was used for the next step without
further purification. .sup.1H NMR indicated a mixture of the keto
and enol form in a ratio of 1:7. .sup.1H NMR of the enol form: (500
MHz, chloroform-d) .delta. 7.39-7.36 (m, 1H), 7.31-7.26 (m, 1H),
6.74 (d, J=2.2 Hz, 1H), 2.93-2.87 (m, 2H), 2.68 (td, J=7.0, 0.8 Hz,
2H); LC-MS: method A, RT=1.19 and 1.35 min, MS (ESI) m/z: 165.0
(M+H).sup.+.
Intermediate 6B: 4-hydroxybenzofuran-5-carbaldehyde
##STR00385##
[1806] To a suspension of DDQ (2.074 g, 9.14 mmol) in dioxane (6.0
mL) was added Intermediate 6A (1.2 g, 7.31 mmol) in dioxane (7.0
mL) dropwise. The reaction mixture was stirred at room temperature
for 2.0 h. TLC indicated a completion of the reaction. It was
diluted with EtOAc, stirred for 15 min. The precipitate was
filtered and the filtrate was concentrated. The crude was
triturated with chloroform and the precipitate was removed by
filtration. The filtrate was concentrated, dissolved in a small
amount of chloroform and charged to a 80 g silica gel cartridge
which was eluted with hexanes for 3 min., then a 15 min gradient
from 0% to 40%. The desired fractions were combined and
concentrated to give Intermediate 6B (0.66 g, 4.07 mmol, 55.7%
yield) as a slightly brown solid. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 12.01 (s, 1H), 9.94 (s, 1H), 7.63 (d, J=2.2
Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.7, 1.0 Hz, 1H), 7.03
(dd, J=2.2, 0.8 Hz, 1H); LC-MS: method A, RT=1.65 min, MS (ESI)
m/z: 163.0 (M+H).sup.+.
Intermediate 6C: 4-methoxybenzofuran-5-carbaldehyde
##STR00386##
[1808] To Intermediate 6B (0.66 g, 4.07 mmol) in DMF (6.0 mL) was
added potassium carbonate (1.547 g, 11.19 mmol), followed by
iodomethane (0.445 mL, 7.12 mmol). The mixture was allowed to stir
at room temperature overnight. The reaction mixture was diluted
with EtOAc/water. The organic layer was collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent,
Intermediate 6C (0.68 g, 3.86 mmol, 95% yield) was obtained as a
white solid. It was used for the next step without further
purification. .sup.1H NMR (500 MHz, chloroform-d) .delta. 10.51 (d,
J=0.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H),
7.28-7.24 (m, 1H), 7.08 (dd, J=2.2, 0.8 Hz, 1H), 4.29 (s, 3H);
LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 177.0 (M+H).sup.+.
Intermediate 6D: 4-methoxybenzofuran-5-yl formate
##STR00387##
[1810] To a stirred solution of Intermediate 6C (0.31 g, 1.760
mmol) in dichloromethane (4.0 mL) was added mCPBA (0.557 g, 2.420
mmol). Trifluoroacetic acid (0.136 mL, 1.760 mmol) in
dichloromethane (2.0 mL) was added. The reaction mixture was
stirred at room temperature for 2.0 h. Sodium thiosulfite (10%, 1.0
mL) was added to quench the reaction. Solvent was removed under
vacuum. The residue was partitioned between EtOAc/saturated sodium
bicarbonate. The organic layer was collected, washed with saturated
sodium bicarbonate, brine and dried over sodium sulfate. After
evaporation of solvent, Intermediate 6D (0.34 g, 1.769 mmol, 101%
yield) was obtained as brown oil that was used for next step
without further purification. LC-MS: method A, RT=1.53 min, MS
(ESI) m/z: 215.0 (M+Na).sup.+.
Intermediate 6E: 4-methoxybenzofuran-5-ol
##STR00388##
[1812] To Intermediate 6D (0.34 g, 1.769 mmol) in MeOH (5.0 mL) was
added potassium carbonate (0.428 g, 3.10 mmol). The mixture was
allowed to stir at room temperature for 20 min. MeOH was removed
under vacuum. The residue was partitioned between EtOAc/water. The
organic layer was collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
silica gel cartridge which was eluted with hexanes for 2 min., then
a 15 min gradient from 0% to 40%. The desired fractions were
combined and concentrated to give Intermediate 6E (0.22 g, 1.340
mmol, 76% yield) as viscous oil. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.57 (d, J=2.2 Hz, 1H), 7.13 (dd, J=8.7, 1.0
Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.88 (dd, J=2.2, 0.8 Hz, 1H), 4.13
(s, 3H); LC-MS: method A, RT=1.40 min, MS (ESI) m/z: 187.0
(M+Na).sup.+.
Intermediate 6F: 4-methoxy-5-(methoxymethoxy)benzofuran
##STR00389##
[1814] To Intermediate 6E (0.21 g, 1.279 mmol) in DMF (4.0 mL) at
0.degree. C. was added sodium hydride (0.070 g, 1.759 mmol, 60% in
mineral). The reaction mixture was stirred at 0.degree. C. for 5
min, and at room temperature for 10 min. The mixture turned to deep
blue color. Chloromethyl methyl ether (0.136 mL, 1.791 mmol) was
added slowly, and the reaction mixture was stirred at room
temperature for 30 min. HPLC and TLC indicated a completion of the
reaction. The mixture was diluted with EtOAc, washed with water,
brine. The organic layer was dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform and charged to a 12 g silica gel cartridge
which was eluted with hexanes for 3 min., then a 12 min gradient
from 0% to 30%. The desired fractions were combined and
concentrated to give Intermediate 6F (0.24 g, 1.153 mmol, 90%
yield). .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.56 (d, J=2.2
Hz, 1H), 7.18-7.13 (m, 2H), 6.91 (dd, J=2.2, 0.6 Hz, 1H), 5.21 (s,
2H), 4.10 (s, 3H), 3.59 (s, 3H); LC-MS: method A, RT=1.70 min, MS
(ESI) m/z: 231.0 (M+H).sup.+.
Intermediate 6G:
(4-methoxy-5-(methoxymethoxy)benzofuran-2-yl)boronic acid
##STR00390##
[1816] To Intermediate 6F (0.236 g, 1.133 mmol) in THF (4.0 mL) at
-78.degree. C. was added 1.6 N n-BuLi in hexanes (1.240 mL, 1.984
mmol) dropwise. The reaction mixture was stirred at -78.degree. C.
for 30 min, followed by addition of triisopropyl borate (0.790 mL,
3.40 mmol). The reaction mixture was stirred for 30 min, and the
cooling bath was removed to allow warm up to room temperature for
1.0 h. TLC and HPLC indicated a completion of the reaction. The
reaction mixture was diluted with EtOAc and quenched with 4.0 mL of
0.5 N HCl. After stirring at room temperature for 10 min, the
organic layer was collected, washed with brine and dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 4 g
silica gel cartridge which was eluted with 5% for 2 min., then a 5
min gradient from 5% to 85%. The desired fractions were combined,
concentrated and lyophilized to give Intermediate 6G (0.23 g, 0.913
mmol, 81% yield) as a white solid. .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.39 (s, 1H), 7.06 (s, 2H), 5.06 (s, 2H),
4.72 (br. s., 1H), 3.98 (s, 3H), 3.46 (s, 3H); LC-MS: method A,
RT=1.42 min, MS (ESI) m/z: 177.0.
Intermediate 6H
2-(difluoromethoxy)-5-(4-methoxy-5-(methoxymethoxy)benzofuran-2-yl)-7-meth-
ylquinoxaline
##STR00391##
[1818] A mixture of Intermediate I-1G (30 mg, 0.104 mmol),
Intermediate 6G (32.7 mg, 0.130 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.93 mg, 7.26 .mu.mol) in
toluene (1.8 mL) and EtOH (0.600 mL) was degassed with argon for
2.0 min. To this solution was added sodium carbonate (2M, 0.104 mL,
0.208 mmol). The mixture was heated in a microwave reactor at
100.degree. C. for 30 min, at which time HPLC and LCMS indicated a
completion of the reaction. The reaction mixture was diluted with
EtOAc/water. The organic layer was collected, dried over sodium
sulfate. The crude residue was dissolved in DMSO/acetonitrile (2
mL/3 mL), purified using a preparative HPLC (method A, 50-100% B in
10 min; RT=9.5 min). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Intermediate 6H (26 mg, 0.060 mmol, 57.8% yield) as yellow
lyophilate. .sup.1H NMR (500 MHz, acetonitrile-d.sub.3) .delta.
8.75 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.25 (d, J=0.8 Hz, 1H), 7.72
(dd, J=1.9, 1.1 Hz, 1H), 7.71 (t, J.sub.HF=71.80 Hz, 1H), 7.29-7.25
(m, 1H), 7.22-7.19 (m, 1H), 5.20 (s, 2H), 4.14 (s, 3H), 3.55 (s,
3H), 2.67 (s, 3H); .sup.19F NMR (471 MHz, acetonitrile-d.sub.3)
.delta. -90.01 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.19 min,
MS (ESI) m/z: 417.1 (M+H).sup.+. Analytical HPLC (method A):
Sunfire, RT=12.38 min, 99% purity; XBridge, RT=9.66 min, 94%
purity.
Intermediate 6I
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzofuran-5-ol
##STR00392##
[1820] To Intermediate 6H (16 mg, 0.038 mmol) in THF (1.5 mL) and
MeOH (0.5 mL) was added 6.0 N HCl (0.640 mL, 3.84 mmol). The
reaction mixture was stirred at 60.degree. C. for 1.0 h. HPLC
indicated a completion of the reaction. It was diluted with EtOAc,
washed with water, brine. The organic layer was collected, dried
over sodium sulfate. After evaporation of solvent, Intermediate 6I
(13 mg, 0.035 mmol, 91% yield) was obtained as a brown solid that
was used for next step without further purification. .sup.1H NMR
(500 MHz, acetonitrile-d.sub.3) .delta. 8.72 (s, 1H), 8.21 (d,
J=5.0 Hz, 2H), 7.69 (t, J.sub.HF=71.53 Hz, 1H), 7.68 (br. s., 1H),
7.18 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.53 (br. s., 1H),
4.14 (s, 3H), 2.65 (s, 3H); .sup.19F NMR (471 MHz,
acetonitrile-d.sub.3) .delta. -89.92 (br. s., 2F); LC-MS: method A,
RT=1.86 min, MS (ESI) m/z: 373.0 (M+H).sup.+.
Example 6
[1821] To a stirred solution of Intermediate 6I (13 mg, 0.035 mmol)
and cesium carbonate (28.4 mg, 0.087 mmol) in DMF (0.8 mL) at room
temperature was added methyl iodide (3.82 .mu.l, 0.061 mmol) in
acetonitrile (0.03 mL). The reaction mixture was stirred at room
temperature for 1.0 h. HPLC and LCMS indicated a completion of the
reaction. The mixture was diluted with EtOAc, quenched with 0.2 N
HCl (2.0 mL). The organic layer was collected, dried over sodium
sulfate. After evaporation of solvent, the crude was purified using
a preparative HPLC (method A, 60-100% B in 10 min; RT=8.5 min). The
desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 6 (9.5 mg, 0.024 mmol,
68.3% yield) as yellow lyophilate. .sup.1H NMR (500 MHz,
acetonitrile-d.sub.3) .delta. 8.74 (s, 1H), 8.24 (d, J=1.7 Hz, 1H),
8.19 (s, 1H), 7.71 (t, J.sub.HF=71.80 Hz, 1H), 7.70 (s, 1H), 7.27
(d, J=8.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 4.09 (s, 3H), 3.91 (s,
3H), 2.66 (s, 3H); .sup.19F NMR (471 MHz, acetonitrile-d.sub.3)
.delta. -90.01 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.15 min,
MS (ESI) m/z: 387.0 (M+H).sup.+. Analytical HPLC (method A):
Sunfire, RT=12.88 min, 100% purity; XBridge, RT=10.21 min, 96%
purity.
Example 7
6-(benzyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ole
##STR00393##
[1823] To a stirred solution of Intermediate I-4D (10 mg, 0.028
mmol) and cesium carbonate (22.67 mg, 0.070 mmol) in DMF (0.6 mL)
at room temperature was added benzyl bromide (5.79 .mu.l, 0.049
mmol) in acetonitrile (0.03 mL). The reaction mixture was stirred
at room temperature for 3 h. HPLC and LCMS indicated a completion
of the reaction. The mixture was diluted with EtOAc, quenched with
0.2 N HCl (2.0 mL). The organic layer was collected, dried over
sodium sulfate. After evaporation of solvent, the crude was
purified via preparative LC/MS (method D), 55-95% B over 10
minutes. Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 7 (12.1 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.96 (s, 1H), 8.73 (d,
J=1.4 Hz, 1H), 8.05-8.02 (m, 1H), 7.90 (d, J=5.8 Hz, 1H), 7.89 (t,
J.sub.HF=71.53 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.53 (d, J=7.4 Hz,
2H), 7.43 (t, J=7.4 Hz, 2H), 7.39-7.35 (m, 1H), 7.26 (dd, J=8.8,
2.5 Hz, 1H), 5.23 (s, 2H), 2.67 (s, 3H); LC-MS: Method A, 0 to 100%
B. RT=3.33 min, MS (ESI) m/z: 450.0 (M+H).sup.+. Analytical HPLC
purity (method B): 100%.
Example 8
4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR00394##
[1824] Intermediate 8A: 4-chloro-2-iodobenzo[d]thiazole
##STR00395##
[1826] To a suspension of 4-chlorobenzo[d]thiazol-2-amine (0.66 g,
3.57 mmol) and p-TSA monohydrate (2.040 g, 10.72 mmol) in
acetonitrile (16 mL) at 10.degree. C. (cooled with ice water) was
added dropwise a solution of sodium nitrite (0.493 g, 7.15 mmol)
and potassium iodide (1.483 g, 8.94 mmol) in water (4 mL) over a
period of 25 min. The reaction mixture was stirred at 10.degree. C.
for 10 min, and allowed to warm up to room temperature and stirred
over the weekend. To the reaction mixture was added sodium
bicarbonate (pH to 9.0), water and EtOAc. The organic layer was
collected, washed with water, saturated Na.sub.2S.sub.2O.sub.3,
water, brine and dried over sodium sulfate. After evaporation of
solvent, the crude product was dissolved in a small amount of
chloroform/toluene/MeOH and charged to a 40 silica gel cartridge
which was eluted with hexanes for 3 min., then a 18 min gradient
from 0% to 30%. The desired fractions were combined and
concentrated to give Intermediate 8A (0.571 g, 1.932 mmol, 54.1%
yield) as a white solid. .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.77 (dd, J=8.1, 1.0 Hz, 1H), 7.49 (dd, J=7.8, 1.0 Hz, 1H),
7.38-7.33 (m, 1H); LC-MS: method A, RT=1.94 min, MS (ESI) m/z:
296.0 and 298.0 (M+H).sup.+.
Example 8
[1827] To Intermediate I-1 (16 mg, 0.048 mmol), Intermediate 8A (20
mg, 0.067 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.0 mg, 3.67 .mu.mol) was added
toluene (1.2 mL) and EtOH (0.4 mL). The mixture was sonicated for 1
min, and flushed with argon. To this was added sodium carbonate
(2M, 0.052 mL, 0.105 mmol). The reaction mixture was heated in a
microwave reactor at 110.degree. C. for 30 min. HPLC and LCMS
indicated a completion of the reaction. To the reaction mixture was
added EtOAc/water. The organic layer was collected, dried over
sodium sulfate. After evaporation of solvent, the crude material
was purified via preparative LC/MS (method D, 55-90% B over 10
minutes). Fractions containing the desired product were combined
and dried via centrifugal evaporation to yield the Example 8 (4.2
mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.99 (s, 1H), 8.79
(d, J=1.4 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.90 (t,
J.sub.HF=71.53 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.8 Hz,
1H), 2.71 (s, 3H); LC-MS: Method H, 0 to 100% B. RT=3.66 min, MS
(ESI) m/z: 378.0 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 9
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazolo[4,5-b]pyridine
##STR00396##
[1828] Intermediate 9A: 2-chlorothiazolo[4,5-b]pyridine
##STR00397##
[1830] To a slurry of thiazolo[4,5-b]pyridine-2-thiol (343 mg,
2.039 mmol) in dichloromethane (0.5 mL) was added sulfuryl chloride
(3.32 mL, 40.8 mmol). The suspension was stirred at 50.degree. C.
for 2.0 h, and at room temperature overnight. To the yellow
suspension was added ice water, stirred at room temperature for 15
min to decompose the excess sulfuryl chloride. EtOAc and 4.0 N NaOH
were added to adjust the pH to 10-12. The organic layer was
collected, washed with brine, dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform and charged to a 12 g silica gel cartridge
which was eluted with 5% for 3 min., then a 12 min gradient from 5%
to 60%. The desired fractions were combined and concentrated to
give Intermediate 9A (265 mg, 1.553 mmol, 76% yield) as a white
solid. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.76 (dd, J=5.0,
1.7 Hz, 1H), 8.19 (dd, J=8.0, 1.7 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz,
1H); LC-MS: method A, RT=1.22 min, MS (ESI) m/z: 171 and 173
(M+H).sup.+.
Example 9
[1831] To Intermediate I-1 (17 mg, 0.051 mmol), Intermediate 9A
(11.22 mg, 0.066 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.30 mg, 4.05 .mu.mol) was
added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.056 mL, 0.111 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The mixture was stirred at room
temperature for 15 min. The organic layer was collected. After
evaporation of solvent, the crude material was purified via
preparative LC/MS (method D, 40-90% B over 10 minutes) to yield the
Example 9 (11.2 mg). .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.93 (d, J=1.7 Hz, 1H), 8.73 (s, 1H), 8.72 (dd, J=4.7, 1.4
Hz, 1H), 8.47 (dd, J=8.0, 1.4 Hz, 1H), 7.89 (s, 1H), 7.71 (t,
J.sub.HF=71.53 Hz, 1H), 7.61 (s, 1H), 7.44 (dd, J=8.0, 4.7 Hz, 1H),
2.71 (s, 3H); LC-MS: Method H, 0 to 100% B. RT=2.59 min, MS (ESI)
m/z: 345.0 (M+H).sup.+. Analytical HPLC purity (method B): 95%.
Example 10
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]-
thiazole
##STR00398##
[1833] To Intermediate I-1 (25 mg, 0.074 mmol), Intermediate I-3
(24 mg, 0.093 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (4.86 mg, 5.95 .mu.mol) was
added toluene (1.2 mL) and EtOH (0.4 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.082 mL, 0.164 mmol). The reaction mixture was
heated in a microwave reactor at 110.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. EtOAc/brine was
added to the mixture. The organic layer was collected, dried over
sodium sulfate. After evaporation of solvent, the crude was
dissolved in DMF (3.5 mL) and was purified via preparative LC/MS
(method D, 60-100% B over 10 minutes) to yield Example 10 (15 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.96 (s, 1H), 8.73 (s,
1H), 7.89 (s, 1H), 7.87 (t, J.sub.HF=71.89 Hz, 1H), 7.55 (d, J=1.9
Hz, 1H), 7.02 (s, 1H), 3.86 (s, 3H), 2.75 (s, 3H), 2.68 (s, 3H);
LC-MS: method A, RT=2.66 min, MS (ESI) m/z: 388.0 (M+H).sup.+.
Analytical HPLC purity (method B): 100%.
Example 11
tert-butyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothia-
zolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00399##
[1834] Intermediate 11A: tert-butyl
2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
##STR00400##
[1836] tert-Butyl nitrite (0.181 mL, 1.371 mmol) was added to
copper (II) bromide (297 mg, 1.332 mmol) in dry acetonitrile (3.0
mL) under argon. The reaction mixture was stirred at room
temperature for 10 min. A suspension of tert-butyl
2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (200
mg, 0.783 mmol) in dry acetonitrile (4.0 mL) was added dropwise.
The reaction mixture was stirred at room temperature for 1.0 h.
Acetonitrile was removed under vacuum, the reaction mixture was
diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was
collected, washed with 0.5 N HCl (2.times.), saturated sodium
bicarbonate, brine and dried over sodium sulfate. After evaporation
of solvent, the crude product was dissolved in a small amount of
chloroform and charged to a 12 g silica gel cartridge which was
eluted with hexanes for 2 min., then a 12 min gradient from 0% to
50%. The desired fractions were combined, concentrated and
lyophilized to give Intermediate 11A (85 mg, 0.266 mmol, 34.0%
yield) as a white solid. .sup.1H NMR (500 MHz,
acetonitrile-d.sub.3) .delta. 4.56 (t, J=1.8 Hz, 2H), 3.70 (t,
J=5.8 Hz, 2H), 2.81-2.76 (m, 2H), 1.47 (s, 9H); LC-MS: method A,
RT=1.86 min, MS (ESI) m/z: 319.0 and 321.0 (M+H).sup.+.
Example 11
[1837] To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 11A
(34.2 mg, 0.107 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.83 mg, 7.14 .mu.mol) was
added toluene (2.1 mL) and EtOH (0.7 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.098 mL, 0.196 mmol). The reaction mixture was
heated in a microwave reactor at 120.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate. After evaporation of solvent, the crude
product was purified via a prep LC/MS (method D) to give Example 11
(23.4 mg, 0.052 mmol, 57.9% yield): .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.66 (s, 1H), 8.49 (d, J=1.7 Hz, 1H),
7.76 (d, J=0.8 Hz, 1H), 7.69 (t, J.sub.HF=71.80 Hz, 1H), 4.76 (s,
2H), 3.83 (t, J=5.8 Hz, 2H), 2.99 (t, J=5.6 Hz, 2H), 2.65 (s, 3H),
1.51 (s, 9H); LC-MS: method A, RT=2.51 min, MS (ESI) m/z: 449.0
(M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 12
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxy-4-methylbenzo[d]-
thiazole
##STR00401##
[1838] Intermediate 12A:
N-((5-methoxy-2-methylphenyl)carbamothioyl)benzamide
##STR00402##
[1840] To a solution of 5-methoxy-2-methylaniline (1.47 g, 10.72
mmol) in acetone was added dropwise benzoyl isothiocyanate (1.924
g, 11.79 mmol). The reaction mixture was stirred at room
temperature for 30 min. HPLC and LCMS indicated a completion of the
reaction. Acetone was removed under vacuum. The crude was
triturated with EtOAc/hexanes (1:4). The precipitate was collected
by filtration, dried under vacuum to give Intermediate 12A (3.1 g,
10.32 mmol, 96% yield) as a green solid. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 12.33 (br. s., 1H), 9.14 (br. s., 1H),
7.96-7.92 (m, 2H), 7.71-7.67 (m, 1H), 7.61-7.56 (m, 3H), 7.21 (d,
J=8.5 Hz, 1H), 6.83 (dd, J=8.4, 2.6 Hz, 1H), 3.84 (s, 3H), 2.33 (s,
3H); LC-MS: method A, RT=2.11 min, MS (ESI) m/z:
301(M+H).sup.+.
Intermediate 12B: 1-(5-methoxy-2-methylphenyl)thiourea
##STR00403##
[1842] To a solution of Intermediate 12A (3.1 g, 10.32 mmol) in THF
(20 mL) and MeOH (10 mL) heated at 70.degree. C. was added 4.0 N
NaOH (7.74 mL, 31.0 mmol). The reaction mixture was stirred at
70.degree. C. for 2.0 h. HPLC and TLC indicated a completion of the
reaction. The mixture was then left stirring at room temperature
overnight. THF and MeOH were removed under vacuum. The crude
product was then suspended in water. The precipitate was collected
by filtration, washed with water and dried in the air under vacuum
and then dried under high vacuum to give Intermediate 12B (1.6 g,
8.15 mmol, 79% yield) as a solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.19 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.83
(d, J=2.2 Hz, 1H), 6.76 (dd, J=8.3, 2.8 Hz, 1H), 3.31 (s, 3H), 2.11
(s, 3H); LC-MS: method A, RT=1.16 min, MS (ESI) m/z: 197.0
(M+H).sup.+.
Intermediate 12C: 7-methoxy-4-methylbenzo[d]thiazol-2-amine
##STR00404##
[1844] To a suspension of Intermediate 12B (1.43 g, 7.29 mmol) in
AcOH (20 mL) at room temperature was added benzyltrimethylammonium
tribromide (2.84 g, 7.29 mmol) in acetonitrile (15 mL) dropwise (15
min). The reaction mixture was stirred at room temperature
overnight. HPLC and LCMS indicated a completion of the reaction.
Most of the solvent was removed under vacuum. The mixture was
diluted with EtOAc, and the pH was adjusted to 8 with 1.0 N NaOH.
The insoluble material was removed by filtration. The organic layer
of the filtrate was collected, washed with saturated sodium
bicarbonate, brine, dried over sodium sulfate. After evaporation of
solvent, Intermediate 12C (1.42 g, 7.31 mmol, 100% yield) was
obtained as a solid. .sup.1H NMR and HPLC indicated >90% purity.
It was used for the next step without further purification. .sup.1H
NMR (500 MHz, chloroform-d) .delta. 7.09 (dd, J=8.1, 0.7 Hz, 1H),
6.60 (d, J=8.3 Hz, 1H), 3.93 (s, 3H), 2.51 (s, 3H); LC-MS: method
A, RT=1.28 min, MS (ESI) m/z: 195.0 (M+H).sup.+.
Intermediate 12D: 2-bromo-7-methoxy-4-methylbenzo[d]thiazole
##STR00405##
[1846] Tert-butyl nitrite (0.225 mL, 1.699 mmol) was added to a
solution of copper (II) bromide (354 mg, 1.586 mmol) in
acetonitrile (5.0 mL). The reaction mixture was stirred at room
temperature for 10 min, followed by addition of Intermediate 12C
(220 mg, 1.133 mmol) in acetonitrile (3.0 mL). The reaction mixture
was stirred at room temperature 1.0 h. HPLC and LCMS indicated a
complete conversion of starting material to the desired mono-bromo
and undesired di-bromo product. Acetonitrile was removed under
vacuum, the reaction mixture was diluted with EtOAc, quenched with
1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl
(2.times.), saturated sodium bicarbonate, brine and dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
silica gel cartridge which was eluted with hexanes for 2 min., then
a 18 min gradient from 0% to 20%. TLC indicated the two products
were not separated by ISCO column. The crude residue was then
purified using a preparative HPLC (method A, 50-100% B in 10 min.,
RT=7.0 min). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Intermediate
12D (120 mg, 0.465 mmol, 41.0% yield). .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.22 (dd, J=8.0, 0.8 Hz, 1H), 6.78 (d, J=8.0
Hz, 1H), 3.97 (s, 3H), 2.65 (d, J=0.8 Hz, 3H); LC-MS: method A,
RT=2.17 min, MS (ESI) m/z: 258.0 and 260.0 (M+H).sup.+.
Example 12
[1847] To Intermediate I-1 (20 mg, 0.059 mmol), Intermediate 12D
(19.97 mg, 0.077 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.89 mg, 4.76 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.074 mL, 0.149 mmol). The reaction mixture was
heated in a microwave reactor at 125.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate. After evaporation of solvent, the crude
was dissolved in DMF (4.0 mL) and purified via preparative LC/MS
(method D, 60-100% B over 25 minutes). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to yield Example 12 (2.5 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.03 (s, 1H), 8.81 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.90
(t, J.sub.HF=71.53 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0
Hz, 1H), 3.99 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H); LC-MS: method A,
RT=2.77 min, MS (ESI) m/z: 388.0 (M+H).sup.+.
Example 13
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-difluoro-7-methoxybenz-
o[d]thiazol
##STR00406##
[1848] Intermediate 13A:
4,6-difluoro-7-methoxybenzo[d]thiazol-2-amine
##STR00407##
[1850] To 2,4-difluoro-5-methoxyaniline (270 mg, 1.697 mmol) in
acetonitrile (6 mL) was added ammonium thiocyanate (194 mg, 2.55
mmol). The reaction mixture was stirred at room temperature for 10
min. Then benzyltrimethylammonium tribromide (662 mg, 1.697 mmol)
in acetonitrile (3.0 mL) was added dropwise (10 min). The mixture
was then stirred at room temperature overnight. HPLC and LCMS
indicated a completion of the reaction. The mixture was diluted
with EtOAc/saturated sodium bicarbonate. The organic layer was
collected, washed with brine, dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform/MeOH, and charged to a 12 g silica gel
cartridge which was eluted with 5% for 3 min., then a 12 min
gradient from 5% to 75%. The desired fractions were combined and
concentrated to give Intermediate 13A (240 mg, 1.110 mmol, 65.4%
yield) as a pale solid. .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 6.98 (dd, J=12.1, 10.5 Hz, 1H), 3.99 (d, J=1.7 Hz, 3H);
.sup.19F NMR (471 MHz, methanol-d.sub.4) .delta. -132.46 (s, 1F),
-139.29 (s, 1F); LC-MS: method A, RT=1.54 min, MS (ESI) m/z: 217.0
(M+H).sup.+.
Intermediate 13B:
2-chloro-4,6-difluoro-7-methoxybenzo[d]thiazole
##STR00408##
[1852] To a solution of copper (II) chloride (82 mg, 0.611 mmol) in
acetonitrile (6.0 mL) at 40.degree. C. was added tert-butyl nitrite
(0.087 mL, 0.661 mmol), followed by Intermediate 13A (110 mg, 0.509
mmol) as a solid. The reaction mixture was stirred at 40.degree. C.
for 1.0 h, and left stirring at room temperature overnight. It was
diluted with EtOAc, washed with 0.5 HCl, saturated sodium
bicarbonate and brine. After evaporation of solvent, Intermediate
13B (12 mg, 0.051 mmol, 10.01% yield) was obtained as yellow solid.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.07 (dd, J=12.1, 9.6
Hz, 1H), 4.10 (d, J=2.2 Hz, 3H); .sup.19F NMR (471 MHz,
chloroform-d) .delta. -125.09 (s, 1F), -130.33 (s, 1F); LC-MS:
method A, RT=2.01 min, MS (ESI) m/z: 236.0 and 238.0
(M+H).sup.+.
Example 13
[1853] To Intermediate I-1 (12 mg, 0.036 mmol), Intermediate 13B
(11.36 mg, 0.048 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (2.332 mg, 2.86 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.045 mL, 0.089 mmol). The reaction mixture was
heated in a microwave reactor at 125.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate. After evaporation of solvent, the crude
residue was purified using a preparative HPLC (method A, 70-100% B
in 10 min; RT=9.0 min). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Intermediate 13 (2.0 mg, 4.84 .mu.mol, 13.55% yield). .sup.1H NMR
(500 MHz, acetonitrile-d.sub.3) .delta. 8.84 (d, J=1.7 Hz, 1H),
8.82 (s, 1H), 7.91 (dd, J=1.9, 0.8 Hz, 1H), 7.73 (t, J.sub.HF=71.80
Hz, 1H), 7.27 (dd, J=12.0, 10.3 Hz, 1H), 4.15 (d, J=1.7 Hz, 3H),
2.73 (s, 3H); .sup.19F NMR (471 MHz, acetonitrile-d.sub.3) .delta.
-89.97 (s, 2F), -127.74 (s, 1F), -133.31 (s, 1F); LC-MS: Method A,
50 to 100% B. RT=2.30 min, MS (ESI) m/z: 410.0 (M+H).sup.+.
Analytical HPLC (method A): Sunfire, RT=13.23 min, 99% purity;
XBridge, RT=8.56 min, 99% purity.
Example 14
tert-butyl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-7-yl) carbamate
##STR00409##
[1854] Intermediate 14A: methyl
2-bromobenzo[d]thiazole-7-carboxylate
##STR00410##
[1856] Tert-butyl nitrite (1.111 mL, 8.40 mmol) was added to copper
(II) bromide (1.770 g, 7.92 mmol) in dry acetonitrile (15 mL) under
argon. The reaction mixture was stirred at room temperature for 10
min. A suspension of methyl 2-aminobenzo[d]thiazole-7-carboxylate
(1.0 g, 4.80 mmol) in dry acetonitrile (15 mL) was added dropwise.
The reaction mixture was stirred at room temperature for 1.5 h,
then at 50.degree. C. for 45 min. HPLC and LCMS indicated a
completion of the reaction. Acetonitrile was removed under vacuum,
the reaction mixture was diluted with EtOAc, quenched with 1.0 N
HCl. The organic layer was collected, washed with 0.5 N HCl
(2.times.), saturated sodium bicarbonate, brine and dried over
sodium sulfate. After evaporation of solvent, Intermediate 14A (1.2
g, 4.41 mmol, 92% yield) was obtained as a brown solid. It was used
for next step without further purification. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 8.19 (dd, J=8.0, 1.1 Hz, 1H), 8.13 (dd,
J=7.7, 1.1 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 4.05 (s, 3H); LC-MS:
method A, RT=2.02 min, MS (ESI) m/z: 272.0 274.0 (M+H).sup.+.
Intermediate 14B: 2-bromobenzo[d]thiazole-7-carboxylic acid
##STR00411##
[1858] To a solution of Intermediate 14A (0.64 g, 2.352 mmol) in
THF (12 mL) was added lithium hydroxide monohydrate (0.296 g, 7.06
mmol) dissolved in water (4.0 mL). The reaction mixture was stirred
at room temperature for 2.5 h. HPLC indicated a completion of the
reaction. The mixture was diluted with EtOAc, quenched with 0.5N
HCl (20 mL). The organic layer was collected, washed with brine,
dried over sodium sulfate. After evaporation of solvent,
Intermediate 14B (0.60 g, 2.325 mmol, 99% yield) was obtained as a
yellow solid. It was used for next step without further
purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.28 (dd,
J=8.3, 1.1 Hz, 1H), 8.12 (dd, J=7.7, 1.1 Hz, 1H), 7.71 (t, J=7.8
Hz, 1H); LC-MS: method A, RT=1.76 min, MS (ESI) m/z: 258.0 and
260.0 (M+H).sup.+.
Intermediate 14C: tert-butyl
(2-bromobenzo[d]thiazol-7-yl)carbamate
##STR00412##
[1860] To a suspension of Intermediate 14B (80 mg, 0.310 mmol) in
THF (2.0 mL) was added TEA (0.065 mL, 0.465 mmol). The mixture
turned to a clear solution. To this solution was added
trimethylsilyl azide (0.045 mL, 0.341 mmol) and T.sub.3P 50% wt in
EtOAc (0.203 mL, 0.341 mmol). The reaction mixture was stirred at
room temperature for 5 min, then tert-butanol (0.039 mL, 0.403
mmol) was added. The mixture was heated at 80.degree. C. for 2.0 h.
Another 2.0 equivalents of triethylamine and 3 equivalents of
t-BuOH were added, and the mixture was heated at 80.degree. C. for
8.0 h. The reaction mixture was diluted with EtOAc, washed with 0.5
N HCl, brine. The organic layer was dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform and charged to a 12 g silica gel
cartridge which was eluted with hexanes for 2 min., then a 15 min
gradient from 0% to 30%. The desired fractions were combined and
concentrated to give Intermediate 14C (36 mg, 0.109 mmol, 35.3%
yield): a white solid. .sup.1H NMR (500 MHz, chloroform-d) .delta.
7.79 (dd, J=7.8, 1.2 Hz, 1H), 7.51-7.43 (m, 2H), 6.48 (br. s., 1H),
1.58 (s, 9H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 329.0 and
331.0 (M+H).sup.+.
Example 14
[1861] To Intermediate I-1 (28 mg, 0.083 mmol), Intermediate 14C
(32.9 mg, 0.100 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.44 mg, 6.66 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.104 mL, 0.208 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 35 min. The
mixture was diluted with EtOAc, washed with brine. The organic
layer was dried over sodium sulfate. After evaporation of solvent,
the crude product was dissolved in a small amount of chloroform and
charged to a 4 g silica gel cartridge which was eluted with hexanes
for 2 min., then a 10 min gradient from 0% to 30%. The desired
fractions were combined and concentrated to give 20 mg of the crude
product. This crude product was further purified by prep HPLC. The
crude residue was purified using a preparative HPLC (method A,
60-100% B in 10 min; RT=8.5 min). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 14 (11 mg, 28% yield). .sup.1H NMR (500 MHz, chloroform-d)
.delta. 8.78 (d, J=1.7 Hz, 1H), 8.72 (s, 1H), 7.98 (d, J=8.3 Hz,
1H), 7.88 (dd, J=1.8, 1.0 Hz, 1H), 7.69 (t, J.sub.HF=71.53 Hz, 1H),
7.56 (t, J=8.0 Hz, 1H), 2.71 (s, 3H), 1.62 (s, 9H); LC-MS: Method
A, 50 to 100% B. RT=2.00 min, MS (ESI) m/z: 459.0 (M+H).sup.+.
Analytical HPLC (method A): Sunfire, RT=11.9 min, 100% purity;
XBridge, RT=7.46 min, 97% purity.
Example 15
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(thiazol-4-ylmethoxy)ben-
zo[d]thiazo
##STR00413##
[1862] Intermediate 15A: 2-bromo-3-methoxyaniline
##STR00414##
[1864] To a suspension of 2-bromo-1-methoxy-3-nitrobenzene (3.90 g,
16.81 mmol) and iron powder (2.82 g, 50.4 mmol) in EtOH (50 mL) was
added concentrated HCl (3.08 mL, 37.0 mmol). The mixture was heated
at 85.degree. C. for 2.0 h. HPLC indicated a completion of the
reaction. After cooled to room temperature, the solvent was removed
under vacuum. The residue was suspended in EtOAc and saturated
sodium bicarbonate. The insoluble material was removed by
filtration through a pad of wet celite. The organic layer of the
filtrate was collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, Intermediate 15A (3.25 g,
16.09 mmol, 96% yield) was obtained as brown oil. It was used for
the next step without further purification. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.08 (t, J=8.1 Hz, 1H), 6.45 (dd, J=8.0, 1.4
Hz, 1H), 6.34 (dd, J=8.3, 1.1 Hz, 1H), 3.89 (s, 2H); LC-MS: method
A, RT=1.21 min, MS (ESI) m/z: 202.0 and 204.0 (M+H).sup.+.
Intermediate 15B: 7-methoxybenzo[d]thiazole-2-thiol
##STR00415##
[1866] A solution of Intermediate 15A (3.25 g, 16.09 mmol) and
potassium O-ethyl carbonodithioate (6.45 g, 40.2 mmol) in DMF (20
mL) was heated at 135.degree. C. under argon for 6.0 h. HPLC and
LCMS indicated a completion of the reaction. The mixture was cooled
to room temperature, diluted with 20 mL water, followed by addition
of 30 mL 1.0 N HCl. The precipitate formed was collected by
filtration, washed with water, dried under vacuum and then chased
with toluene (3.times.) to yield Intermediate 15B (3.1 g, 15.71
mmol, 98% yield) as a brown solid. It was used for the next step
without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 13.77 (br. s., 1H), 7.38 (t, J=8.1 Hz, 1H), 6.94 (t, J=8.1
Hz, 2H), 3.91 (s, 3H); LC-MS: method A, RT=1.63 min, MS (ESI) m/z:
198.0 (M+H).sup.+.
Intermediate 15C: 7-methoxy-2-(methylthio)benzo[d]thiazole
##STR00416##
[1868] To a solution of Intermediate 15B (2.01 g, 10.19 mmol) in
DMF (40 mL) at room temperature was added potassium carbonate (3.52
g, 25.5 mmol). After stirring at room temperature for 10 min,
iodomethane (0.796 mL, 12.74 mmol) was added. The reaction mixture
was stirred at room temperature for 20 min, at which time HPLC
indicated a completion of the reaction. It was diluted with EtOAc,
washed with water, brine and dried over sodium sulfate. After
evaporation of solvent, Intermediate 15C (2.2 g, 10.41 mmol, 102%
yield) was obtained as a brown solid. It was used for the next step
without purification. .sup.1H NMR (500 MHz, chloroform-d) .delta.
7.53 (dd, J=8.0, 0.8 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 6.79 (dd,
J=8.0, 0.6 Hz, 1H), 3.99 (s, 3H), 2.82 (s, 3H); LC-MS: method A,
RT=2.00 min, MS (ESI) m/z: 212.0 (M+H).sup.+.
Intermediate 15D: 7-methoxy-2-(methylsulfonyl)benzo[d]thiazole
##STR00417##
[1870] To a solution of Intermediate 15C (2.2 g, 10.41 mmol)
dissolved in MeOH (100 mL) was added dropwise a solution of OXONE
(19.20 g, 31.2 mmol) suspended in water (100 mL). The reaction
mixture was stirred at room temperature over the weekend. HPLC and
TLC indicated a completion of the reaction. The reaction was
quenched by addition of dimethyl sulfide (4.62 mL, 62.5 mmol).
After stirring at room temperature for 45 min, methanol was removed
under vacuum. The mixture was diluted with EtOAc/water. The
insoluble material was removed by filtration. The filtrate was
collected. The organic layer was washed with water (2.times.),
saturated sodium bicarbonate, brine and dried over sodium sulfate.
After evaporation of solvent, Intermediate 15D (2.5 g, 10.28 mmol,
99% yield) was obtained as a pale solid. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.83 (dd, J=8.3, 0.8 Hz, 1H), 7.59 (t, J=8.1
Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.42 (s, 3H); LC-MS:
method A, RT=1.55 min, MS (ESI) m/z: 243.9 (M+H).sup.+.
Intermediate 15E: 2-hydrazinyl-7-methoxybenzo[d]thiazole
##STR00418##
[1872] To a suspension of Intermediate 15D (2.5 g, 10.28 mmol) in
EtOH (15 mL) was added hydrazine monohydrate (15.55 mL, 308 mmol).
The mixture was sonicated for 2 min, heated in oil bath at
100.degree. C. for 1.0 h. HPLC and LCMS indicated a completion of
the reaction. Solvent was removed under vacuum. The crude was
redissolved in MeOH, and MeOH was removed under vacuum. To the
crude was then added ice-cold water (6.0 mL). The precipitate
formed was collected by filtration, washed with water, dried over
air for 30 min and then at high vacuum over night to give
Intermediate 15E (1.67 g, 8.55 mmol, 83% yield) as a pale yellow
solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.97 (s, 1H),
7.17 (t, J=8.0 Hz, 1H), 6.97 (dd, J=8.0, 0.8 Hz, 1H), 6.64 (dd,
J=8.3, 0.6 Hz, 1H), 5.01 (s, 2H), 3.32 (s, 3H); LC-MS: method A, 0
to 100% B. RT=1.15 min, MS (ESI) m/z: 196.0 (M+H).sup.+.
Intermediate 15F: 2-chloro-7-methoxybenzo[d]thiazole
##STR00419##
[1874] To Intermediate 15E (1.6 g, 8.19 mmol) suspended in
dichloromethane (8.0 mL) in a round-bottom flask was added thionyl
chloride (8.37 mL, 115 mmol) slowly. The reaction mixture was
heated in a pre-heated oil bath at 55.degree. C. for 30 min. HPLC
indicated a completion of the reaction. Thionyl chloride was
removed under vacuum, chased with EtOAc once to give a yellow
solid. The solid was dissolved in EtOAc, washed with saturated
sodium bicarbonate, brine, dried over sodium sulfate. After
evaporation of solvent, Intermediate 15F (1.6 g, 8.01 mmol, 98%
yield) was obtained as yellow solid. It was used for the next step
without further purification. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.53-7.48 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.79 (d, J=8.2
Hz, 1H), 3.91 (s, 3H); LC-MS: method A, RT=1.98 min, MS (ESI) m/z:
199.9 201.9 (M+H).sup.+.
Intermediate 15G: 2-chlorobenzo[d]thiazol-7-ol
##STR00420##
[1876] Aluminum chloride (2.67 g, 20.03 mmol) was added to a
solution of Intermediate 15F (1.6 g, 8.01 mmol) in toluene (40 mL).
The mixture was heated at 85.degree. C. for 1.5 h. HPLC indicated a
complete conversion of starting material. The reaction mixture was
cooled to room temperature, quenched with ice-cold 1.0 N HCl (30
mL) and EtOAc (50 mL), and stirred at room temperature for 30 min.
The organic layer was collected, washed with water, saturated
sodium bicarbonate, brine and dried over sodium sulfate. After
evaporation of solvent, the crude product was triturated with
EtOAc/hexanes (1:3). The precipitate was collected to give
Intermediate 15G (1.3 g). The filtrate was concentrated, dissolved
in a small amount of chloroform and charged to a 12 g silica gel
cartridge which was eluted with 5% for 2 min., then a 12 min
gradient from 5% to 50%. The desired fractions were combined and
concentrated to give additional product (96 mg). LC-MS: method A,
RT=1.66 min, MS (ESI) m/z: 186.0 and 188.0 (M+H).sup.+.
Intermediate 15H:
7-((tert-butyldimethylsilyl)oxy)-2-chlorobenzo[d]thiazole
##STR00421##
[1878] To a stirred solution of Intermediate 15G (1.39 g, 7.49
mmol) in DMF (20 mL) was added TBDMS-Cl (1.467 g, 9.73 mmol) and
imidazole (0.892 g, 13.10 mmol). The reaction mixture was left
stirring at room temperature for 1.0 h. The mixture was partitioned
between EtOAc/water. The organic layer was washed with brine and
dried over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform and charged
to a 40 g silica gel cartridge which was eluted with hexanes for 3
min., then a Intermediate 15 min gradient from 0% to 15%. The
desired fractions were combined and concentrated to give
Intermediate 15H (2.14 g, 7.14 mmol, 95% yield) as brown oil.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.60 (dd, J=8.3, 0.8
Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 6.85 (dd, J=8.0, 0.8 Hz, 1H), 1.07
(s, 9H), 0.29 (s, 6H); LC-MS: Method A, 50 to 100% B. RT=2.38 min,
MS (ESI) m/z: 300.0 and 302.0 (M+H).sup.+.
Intermediate 15I
7-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-
-5-yl)benzo[d]thiazole
##STR00422##
[1880] To Intermediate I-1 (1.05 g, 3.12 mmol), Intermediate 15H
(1.077 g, 3.59 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (0.128 g, 0.156 mmol) was added
toluene (9 mL), EtOH (3 mL) and sodium carbonate (2M, 3.12 mL, 6.25
mmol). The mixture was degassed with argon for 5 min. The reaction
mixture was heated in a microwave reactor at 135.degree. C. for 70
min. HPLC indicated completion of reaction. To the reaction mixture
was added EtOAc/water/brine. The insoluble was removed by
filtration with a pad of celite. The organic layer was collected,
washed with brine, dried over sodium sulfate. After evaporation of
solvent, the crude product was dissolved in a small amount of
toluene/chloroform and charged to a 80 g silica gel cartridge which
was eluted with hexanes for 3 min., then a 20 min gradient from 0%
to 75%. The desired fractions were combined and concentrated to
give Intermediate 15I (0.98 g, 2.069 mmol, 66.2% yield) as a bright
yellow solid. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.81 (d,
J=1.9 Hz, 1H), 8.76 (s, 1H), 7.83-7.80 (m, 2H), 7.68 (t,
J.sub.HF=71.80 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.86 (dd, J=7.8,
0.7 Hz, 1H), 2.71 (s, 3H), 1.13 (s, 9H), 0.35 (s, 6H); .sup.19F NMR
(471 MHz, chloroform-d) .delta. -89.74 (s, 2F); LC-MS: Method A, 80
to 100% B. RT=2.41 min, MS (ESI) m/z: 474.0 (M+H).sup.+.
Intermediate 15J:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ol
##STR00423##
[1882] To a solution of Intermediate 15I (1.96 g, 4.14 mmol) in THF
(15 mL) at room temperature was added acetic acid (0.521 mL, 9.10
mmol), followed by addition of 1.0 N TBAF in THF (4.97 mL, 4.97
mmol) dropwise. The reaction mixture was stirred at room
temperature for 20 min, at which time HPLC and LCMS indicated a
completion of the reaction. The mixture was diluted with EtOAc,
washed with water, saturated sodium bicarbonate (2.times.), brine,
and dried over sodium sulfate. After evaporation of the solvent,
the crude product was triturated with EtOAc/hexanes (1:4). The
precipitate was collected by filtration to give Intermediate 15J
(1.40 g, 3.893 mmol, 94.0% yield). The filtrate was further
concentrated and purified with a 12 g ISCO column eluting with
5%-50% EtOAc in hexanes over 12 min. to give additional product (60
mg). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.78 (s, 1H),
8.72 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.79 (t, J.sub.HF=71.80 Hz,
1H), 7.60 (dd, J=8.3, 0.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 6.84
(dd, J=7.7, 0.6 Hz, 1H), 2.70 (s, 3H); .sup.19F NMR (471 MHz,
methanol-d.sub.4) .delta. -91.07 (s, 2F); LC-MS: Method A, 50 to
100% B. RT=1.68 min, MS (ESI) m/z: 360.0 (M+H).sup.+.
Example 15
[1883] A solution of 4-hydroxymethyl thiazole (24.03 mg, 0.209
mmol) and DIAD (0.041 mL, 0.209 mmol) in THF (1.0 mL) was added
dropwise to a mixture of Intermediate 15J (25 mg, 0.070 mmol) and
triphenylphosphine (36.5 mg, 0.139 mmol) in THF (0.5 mL) heated at
65.degree. C. At the end of addition, HPLC and LCMS indicated a
complete conversion of starting material to the product. Solvent
was removed under vacuum and the crude was dissolved in
DMSO/acetonitrile (2 mL/1 mL), filtered and purified by prep HPLC
(method A, 65-100% B in 10 min; RT=7.2 min). The desired fractions
were placed in a SpeedVac overnight to remove solvent, then
lyophilized to give Example 15 (10 mg, 0.022 mmol, 31.2% yield) as
yellow lyophilate. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.94
(d, J=2.2 Hz, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 7.86-7.82
(m, 2H), 7.69 (t, J.sub.HF=71.53 Hz, 1H), 7.59-7.56 (m, 1H), 7.49
(t, J=8.0 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 5.57 (d, J=0.6 Hz, 2H),
2.71 (s, 3H); .sup.19F NMR (471 MHz, chloroform-d) .delta. -89.74
(s, 2F); LC-MS: Method A, 50 to 100% B. RT=1.94 min, MS (ESI) m/z:
457.0 (M+H).sup.+. Analytical HPLC (method A): Sunfire, RT=11.07
min, 99% purity; XBridge, RT=7.14 min, 99% purity.
Example 16
tetrahydrofuran-3-yl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)-
oxy)ethyl)carbamate
##STR00424##
[1885] To a stirred solution of THF-3-ol (8.21 mg, 0.093 mmol) in
dichloromethane (0.6 mL) was added 20% phosgene in toluene (0.078
mL, 0.149 mmol). The reaction mixture was stirred at room
temperature for 1.5 h. Solvent was removed under vacuum. The
chloroformate obtained was dissolved in dichloromethane (0.5 mL)
and added to a solution of Intermediate I-4 (15 mg, 0.037 mmol) and
TEA (0.026 mL, 0.186 mmol) in dichloromethane (0.6 mL). The
reaction mixture was stirred at room temperature for 30 min.
Solvent was removed under vacuum. The crude was dissolved in
acetonitrile/DMSO (1 mL/0.5 mL) and was purified by prep HPLC
(method A, 60-100% B in 10 min; RT=6 min). The desired fractions
were placed in a SpeedVac overnight to remove solvent, then
lyophilized to give Example 16 (3.0 mg, 5.69 .mu.mol, 15.27%
yield). .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.76 (d, J=1.9
Hz, 1H), 8.71 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.84 (dd, J=1.9, 0.8
Hz, 1H), 7.68 (t, J.sub.HF=71.53 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H),
7.17 (dd, J=9.1, 2.5 Hz, 1H), 5.35-5.24 (m, 2H), 4.18 (t, J=5.0 Hz,
2H), 3.99-3.86 (m, 3H), 3.69 (q, J=5.0 Hz, 2H), 2.71 (s, 3H), 2.20
(dd, J=14.2, 6.2 Hz, 1H), 2.11-2.04 (m, 1H); .sup.19F NMR (471 MHz,
chloroform-d) .delta. -89.77 (s, 2F); LC-MS: method A, RT=2.31 min,
MS (ESI) m/z: 517.0 (M+H).sup.+. Analytical HPLC (method A):
Sunfire, RT=8.80 min, 98% purity; XBridge, RT=5.64 min, 98%
purity.
Example 17
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-phenoxyethoxy)benzo[d-
]thiazole
##STR00425##
[1887] A solution of 2-phenoxyethanol (20.76 mg, 0.150 mmol) and
DIAD (0.029 mL, 0.150 mmol) in THF (1.0 mL) was added dropwise to a
mixture of Intermediate 15J (18 mg, 0.050 mmol) and
triphenylphosphine (26.3 mg, 0.100 mmol) in THF (0.5 mL) heated at
65.degree. C. At the end of addition, HPLC and LCMS indicated a
complete conversion of starting material to the product. Solvent
was removed under vacuum and the crude was dissolved in
DMSO/acetonitrile (1 mL/1 mL), filtered and purified by prep HPLC
(method A, 80-100% B in 10 min; RT=8 min). The desired fractions
were placed in a SpeedVac overnight to remove solvent, then
lyophilized to give Example 17 (13 mg, 0.026 mmol, 52.5% yield) as
yellow lyophilate. .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.66 (d, J=1.7 Hz, 1H), 8.62 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=8.3
Hz, 1H), 7.57 (t, J.sub.HF=71.80 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H),
7.24 (t, J=8.0 Hz, 2H), 6.95-6.89 (m, 3H), 6.85 (d, J=8.0 Hz, 1H),
4.51-4.47 (m, 2H), 4.41-4.36 (m, 2H), 2.59 (s, 3H); .sup.19F NMR
(471 MHz, methanol-d.sub.4) .delta. -93.93 (s, 2F); LC-MS: Method
A, 50 to 100% B. RT=2.35 min, MS (ESI) m/z: 480.0 (M+H).sup.+.
Analytical HPLC (method A): Sunfire, RT=5.27 min, 97% purity;
XBridge, RT=2.99 min, 97% purity.
Example 18
7-(2-(benzyloxy)ethoxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazole
##STR00426##
[1889] A solution of 2-(benzyloxy)ethanol (22.87 mg, 0.150 mmol)
and DIAD (0.029 mL, 0.150 mmol) in THF (1.0 mL) was added dropwise
to a mixture of Intermediate 15J (18 mg, 0.050 mmol) and
triphenylphosphine (26.3 mg, 0.100 mmol) in THF (0.5 mL) heated at
65.degree. C. At the end of addition, HPLC and LCMS indicated a
complete conversion of starting material to the product. Solvent
was removed under vacuum and the crude was dissolved in
DMSO/acetonitrile (1 mL/1 mL), filtered and purified by prep HPLC
(method A, 65-100% B in 10 min; RT=7.2 min). The desired fractions
were placed in a SpeedVac overnight to remove solvent, then
lyophilized to give Example 18 (5.0 mg, 9.83 .mu.mol, 19.62% yield)
as yellow lyophilate. .sup.1H NMR (500 MHz, chloroform-d) .delta.
8.87 (d, J=1.9 Hz, 1H), 8.74 (s, 1H), 7.84 (dd, J=2.2, 1.1 Hz, 1H),
7.82 (d, J=8.0 Hz, 1H), 7.69 (t, J.sub.HF=71.80 Hz, 1H), 7.50-7.45
(m, 3H), 7.44-7.39 (m, 2H), 7.36-7.32 (m, 1H), 6.90 (d, J=8.0 Hz,
1H), 4.75 (s, 2H), 4.47-4.42 (m, 2H), 4.03-3.98 (m, 2H), 2.72 (s,
3H); .sup.19F NMR (471 MHz, chloroform-d) .delta. -89.74 (s, 2F);
LC-MS: Method A, 50 to 100% B. RT=2.33 min, MS (ESI) m/z: 494.0
(M+H).sup.+. Analytical HPLC (method A): Sunfire, RT=5.58 min, 96%
purity; XBridge, RT=3.01 min, 98% purity.
Example 19
(Tetrahydrofuran-2-yl)methyl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
##STR00427##
[1891] To a solution of (THF-2-yl)methanol (0.194 mL, 1.997 mmol)
in dichloromethane (2.0 mL) was added phosgene, 20% in toluene
(3.15 mL, 5.99 mmol). The reaction mixture was stirred at room
temperature for 18 h. Solvent was removed under vacuum to give the
chloroformate (0.32 g, 1.944 mmol, 97% yield) as a colorless liquid
that was used for the next step without further purification.
[1892] To a solution of Intermediate I-4 (15 mg, 0.037 mmol) in
dichloromethane (0.5 mL) was added DIEA (0.052 mL, 0.298 mmol).
After stirring at room temperature for 5 min, the chloroformate
obtained above (18.40 mg, 0.112 mmol) was added. The reaction
mixture was stirred at room temperature for 15 min. HPLC and LCMS
indicated a completion of the reaction. Solvent was removed under
vacuum. The crude was dissolved in acetonitrile/DMSO (1 mL/1.0 mL)
and was purified by prep HPLC (method A, 60-100% B in 10 min;
RT=6.5 min). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Example 19
(14 mg, 0.026 mmol, 68.7% yield) as yellow lyophilate. .sup.1H NMR
(500 MHz, chloroform-d) .delta. 8.73 (d, J=1.9 Hz, 1H), 8.67 (s,
1H), 8.09 (d, J=9.1 Hz, 1H), 7.82 (dd, J=1.9, 1.1 Hz, 1H), 7.67 (t,
J.sub.HF=71.80 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 7.16 (dd, J=8.9,
2.3 Hz, 1H), 5.40 (br. s., 1H), 4.25 (dd, J=11.3, 3.0 Hz, 1H),
4.19-4.15 (m, 3H), 4.03 (dd, J=11.1, 7.6 Hz, 1H), 3.96-3.90 (m,
1H), 3.88-3.82 (m, 1H), 3.69 (q, J=5.4 Hz, 2H), 2.69 (s, 3H),
2.07-2.00 (m, 1H), 1.99-1.91 (m, 2H); .sup.19F NMR (471 MHz,
chloroform-d) .delta. -89.77 (s, 2F); LC-MS: Method A, 50 to 100%
B. RT=1.88 min, MS (ESI) m/z: 531.0 (M+H).sup.+. Analytical HPLC
(method A): Sunfire, RT=4.06 min, 97% purity; XBridge, RT=3.02 min,
97% purity.
Example 20
tetrahydro-2H-pyran-4-yl
(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)-
oxy)ethyl)carbamate
##STR00428##
[1894] To a solution of tetrahydro-2H-pyran-4-ol (0.196 mL, 2.056
mmol) and in dichloromethane (2.0 mL) was added phosgene, 20% in
toluene (3.25 mL, 6.17 mmol). The reaction mixture was stirred at
room temperature for 18 h. Solvent was removed under vacuum to give
the chloroformate (0.33 g, 2.005 mmol, 98% yield) as a colorless
liquid that was used for the next step without further
purification.
[1895] To a solution of Intermediate I-4 (15 mg, 0.037 mmol) in
dichloromethane (0.5 mL) was added DIEA (0.052 mL, 0.298 mmol).
After stirring at room temperature for 5 min, the chloroformate
(18.40 mg, 0.112 mmol) was added. The reaction mixture was stirred
at room temperature for 15 min. HPLC and LCMS indicated a
completion of the reaction. Solvent was removed under vacuum. The
crude was dissolved in acetonitrile/DMSO (1 mL/1.0 mL) and was
purified by prep HPLC (method A, 60-100% B in 10 min; RT=6.5 min).
The desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 20 (4.0 mg, 7.39 .mu.mol,
19.82% yield) as yellow lyophilate. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 8.78 (d, J=1.7 Hz, 1H), 8.71 (s, 1H), 8.11
(d, J=9.1 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.67 (t,
J.sub.HF=71.80 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.19 (dd, J=8.8,
2.5 Hz, 1H), 5.24 (br. s., 1H), 4.91 (br. s., 1H), 4.19 (t, J=5.1
Hz, 3H), 3.99-3.93 (m, 4H), 3.70 (q, J=5.3 Hz, 3H), 3.58 (t, J=9.5
Hz, 3H), 2.71 (s, 3H), 1.98 (d, J=10.7 Hz, 2H), 1.76-1.68 (m, 2H);
.sup.19F NMR (471 MHz, chloroform-d) .delta. -89.78 (s, 2F); LC-MS:
Method A, 50 to 100% B. RT=1.86 min, MS (ESI) m/z: 531.0
(M+H).sup.+. Analytical HPLC (method A): Sunfire, RT=4.09 min, 97%
purity; XBridge, RT=3.04 min, 98% purity.
Example 21
tetrahydro-2H-pyran-4-yl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-7-yl)carbamate
##STR00429##
[1896] Intermediate 21A
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-amine
##STR00430##
[1898] To a suspension of Example 14 (90 mg, 0.196 mmol) in ethyl
acetate (1.0 mL) and MeOH (1.0 mL) was added 4.0 N HCl in dioxane
(2.454 mL, 9.82 mmol). The reaction mixture was stirred at room
temperature overnight. After evaporation of solvent, the crude
residue was purified using a preparative HPLC (method A, 50-100% B
in 10 min; RT=6 min). The desired fractions were placed in a
SpeedVac overnight to remove solvent. TFA was removed by
redissolving in EtOAc and washing with saturated sodium
bicarbonate. After evaporation of solvent and lyophilization,
Intermediate 21A (47 mg, 0.125 mmol, 63.5% yield) was obtained as
yellow lyophilate. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.84
(s, 1H), 8.70 (s, 1H), 7.81 (s, 1H), 7.66 (t, J.sub.HF=71.80 Hz,
1H), 7.64 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.7
Hz, 1H), 2.69 (s, 3H); LC-MS: Method A, 40 to 100% B. RT=1.60 min,
MS (ESI) m/z: 359.0 (M+H).sup.+. Analytical HPLC (method A):
Sunfire, RT=5.54 min, 95% purity; XBridge, RT=4.54 min, 95%
purity.
Example 21
[1899] To a solution of Intermediate 21A (15 mg, 0.042 mmol) in THF
(0.8 mL) was added TEA (0.035 mL, 0.251 mmol). After stirring at
room temperature for 2 min, the chloroformate prepared in Example
20 (20.67 mg, 0.126 mmol) was added. The reaction mixture was
stirred at 50.degree. C. for 1.0 h. HPLC and LCMS indicated a
completion of the reaction. The reaction mixture was quenched with
1.0 N HCl (0.25 mL). Solvent was removed under vacuum. The crude
was purified via preparative LC/MS (method D, 40-75% B over 10
minutes). Fractions containing the desired product were combined
and dried via centrifugal evaporation to give Example 21 (8 mg).
.sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.72 (s, 2H), 7.92
(d, J=8.5 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.71 (t, J.sub.HF=71.53
Hz, 1H), 7.58-7.53 (m, 1H), 7.53-7.48 (m, 1H), 5.01 (dt, J=8.4, 4.3
Hz, 1H), 4.25 (s, 2H), 3.98 (br. s., 2H), 3.66-3.59 (m, 1H), 2.69
(s, 3H), 2.08 (dd, J=9.1, 4.1 Hz, 1H), 1.83 (ddt, J=13.2, 8.8, 4.3
Hz, 1H); LC-MS: method A, RT=2.18 min, MS (ESI) m/z: 487.2
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 22
(Tetrahydrofuran-2-yl)methyl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)carb-
amate
##STR00431##
[1901] To a solution of Intermediate 21A (15 mg, 0.042 mmol) in THF
(0.5 mL) was added TEA (0.035 mL, 0.251 mmol). After stirring at
room temperature for 2 min, the chloroformate prepared in Example
19 (15.16 mg, 0.092 mmol) was added. The reaction mixture was
stirred at room temperature for 45 min. The reaction mixture was
quenched with 1.0 N HCl (0.25 mL). Solvent was removed under
vacuum. The crude was purified via preparative LC/MS (method D,
40-75% B over 13 minutes). Fractions containing the desired product
were combined and dried via centrifugal evaporation to yield
Example 22 (9 mg). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.73 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85
(s, 1H), 7.71 (t, J.sub.HF=71.53 Hz, 1H), 7.57 (d, J=10.7 Hz, 1H),
7.53-7.48 (m, 1H), 4.31 (dd, J=11.3, 3.3 Hz, 1H), 4.28-4.22 (m,
1H), 4.17-4.11 (m, 1H), 3.94 (br. s., 1H), 3.86 (d, J=7.2 Hz, 1H),
2.69 (s, 3H), 2.10 (dd, J=12.1, 5.8 Hz, 1H), 1.98 (d, J=7.2 Hz,
2H), 1.78-1.69 (m, 1H); LC-MS: method A, RT=2.18 min, MS (ESI) m/z:
487.3 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 23
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methoxythiazolo[5,4-b]py-
ridine
##STR00432##
[1902] Intermediate 23A:
5-methoxythiazolo[5,4-b]pyridin-2-amine
##STR00433##
[1904] To 6-methoxypyridin-3-amine (636 mg, 5.12 mmol) in
acetonitrile (14 mL) was added ammonium thiocyanate (585 mg, 7.68
mmol). The reaction mixture was stirred at room temperature for 10
min. Then benzyltrimethylammonium tribromide (1998 mg, 5.12 mmol)
in acetonitrile (5.0 mL) was added dropwise (10 min). The mixture
was then stirred at room temperature overnight. HPLC and LCMS
indicated a single major peak with the desired mass. The mixture
was diluted with EtOAc/saturated sodium bicarbonate. The organic
layer was collected, washed with saturated sodium bicarbonate,
brine, dried over sodium sulfate. After evaporation of solvent,
Intermediate 23A (900 mg, 4.97 mmol, 97% yield) was obtained as a
brown solid. .sup.1H NMR indicated >90% purity. It was used for
the next step without further purification. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.61 (d, J=8.5 Hz, 1H), 7.41 (s, 2H), 6.69
(d, J=8.5 Hz, 1H), 3.83 (s, 3H); LC-MS: method A, RT=1.08 min, MS
(ESI) m/z: 181.9 (M+H).sup.+.
Intermediate 23B: 2-bromo-5-methoxythiazolo[5,4-b]pyridine
##STR00434##
[1906] Tert-butyl nitrite (0.175 mL, 1.324 mmol) was added to
copper (II) bromide (266 mg, 1.192 mmol) in dry acetonitrile (5 mL)
under argon. The reaction mixture was stirred at room temperature
for 10 min. Intermediate 23A (160 mg, 0.883 mmol) was added. The
reaction mixture was stirred at room temperature for 4.0 h. HPLC
and LCMS indicated a completion of the reaction. Acetonitrile was
removed under vacuum, the reaction mixture was diluted with EtOAc,
quenched with 0.5N HCl. After stirring at room temperature for 10
min, some insoluble impurity was removed by filtration through a
pad of wet celite. The organic layer of the filtrate was collected,
washed with saturated sodium bicarbonate, brine and dried over
sodium sulfate. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 30% EtOAc in hexane
over 15 min using a 12 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 23B
(194 mg, 0.792 mmol, 90% yield) as yellow solid. .sup.1H NMR (500
MHz, chloroform-d) .delta. 8.08 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.8
Hz, 1H), 4.02 (s, 3H); LC-MS: method A, RT=1.92 min, MS (ESI) m/z:
244.8 and 246.8 (M+H).sup.+.
Example 23
[1907] To Intermediate I-1 (25 mg, 0.074 mmol), Intermediate 23B
(22.79 mg, 0.093 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.04 mg, 3.72 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.082 mL, 0.164 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. After
cooled to room temperature, it was diluted with EtOAc, washed with
saturated sodium bicarbonate, brine. The organic layer was dried
over sodium sulfate, concentrated and purified via preparative
LC/MS (method D, 50-90% B over 10 minutes, then a 5-minute hold at
100% B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 23 (8.0 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.98 (s, 1H), 8.71 (s,
1H), 8.40 (d, J=8.8 Hz, 1H), 7.93 (s, 1H), 7.89 (t, J.sub.HF=71.25
Hz, 1H), 7.06 (d, J=9.1 Hz, 1H), 4.01 (s, 3H), 2.68 (s, 3H); LC-MS:
method A, RT=2.39 min, MS (ESI) m/z: 375.0 (M+H).sup.+. Analytical
HPLC purity (method B): 100%.
Example 24
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxythiazolo[4,5-c]py-
ridine
##STR00435##
[1908] Intermediate 24A:
7-methoxythiazolo[4,5-c]pyridine-2-thiol
##STR00436##
[1910] A solution of 4-chloro-5-methoxypyridin-3-amine (0.25 g,
1.576 mmol) and potassium O-ethyl carbonodithioate (0.695 g, 4.34
mmol) in DMF (2) was heated at 135.degree. C. under argon for 3.0
h. HPLC and LCMS indicated a completion of the reaction. The
mixture was cooled to room temperature, diluted with 2.0 mL water,
followed by addition of 10 mL 1.0 N HCl. The precipitated formed
was stirred at room temperature for 15 min, then collected by
filtration, washed with water, dried under vacuum and then
lyophilized to give Intermediate 24A (0.27 g, 1.362 mmol, 86%
yield) as a brown solid. It was used for the next step without
further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.24 (s, 1H), 8.23 (s, 1H), 4.02 (s, 3H); LC-MS: method A, RT=1.20
min, MS (ESI) m/z: 198.9 (M+H).sup.+.
Intermediate 24B: 2-chloro-7-methoxythiazolo[4,5-c]pyridine
##STR00437##
[1912] To a slurry of Intermediate 24A (60 mg, 0.303 mmol) in
dichloromethane (0.3 mL) was added sulfuryl chloride (0.492 mL,
6.05 mmol). The suspension was stirred at room temperature
overnight. To the yellow suspension was added ice/water, stirred at
room temperature for 15 min to decompose the excess sulfuryl
chloride (exothermic!). EtOAc and 4.0 N NaOH were added to adjust
the pH to 10-12. The organic layer was collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent, the
crude product was dissolved in a small amount of chloroform and
charged to a 4 g silica gel cartridge which was eluted with 5%
EtOAc in hexanes for 2 min., then a 10 min gradient from 5% to 60%.
The desired fractions were combined and concentrated to give
Intermediate 24B (40 mg, 0.199 mmol, 65.9% yield) as a white solid.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 8.95 (s, 1H), 8.24 (s,
1H), 4.11 (s, 3H); LC-MS: method A, RT=1.21 min, MS (ESI) m/z:
200.9 and 202.9 (M+H).sup.+.
Example 24
[1913] To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 24B
(22.38 mg, 0.112 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.64 mg, 4.46 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.098 mL, 0.196 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. After
cooled to room temperature, it was diluted with EtOAc, washed with
saturated sodium bicarbonate, brine. The organic layer was dried
over sodium sulfate, concentrated and purified via preparative
LC/MS (method D, 35-80% B over 10 minutes, then a
[1914] After a five-minute hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to yield Example 24 (4.1 mg). .sup.1H NMR (400 MHz,
acetonitrile-d.sub.3) .delta. 9.23 (s, 1H), 8.91 (s, 1H), 8.86 (s,
1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.73 (t, J.sub.HF=71.50 Hz, 1H),
4.24 (s, 3H); .sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta.
-77.11 (br. s., 3F, TFA), -90.66 (s, 2F); LC-MS: method A, RT=1.95
min, MS (ESI) m/z: 374.9 (M+H).sup.+. Analytical HPLC purity
(method B): 91%.
Example 25
tert-butyl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrah-
ydrobenzofuran-4-yl)carbamate
##STR00438##
[1915] Intermediate 25A: 4,5,6,7-tetrahydrobenzofuran-4-ol
##STR00439##
[1917] To a solution of 6,7-dihydrobenzofuran-4(5H)-one (4.94 g,
36.3 mmol) in MeOH (110 mL) at 0.degree. C. was added NaBH.sub.4
(1.579 g, 41.7 mmol) in 3 portions. The reaction mixture was
stirred at 0.degree. C. for 2.0 h. TLC indicated a completion of
the reaction. MeOH was removed under reduced pressure. To the
residue was added EtOAc, water. The pH was adjusted to 7 with
saturated ammonium chloride/0.5 N HCl. The organic layer was
collected, washed with brine, dried over sodium sulfate. After
evaporation of solvent, Intermediate 25A (4.96 g, 35.9 mmol, 99%
yield) was obtained as a clear oil. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.29-7.26 (d, J=1.77 Hz, 1H), 6.41 (d, J=1.77
Hz, 1H), 4.77-4.71 (m, 1H), 2.69-2.61 (m, 1H), 2.59-2.50 (m, 1H),
2.04-1.89 (m, 2H), 1.87-1.75 (m, 2H), 1.64 (br. s., 1H); LC-MS:
method A, RT=1.24 min, MS (ESI) m/z: No (M+H).sup.+.
Intermediate 25B:
tert-butyldimethyl((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)silane
##STR00440##
[1919] To a solution of Intermediate 25A (4.96 g, 35.9 mmol) in DMF
(60 mL) was added imidazole (3.67 g, 53.8 mmol) and TBDMS-Cl (6.76
g, 44.9 mmol). The reaction mixture was stirred at room temperature
for 1.5 h. TLC and HPLC indicated a completion of the reaction. The
reaction mixture was diluted with EtOAc and quenched with water.
The organic layer was collected, washed with brine, dried over
sodium sulfate and concentrated in vacuum. The crude product was
purified by flash chromatography (loading in chloroform, 0% to 10%
EtOAc in hexane over 20 min using a 120 g silica gel cartridge).
The desired fractions were combined and concentrated to yield
Intermediate 25B (8.34 g, 33.0 mmol, 92% yield) as a clear oil.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.27-7.25 (m, 1H), 6.33
(d, J=1.9 Hz, 1H), 4.79-4.75 (m, 1H), 2.68-2.61 (m, 1H), 2.57-2.50
(m, 1H), 2.10-2.02 (m, 1H), 1.95-1.89 (m, 1H), 1.81-1.68 (m, 2H),
0.95 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H); LC-MS: Method A, 40 to
100% B. RT=2.30 min, MS (ESI) m/z: No (M+H).sup.+.
Intermediate 25C:
tert-butyl((2-iodo-4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)
dimethylsilane
##STR00441##
[1921] To Intermediate 25B (300 mg, 1.188 mmol) in THF (4.0 mL) at
-78.degree. C. was added 1.6 N n-BuLi in hexanes (1.114 mL, 1.783
mmol). The mixture was warmed up to 0.degree. C. with an ice bath
and stirred for 20 min. The mixture was cooled to -78.degree. C.
with dry ice/acetone bath, and iodine (362 mg, 1.426 mmol) in 1 ml
THF was added slowly, The reaction mixture was stirred at
-78.degree. C. for 10 min, then at 0.degree. C. for 30 min. The
reaction mixture was diluted with EtOAc, quenched with saturated
ammonium chloride. The organic layer was washed with 10%
Na.sub.2S.sub.2O.sub.3, brine, dried over sodium sulfate. After
evaporation of solvent, Intermediate 25C (414 mg, 0.996 mmol, 84%
yield) was obtained as a brown oil. .sup.1H NMR indicated >90%
purity. It was used for next step without further purification.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 6.47 (s, 1H), 4.74-4.70
(m, 1H), 2.71-2.65 (m, 1H), 2.61-2.54 (m, 1H), 2.06-1.99 (m, 1H),
1.92-1.86 (m, 1H), 1.77-1.64 (m, 2H), 0.95 (s, 9H), 0.15 (s, 3H),
0.14 (s, 3H); LC-MS: Method A, 80 to 100% B. RT=1.76 min, MS (ESI)
m/z: No (M+H).sup.+.
Intermediate 25D
5-(4-((tert-butyldimethylsilyl)oxy)-4,5,6,7-tetrahydrobenzofuran-2-yl)-2-(-
difluoromethoxy)-7-methylquinoxaline
##STR00442##
[1923] To Intermediate 25C (410 mg, 1.084 mmol) and Intermediate
I-1 (335 mg, 0.997 mmol) was added toluene (3 mL) and EtOH (1 mL).
The reaction mixture was stirred at room temperature until solids
are dissolved then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (35.4 mg, 0.043 mmol) was added.
The flask was degassed and flushed with argon. Finally sodium
carbonate (2M, 1.084 mL, 2.167 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
put in microwave reactor at 130.degree. C. for 30 min. To the
reaction mixture was added EtOAc/water, stirred at room temperature
for 10 min. The insoluble material was removed by filtration. The
filtrate was extracted with EtOAc, washed with brine and
concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 15% EtOAc in hexane
over 15 min using a 40 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 25D
(320 mg, 0.591 mmol, 54.5% yield): LC-MS: Method A, 80 to 100% B.
RT=2.74 min, MS (ESI) m/z: 461.22 (M+H).sup.+.
Intermediate 25E
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofur-
an-4-ol
##STR00443##
[1925] To a solution of Intermediate 25D (320 mg, 0.695 mmol) in
THF (2.0 mL) at room temperature was added 1.0 N TBAF in THF (0.834
mL, 0.834 mmol). The reaction mixture was stirred at room
temperature for 4.0 h. HPLC indicated a completion of reaction. The
mixture was diluted with EtOAc, washed with saturated sodium
bicarbonate, brine, dried over sodium sulfate and concentrated. The
crude product was purified by flash chromatography (loading in
chloroform, 0% to 30% EtOAc in hexane over 12 min using a 12 g
silica gel cartridge). The desired fractions were combined and
concentrated to yield Intermediate 25E (80 mg, 0.226 mmol, 32.6%
yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.57 (s,
1H), 7.97 (d, J=1.7 Hz, 1H), 7.67 (t, J.sub.HF=71.28 Hz, 1H), 7.67
(s, 1H), 7.53 (s, 1H), 4.78 (t, J=4.7 Hz, 1H), 2.81-2.74 (m, 1H),
2.72-2.64 (m, 1H), 2.59 (s, 3H), 2.14-2.07 (m, 1H), 2.02-1.95 (m,
1H), 1.91-1.77 (m, 2H); LC-MS: method A, RT=2.13 min, MS (ESI) m/z:
347.3 (M+H).sup.+.
Intermediate 25F: tert-butyl
N-[(tert-butoxy)carbonyl]-N-{2-[2-(difluoromethoxy)-7-methylquinoxalin-5--
yl]-4,5,6,7-tetrahydro-1-benzofuran-4-yl}carbamate
##STR00444##
[1927] A solution of Intermediate 25E (74 mg, 0.214 mmol) and DIAD
(0.091 mL, 0.470 mmol) in THF (2.0 mL) was added dropwise to a
mixture of di-tert-butyl iminodicarboxylate (81 mg, 0.374 mmol) and
triphenylphosphine (112 mg, 0.427 mmol) in THF (1.0 mL) heated at
50.degree. C. At the end of addition, HPLC and LCMS indicated a
complete conversion of starting material to the product. After
evaporation of solvent, the crude product was purified by flash
chromatography (loading in chloroform, 0% to 30% EtOAc in hexanes
over 18 min using a 12 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 25F
(12 mg, 0.022 mmol, 10.29% yield) as yellow solid. .sup.1H NMR (500
MHz, chloroform-d) .delta. 8.58 (s, 1H), 7.98 (d, J=1.7 Hz, 1H),
7.65 (t, J.sub.HF=71.80 Hz, 1H), 7.56 (s, 1H), 7.52 (dd, J=1.8, 1.0
Hz, 1H), 5.41-5.35 (m, 1H), 2.77-2.73 (m, 2H), 2.60 (s, 3H),
2.20-2.11 (m, 4H), 1.47-1.44 (s, 18H); LC-MS: Method A, 50 to 100%
B. RT=2.47 min, MS (ESI) m/z: 446.2 (M-Boc).sup.+.
Example 25
[1928] To Intermediate 25F (12 mg, 0.022 mmol) was added
dichloromethane (1.0 mL) containing TFA (3.39 .mu.l, 0.044 mmol).
The solution was aged at room temperature overnight. Solvent was
removed under vacuum. The crude material was purified via
preparative LC/MS (method D, 55-95% B over 10 minutes, then a
5-minute hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to yield
Example 25 (5.3 mg). .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.56 (s, 1H), 7.96 (s, 1H), 7.66 (t, J.sub.HF=72.80 Hz,
1H), 7.56-7.52 (m, 2H), 4.70 (br. s., 1H), 2.75-2.68 (m, 2H), 2.58
(s, 3H), 2.03 (d, J=9.4 Hz, 2H), 1.94-1.87 (m, 1H), 1.74 (dd,
J=10.2, 6.3 Hz, 1H); LC-MS: method A, RT=2.59 min, MS (ESI) m/z:
468.3 (M+Na).sup.+. Analytical HPLC purity (method B): 100%.
Example 26
4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00445##
[1929] Intermediate 26A:
2-chloro-6-methoxy-4-methylbenzo[d]thiazole
##STR00446##
[1931] To a solution of copper (II) chloride (1.661 g, 12.35 mmol)
in acetonitrile (8 mL) at 40.degree. C. was added tert-butyl
nitrite (1.769 mL, 13.38 mmol), followed by Intermediate I-3A (2 g,
10.30 mmol) as a solid. The mixture was stirring at 40.degree. C.
for 2.0 h. HPLC and LCMS indicated a complete conversion of
starting material. The mixture was diluted with EtOAc, washed with
0.5 HCl, saturated sodium bicarbonate and brine. After evaporation
of solvent, Intermediate 26A (2.4 g, 11.23 mmol, 99% yield) was
obtained as a brown solid. .sup.1H NMR indicated >95% purity.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.07 (d, J=2.5 Hz, 1H),
6.93-6.77 (m, 1H), 3.85 (s, 3H), 2.66 (s, 3H); LC-MS: method B, 0
to 100% B), retention time: 2.08 min, [M+1].sup.+=213.9
Intermediate 26B: 2-chloro-4-methylbenzo[d]thiazol-6-ol
##STR00447##
[1933] Aluminum chloride (4.49 g, 33.7 mmol) was added to a
solution of Intermediate 26A (2.4 g, 11.23 mmol) in toluene (50
mL). The mixture was heated at 110.degree. C. for 1.5 h. TLC
indicated a complete conversion of starting material. The reaction
mixture was cooled to room temperature, quenched with ice-cold 1.0
N HCl (50 mL), stirred at room temperature for 30 min. The
precipitate was collected by filtration, washed with water
(3.times.), saturated sodium bicarbonate (3.times.), water
(3.times.) and air-dried for 1.0 h under vacuum. It was further
dried under high vacuum overnight to give Intermediate 26B as a
brown solid (1.9 g). .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 7.06 (d, J=2.3 Hz, 1H), 6.82 (s, 1H), 2.57 (s, 3H). LC-MS:
Method A, 50 to 100% B. RT=1.72 min, MS (ESI) m/z: 200.0 and 202.0
(M+H).sup.+.
Intermediate 26C:
6-((tert-butyldimethylsilyl)oxy)-2-chloro-4-methylbenzo[d]thiazole
##STR00448##
[1935] To a stirred solution of Intermediate 26B (2.2 g, 11.02
mmol) in DMF (50 mL) was added TBDMS-Cl (2.325 g, 15.43 mmol) and
imidazole (1.313 g, 19.28 mmol). The reaction mixture was left
stirring at room temperature for 1.0 h. HPLC and TLC indicated a
completion of the reaction. The mixture was partitioned between
EtOAc/water. The organic layer was washed with brine and dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 120 g
ISCO column which was eluted with hexanes for 3 min., then a 30 min
gradient from 0% to 50% EtOAc in hexanes. The desired fractions
were combined and concentrated to give Intermediate 26C (1.57 g,
5.00 mmol, 45.4% yield) as an orange solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.09-6.94 (m, 1H), 6.81 (dd, J=2.5, 0.8 Hz,
1H), 2.64 (s, 3H), 1.01 (s, 9H), 0.23 (s, 6H). LC-MS: Method A, 50
to 100% B. RT=2.72 min, MS (ESI) m/z: 314.0 and 316.0.0
(M+H).sup.+.
Intermediate 26D
6-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-
-5-yl)-4-methylbenzo[d]thiazole
##STR00449##
[1937] To Intermediate I-1 (310 mg, 0.922 mmol), Intermediate 26C
(333 mg, 1.061 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (37.7 mg, 0.046 mmol) was added
toluene (3 mL), EtOH (1 mL) and sodium carbonate (2M, 0.922 mL,
1.844 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 135.degree.
C. for 40 min. To the reaction mixture was added EtOAc/water/brine.
The insoluble was removed by filtration with a pad of celite. The
organic layer was collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
ISCO column which was eluted with hexanes for 3 min., then a 20 min
gradient from 0% to 75% EtOAc in hexanes. The desired fractions
were combined and concentrated to yield Intermediate 26D (450 mg,
0.923 mmol, 100% yield) as a bright yellow solid. LC-MS: Method A,
50 to 100% B. RT=2.72 min, MS (ESI) m/z: 488.0 (M+H).sup.+.
[1938] Intermediate 26E:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6--
ol
##STR00450##
[1940] To a solution of Intermediate 26D (450 mg, 0.923 mmol) in
THF (5 mL) at room temperature was added acetic acid (0.116 mL,
2.030 mmol), followed by addition of 1.0 N TBAF in THF (1.107 mL,
1.107 mmol) dropwise. The reaction mixture was stirred at room
temperature for 30 min. LCMS indicated a completion of reaction.
The mixture was diluted with EtOAc, washed with water, saturated
sodium bicarbonate (2.times.), brine, and dried over sodium
sulfate. After evaporation of the solvent, the crude product was
purified with a 12 g ISCO column eluting from 5% EtOAc to 50% EtOAc
in hexanes to give Intermediate 26E (290 mg, 0.777 mmol, 84%
yield). .sup.1H NMR (500 MHz, acetonitrile-d.sub.3) .delta. 8.81
(d, J=1.9 Hz, 1H), 8.74 (s, 1H), 7.80 (dd, J=1.8, 1.0 Hz, 1H),
7.89-7.51 (m, 1H), 7.28 (d, J=1.9 Hz, 1H), 6.88 (dd, J=2.5, 0.8 Hz,
1H), 2.76 (s, 3H), 2.69 (s, 3H). LC-MS: Method A, 50 to 100% B.
RT=1.44 min, MS (ESI) m/z: 373.9 (M+H).sup.+.
Intermediate 26F
2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy) ethanamine hydrochloride
##STR00451##
[1942] A solution of DIAD (0.391 mL, 2.009 mmol) was added to a
mixture of Intermediate 26E (250 mg, 0.670 mmol). Tert-butyl
(2-hydroxyethyl)carbamate (108 mg, 0.670 mmol) and
triphenylphosphine (351 mg, 1.339 mmol) in toluene (5 mL) was added
dropwise. The reaction mixture was heated 110.degree. C. for 30
min. The mixture was concentrated and dissolved in 1 ml of DCM and
purified by 40 g ISCO column eluted with 0-70% EtOAc in hexanes for
20 min. The desired fraction was concentrated. The sample was
redissolved in 5 ml of DCM and 4N HCl/dioxane (8.37 mL, 33.5 mmol)
was added. The reaction mixture was stirred at room temperature for
3 h. Solvent was removed under vacuum to give Intermediate 26F (250
mg, 0.552 mmol, 82% yield) as a solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.65 (d, J=1.8 Hz, 1H), 8.52 (s, 1H), 7.62
(d, J=0.8 Hz, 1H), 7.54 (t, J.sub.HF=72 Hz, 1H), 7.13 (d, J=2.0 Hz,
1H), 6.86 (d, J=1.5 Hz, 1H), 5.02-4.95 (m, 2H), 3.98 (t, J=5.1 Hz,
2H), 2.72 (s, 4H), 2.58 (s, 4H); LC-MS: Method A, 50 to 100% B.
RT=2.12 min, MS (ESI) m/z: 416.9 (M+H).sup.+.
Example 26
[1943] To a solution of Intermediate 26F (15 mg, 0.033 mmol) and
DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of
4-fluorobenzene-1-sulfonyl chloride (7.73 mg, 0.040 mmol) in 0.2 ml
of DCM. The reaction mixture was stirred at room temperature for 1
h, diluted with EtOAc and water, extracted with EtOAc. The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was dissolved in 1 ml of MeOH and
sodium methoxide (0.199 mL, 0.099 mmol) was added. The reaction
mixture was stirred at room temperature for 1h. The crude material
was purified via preparative LC/MS (method C, 45-85% B over 20
minutes, then a 5-minute hold at 100% B). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to yield Example 26 (7.0 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.72 (s, 1H), 8.58 (s, 1H), 7.91 (dd, J=8.3, 5.5 Hz, 2H),
7.81 (s, 1H), 7.46-7.41 (m, 3H), 6.86 (s, 1H), 4.09 (s, 3H), 4.06
(t, J=5.2 Hz, 2H), 3.23 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s,
3H); LC-MS: method A, RT=2.360 min, MS (ESI) m/z: 539.2
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 27
N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)-
oxy)ethyl)benzenesulfonamide
##STR00452##
[1944] Intermediate 27A: tert-butyl
(2-(3-chloro-4-nitrophenoxy)ethyl)carbamate
##STR00453##
[1946] To a solution of tert-butyl (2-hydroxyethyl)carbamate (918
mg, 5.70 mmol) in THF (8 mL) was added 0.5 M potassium
bis(trimethylsilyl)amide in toluene (12.53 mL, 6.27 mmol). The
reaction mixture was stirred at room temperature for 20 min.
2-Chloro-4-fluoro-1-nitrobenzene (500 mg, 2.85 mmol) was added and
the reaction mixture was stirred at room temperature for 0.5 h,
then at 55.degree. C. for 1.5 h. The mixture was diluted with
EtOAc, quenched with saturated ammonium chloride. The organic layer
was washed with saturated sodium bicarbonate, brine, dried over
sodium sulfate and concentrated. The crude product was purified by
flash chromatography (loading in chloroform, 0% to 45% EtOAc in
hexane over 15 min using a 40 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 27A
(425 mg, 1.342 mmol, 47.1% yield) as yellow liquid. .sup.1H NMR
(500 MHz, chloroform-d) .delta. 8.04-8.00 (d, J=9.1 Hz, 1H), 7.05
(d, J=2.8 Hz, 1H), 6.90 (dd, 2.5 Hz, 1H), 4.14-4.10 (m, 2H), 3.58
(q, J=5.3 Hz, 2H), 1.50 (s, 9H); LC-MS: method A, RT=1.97 min, MS
(ESI) m/z: 261.1 and 263.1 (M-t-Bu).sup.+.
Intermediate 27B: tert-butyl
(2-(4-amino-3-chlorophenoxy)ethyl)carbamate
##STR00454##
[1948] To a solution of Intermediate 27A (0.42 g, 1.326 mmol) in
MeOH (10 mL) was added ammonium chloride (1.135 g, 21.22 mmol) and
zinc dust (0.694 g, 10.61 mmol). The reaction mixture was stirred
at room temperature for 30 min. HPLC and LCMS indicated a
completion of the reaction. MeOH was removed under vacuum. The
residue was diluted with EtOAc/saturated sodium bicarbonate and
stirred at room temperature for 10 min. The mixture was filtered to
remove insoluble material. The filtrate was collected, organic
layer was washed with brine, dried over sodium sulfate,
concentrated to give Intermediate 27B (380 mg, 1.325 mmol, 100%
yield) as oil. .sup.1H NMR (500 MHz, chloroform-d) .delta. 6.87 (d,
J=2.5 Hz, 1H), 6.75-6.68 (m, 2H), 4.98 (br. s., 1H), 3.95 (t, J=5.2
Hz, 2H), 3.51 (t, J=5.0 Hz, 2H), 1.48 (s, 9H); LC-MS: method A,
RT=1.47 min, MS (ESI) m/z: 187.1 and 189.1 (M-Boc).sup.+.
Intermediate 27C:
tert-butyl(2-((2-amino-4-chlorobenzo[d]thiazol-6-yl)oxy)ethyl)
carbamate
##STR00455##
[1950] To Intermediate 27B (465 mg, 1.622 mmol) in acetonitrile
(5.0 mL) was added ammonium thiocyanate (216 mg, 2.84 mmol). The
reaction mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (854 mg, 2.189 mmol) in
acetonitrile (2.0 mL) was added dropwise (5 min). The reaction
mixture was stirred at room temperature for 30 min. HPLC and LCMS
indicated ca 30% starting material present. Then another portion of
ammonium thiocyanate (211 mg, 2.77 mmol) and
benzyltrimethylammonium tribromide (415 mg, 1.06 mmol) were added.
The reaction mixture was left stirring at room temperature
overnight. Acetonitrile was removed under vacuum. The mixture was
diluted with EtOAc, THF/saturated sodium bicarbonate. The insoluble
material was removed by filtration. The organic layer of the
filtrate was collected, washed with brine, dried over sodium
sulfate and concentrated to give Intermediate 27C (460 mg, 1.204
mmol, 74.3% yield) as yellow solid that was used for the next step
without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.59 (s, 2H), 7.30 (d, J=2.5 Hz, 1H), 7.01-6.96 (m, 1H),
6.92 (d, J=2.5 Hz, 1H), 3.95 (t, J=5.8 Hz, 2H), 3.27 (q, J=5.5 Hz,
2H), 1.39 (s, 9H); LC-MS: method A, RT=1.67 min, MS (ESI) m/z:
344.1 (M+H).sup.+.
Intermediate 27D: tert-butyl
(2((2-bromo-4-chlorobenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
##STR00456##
[1952] Tert-butyl nitrite (0.249 mL, 1.885 mmol) was added to
copper (II) bromide (421 mg, 1.885 mmol) in acetonitrile (6 mL)
under argon. The reaction mixture was stirred at room temperature
for 10 min. Intermediate 27C (405 mg, 1.178 mmol) suspended in
acetonitrile (6 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 20 min. HPLC and LCMS indicated a
completion of the reaction. The reaction mixture was diluted with
EtOAc, quenched with 0.5N HCl. After stirring at room temperature
for 10 min, the organic layer of the filtrate was collected, washed
with 0.5 N HCl, saturated sodium bicarbonate, brine, dried over
sodium sulfate and concentrated. The crude product was purified by
flash chromatography (loading in chloroform, 0% to 35% EtOAc in
hexane over 18 min using a 24 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 27D
(411 mg, 1.008 mmol, 86% yield) as a semi solid which was
lyophilized to a solid. .sup.1H NMR (500 MHz, chloroform-d) .delta.
7.18 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 4.98 (br. s., 1H),
4.09 (t, J=5.1 Hz, 2H), 3.58 (q, J=5.0 Hz, 2H), 1.48 (s, 9H);
LC-MS: method A, RT=1.72 min, MS (ESI) m/z: 407.0 and 409.0
(M+H).sup.+.
Intermediate 27E: tert-butyl
(2-((4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy) ethyl)carbamate
##STR00457##
[1954] To Intermediate 27D (358 mg, 0.878 mmol) and Intermediate
I-1 (295 mg, 0.878 mmol) was added toluene (6 mL) and EtOH (2 mL).
The reaction mixture was stirred at room temperature until solids
are dissolved then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (35.9 mg, 0.044 mmol) was added.
The flask was degassed and flushed with argon. Sodium carbonate
(2M, 0.878 mL, 1.756 mmol) was added dropwise. The reaction vessel
was sealed and bubbled with argon for 5 min, then put in microwave
reactor at 120.degree. C. for 35 min. HPLC and TLC indicated a
completion of the reaction. To the reaction mixture was added
EtOAc/water, stirred at room temperature for 10 min. The insoluble
material was removed by filtration. The filtrate was extracted with
EtOAc, washed with brine and concentrated. The crude product was
purified by flash chromatography (loading in chloroform, 0% to 35%
EtOAc in hexanes over 15 min using a 24 g silica gel cartridge).
The desired fractions were combined and concentrated to yield
Intermediate 27E (421 mg, 0.784 mmol, 89% yield) as yellow solid.
.sup.1H NMR (400 MHz, acetonitrile-d.sub.3) .delta. 8.77 (d, J=1.5
Hz, 1H), 8.72 (s, 1H), 7.82 (dd, J=1.9, 1.0 Hz, 1H), 7.71 (t,
J.sub.HF=71.53 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.23 (d, J=2.4 Hz,
1H), 4.12 (t, J=5.5 Hz, 2H), 3.49 (q, J=5.6 Hz, 2H), 2.71 (s, 3H),
1.45 (s, 9H); .sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta.
-90.04 (s, 2F); LC-MS: Method A, 40 to 100% B. RT=2.44 min, MS
(ESI) m/z: 537.2 (M+H).sup.+.
Intermediate 27F: tert-butyl
(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
##STR00458##
[1956] To Intermediate 27E (400 mg, 0.745 mmol) in DMF (5.0 mL) was
added 0.5 N NaOMe in MeOH (3.28 mL, 1.639 mmol). The reaction
mixture was stirred at room temperature for 40 min, diluted with
THF (3.0 mL) and EtOAc (10 mL) and quenched with 1.0 N HCl (1.862
mL, 1.862 mmol). THF (50 mL) was added followed with brine. The
mixture turned to a clean solution. The organic layer was washed
with brine, dried over sodium sulfate and concentrated to give
Intermediate 27F (370 mg, 0.739 mmol, 99% yield) as yellow solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.57 (d,
J=1.9 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.72 (d, J=2.5 Hz,
1H), 7.29 (d, J=2.5 Hz, 1H), 4.10 (t, J=5.78 Hz, 2H), 4.09 (s, 3H),
3.38-3.34 (m, 2H), 2.65 (s, 3H), 1.40 (s, 9H); LC-MS: Method A, 40
to 100% B. RT=2.44 min, MS (ESI) m/z: 501.2 and 503.2
(M+H).sup.+.
Intermediate 27G
2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy-
)ethanamin e hydrochloride
##STR00459##
[1958] To Intermediate 27F (0.32 g, 0.639 mmol) was added 4.0 N HCl
in dioxane (15.97 mL, 63.9 mmol), followed by MeOH (8.0 mL). The
reaction mixture was stirred at 45.degree. C. for 15 min, and then
at room temperature for 30 min. HPLC indicated a completion of
reaction. Solvent was removed under vacuum. The crude was
partitioned between EtOAc/saturated sodium bicarbonate. The organic
layer was washed with brine, dried over sodium sulfate,
concentrated and lyophilized to give Intermediate 27G (50 mg, 0.114
mmol, 17.90% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.19 (d, J=1.8 Hz, 1H), 8.05 (s, 1H), 7.31 (s, 1H), 7.26
(d, J=2.4 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 4.27 (t, J=5.0 Hz, 2H),
3.94 (s, 3H), 3.44 (t, J=5.0 Hz, 2H), 2.44 (s, 3H); LC-MS: method
A, RT=1.99 min, MS (ESI) m/z: 401.1 and 403.1 (M+H).sup.+.
Example 27
[1959] To Intermediate 27G (24 mg, 0.055 mmol) in DMF (0.8 mL) was
added DIEA (0.058 mL, 0.329 mmol). After stirring at room
temperature for 2 min, benzenesulfonyl chloride (10.61 .mu.l, 0.082
mmol) was added and the reaction mixture was stirred at room
temperature for 20 min. The reaction mixture was quenched with MeOH
(1.0 mL). The crude material was purified via preparative LC/MS
(method C, 40-85% B over 20 minutes, then a 5-minute hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 27 (6.4 mg, 22%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H),
8.57 (d, J=1.7 Hz, 1H), 7.87-7.85 (m, 1H), 7.85-7.83 (m, 2H),
7.64-7.58 (m, 4H), 7.15 (d, J=2.2 Hz, 1H), 4.11-4.07 (m, 5H), 3.22
(br. s., 2H), 2.65 (s, 3H); LC-MS: method A, RT=2.55 min, MS (ESI)
m/z: 541.0 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 28
N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)-
oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00460##
[1961] To Intermediate 27G (30 mg, 0.069 mmol) in DMF (0.8 mL) was
added DIEA (0.060 mL, 0.343 mmol). After stirring at room
temperature for 4 min, 4-fluorobenzenesulfonyl chloride (14.68 mg,
0.075 mmol) was added and the reaction mixture was stirred at room
temperature for 30 min. The reaction was quenched with MeOH (1.0
mL) and purified via preparative LC/MS (method C, 45-85% B over 20
minutes, then a 5-minute hold at 100% B). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to yield Example 28 (8.9 mg, 22% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.73 (s, 1H), 8.57 (d, J=1.7 Hz, 1H),
7.97-7.89 (m, 3H), 7.84 (s, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.45-7.40
(m, 2H), 7.14 (d, J=2.2 Hz, 1H), 4.11-4.07 (m, 5H), 3.24 (t, J=5.2
Hz, 2H), 2.65 (s, 3H); LC-MS: method A, RT=2.50 min, MS (ESI) m/z:
559.0 and 561.0 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 29
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenz-
o[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00461##
[1963] To Intermediate I-2 (41 mg, 0.177 mmol), Intermediate I-5
(79 mg, 0.177 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.21 mg, 8.83 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.177 mL, 0.353 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate, concentrated. The crude residue was
dissolved in DMSO/MeOH (3.5 mL each), purified using a preparative
HPLC (method A, 65-100% B in 10 min; then 100% B in 2 min, RT=7.2
min). The desired fractions were placed in a SpeedVac overnight to
remove solvent, then lyophilized to give Example 29 (59 mg, 0.106
mmol, 59.8% yield). .sup.1H NMR (400 MHz, acetonitrile-d.sub.3)
.delta. 9.05 (s, 1H), 8.88 (s, 1H), 7.98-7.89 (m, 3H), 7.26 (td,
J=8.7, 1.8 Hz, 3H), 6.85 (s, 1H), 5.95 (br. s., 1H), 4.82 (s, 2H),
4.07 (t, J=4.6 Hz, 2H), 3.56 (s, 3H), 3.39-3.31 (m, 2H), 2.80 (s,
3H), 2.72 (s, 3H); .sup.19F NMR (471 MHz, acetonitrile-d.sub.3)
.delta. -107.47 (s, 1F); LC-MS: method A, RT=2.32 min, MS (ESI)
m/z: 553.1 (M+H).sup.+. Analytical HPLC (method A): Sunfire,
RT=10.81 min, 99% purity; XBridge, RT=6.64 min, 99% purity.
Example 30
N-(2-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)o-
xy)ethyl)-4-fluorobenzenesulfonamide
##STR00462##
[1964] Intermediate 30A
N-(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00463##
[1966] To Intermediate I-1 (40 mg, 0.119 mmol), Intermediate I-5
(48.2 mg, 0.108 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.07 mg, 8.65 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.119 mL, 0.238 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate, concentrated. The crude product was
purified by flash chromatography (loading in chloroform, 0% to 75%
EtOAc in hexane over 20 min using a 12 g silica gel cartridge). The
desired fractions were combined and concentrated to yield
Intermediate 30A (50 mg, 0.087 mmol, 80% yield) as yellow solid.
LC-MS: method A, RT=2.71 min, MS (ESI) m/z: 575.1 (M+H).sup.+.
Example 30
[1967] To Intermediate 30A (14 mg, 0.024 mmol) dissolved in EtOH
(0.5 mL) and THF (0.4 mL) was added sodium ethoxide in ethanol
(0.027 mL, 0.073 mmol) (21% by weight). The reaction mixture was
stirred at room temperature for 15 min., another portion of sodium
ethoxide in ethanol (0.027 mL, 0.073 mmol) was added. The mixture
was left stirring at room temperature overnight. LCMS indicated a
completion of the reaction. Solvent was removed and the residue was
dissolved in DMSO/MEOH (1:1) and purified via preparative LC/MS
(method D, 65-100% B over 10 minutes, then a 5-minute hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 30 (11.3 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.69 (s, 1H), 8.58 (d,
J=1.1 Hz, 1H), 7.91 (dd, J=8.5, 5.5 Hz, 2H), 7.78 (s, 1H),
7.46-7.41 (m, 3H), 6.86 (s, 1H), 4.54 (q, J=7.1 Hz, 2H), 4.05 (t,
J=5.2 Hz, 2H), 3.23 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H),
1.45 (t, J=7.2 Hz, 3H); LC-MS: method A, RT=2.48 min, MS (ESI) m/z:
553.3 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 31
N-(2-((2-(2-ethyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethyl)-4-fluorobenzenesulfonamide
##STR00464##
[1968] Intermediate 31A: tert-butyl
(2-bromo-4-methyl-6-nitrophenyl)(2-oxobutyl)carbamate
##STR00465##
[1970] To Intermediate I-1B (1.28 g, 3.87 mmol) in DMF (15 mL) at
room temperature was added Cs.sub.2CO.sub.3 (2.204 g, 6.76 mmol).
The brown solution was stirred at room temperature for 5 min,
followed by addition of 1-bromobutan-2-one (0.592 mL, 5.80 mmol) in
acetonitrile (0.4 mL). The brown solution turned yellow. The
reaction mixture was stirred at room temperature for 15 min. TLC
indicated a completion of the reaction The mixture was diluted with
EtOAc, washed with water, brine, dried over sodium sulfate and
concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 40% EtOAc in hexane
over 10 min using a 40 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 31A
(1.5 g, 3.74 mmol, 97% yield) as yellow liquid. .sup.1H NMR (400
MHz, chloroform-d) indicated presence of two rotamers. .delta.
7.73-7.67 (m, 2H), 4.51-4.05 (m, 2H), 2.57-2.49 (m, 2H), 2.47 and
2.42 (s, 3H), 1.53 and 1.37 (s, 9H), 1.18 and 1.13 (t, J=7.26 Hz,
3H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 310.0 and 303.0
(M-Boc).sup.+.
Intermediate 31B: 5-bromo-2-ethyl-7-methylquinoxaline
##STR00466##
[1972] To Intermediate 31A (1.55 g, 3.86 mmol) in ethyl acetate (8
mL) was added 4.0 N HCl in dioxane (11.59 mL, 46.4 mmol) and the
reaction mixture was stirred at room temperature for 45 min. HPLC
indicated a completion of the reaction. Solvent was removed under
vacuum to give the deprotected intermediate as yellow oil. The
deprotected intermediate was dissolved in THF (20 mL). Tin (II)
chloride dihydrate (2.88 g, 12.75 mmol) was added, followed by
concentrated HCl (0.476 mL, 5.79 mmol). The mixture was placed and
stirred in oil bath pre-heated at 45.degree. C. for 1.0 h. HPLC and
LCMS indicated a completion of the reaction. The reaction mixture
was diluted with EtOAc/water and neutralized with saturated sodium
bicarbonate. The reaction mixture was stirred at room temperature
for 15 min, the precipitate was removed by a separatory funnel. The
organic layer was washed with saturated sodium bicarbonate, brine,
dried over sodium sulfate and concentrated to give Intermediate 31B
(0.93 g, 3.70 mmol, 96% yield) as a light yellow solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.70 (s, 1H), 7.80 (d, J=1.8 Hz,
1H), 7.72 (dd, J=1.8, 0.9 Hz, 1H), 2.99 (q, J=7.7 Hz, 2H), 2.50 (s,
3H), 1.36 (t, J=7.6 Hz, 3H); LC-MS: method A, RT=1.93 min, MS (ESI)
m/z: 251.1 and 253.1 (M+H).sup.+.
Intermediate 31C: (2-ethyl-7-methylquinoxalin-5-yl)boronic acid
##STR00467##
[1974] A mixture of Intermediate 31B (129 mg, 0.514 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (261
mg, 1.027 mmol), potassium acetate (101 mg, 1.027 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (16.78 mg, 0.021 mmol) in
dioxane (3.0 mL) was degassed by bubbling argon for 10 min. The
reaction vial was sealed and heated in microwave reactor at
130.degree. C. for 30 min. LCMS indicated complete conversion of
starting material. The mixture was diluted with EtOAc/water,
insoluble material was removed by filtration. The filtrate was
extracted with EtOAc, washed with brine and dried over sodium
sulfate.
[1975] The crude residue was dissolved in MeOH/DMSO (1:1) and
purified using a preparative HPLC (method A, 20-100% B in 10 min;
then 100% B in 2 min; RT=3.5 min). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Intermediate 31C (50 mg, 0.231 mmol, 45.1% yield) as a
solid. .sup.1H NMR in CDCl.sub.3 suggested presence of isomeric
forms. HPLC and LCMS indicated a single peak. LC-MS: method A,
RT=1.86 min, MS (ESI) m/z: 217.0 (M+H).sup.+.
Example 31
[1976] To Intermediate 31C (8.73 mg, 0.040 mmol), Intermediate I-5
(18 mg, 0.040 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (2.64 mg, 3.23 .mu.mol) was
added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.040 mL, 0.081 mmol). The reaction mixture was
heated in a microwave reactor at 120.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate, concentrated. The crude product was
purified via preparative LC/MS (method D, 60-100% B over 10
minutes, then a 5-minute hold at 100% B). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to yield Example 31 (15.2 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.02 (s, 1H), 8.75 (s, 1H), 8.04 (br. s., 1H), 7.99 (s,
1H), 7.91 (dd, J=8.7, 5.4 Hz, 2H), 7.47-7.41 (m, 3H), 6.87 (s, 1H),
4.06 (t, J=5.1 Hz, 2H), 3.23 (t, J=5.1 Hz, 2H), 3.09 (q, J=7.7 Hz,
2H), 2.74 (s, 3H), 2.68 (s, 3H), 1.40 (t, J=7.6 Hz, 3H); LC-MS:
method A, RT=2.59 min, MS (ESI) m/z: 537.3 (M+H).sup.+. Analytical
HPLC purity (method B): 100%.
Example 32
methyl
5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol--
2-yl)-7-methylquinoxaline-2-carboxylate
##STR00468##
[1977] Intermediate 32A:
(2-(methoxycarbonyl)-7-methylquinoxalin-5-yl)boronic acid
##STR00469##
[1979] A mixture of methyl
5-bromo-7-methylquinoxaline-2-carboxylate (103 mg, 0.366 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (205
mg, 0.806 mmol), potassium acetate (90 mg, 0.916 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (11.97 mg, 0.015 mmol) in
dioxane (3.0 mL) was degassed by bubbling argon for 10 min. The
reaction vial was sealed and heated in microwave reactor at
130.degree. C. for 30 min. LCMS indicated complete conversion of
starting material. The mixture was diluted with EtOAc/water,
insoluble material was removed by filtration. The filtrate was
extracted with EtOAc, washed with brine and dried over sodium
sulfate. The crude residue was dissolved in MeOH/DMSO (1:1) and
purified using a preparative HPLC (method A, 30-100% B in 10 min;
then 100% B in 2 min; RT=3.5 min). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Intermediate 32A (46 mg, 0.187 mmol, 51.0% yield) as a
white solid. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 9.43
(s, 1H), 8.30 (br. s., 1H), 8.07 (br. s., 1H), 4.11 (s, 3H), 2.64
(s, 3H); LC-MS: method A, RT=1.64 min, MS (ESI) m/z: 247.1 boronic
acid (M+H).sup.+.
Intermediate 32B
5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-
-methylquinoxaline-2-carboxylic acid
##STR00470##
[1981] To Intermediate 32A (24 mg, 0.098 mmol), Intermediate I-5
(43.4 mg, 0.098 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.98 mg, 4.88 .mu.mol) was
added toluene (1.5 mL) and MeOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.098 mL, 0.195 mmol). The reaction mixture was
heated in a microwave reactor at 120.degree. C. for 30 min. LCMS
indicated a completion of the reaction to the acid. The mixture was
diluted with EtOAc/THF (40 Ml/20 mL), acidified with 0.5 N HCl. The
organic layer was washed with brine, dried over sodium sulfate and
concentrated, purified via preparative LC/MS (method D, 15-55% B
over 20 minutes, then a 5-minute hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to yield Intermediate 32B (38.5 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.49 (s, 1H), 8.91 (s,
1H), 8.16 (br. s., 1H), 8.05 (t, J=5.2 Hz, 1H), 7.98-7.89 (m, 3H),
7.48-7.41 (m, 2H), 6.87 (d, J=1.1 Hz, 1H), 4.07 (t, J=5.2 Hz, 2H),
3.25-3.21 (m, 2H), 2.74 (s, 3H), 2.73 (s, 3H); LC-MS: method A,
RT=2.04 min, MS (ESI) m/z: 553.2 (M+H).sup.+.
Example 32
[1982] To a suspension of Intermediate 32B (28 mg, 0.051 mmol) in
CH.sub.2Cl.sub.2 (2.0 mL) and MeOH (0.5 mL) at room temperature was
added (diazomethyl)trimethylsilane 2.0 M in diethyl ether (0.076
mL, 0.152 mmol). The suspension turned clear. The reaction mixture
was stirred at room temperature for 1.0 h. HPLC and LCMS indicated
a completion of the reaction. Solvent was removed under vacuum. The
crude was purified via preparative LC/MS (method D, 50-90% B over
10 minutes, then a 5-minute hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to yield Example 32 (16.4 mg). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.50 (s, 1H), 8.92 (d, J=1.1 Hz, 1H), 8.18
(s, 1H), 7.92 (dd, J=8.5, 5.2 Hz, 2H), 7.48-7.45 (m, 2H), 7.45-7.42
(m, 2H), 6.87 (s, 1H), 4.07 (t, J=5.4 Hz, 2H), 4.04 (s, 3H), 3.24
(br. s., 2H), 2.74 (s, 3H), 2.73 (s, 3H); LC-MS: method A, RT=2.28
min, MS (ESI) m/z: 567.2 (M+H).sup.+. Analytical HPLC purity
(method B): 100%.
Example 33
N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol--
6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00471##
[1983] Intermediate 33A: cyclopropanol
##STR00472##
[1985] To a solution of cyclopropylboronic acid (0.65 g, 7.57 mmol)
in 10% NaOH (5.0 mL) at 0.degree. C. was added a solution of 30%
hydrogen peroxide (21.44 mL, 189 mmol) dropwise. The reaction
mixture was stirred at 0.degree. C. for 1.5 h. The reaction mixture
was diluted with diethyl ether, quenched with saturated NaHSO.sub.3
(15 mL) at 0.degree. C. After stirring for 15 min, the organic
layer was collected, washed with brine, dried over sodium sulfate
and concentrated at 0.degree. C. to give Intermediate 33A (0.16 g,
2.75 mmol, 36.4% yield) as colorless liquid. It was used for the
next step without further purification. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 3.62-3.41 (m, 1H), 0.69-0.40 (m, 4H).
Example 33
[1986] To 60% sodium hydride (15.66 mg, 0.392 mmol) was added
Intermediate 33A (37.9 mg, 0.653 mmol) in DMF (0.5 mL). The
reaction mixture was stirred at room temperature for 15 min. A
solution of Intermediate 30A (15 mg, 0.026 mmol) in DMF (1.0 mL)
was added. The reaction mixture was stirred at room temperature for
25 min. LCMS indicated a completion of the reaction. The reaction
mixture was diluted with EtOAc, quenched with 0.5 N HCl. The
organic layer was collected, washed with brine, dried over sodium
sulfate and concentrated. The crude was dissolved in
DMF/acetonitrile (1:1, 2.2 mL) and purified via preparative LC/MS
(method D, 60-100% B over 10 minutes, then a 5-minute hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 33 (8.6 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.59 (s,
1H), 7.90 (dd, J=8.5, 5.2 Hz, 2H), 7.83 (s, 1H), 7.45-7.40 (m, 3H),
6.85 (s, 1H), 4.53-4.49 (m, 1H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (t,
J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H), 0.93-0.88 (m, 2H),
0.87-0.82 (m, 2H); LC-MS: method A, RT=2.67 min, MS (ESI) m/z:
565.1 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 34
4-fluoro-N-(2-((2-(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenz-
o[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00473##
[1987] Intermediate 34A: methyl
2-((5-bromo-7-methylquinoxalin-2-yl)oxy)acetate
##STR00474##
[1989] To sodium hydride, 60% (411 mg, 10.27 mmol) in DMF (15 mL)
cooled with a water bath was added methyl 2-hydroxyacetate (0.959
mL, 12.45 mmol). The reaction mixture was stirred for 20 min. A
solution of Intermediate I-1G (900 mg, 3.11 mmol) in DMF (5 mL) was
added at room temperature. The reaction mixture was stirred at room
temperature for 0.5 h. HPLC indicated a completion of the reaction.
The reaction mixture was diluted with EtOAc, quenched with 0.5 N
HCl. The organic layer was washed with brine, dried over sodium
sulfate and concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 30% EtOAc in hexane
over 12 min using a 40 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 34A
(811 mg, 2.61 mmol, 84% yield) as a white solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.51 (s, 1H), 7.63 (d, J=1.5 Hz, 1H),
7.44 (dd, 0.9 Hz, 1H), 4.97 (s, 2H), 3.71 (s, 3H), 2.41 (s, 3H);
LC-MS: method A, RT=1.97 min, MS (ESI) m/z: 311.0 and 313.0
(M+H).sup.+.
Intermediate 34B: 2-((5-bromo-7-methylquinoxalin-2-yl)oxy)acetic
acid
##STR00475##
[1991] To Intermediate 34A (811 mg, 2.61 mmol) dissolved in THF (16
mL) at room temperature was added 1.0 N NaOH (4.56 mL, 4.56 mmol).
The reaction mixture was stirred at room temperature for 15 min.
HPLC and LCMS indicated a completion of the reaction. The mixture
was diluted with EtOAc/water, quenched with 1.0 N HCl (4.95 mL,
4.95 mmol). The organic layer was collected, washed with brine,
dried over sodium sulfate and concentrated to give Intermediate 34B
(730 mg, 2.457 mmol, 94% yield) as a white solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.63 (s, 1H), 7.77 (d, J=1.5 Hz, 1H),
7.58 (dd, J=1.5, 0.9 Hz, 1H), 5.12 (s, 2H), 2.53 (s, 3H); LC-MS:
method A, RT=1.81 min, MS (ESI) m/z: 297.0 and 299.0
(M+H).sup.+.
Intermediate 34C: 5-bromo-2-(fluoromethoxy)-7-methylquinoxaline
##STR00476##
[1993] To a suspension of Intermediate 34B (400 mg, 1.346 mmol) in
dichloromethane (30 mL) at room temperature was added xenon
difluoride (251 mg, 1.481 mmol). The reaction mixture was stirred
at room temperature for 4.0 h, followed by addition of another
portion of xenon difluoride (251 mg, 1.481 mmol). The reaction
mixture was left stirring at room temperature overnight. The
suspension turned to a clear solution at this point. A third
portion of xenon difluoride (387 mg, 2.289 mmol) was added and the
reaction mixture was stirred at room temperature for 4.0 h. The
reaction was quenched by addition of saturated sodium bicarbonate,
extracted with dichloromethane, dried over sodium sulfate and
concentrated. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 30% EtOAc in hexane
over 15 min using a 24 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 34C
(55 mg, 0.203 mmol, 15.07% yield) as a white solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.60 (s, 1H), 7.82 (d, J=1.5 Hz,
1H), 7.68 (dd, J=1.7, 1.0 Hz, 1H), 6.28 and 6.16 (d, J.sub.HF=51.28
Hz, 2H), 2.56 (s, 3H); .sup.19F NMR (376 MHz, chloroform-d) .delta.
-157.89 (s, 1F); LC-MS: method A, RT=1.97 min, MS (ESI) m/z: 271.0
and 273.0 (M+H).sup.+.
Intermediate 34D:
(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)boronic acid
##STR00477##
[1995] A mixture of Intermediate 34C (48 mg, 0.177 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (71.9
mg, 0.283 mmol), potassium acetate (34.8 mg, 0.354 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.78 mg, 7.08 .mu.mol) in
dioxane (2.0 mL) was degassed by bubbling argon for 5 min. The
reaction mixture was heated in a microwave reactor at 120.degree.
C. for 30 min. HPLC and LCMS indicated complete conversion of
starting material. The mixture was diluted with EtOAc, washed with
brine. The organic layer was dried over sodium sulfate. The crude
residue was purified using a preparative HPLC (method A, 30-100% B
in 10 min; then 100% B in 2 min). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Intermediate 34D (20 mg, 0.085 mmol, 47.9% yield) as a white solid.
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.48 (s, 1H), 8.02
(br. s., 1H), 7.75 (br. s., 1H), 6.24 and 6.14 (d, J.sub.HF=51.50
Hz, 1H), 2.56 (s, 3H); NMR (376 MHz, methanol-d.sub.4) .delta.
-158.05 (br. s., 1F); LC-MS: method A, RT=1.87 min, MS (ESI) m/z:
237.0 (M+H).sup.+.
Example 34
[1996] To Intermediate 34D (9.54 mg, 0.040 mmol), Intermediate I-5
(18 mg, 0.040 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (2.64 mg, 3.23 .mu.mol) was
added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.040 mL, 0.081 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. To the reaction
mixture was added EtOAc/water. The organic layer was collected,
dried over sodium sulfate, concentrated. The crude product was
purified via preparative LC/MS (method G, 60-100% B over 20
minutes, then a 5-minute hold at 100% B). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to yield Example 34 (19.9 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.88 (s, 1H), 8.68 (s, 1H), 7.98-7.87 (m, 3H), 7.48-7.41
(m, 3H), 6.87 (s, 1H), 6.37 and 6.23 (d, J.sub.HF=51.44 Hz, 2H),
4.06 (t, J=5.1 Hz, 2H), 3.24 (t, J=5.1 Hz, 2H), 2.74 (s, 3H), 2.67
(s, 3H); LC-MS: method A, RT=2.52 min, MS (ESI) m/z: 557.1
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 35
2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-6-((2-phenyl-1H-imidazol-5--
yl)methoxy)benzo[d]thiazole
##STR00478##
[1997] Intermediate 35A: 5-(chloromethyl)-2-phenyl-1H-imidazole
hydrochloride
##STR00479##
[1999] To (2-phenyl-1H-imidazol-5-yl)methanol (0.216 g, 1.240 mmol)
at room temperature was added thionyl chloride (0.453 ml, 6.20
mmol). The reaction mixture was stirred at room temperature for 10
min, and then at 65.degree. C. for 2.0 h. The reaction mixture was
diluted with chloroform (5.0 mL) and the resulting solution was
evaporated. Additional co-evaporation with chloroform gave
Intermediate 35A (0.28 g, 1.222 mmol, 99% yield) as a brown solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.21-8.15 (m, 2H), 7.83
(s, 1H), 7.67-7.62 (m, 3H), 4.93 (s, 2H).
Intermediate 35B:
2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
##STR00480##
[2001] To Intermediate 26D (561 mg, 1.150 mmol) dissolved in THF
(4.0 mL) at room temperature was added 5.4 M sodium methoxide in
MeOH (0.746 mL, 4.03 mmol). The reaction mixture turned deep red.
The reaction mixture was stirred at room temperature for 20 min.
HPLC and LCMS indicated a completion of the reaction. The reaction
mixture was diluted with EtOAc, quenched with 1.0 N HCl (2.88 mL,
2.88 mmol). The organic layer was washed with brine, dried and
concentrated to give Intermediate 35B (300 mg, 0.889 mmol, 77%
yield) as yellow solid. .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.47 (d, J=1.5 Hz, 1H), 8.43 (s, 1H), 7.63 (s, 1H), 7.09 (d, J=2.2
Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 3.73 (s, 3H), 2.69 (s, 3H), 2.55
(s, 3H); LC-MS: Method A, 50 to 100% B. RT=2.45 min, MS (ESI) m/z:
338.1 (M+H).sup.+.
Example 35
[2002] To a stirred solution of Intermediate 35B (25 mg, 0.074
mmol) and cesium carbonate (97 mg, 0.296 mmol) in DMF (0.8 mL) at
room temperature was added a solution of Intermediate 35A (37.3 mg,
0.163 mmol) in DMF (0.8 mL) dropwise. The reaction mixture was
stirred at room temperature for 0.5 h, then another portion of
Intermediate 35A (37.3 mg, 0.163 mmol) in DMF (0.8 mL) was added.
The reaction mixture was stirred at room temperature for 1.0 h,
diluted with EtOAc, quenched with ammonium chloride. The organic
layer was collected, washed with brine, dried over sodium sulfate
and concentrated. The crude material was purified via preparative
LC/MS (method D, 50-90% B over 20 minutes, then a 5-minute hold at
100% B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 35 (6.1 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (br. s., 1H), 8.61
(br. s., 1H), 8.02 (d, J=6.9 Hz, 2H), 7.84 (br. s., 2H), 7.74 (br.
s., 1H), 7.61 (d, J=7.4 Hz, 3H), 7.12 (br. s., 1H), 5.26 (br. s.,
2H), 4.09 (br. s., 3H), 2.77 (br. s., 3H), 2.66 (br. s., 3H);
LC-MS: method A, RT=2.54 min, MS (ESI) m/z: 494.2 (M+H).sup.+.
Analytical HPLC purity (method B): 98%.
Example 36
N-benzyl-2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-
-6-yl)oxy)acetamide
##STR00481##
[2003] Intermediate 36A: methyl
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)acetate
##STR00482##
[2005] To a suspension of Intermediate 35B (240 mg, 0.711 mmol) in
DMF (10 mL) was added THF (2.0 mL) and cesium carbonate (695 mg,
2.134 mmol). The solution turned from yellow to brown. Methyl
bromoacetate (0.328 mL, 3.56 mmol) was added dropwise. The reaction
mixture was stirred at room temperature for 20 min, then at
50.degree. C. for 2.0 h. HPLC and LCMS indicated a completion of
the reaction. The reaction mixture was diluted with EtOAc/THF and
water. The product could not dissolve at this stage. The organic
suspension was separated from aqueous solution, concentrated to
remove solvent and water. The crude was triturated with a mixture
of acetonitrile and water. The solid was collected by filtration,
washed with acetonitrile and dried to give Intermediate 36A (280
mg, 0.684 mmol, 96% yield) as yellow solid. .sup.1H NMR was not
taken due to very poor solubility in DMSO-d.sub.6. LC-MS: method A,
RT=1.17 min, MS (ESI) m/z: 410.0 (M+H).sup.+.
Intermediate 36B
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)acetic acid
##STR00483##
[2007] To a suspension of Intermediate 36A (44 mg, 0.107 mmol) in
THF (2.0 mL) and MeOH (0.5 mL) at room temperature was added 1.0 N
NaOH (0.537 mL, 0.537 mmol). The suspension was stirred at room
temperature for 2.0 h with occasional sonicating (3.times.) for 1
min. HPLC and LCMS indicated a complete of reaction. To the
reaction mixture was added 1.0 N HCl (0.537 mL, 0.537 mmol),
followed by addition of EtOAc/water. The organic layer was washed
with brine and dried over sodium sulfate and concentrated. The
crude was lyophilized to give Intermediate 36B (42 mg, 0.102 mmol,
95% yield) as a light yellow lyophilate. .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.57 (d, J=1.9 Hz, 1H), 8.52 (s, 1H),
7.73 (dd, J=1.9, 0.8 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 6.98 (dd,
J=2.5, 0.8 Hz, 1H), 4.68 (s, 2H), 4.11 (s, 3H), 2.80 (s, 3H), 2.64
(s, 3H); LC-MS: method A, RT=1.06 min, MS (ESI) m/z: 396.0
(M+H).sup.+. Analytical HPLC purity (method B): 96%.
Example 36
[2008] To a suspension of Intermediate 36B (12.5 mg, 0.032 mmol)
and phenylmethanamine (0.014 mL, 0.126 mmol) in DMF (1.0 mL) was
added DIEA (0.044 mL, 0.253 mmol), followed by T.sub.3P 50% wt in
EtOAc (0.075 mL, 0.126 mmol). The reaction mixture was stirred at
room temperature for 1.0 h. HPLC and LCMS indicated a completion of
the reaction. The reaction was quenched by addition of 0.1% TFA in
MeOH/water. The crude material was purified via preparative LC/MS
(method D, 60-100% B over 15 minutes, then a 10-minute hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield Example 36 (9.8 mg).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.72 (t,
J=6.2 Hz, 1H), 8.62 (d, J=1.7 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.55
(d, J=2.2 Hz, 1H), 7.33-7.22 (m, 5H), 7.11 (d, J=1.7 Hz, 1H), 4.67
(s, 2H), 4.39 (d, J=6.1 Hz, 2H), 4.10 (s, 3H), 2.77 (s, 3H), 2.66
(s, 3H); LC-MS: method A, RT=2.55 min, MS (ESI) m/z: 485.2
(M+H).sup.+. Analytical HPLC purity (method B): 95%.
Example 37
5-(7-chlorobenzofuran-2-yl)-2-methoxy-7-methylquinoxaline
##STR00484##
[2009] Intermediate 37A: 7-chloro-2-iodobenzofuran
##STR00485##
[2011] To diisopropylamine (0.280 mL, 1.966 mmol) in THF (4.0 mL)
at -78.degree. C. was added 1.6 N n-BuLi in hexanes (1.229 mL,
1.966 mmol). The reaction mixture was stirred at -78.degree. C. for
0.5 h. 7-Chlorobenzofuran (200 mg, 1.311 mmol) in THF (1.0 mL) was
added, The reaction mixture was stirred at -78.degree. C. for 0.5
h. Iodine (665 mg, 2.62 mmol) in THF (1.0 mL) was added dropwise
until the brown color persisted (ca 1.3 eq.) The reaction mixture
was stirred at -78.degree. C. for 0.5 h, then at room temperature
for 0.5 h. The reaction mixture was diluted with EtOAc, quenched
with saturated ammonium chloride (5.0 mL) and 10%
Na.sub.2S.sub.2O.sub.3 (5.0 mL). After stirring at room temperature
for 10 min, the organic layer was washed with brine, dried over
sodium sulfate. After evaporation of solvent, the crude product
Intermediate 37A (360 mg, 1.189 mmol, 91% yield) was obtained as a
slightly brown oil. It was used for the next step without further
purification. .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.40 (dd,
J=7.7, 1.3 Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.11 (m, 1H), 6.99 (s,
1H). LC-MS: method H, 2 to 98% B. RT=1.07 min, MS (ESI) m/z: MW not
observed (M+H).sup.+.
Intermediate 37B:
5-(7-chlorobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
##STR00486##
[2013] To Intermediate I-1 (45.6 mg, 0.180 mmol), Intermediate 37A
(50.0 mg, 0.180 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.87 mg, 7.18 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (2M, 0.157 mL, 0.314 mmol). The reaction mixture was
heated in a microwave reactor at 120.degree. C. for 30 min. HPLC
and LCMS indicated a completion of the reaction. The crude reaction
mixture was diluted with EtOAc/water. The insoluble material was
removed by filtration. The organic layer was washed with brine,
dried over sodium sulfate and concentrated to give Intermediate 37B
(64 mg, 0.177 mmol, 99% yield) as a brown solid. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.93 (s, 1H), 8.24 (d, J=1.9 Hz, 1H),
8.20 (s, 1H), 7.90 (t, J.sub.HF=71.53 Hz, 1H), 7.83-7.81 (m, 1H),
7.79 (dd, J=7.8, 1.0 Hz, 1H), 7.51 (dd, J=7.8, 1.0 Hz, 1H), 7.34
(t, J=7.7 Hz, 1H), 2.67 (s, 3H); LC-MS: method H, RT=2.70 min, MS
(ESI) m/z: 361.0 (M+H).sup.+.
Example 37
[2014] To Intermediate 37B (35 mg, 0.097 mmol) dissolved in THF
(1.5 mL) and MeOH (1.5 mL) at room temperature was added 4.3 M
sodium methoxide in MeOH (0.090 mL, 0.388 mmol). The reaction
mixture was stirred at room temperature for 1.0 h. LCMS indicated
ca 60% conversion. Then another portion of 4.3 M sodium methoxide
in MeOH (0.090 mL, 0.388 mmol) was added and the reaction was
continued at room temperature for 2.0 h. LCMS indicated a
completion of the reaction. Methanol was removed under vacuum. The
reaction mixture was diluted with EtOAc, quenched with 0.5 N HCl
(2.0 mL). The organic layer was washed with saturated sodium
bicarbonate, brine, dried and concentrated. The crude material was
purified via preparative LC/MS (method D, 65-100% B over 20
minutes, then a 8-minute hold at 100% B). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to yield Example 37 (16.0 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.70 (s, 1H), 8.17 (s, 1H), 8.10 (d, J=1.7 Hz, 1H), 7.77
(dd, J=7.8, 1.0 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.49 (dd, J=7.8,
1.0 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H);
LC-MS: method H. RT=2.76 min, MS (ESI) m/z: 325.1 and 327.1
(M+H).sup.+. Analytical HPLC purity (method B): 95%.
Example 38
2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethy-
l (2-methylpyridin-4-yl)carbamate
##STR00487##
[2015] Intermediate 38A:
2-chloro-1-(2,2-diethoxyethoxy)-4-methoxybenzene
##STR00488##
[2017] To a suspension of sodium hydride (60%) (0.189 g, 4.73 mmol)
in DMF (5.0 mL) was added 2-chloro-4-methoxyphenol (0.5 g, 3.15
mmol) dissolved in DMF (3.0 mL) at room temperature. After hydrogen
evolution was ceased (20 min at 40.degree. C. oil bath),
2-bromo-1,1-diethoxyethane (0.593 mL, 3.94 mmol) was added. The
reaction mixture was heated at 160.degree. C. for 18 h. After
cooled to room temperature, the reaction mixture was diluted with
EtOAc/water. The organic layer was washed with saturated sodium
bicarbonate, brine, dried over sodium sulfate and concentrated to
give Intermediate 38A (0.95 g, 3.46 mmol, 110% yield) as a light
yellow oil. It was used for the next step without further
purification. .sup.1H NMR (400 MHz, chloroform-d) .delta. 6.93 (d,
J=3.1 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.73 (dd, J=8.9, 3.0 Hz,
1H), 4.84 (t, J=5.2 Hz, 1H), 4.00 (d, J=5.3 Hz, 2H), 3.83-3.76 (m,
2H), 3.75 (s, 3H), 3.71-3.64 (m, 2H), 1.27-1.22 (t, J=7.04 Hz, 6H).
LC-MS: method H, 2 to 98% B. RT=1.02 min, MS (ESI) m/z: 297.0
(M+Na).sup.+.
Intermediate 38B: 7-chloro-5-methoxybenzofuran
##STR00489##
[2019] A mixture of Amberlyst-15 (1.2 g, 2.91 mmol) in
chlorobenzene (100 mL) was heated at reflux (oil bath temperature
165.degree. C.) to remove water by azeotropic distillation.
Distillate was removed until the volume remaining in the flask was
about 80 mL. To this mixture was then added dropwise over 1.0 h a
solution of Intermediate 38A (0.8 g, 2.91 mmol) in chlorobenzene
(9.0 mL). The reaction mixture was stirred at reflux with constant
water removal for another 2.0 h. After cooled to room temperature,
the Amberlyst-15 was removed by filtration. The filtrated was
concentrated under vacuum, and loaded directly to ISCO column for
purification. The crude product was purified by flash
chromatography (loading in chloroform, 0% to 30% EtOAc in hexane
over 15 min using a 24 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 38B
(0.32 g, 1.752 mmol, 60.2% yield) as a light yellow oil. .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.64 (d, J=2.2 Hz, 1H),
6.97-6.93 (m, 2H), 6.73 (d, J=2.2 Hz, 1H), 3.83 (s, 3H); LC-MS:
method H, 2 to 98% B. RT=0.94 min, MS (ESI) m/z: 183.0
(M+H).sup.+.
Intermediate 38C: 7-chlorobenzofuran-5-ol
##STR00490##
[2021] To Intermediate 38B (0.32 g, 1.752 mmol) and
tetrabutylammonium iodide (0.680 g, 1.840 mmol) in dichloromethane
(4 mL) at -78.degree. C. was added 1.0 M boron trichloride in
heptane (4.12 ml, 4.12 mmol) dropwise. The reaction mixture was
stirred at -78.degree. C. for 45 min. Then the cooling bath was
removed and the reaction mixture was stirred at room temperature
for 3.0 h. HPLC and TLC indicated a completion of the reaction. The
mixture was poured into saturated sodium bicarbonate and ice,
stirred for 20 min, extracted with EtOAc. The organic layer was
collected, washed with 10% Na.sub.2S.sub.2O.sub.3, water, brine and
dried over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform and charged
to a 12 g silica gel cartridge which was eluted with hexanes for 1
min., then a 15 min gradient from 0% to 50% EtOAc in hexanes. The
desired fractions were combined and concentrated to give
Intermediate 38C (0.29 g, 1.720 mmol, 98% yield) as a slightly
brown solid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.64 (d,
J=2.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.71
(d, J=2.2 Hz, 1H).
Intermediate 38D:
tert-butyl((7-chlorobenzofuran-5-yl)oxy)dimethylsilane
##STR00491##
[2023] To a stirred solution of Intermediate 38C (0.30 g, 1.780
mmol) in DMF (4.0 mL) was added TBDMS-Cl (0.402 g, 2.67 mmol) and
imidazole (0.218 g, 3.20 mmol). The reaction mixture was stirred at
room temperature for 1.5 h. HPLC and TLC indicated a completion of
the reaction. The mixture was partitioned between EtOAc/water. The
organic layer was washed with water, brine and dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
silica gel cartridge which was eluted with hexanes for 3 min., then
a 15 min gradient from 0% to 15%. The desired fractions were
combined and concentrated to give Intermediate 38D (0.4 g, 1.414
mmol, 79% yield) as a clear oil. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.64 (d, J=2.2 Hz, 1H), 6.93 (d, J=2.2 Hz,
1H), 6.86 (d, J=2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 1.01 (s, 9H),
0.22 (s, 6H); LC-MS: method H, 2 to 98% B. RT=0.96 min, MS (ESI)
m/z: MS not observed (M+H).sup.+.
Intermediate 38E:
tert-butyl((7-chloro-2-iodobenzofuran-5-yl)oxy)dimethylsilane
##STR00492##
[2025] To diisopropylamine (0.302 mL, 2.121 mmol) in THF (4.0 mL)
at -78.degree. C. was added 1.6 N n-BuLi in hexanes (1.326 mL,
2.121 mmol). The reaction mixture was stirred at -78.degree. C. for
20 min. Intermediate 38D (0.4 g, 1.414 mmol) in THF (1.0 mL) was
added dropwise, The reaction mixture was stirred at -78.degree. C.
for 0.5 h. Iodine (0.610 g, 2.404 mmol) in THF (1.0 mL) was added
dropwise until the brown color persisted (ca 1.2 eq), and the
reaction mixture was stirred at -78.degree. C. for 0.5 h, then at
room temperature for 0.5 h. The reaction mixture was diluted with
EtOAc, quenched with saturated ammonium chloride (5.0 mL) and 10%
Na.sub.2S.sub.2O.sub.3 (5.0 mL). After stirring at room temperature
for 10 min, the organic layer was washed with brine, dried over
sodium sulfate. After evaporation of solvent, Intermediate 38E
(0.51 g, 1.148 mmol, 81% yield) was obtained as a slightly brown
oil. It was used for the next step without further purification.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 6.89 (s, 1H), 6.84 (d,
J=2.2 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 1.00 (s, 9H), 0.21 (s, 6H).
LC-MS: method H, 2 to 98% B. RT=1.36 min, MS (ESI) m/z: no desired
MS observed (M+H).sup.+.
Intermediate 38F
5-(5-((tert-butyldimethylsilyl)oxy)-7-chlorobenzofuran-2-yl)-2-(difluorome-
thoxy)-7-methylquinoxaline
##STR00493##
[2027] To Intermediate I-1 (0.311 g, 1.223 mmol), Intermediate 38E
(0.5 g, 1.223 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (0.040 g, 0.049 mmol) was added
toluene (4.5 mL) and EtOH (1.5 mL). The mixture was sonicated for 1
min, and flushed with argon. To this was added sodium carbonate
(2M, 1.070 mL, 2.141 mmol). The reaction mixture was heated in a
microwave reactor at 120.degree. C. for 30 min. HPLC and LCMS
indicated a completion of the reaction. The crude reaction mixture
was directly loaded on an ISCO column for purification. The crude
product was purified by flash chromatography (loading in
chloroform, 0% to 25% EtOAc in hexane over 15 min using a 24 g
silica gel cartridge). The desired fractions were combined and
concentrated to yield Intermediate 38F (0.36 g, 0.733 mmol, 59.9%
yield) as an yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.63 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.02 (s, 1H), 7.66
(dd, J=1.8, 0.9 Hz, 1H), 7.65 (t, J.sub.HF=71.75 Hz, 1H), 6.99 (d,
J=2.2 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 2.66 (s, 3H), 1.02 (s, 9H),
0.23 (s, 6H); .sup.19F NMR (376 MHz, chloroform-d) .delta. -89.72
(s, 1F); LC-MS: method H, 2 to 98% B. RT=1.51 min, MS (ESI) m/z:
491.1 and 493.1 (M+H).sup.+.
Intermediate 38G:
7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol
##STR00494##
[2029] To Intermediate 38F (0.36 g, 0.733 mmol) dissolved in THF
(3.0 mL) and MeOH (3.0 mL) at room temperature was added 4.3 M
sodium methoxide in MeOH (0.767 mL, 3.30 mmol). The reaction
mixture was stirred at room temperature for 4.0 h. HPLC and LCMS
indicated a completion of the reaction. The reaction mixture was
quenched with 1.0 N HCl (2.93 mL, 2.93 mmol), diluted with EtOAc.
The organic layer was washed with brine, dried and concentrated to
give Intermediate 38G (0.26 g, 0.687 mmol, 94% yield) as yellow
solid. This was used for the next step without further
purification. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.43 (s,
1H), 8.08 (d, J=1.8 Hz, 1H), 7.90 (s, 1H), 7.57 (d, J=0.9 Hz, 1H),
6.90 (d, J=2.2 Hz, 1H), 6.84-6.80 (m, 1H), 4.05 (s, 3H), 2.56 (s,
3H); LC-MS: method H, 2 to 98% B. RT=1.14 min, MS (ESI) m/z: 341.0
and 343.0 (M+H).sup.+.
Intermediate 38H
2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)etha-
nol
##STR00495##
[2031] To a suspension of Intermediate 38G (145 mg, 0.426 mmol) in
DMF (3.0 mL) and THF (2.0 mL) was added cesium carbonate (277 mg,
0.851 mmol). The reaction mixture was stirred at room temperature
for 20 min. Then 2-bromoethyl acetate (0.063 mL, 0.574 mmol) in THF
(0.5 mL) was added dropwise. The reaction mixture was stirred at
room temperature for 30 min, then at 65.degree. C. for 1.5 h. HPLC
and LCMS indicated completion of reaction. After cooled to room
temperature, the reaction mixture was diluted with EtOAc and water,
extracted with EtOAc (6.times.). The combined organic layer was
washed with brine and dried with sodium sulfate and concentrated to
give yellow solid as the acetate. The crude acetate was suspended
in a mixture of THF (3.0 mL) and MeOH (0.8 mL). To this suspension
was added 1.0 N NaOH (0.851 mL, 0.851 mmol). The reaction mixture
was stirred at room temperature for 30 min. The suspension turned
to a clear brown solution. HPLC and LCMS indicated a clean
conversion of the ester to acid. The reaction was quenched with 1.0
N HCl (0.638 mL, 0.638 mmol) diluted in 1.0 mL of water, extracted
with EtOAc, washed with saturated sodium bicarbonate, brine, dried
over sodium sulfate and concentrated. The crude product was
purified by flash chromatography (loading in chloroform, 10% to 60%
EtOAc in hexane over 10 min using a 12 g silica gel cartridge). The
desired fractions were combined and concentrated to yield
Intermediate 38H (110 mg, 0.286 mmol, 67.2% yield) as a lightly
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.67 (s,
1H), 8.07 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.70 (dd, J=1.8, 0.9 Hz,
1H), 7.29 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 4.90 (t, J=5.5
Hz, 1H), 4.07 (s, 3H), 4.06 (m, 2H), 3.78-3.74 (m, 2H), 2.61 (s,
3H); LC-MS: method H, 2 to 98% B. RT=1.14 min, MS (ESI) m/z: 385.0
and 387.0 (M+H).
Intermediate 38I
2-{[7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-1-benzofuran-5-yl]oxy}e-
thyl chloroformate
##STR00496##
[2033] To a solution Intermediate 38H (100 mg, 0.260 mmol) in THF
(3.0 mL) at room temperature was added 15% phosgene in toluene
(0.733 mL, 1.039 mmol). The reaction mixture was left stirring at
room temperature overnight. HPLC and LCMS indicated the reaction
was complete. Solvent was completely removed under high vacuum to
give Intermediate 38I (116 mg, 0.259 mmol, 100% yield) as a
slightly yellow solid. It was used for the next step without
purification. LC-MS: method H, 2 to 98% B. RT=1.30 min, MS (ESI)
m/z: 447.1 (M+H).sup.+.
Example 38
[2034] To a solution of 2-methylpyridin-4-amine (19.34 mg, 0.179
mmol) in DCM (0.8 mL) was added DIEA (0.062 mL, 0.358 mmol),
followed by addition of Intermediate 38I (16 mg, 0.036 mmol) in THF
(0.8 mL). The reaction mixture was stirred at room temperature for
1.0 h. HPLC and LCMS indicated a completion of reaction. The
reaction was quenched by addition of a small amount of
MeOH/water/0.1% TFA. Solvent was removed under vacuum. The crude
material was purified via preparative LC/MS (method D, 50-90% B
over 18 minutes, then a 5-minute hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to yield Example 38 (10 mg). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.37 (br. s., 1H), 8.68 (s, 1H),
8.29 (d, J=5.5 Hz, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H),
7.39-7.32 (m, 3H), 7.16 (d, J=1.9 Hz, 1H), 4.51 (d, J=4.4 Hz, 2H),
4.34 (d, J=3.9 Hz, 2H), 4.07 (s, 3H), 2.62 (s, 3H), 2.42 (s, 3H);
LC-MS: method H, RT=2.16 min, MS (ESI) m/z: 519.2 (M+H).sup.+.
Analytical HPLC purity (method B): 99%.
Example 39
N-(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)e-
thyl)benzenesulfonamide
##STR00497##
[2035] Intermediate 39A: tert-butyl
(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzofuran-5-yl)oxy)ethyl)carbamate
##STR00498##
[2037] A solution of tert-butyl (2-hydroxyethyl)carbamate (85 mg,
0.528 mmol) and DIAD (0.123 mL, 0.634 mmol) in THF (1.0 mL) was
added dropwise to a mixture of Intermediate 38G (72 mg, 0.211 mmol)
and triphenylphosphine (163 mg, 0.623 mmol) in THF (2.0 mL) heated
at 70.degree. C. The reaction mixture was stirred at 70.degree. C.
for 15 min, at which time HPLC and LCMS indicated a completion of
the reaction. Solvent was removed under vacuum. The crude product
was purified by flash chromatography (loading in chloroform, 5% to
45% EtOAc in hexane over 15 min using a 12 g silica gel cartridge).
The desired fractions were combined and concentrated to yield
Intermediate 39A (80 mg, 0.152 mmol, 72.0% yield) as a pale yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.63 (s, 1H),
8.05 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.25 (d, J=2.4
Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 4.03-4.00 (m, 2H), 3.34 (t, J=5.6
Hz, 2H), 2.60 (s, 3H), 1.40 (s, 9H); LC-MS: method H, 2 to 98% B.
RT=1.29 min, MS (ESI) m/z: 484.1(M+H).sup.+.
Intermediate 39B
2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)etha-
namine
##STR00499##
[2039] To Intermediate 39A (80 mg, 0.165 mmol) in DCM (2 mL) was
added 2,6-lutidine (0.077 mL, 0.661 mmol) followed by TMS-OTf
(0.119 mL, 0.661 mmol). The reaction mixture was stirred at room
temperature for 1h. The mixture was diluted with EtOAc and
NaHCO.sub.3 and extracted with EtOAc. The combined organic layer
was washed with brine and concentrated. The residual was treated
with 1.0 ml of MeOH, stirred at room temperature for 15 min, and
concentrated to give Intermediate 39B (60 mg) as yellow solid. the
crude sample was used for next step without purification.
Example 39
[2040] To a suspension of Intermediate 39B (18 mg, 0.047 mmol) in
DMF (1.0 mL) and THF (1.0 mL) was added DIEA (0.066 mL, 0.375
mmol), followed by benzenesulfonyl chloride (8.27 .mu.l, 0.064
mmol). The reaction mixture was stirred at room temperature for 2.0
h. Solvent was removed and the crude was purified via preparative
LC/MS (method D, 55-95% B over 10 minutes, then a 7-minute hold at
100% B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to yield 39 (22.8 mg). .sup.1H
NMR (500 MHz, chloroform-d) .delta. 8.51 (s, 1H), 8.16 (s, 1H),
8.02 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.65 (s, 1H), 7.62-7.57 (m,
1H), 7.55-7.50 (m, 2H), 6.91 (d, J=1.9 Hz, 1H), 6.83 (d, J=2.2 Hz,
1H), 4.99 (t, J=6.1 Hz, 1H), 4.12 (s, 3H), 4.03 (t, J=5.1 Hz, 2H),
3.42 (q, J=5.5 Hz, 2H), 2.63 (s, 3H); LC-MS: method H, RT=2.66 min,
MS (ESI) m/z: 524.2 (M+H).sup.+. Analytical HPLC purity (method
B):100%.
Example 40
5-(benzo[b]thiophen-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
##STR00500##
[2042] To a solution of benzo[b]thiophen-2-yltributylstannane (35.1
mg, 0.083 mmol) and Intermediate I-1G (20 mg, 0.069 mmol) in
1,4-dioxane (1 mL) was added Pd(Ph.sub.3P).sub.4 (9.59 mg, 8.30
.mu.mol). The mixture was heated at 150.degree. C. for 1 h in a
microwave reactor. LCMS indicated a completion of the reaction. The
mixture was diluted with acetonitrile and filtered. The filtrate
was concentrated and purified by a preparative HPLC (method A,
65-100% B in 8 min.). The desired fractions were collected, dried
and lyophilized to give 40 (18 mg, 0.050 mmol, 72.2% yield).
.sup.1H NMR (400 MHz, chloroform-d) .delta. 8.66 (s, 1H), 8.07 (s,
1H), 8.00-7.46 (m, 5H), 7.45-7.32 (m, 2H), 2.64 (s, 3H). .sup.19F
NMR (376 MHz, chloroform-d) .delta. -90.43 (s, 2F). LC-MS: method
B, RT=2.55 min, MS (ESI) m/z: 343.0 (M+H).sup.+. Analytical HPLC
purity (method A): 99%.
Example 41
2-(difluoromethoxy)-5-(7-methoxybenzofuran-2-yl)-7-methylquinoxaline
##STR00501##
[2044] To (7-methoxybenzofuran-2-yl)boronic acid (13.28 mg, 0.069
mmol) and Intermediate I-1G was added toluene (0.75 mL) and EtOH
(0.25 mL). The reaction mixture was stirred at room temperature
until solids are dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.78 mg, 8.30 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate 2M (0.069 mL, 0.138 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 140.degree. C. for 30 min. The
reaction mixture was cooled to room temperature, diluted with EtOAc
and water, extracted with EtOAc (3.times.). The combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified by 12 g ISCO column
eluted with 0-70% EtOAc in hexane for 15 min. The desired fraction
was collected, dried and purified by preparative HPLC (method A,
30-100% B in 10 min.) to give Example 41 (8 mg, 0.022 mmol, 31.5%
yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.66 (s, 1H),
8.34 (d, J=1.8 Hz, 1H), 8.10 (s, 1H), 7.91-7.47 (m, 2H), 7.29 (s,
1H), 7.23-7.17 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 4.10 (s, 3H), 2.65
(s, 3H). .sup.19F NMR (376 MHz, chloroform-d) -90.12 (s, 2F).
LC-MS: method B, RT=2.53 min, MS (ESI) m/z: 357.0 (M+H).sup.+.
Analytical HPLC purity (method A): 98%.
Example 42
2-(difluoromethoxy)-5-(4-methoxybenzofuran-2-yl)-7-methylquinoxaline
##STR00502##
[2045] Intermediate 42A:
(benzofuran-4-yloxy)(tert-butyl)dimethylsilane
##STR00503##
[2047] To a solution of benzofuran-4-ol (200 mg, 1.491 mmol) in DMF
(5 mL) was added TBDMS-Cl (337 mg, 2.237 mmol) and imidazole (203
mg, 2.98 mmol). The mixture was stirred at room temperature for 2
h. LCMS indicated a completion of the reaction. The mixture was
diluted by EtOAc and water, extracted with EtOAc, the combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a 12 g ISCO column
eluted with 0-50% EtOAc/Hex, the desired fraction was collected to
give Intermediate 42A (270 mg, 1.087 mmol, 72.9% yield). .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.53 (d, J=2.3 Hz, 1H),
7.18-7.10 (m, 2H), 6.79 (d, J=1.8 Hz, 1H), 6.72-6.60 (m, 1H), 1.06
(s, 10H), 0.31-0.18 (m, 6H). LC-MS: method B, RT=2.55 min, MS (ESI)
m/z: 249 (M+H).sup.+.
Intermediate 42B:
4-(tert-butyldimethylsilyloxy)benzofuran-2-ylboronic acid
##STR00504##
[2049] To a solution of Intermediate 42A (270 mg, 1.087 mmol) in
THF (4 mL) was added n-BuLi (0.815 mL, 1.304 mmol) at -78.degree.
C. After 30 min stirring, trimethyl borate (0.243 mL, 2.174 mmol)
was added, and the reaction mixture was slowly warmed up to room
temperature over 1h. HCl (5.43 mL, 5.43 mmol) was added and the
mixture was stirred at room temperature for 30 min. The mixture was
diluted with EtOAc and water, extracted with EtOAc and the combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a 12 g ISCO column
eluted with 0-70% EtOAc/Hex. The desired fraction was collected to
give Intermediate 42B (190 mg, 0.650 mmol, 59.8% yield). LC-MS:
method C, RT=2.35 min, MS (ESI) m/z: 293 (M+H).sup.+.
Intermediate 42C
5-(4-(tert-butyldimethylsilyloxy)benzofuran-2-yl)-2-(difluoromethoxy)-7-me-
thylquinoxaline
##STR00505##
[2051] To Intermediate I-1 (50 mg, 0.173 mmol) and Intermediate 42B
(60.7 mg, 0.208 mmol) was added toluene (0.75 mL) and EtOH (0.25
mL). The reaction mixture was stirred at room temperature until
solids are dissolved, then [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium (II) complex with dichloromethane (1:1)
(16.95 mg, 0.021 mmol) was added. The flask was degassed and
flushed with argon. Finally sodium carbonate (0.173 mL, 2M, 0.346
mmol) was added dropwise. The reaction vessel was sealed and
bubbled with argon for 5 min, then placed in microwave reactor at
120.degree. C. for 30 min. LCMS indicated a completion of the
reaction. The reaction mixture was cooled to room temperature and
was diluted with EtOAc and water, extracted with EtOAc (3.times.),
the combined organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated. The crude sample was purified with a
12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The
desired fraction was collected to give Intermediate 42C (79 mg,
0.173 mmol, 100% yield). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.66 (s, 1H), 8.23 (d, J=1.8 Hz, 1H), 8.09 (s, 1H),
7.88-7.47 (m, 2H), 7.23-7.18 (m, 2H), 6.69 (dd, J=6.3, 2.3 Hz, 1H),
2.65 (s, 3H), 1.12-1.09 (m, 9H), 0.29 (s, 6H). .sup.19F NMR (376
MHz, acetonitrile-d.sub.3) .delta. -90.43 (s, 2F). LC-MS: method C,
RT=2.68 min.
Intermediate 42D:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-4-ol
##STR00506##
[2053] To a solution of Intermediate 42C (76 mg, 0.166 mmol) in
MeOH (1 mL) and THF was added HCl (0.277 mL, 12M, 3.33 mmol). The
mixture was stirred at room temperature for 1h. LCMS indicated a
completion of the reaction. The mixture was diluted with EtOAc and
saturated NaHCO.sub.3, extracted with EtOAc, the combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. Intermediate 42D (50 mg, 0.142 mmol, 85% yield) was
obtained and used for next step without purification. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.65 (s, 1H), 8.25 (d, J=1.8 Hz,
1H), 8.20 (s, 1H), 7.87-7.47 (m, 2H), 7.23-7.18 (m, 2H), 6.72-6.65
(m, 1H), 2.66 (s, 3H). .sup.19F NMR (376 MHz, chloroform-d) -90.12
(s, 2F). LC-MS: method B, RT=4.44 min, MS (ESI) m/z: 343.1
(M+H).sup.+.
Example 42
[2054] To a solution of Intermediate 42D (10 mg, 0.029 mmol) in
acetonitrile (1 mL) was added Cs.sub.2CO.sub.3 (28.6 mg, 0.088
mmol) and MeI (1.827 .mu.l, 0.029 mmol). The mixture was stirred at
45.degree. C. for 1 h. The mixture was diluted with 1 ml of DMSO
and 1 ml of acetonitrile, filtered and purified with a preparative
HPLC (method A, 65-100% B in 8 min.). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Example 42 (5.6 mg, 0.015 mmol, 52.7% yield). .sup.1H NMR
(chloroform-d, 400 MHz): .delta.=8.65 (s, 1H), 8.25 (s, 1H), 8.20
(s, 1H), 7.46-7.86 (m, 2H), 7.28-7.32 (m, 1H), 7.19-7.23 (m, 1H),
6.71 (d, J=7.8 Hz, 1H), 4.02 (s, 3H), 2.65 ppm (s, 3H). .sup.19F
NMR (chloroform-d, 400 MHz) -90.12 (s, 2F). LC-MS: method B,
RT=4.56 min, MS (ESI) m/z: 357.1 (M+H).sup.+. Analytical HPLC
purity (method A): 98%.
Example 43
5-(4-(benzyloxy)benzofuran-2-yl)-2-methoxy-7-methylquinoxaline
##STR00507##
[2056] To a solution of Intermediate 42D (10 mg, 0.029 mmol) in
acetonitrile (1 mL) was added Cs.sub.2CO.sub.3 (28.6 mg, 0.088
mmol) and benzyl bromide (3.47 .mu.l, 0.029 mmol). The mixture was
stirred at 45.degree. C. for 1 h. The mixture was diluted with 1.0
ml of MeOH and water, extracted with EtOAc. The combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The mixture was purified with preparative HPLC
(method A, 65-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
43 (2.5 mg, 5.86 .mu.mol, 20.07% yield). .sup.1H NMR (chloroform-d,
400 MHz): .delta.=8.53 (s, 1H), 8.19 (s, 1H), 8.12 (d, J=1.8 Hz,
1H), 7.62 (s, 1H), 7.49-7.57 (m, 2H), 7.40-7.47 (m, 2H), 7.33-7.39
(m, 1H), 7.21-7.25 (m, 2H), 6.72-6.80 (m, 1H), 5.28 (s, 2H), 4.12
(s, 3H), 2.63 ppm (s, 3H). LC-MS: method C, RT=3.25 min, MS (ESI)
m/z: 397.1 (M+H).sup.+. Analytical HPLC purity (method A):
93.0%.
Example 44
5-(5-(benzyloxy)benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
##STR00508##
[2057] Intermediate 44A: benzofuran-5-ol
##STR00509##
[2059] To an ice-cooled solution of 5-methoxybenzofuran (0.71 g,
4.79 mmol) in dichloromethane (8.0 mL) was added 1.0 M boron
tribromide in dichloromethane (4.79 mL, 4.79 mmol). The mixture was
stirred at 0.degree. C. for 1.0 h. HPLC indicated ca 30-40%
starting material still remaining. Then another portion of 1.0 M
boron tribromide in dichloromethane (4.79 mL, 4.79 mmol) was added
and the mixture was stirred from 0.degree. C. to room temperature
over an hour. HPLC indicated a complete conversion of starting
material. The mixture was poured into ice water, stirred for 15
min, extracted with dichloromethane. The organic layer was dried
over sodium sulfate. After evaporation of solvent, Intermediate 44A
(0.33 g, 2.460 mmol, 51.3% yield) was obtained as slightly brown
oil. It was used for the next step without further purification.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.60 (d, J=2.2 Hz, 1H),
7.36 (d, J=8.8 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.82 (dd, J=8.8,
2.8 Hz, 1H), 6.69-6.67 (m, 1H), 4.78 (s, 1H); LC-MS: Method A, 50
to 100% B. RT=2.32 min, MS (ESI) m/z: no (M+H).sup.+.
Intermediate 44B:
(benzofuran-5-yloxy)(tert-butyl)dimethylsilane
##STR00510##
[2061] To a stirred solution of Intermediate 44A (0.33 g, 2.460
mmol) in DMF (8.0 mL) was added TBDMS-Cl (0.519 g, 3.44 mmol) and
imidazole (0.285 g, 4.18 mmol). The reaction mixture was left
stirring at room temperature for 2.0 h. The mixture was partitioned
between EtOAc/water. The organic layer was washed with brine, dried
over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform and charged
to a 24 g silica gel cartridge which was eluted with hexanes for 3
min., then a 15 min gradient from 0% to 20% EtOAc in hexanes. The
desired fractions were combined and concentrated to give
Intermediate 44B (0.48 g, 1.932 mmol, 79% yield) as a clear oil.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.60 (d, J=1.9 Hz, 1H),
7.36 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.83 (dd, J=8.7,
2.3 Hz, 1H), 6.70-6.69 (m, 1H), 1.03 (s, 9H), 0.23 (s, 6H); LC-MS:
Method A, 50 to 100% B. RT=2.19 min, MS (ESI) m/z: 249
(M+H).sup.+.
Intermediate 44C:
5-(tert-butyldimethylsilyloxy)benzofuran-2-ylboronic acid
##STR00511##
[2063] To Intermediate 44B (0.48 g, 1.932 mmol) in THF (7.0 mL) at
-78.degree. C. was added 1.6 N n-BuLi in hexanes (1.993 mL, 3.19
mmol) dropwise. The solution turned to brown. The mixture was
stirred at -78.degree. C. for 10 min, followed by addition of
triisopropyl borate (1.346 mL, 5.80 mmol). The mixture was stirred
for 20 min, and the cooling bath was removed to allow warm up to
room temperature over 0.5 h. It was diluted with EtOAc, quenched
with 20 mL of 0.5 N HCl. After stirring at room temperature for 10
min, the organic layer was collected, washed with brine, dried over
sodium sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
silica gel cartridge which was eluted with hexanes for 3 min., then
a 12 min gradient from 0% to 60% EtOAc in hexanes. The desired
fractions were combined, concentrated and lyophilized to give
Intermediate 44C (0.416 g, 1.424 mmol, 73.7% yield) as a white
solid. .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.39 (d,
J=8.8 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.88 (dd,
J=8.8, 2.5 Hz, 1H), 1.03 (s, 9H), 0.22 (s, 6H); LC-MS: Method A, 0
to 100% B. RT=2.30 min, MS (ESI) m/z: 293.1 (M+H).sup.+.
Intermediate 44D:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-ol
##STR00512##
[2065] A mixture of Intermediate I-1G (324 mg, 1.122 mmol),
Intermediate 44C (410 mg, 1.403 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (36.7 mg, 0.045 mmol) in toluene
(6 mL) and EtOH (2.000 mL) was degassed with argon for 2.0 min. To
this solution was added sodium carbonate (2.0 M, 0.982 mL, 1.964
mmol). The mixture was then heated in an oil bath at 85.degree. C.
overnight. The crude reaction mixture was diluted with EtOAc/water.
The organic layer was collected, dried over sodium sulfate. After
evaporation of solvent, the crude product was obtained as brown oil
that solidified when treated with MeOH. It was used for the next
step without further purification.
[2066] To the crude product obtained above (0.55 g, 1.205 mmol) in
MeOH (4.0 mL) and THF (4.00 mL) was added 12 N HCl (1.004 mL, 12.05
mmol). The mixture was stirred at room temperature for 30 min. TLC
indicated ca 40% starting material remaining. Another portion of 12
N HCl (1.004 mL, 12.05 mmol) was added. The reaction was continued
at room temperature for 1.5 h. TLC indicated a clean reaction.
Methanol was removed under vacuum, the crude was diluted with
EtOAc, washed with water and brine. The organic layer was
collected, dried over sodium sulfate. After evaporation of solvent,
the crude product was dissolved in a small amount of chloroform/THF
and charged to a 12 g silica gel cartridge which was eluted with
hexanes for 3 min., then a 10 min gradient from 0% to 60% EtOAc in
hexanes. The desired fractions were combined and concentrated to
give Intermediate 44D (0.423 g, 1.236 mmol, 103% yield) as a yellow
solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.26 (s, 1H),
8.90 (s, 1H), 8.21 (d, J=1.7 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.89
(t, J.sub.HF=71.53 Hz, 1H), 7.75 (dd, J=1.9, 1.1 Hz, 1H), 7.47 (d,
J=8.8 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.84 (dd, J=8.8, 2.5 Hz,
1H), 2.63 (s, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta.
-87.80 (s, 2F); LC-MS: Method A, 0 to 100% B. RT=2.30 min, MS (ESI)
m/z: 343.0 (M+H).sup.+.
Example 44
[2067] To a solution of Intermediate 44D (20 mg, 0.058 mmol) in
acetonitrile (1 mL) was added Cs.sub.2CO.sub.3 (57.1 mg, 0.175
mmol) and (bromomethyl)benzene (100 mg, 0.584 mmol). The mixture
was stirred at 45.degree. C. for 1 h. The mixture was diluted with
1 ml of DMSO and 1 ml of acetonitrile and filtered. The filtrate
was purified with a preparative HPLC (method A, 65-100% B in 8
min.). The desired fractions were placed in a SpeedVac overnight to
remove solvent, then lyophilized to give Example 44 (17 mg, 0.037
mmol, 63.9% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.63 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.66-7.34 (m, 8H), 7.20
(d, J=2.2 Hz, 1H), 7.07-7.02 (m, 1H), 5.14 (s, 2H), 2.64 (s, 3H).
.sup.19F NMR (chloroform-d, 400 MHz):) -90.12 (s, 2F). LC-MS:
method C, RT=2.84 min, MS (ESI) m/z: 433.0 (M+H).sup.+. Analytical
HPLC purity (method A): 100%.
Example 45
2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-2-yl)-7-methylquinoxaline
##STR00513##
[2069] To 2-bromoimidazo[1,2-a]pyridine (17.58 mg, 0.089 mmol) and
Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL)
and EtOH (0.25 mL). The reaction mixture was stirred at room
temperature until solids are dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.83 mg, 7.14 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.059 mL, 2M, 0.119 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 30-100% B in 10 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 45 (6.5 mg, 0.019 mmol, 32.1% yield). .sup.1H NMR (400 MHz,
acetonitrile-d.sub.3) .delta. 8.90 (br. s., 1H), 8.71 (br. s., 1H),
8.58 (d, J=6.8 Hz, 1H), 8.43 (s, 1H), 8.03 (br. s., 1H), 7.50 (s,
2H), 7.31 (t, J=6.8 Hz, 1H), 2.63 (s, 3H). .sup.19F NMR (376 MHz,
acetonitrile-d.sub.3) .delta. -90.60 (br. s., 2F). LC-MS: method C,
RT=1.66 min, MS (ESI) m/z: 327.0 (M+H).sup.+. Analytical HPLC
purity (method A): 99%.
Example 46
Methyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-ylox-
y)ethylcarbamate
##STR00514##
[2070] Intermediate 46A: tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethy-
lcarbamate
##STR00515##
[2072] To a solution of triphenylphosphine (53.6 mg, 0.205 mmol) in
THF (1.0 mL) at 0.degree. C., was added DIAD (0.040 mL, 0.205 mmol)
dropwise. The mixture was stirred at 0.degree. C. for 10 min. A
solution of Intermediate 44D (35 mg, 0.102 mmol) and tert-butyl
(2-hydroxyethyl)carbamate (33.0 mg, 0.205 mmol) in THF (1.0 mL) was
added dropwise. The mixture was stirred at 0.degree. C. to room
temperature for 30 min, then heated up to 55.degree. C. overnight.
After evaporation of solvent, the crude was dissolved in
DMSO/acetonitrile (1.5 mL/1.5 mL) and purified using a preparative
HPLC (method A, 30-100% B in 10 min.). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Intermediate 46A (18 mg, 0.037 mmol, 36.3% yield) as a
yellow lyophilate. .sup.1H NMR (chloroform-d, 400 MHz):
.delta.=8.65 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.40-7.91 (m,
3H), 7.13 (d, J=2.5 Hz, 1H), 6.90-7.03 (m, 1H), 5.05 (br. s., 1H),
4.02-4.20 (m, 2H), 3.59 (br. s., 2H), 2.66 (s, 3H), 1.48 ppm (s,
9H). .sup.19F NMR (chloroform-d, 376 MHz): .delta.=-90.15 ppm (s,
2F). LC-MS: method B, RT=2.58 min, MS (ESI) m/z: 486.1
(M+H).sup.+.
Intermediate 46B
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethan-
amine
##STR00516##
[2074] To a solution of Intermediate 46A (13 mg, 0.027 mmol) in DCM
(2 mL) was added TFA (0.206 mL, 2.68 mmol) and the mixture was
stirred at room temperature overnight. Solvent was removed. The
residual was purified with a preparative HPLC (method A, 30-100% B
in 10 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Intermediate
46B (8 mg, 0.020 mmol, 75% yield). .sup.1H NMR
(acetonitrile-d.sub.3, 400 MHz): .delta.=8.71 (s, 1H), 8.25 (s,
1H), 8.06 (s, 1H), 7.49-7.89 (m, 3H), 7.27 (d, J=2.5 Hz, 1H), 7.03
(dd, J=8.8, 2.5 Hz, 1H), 4.27 (t, J=4.8 Hz, 2H), 3.40 (t, J=4.9 Hz,
2H), 2.65 ppm (s, 3H). .sup.19F NMR (acetonitrile-d.sub.3, 376
MHz): .delta.=-76.15 (br. s., 3F), -90.48 ppm (s, 2F). LC-MS:
method C, RT=2.02 min, MS (ESI) m/z: 386.0 (M+H).sup.+. Analytical
HPLC purity (method A): 98%.
Example 46
[2075] To a suspension of Intermediate 46B (6.5 mg, 0.013 mmol) in
DCM (1 mL) was added Et.sub.3N (9.07 .mu.l, 0.065 mmol) followed by
methyl chloroformate (2.016 .mu.l, 0.026 mmol). The mixture was
stirred at room temperature for 1 h. Solvent was removed and the
residual was purified with a preparative HPLC (method A, 50-100% B
in 8 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Example 46
(4.0 mg, 8.75 .mu.mol, 67.2% yield). .sup.1H NMR
(acetonitrile-d.sub.3, 400 MHz): .delta.=8.71 (s, 1H), 8.25 (d,
J=1.8 Hz, 1H), 8.04 (s, 1H), 7.44-7.91 (m, 3H), 7.23 (d, J=2.5 Hz,
1H), 6.98 (dd, J=8.8, 2.5 Hz, 1H), 4.08 (t, J=5.6 Hz, 2H), 3.61 (s,
3H), 3.50 (q, J=5.7 Hz, 2H), 2.64 ppm (s, 3H). .sup.19F NMR
(acetonitrile-d.sub.3, 376 MHz): .delta.=-90.47 ppm (s, 2F). LC-MS:
method C, RT=2.42 min, MS (ESI) m/z: 444.1 (M+H).sup.+. Analytical
HPLC purity (method A): 98%.
Example 47
5-(1H-benzo[d]imidazol-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
##STR00517##
[2077] To 2-chloro-1H-benzo[d]imidazole (10.89 mg, 0.071 mmol) and
Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL)
and EtOH (0.25 mL). The mixture was stirred at room temperature
until solids are dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.83 mg, 7.14 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.045 mL, 2M, 0.089 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min, then at
140.degree. C. for 20 min. The reaction mixture was cooled to room
temperature and was diluted with EtOAc and water, extracted with
EtOAc (3.times.). The combined organic layer was washed with brine,
dried with MgSO.sub.4 and concentrated. The crude sample was
purified with a preparative HPLC (method A, 20-100% B in 8 min.).
The desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 47 (10 mg, 0.030 mmol,
50.5% yield). .sup.1H NMR (acetonitrile-d.sub.3, 400 MHz):
.delta.=8.85 (d, J=1.5 Hz, 1H), 8.79 (br. s., 1H), 7.46-7.93 (m,
6H), 2.66 ppm (s, 3H). .sup.19F NMR (376 MHz, acetonitrile-d.sub.3)
.delta. -90.69 (s, 2F). LC-MS: method C, RT=1.71 min, MS (ESI) m/z:
327.1 (M+H).sup.+. Analytical HPLC purity (method A): 98%.
Example 48
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazole
##STR00518##
[2079] To 2-chloro-6-methoxybenzo[d]thiazole (14.26 mg, 0.071 mmol)
and Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75
mL) and EtOH (0.25 mL). The mixture was stirred at room temperature
until solids are dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.83 mg, 7.14 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.045 mL, 2M, 0.089 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 65-100% B in 8 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 48 (12.5 mg, 0.033 mmol, 55.1% yield). .sup.1H NMR
(acetonitrile-d.sub.3, 400 MHz): .delta.=8.70-8.83 (m, 2H),
7.95-8.04 (m, 1H), 7.48-7.90 (m, 3H), 7.12-7.21 (m, 1H), 3.90 (s,
3H), 2.69 ppm (s, 3H). .sup.19F NMR (acetonitrile-d.sub.3, 400
MHz):) -90.12 (s, 2F). LC-MS: method C, RT=2.50 min, MS (ESI) m/z:
374.0 (M+H).sup.+. Analytical HPLC purity (method A): 98%.
Example 49
tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5--
yloxy) acetate
##STR00519##
[2081] To a solution of Intermediate 44D (20 mg, 0.058 mmol) in DMF
(1 mL) was added Cs.sub.2CO.sub.3 (57.1 mg, 0.175 mmol) and
tert-butyl 2-bromoacetate (57.0 mg, 0.292 mmol). The mixture was
stirred at 100.degree. C. for 2 h. The mixture was diluted with 1
ml of DMSO and 1 ml of acetonitrile, filtered. The filtrate was
purified with a preparative HPLC (method A, 65-100% B in 6 min.).
The desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 49 (20 mg, 0.043 mmol,
73.5% yield). .sup.1H NMR (chloroform-d, 400 MHz): .delta.=8.64 (s,
1H), 8.23 (d, J=1.5 Hz, 1H), 8.02 (s, 1H), 7.42-7.86 (m, 3H), 7.12
(d, J=2.5 Hz, 1H), 7.01 (dd, J=8.8, 2.5 Hz, 1H), 4.59 (s, 2H), 2.65
(s, 3H), 1.50-1.56 ppm (m, 9H). .sup.19F NMR (chloroform-d, 376
MHz): .delta.=-90.15 ppm (s, 2F). LC-MS: method C, RT=2.61 min, MS
(ESI) m/z: 457.1 (M+H).sup.+. Analytical HPLC purity (method A):
100%.
Example 50
2-(difluoromethoxy)-5-(5-methoxy-1H-benzo[d]imidazol-2-yl)-7-methylquinoxa-
line
##STR00520##
[2083] To 2-chloro-5-methoxy-1H-benzo[d]imidazole (13.04 mg, 0.071
mmol) and Intermediate I-1 (20 mg, 0.059 mmol) was added toluene
(0.75 mL) and EtOH (0.25 mL). The reaction mixture was stirred at
room temperature until solids are dissolved, then
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.83 mg, 7.14 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.059 mL, 2M, 0.119 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 140.degree. C. for 30 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 30-100% B in 8 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 50 (6 mg, 0.016 mmol, 27.5% yield). .sup.1H NMR
(acetonitrile-d.sub.3, 400 MHz): .delta.=8.77 (br. s., 2H), 7.70
(s, 3H), 7.27-7.39 (m, 1H), 7.05-7.18 (m, 1H), 3.90 (s, 3H), 2.65
ppm (s, 3H). .sup.19F NMR (acetonitrile-d.sub.3, 376 MHz):
.delta.=-76.64 (br. s., 3F), -90.69 ppm (s, 2F). LC-MS: method C,
RT=1.78 min, MS (ESI) m/z: 357.0 (M+H).sup.+. Analytical HPLC
purity (method A): 98%
Example 51
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzo[d]thiazole
##STR00521##
[2084] Intermediate 51A: 2-bromo-4-methoxybenzo[d]thiazole
##STR00522##
[2086] To a suspension of 4-methoxybenzo[d]thiazol-2-amine (2.5 g,
13.87 mmol) and p-TSA monohydrate (7.92 g, 41.6 mmol) in
acetonitrile (80 mL) at 10.degree. C. (cooled with ice water) was
added dropwise a solution of sodium nitrite (1.914 g, 27.7 mmol)
and potassium bromide (4.13 g, 34.7 mmol) in water (5 ml) over a
period of 25 min. The reaction mixture was stirred at 10.degree. C.
for 10 min, and allowed to warm up to room temperature and stirred
for 2.0 h. HPLC indicated a completion of reaction. To the reaction
mixture was added sodium bicarbonate (pH to 9.0), water and EtOAc.
The organic layer was collected, washed with water, saturated
Na.sub.2S.sub.2O.sub.3, water, brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform and charged to a 120 g silica gel
cartridge which was eluted with hexanes for 4 min., then an 18 min
gradient from 0% to 40% EtOAc in hexanes. The desired fractions
were combined and concentrated to give Intermediate 51A (2.51 g,
10.28 mmol, 74.1% yield) as a slightly yellow solid. .sup.1H NMR
(500 MHz, chloroform-d) .delta. 7.40-7.37 (m, 2H), 6.92 (dd, J=6.3,
2.5 Hz, 1H), 4.06 (s, 3H); LC-MS: method A, RT=1.79 min, MS (ESI)
m/z: 244.0 and 246.0 (M+H).sup.+.
Example 51
[2087] To Intermediate 51A (10 mg, 0.041 mmol) and Intermediate I-1
(20.66 mg, 0.061 mmol) was added toluene (0.75 mL) and EtOH (0.25
mL). The mixture was stirred at room temperature until solids are
dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (4.01 mg, 4.92 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.031 mL, 2M, 0.061 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min. LCMS
indicated a completion of the reaction. The reaction mixture was
cooled to room temperature and was diluted with EtOAc and water,
extracted with EtOAc (3.times.). The combined organic layer was
washed with brine, dried with MgSO.sub.4 and concentrated. The
crude sample was purified with a preparative HPLC (method A,
50-100% B in 8 min.). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Example 51 (2.5 mg, 6.43 .mu.mol, 15.69% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.93 (d, J=1.65 Hz, 1H), 8.71 (s, 1H),
7.80 (s, 1H), 7.58 (d, J=8.25 Hz, 1H), 7.47-7.86 (m, 1H), 7.39 (t,
J=7.97 Hz, 1H), 6.96 (d, J=7.70 Hz, 1H), 4.13 (s, 3H), 2.68 (s,
3H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -89.62 (s, 2F).
LC-MS: method C, RT=2.45 min, MS (ESI) m/z: 374.0 (M+H).sup.+.
Analytical HPLC purity (method A): 97%.
Example 52
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
##STR00523##
[2088] Intermediate 52A: 2-bromo-4-methylbenzo[d]thiazole
##STR00524##
[2090] To a white suspension of 4-methylbenzo[d]thiazol-2-amine
(0.5 g, 3.04 mmol) and p-TSA monohydrate (1.737 g, 9.13 mmol) in
acetonitrile (20 mL) at 10.degree. C. (cooled with ice water) was
added dropwise a solution of sodium nitrite (0.420 g, 6.09 mmol)
and potassium bromide (0.906 g, 7.61 mmol) in water (5 mL) over a
period of 25 min. The reaction mixture was stirred at 10.degree. C.
for 10 min, and allowed to warm up to room temperature and stirred
for 1.0 h. To the reaction mixture was added sodium bicarbonate (pH
to 9.0), water and EtOAc. The organic layer was collected, washed
with water, saturated Na.sub.2S.sub.2O.sub.3, water, brine, dried
over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform and charged
to a 40 g ISCO column which was eluted with hexanes for 2 min.,
then a 20 min gradient from 0% to 40% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 52A
(640 mg, 2.81 mmol, 92% yield) as a yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.62 (td, J=0.69, 7.71 Hz, 1H),
7.21-7.34 (m, 3H), 2.71 (s, 3H). LC-MS: method C, RT=2.11 min, MS
(ESI) m/z: 227.0 and 229.0 (M+H).sup.+.
Example 52
[2091] To Intermediate 52A (17 mg, 0.074 mmol) and Intermediate I-1
(30 mg, 0.089 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL).
The mixture was stirred at room temperature until solids are
dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.29 mg, 8.92 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.056 mL, 2M, 0.112 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 65-100% B in 8 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 52 (11.5 mg, 0.031 mmol, 41.5% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.86 (d, J=1.52 Hz, 1H), 8.71 (s, 1H),
7.47-7.90 (m, 3H), 7.30-7.36 (m, 2H), 2.90 (s, 3H), 2.72 (s, 3H).
.sup.19F NMR (400 MHz, chloroform-d) .delta. -90.12 (s, 2F). LC-MS:
method C, RT=2.68 min, MS (ESI) m/z: 358.0 (M+H).sup.+. Analytical
HPLC purity (method A): 98%.
Example 53
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazole
##STR00525##
[2092] Intermediate 53A: 2-bromo-4-fluorobenzo[d]thiazole
##STR00526##
[2094] To a suspension of 4-fluorobenzo[d]thiazol-2-amine (0.52 g,
3.09 mmol) and p-TSA monohydrate (1.764 g, 9.28 mmol) in
acetonitrile (20 mL) at 10.degree. C. (cooled with ice water) was
added dropwise a solution of sodium nitrite (0.427 g, 6.18 mmol)
and potassium bromide (0.920 g, 7.73 mmol) in water (5 mL) over a
period of 25 min. The reaction mixture was stirred at 10.degree. C.
for 10 min, and allowed to warm up to room temperature and stirred
for 1.0 h. To the reaction mixture was added sodium bicarbonate (pH
to 9.0), water and EtOAc. The organic layer was collected, washed
with water, saturated Na.sub.2S.sub.2O.sub.3, water, brine, dried
over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform and charged
to a 40 g ISCO column which was eluted with hexanes for 2 min.,
then a 20 min gradient from 0% to 40% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 53A
(640 mg, 2.76 mmol, 89% yield) as a yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.59 (dd, J=0.76, 8.08 Hz, 1H), 7.40
(dt, J=4.55, 8.08 Hz, 1H), 7.20 (ddd, J=1.01, 8.08, 10.11 Hz, 1H).
LC-MS: method C, RT=1.84 min, MS (ESI) m/z: 231.9 and 233.9
(M+H).sup.+.
Example 53
[2095] To Intermediate 53A (17.26 mg, 0.074 mmol) and Intermediate
I-1 (30 mg, 0.089 mmol) was added toluene (0.75 mL) and EtOH (0.25
mL). The mixture was stirred at room temperature until solids are
dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.29 mg, 8.92 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.056 mL, 2M, 0.112 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 50-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 53 (15.0 mg, 0.039 mmol, 53.0% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.92 (d, J=1.77 Hz, 1H), 8.71 (s, 1H),
7.84 (dd, J=0.88, 1.89 Hz, 1H), 7.76 (dd, J=0.88, 7.96 Hz, 1H),
7.48-7.87 (m, 1H), 7.39 (dt, J=4.67, 8.02 Hz, 1H), 7.23 (ddd,
J=1.01, 7.96, 10.48 Hz, 1H), 2.71 (s, 3H). .sup.19F NMR (400 MHz,
chloroform-d) -90.12 (s, 2F). LC-MS: method C, RT=2.53 min, MS
(ESI) m/z: 362.0 (M+H).sup.+. Analytical HPLC purity (method A):
96%.
Example 54
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)-N-me-
thylethanamine
##STR00527##
[2096] Intermediate 54A: tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethy-
l(methyl)carbamate
##STR00528##
[2098] A solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate
(41.0 mg, 0.234 mmol) and DIAD (0.057 mL, 0.292 mmol) in THF (1.0
mL) was added to a mixture of Intermediate 44D (20 mg, 0.058 mmol)
and triphenylphosphine (30.7 mg, 0.117 mmol) in THF (2 mL) at
80.degree. C. using a syringe pump over 4 h. The mixture was
stirred at 80.degree. C. for 1 h. Solvent was removed, the residual
was dissolved in 1 ml of DMF. The crude material was purified via
preparative LC/MS (method D, 65-85% B over 10 min., then an 8-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Intermediate
54A (14.8 mg, 0.028 mmol, 47.2% yield). .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.61 (s, 1H), 8.18 (d, J=1.38 Hz, 1H),
7.97 (s, 1H), 7.62 (s, 1H), 7.49-7.83 (m, 1H), 7.42 (d, J=8.80 Hz,
1H), 7.11 (d, J=2.48 Hz, 1H), 6.92 (dd, J=2.48, 8.80 Hz, 1H), 4.15
(t, J=5.50 Hz, 2H), 3.63 (t, J=5.23 Hz, 2H), 2.99 (s, 3H), 2.61 (s,
3H), 1.45 (s, 9H). LC-MS: method C, RT=2.69 min, MS (ESI) m/z:
500.2 (M+H).sup.+.
Example 54
[2099] To a solution of Intermediate 54A (9 mg, 0.018 mmol) in DCM
(1 mL) was added TFA (1 ml). The mixture was stirred at room
temperature for 1h. Solvent was removed and the crude sample was
purified with preparative HPLC (method A, 30-100% B in 6 min.). The
desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 54 (7 mg, 0.013 mmol,
74.9% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.68
(s, 1H), 8.23 (d, J=1.77 Hz, 1H), 8.06 (s, 1H), 7.70 (s, 1H),
7.56-7.97 (m, 1H), 7.52 (d, J=8.84 Hz, 1H), 7.29 (d, J=2.53 Hz,
1H), 7.07 (dd, J=2.65, 8.97 Hz, 1H), 4.28-4.38 (m, 2H), 3.45-3.58
(m, 2H), 2.83 (s, 3H), 2.64 (s, 3H). .sup.19F NMR (376 MHz,
methanol-d.sub.3) .delta. -76.92 (br. s., 3F), -95.23-88.19 (m,
2F). LC-MS: method C, RT=2.02 min, MS (ESI) m/z: 400.0 (M+H).sup.+.
Analytical HPLC purity (method A): 99%
Example 55
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiaz-
ole
##STR00529##
[2100] Intermediate 55A:
2,7-dibromo-4,6-dimethoxybenzo[d]thiazole
##STR00530##
[2102] To a mixture of 4,6-dimethoxybenzo[d]thiazol-2-amine (0.5 g,
2.378 mmol) and p-TSA monohydrate (1.357 g, 7.13 mmol) in
acetonitrile (20 mL) at 10.degree. C. (cooled with ice water) was
added dropwise a solution of sodium nitrite (0.328 g, 4.76 mmol)
and potassium bromide (0.707 g, 5.95 mmol) in water (5 mL) over a
period of 25 min. The reaction mixture was stirred at 10.degree. C.
for 10 min, and allowed to warm up to room temperature and stirred
for 1.0 h. The mixture was turned to a clear brown solution. To the
reaction mixture was added sodium bicarbonate (pH to 9.0), water
and EtOAc. The organic layer was collected, washed with water,
saturated Na.sub.2S.sub.2O.sub.3, water, brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
ISCO column which was eluted with hexanes for 2 min., then a 20 min
gradient from 0% to 40% EtOAc in hexanes. The desired fraction was
collected and concentrated to Intermediate 55A (110 mg, 13% yield).
.sup.1H NMR (400 MHz, chloroform-d) .delta. 6.60 (s, 1H), 4.06 (s,
3H), 3.98 (s, 3H). LC-MS: method C, RT=2.18 min, MS (ESI) m/z: 351
353 and 355 (M+H).sup.+.
Intermediate 55B
7-bromo-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo-
[d]thiazole
##STR00531##
[2104] To Intermediate 55A (26 mg, 0.074 mmol) and Intermediate I-1
(30 mg, 0.088 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL).
The mixture was stirred at room temperature until solids are
dissolved, then [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium (II) complex with dichloromethane (1:1)
(4.81 mg, 5.89 .mu.mol) was added. The flask was degassed and
flushed with argon. Finally sodium carbonate (0.055 mL, 2M, 0.110
mmol) was added dropwise. The reaction vessel was sealed and
bubbled with argon for 5 min, then placed in microwave reactor at
100.degree. C. for 2h. The reaction mixture was cooled to room
temperature and was diluted with EtOAc and water, extracted with
EtOAc (3.times.). The combined organic layer was washed with brine,
dried with MgSO.sub.4 and concentrated. The crude sample was
purified with a preparative HPLC (method A, 70-100% B in 6 min.).
The desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Intermediate 55B (8 mg, 0.016
mmol, 22.07% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.85 (d, J=1.77 Hz, 1H), 8.73 (s, 1H), 7.79 (dd, J=0.88, 1.90 Hz,
1H), 7.47-7.89 (m, 1H), 6.68 (s, 1H), 4.15 (s, 3H), 4.04 (s, 3H),
2.67 (s, 3H). .sup.19F NMR (400 MHz, chloroform-d) -90.12 (s, 2F).
LC-MS: method C, RT=2.56 min, MS (ESI) m/z: 481.9 and 484.0
(M+H).sup.+.
Example 55
[2105] To a solution of Intermediate 55B (6 mg, 0.012 mmol) in
ethyl acetate (5 ml) was added Pd/C (5 mg) and TEA (10.40 .mu.l,
0.075 mmol) and the mixture was stirred under a hydrogen balloon at
50.degree. C. for 2 h. The reaction mixture was cooled to room
temperature and filtered. The filtrate was concentrated. The crude
material was purified via preparative LC/MS (method D, 45-90% B
over 10 min., then a 10-min hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to Example 55 (0.2 mg, 0.496 .mu.mol, 3.99% yield).
.sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.76 (d, J=1.65 Hz,
1H), 8.67 (s, 1H), 7.77 (d, J=0.83 Hz, 1H), 7.48-7.85 (m, 1H), 7.03
(s, 1H), 6.59 (d, J=2.20 Hz, 1H), 4.05 (s, 3H), 3.89 (s, 3H).
LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 404 (M+H).sup.+.
Analytical HPLC purity (method A): 100%.
Example 56
2-methoxy-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline
##STR00532##
[2106] Intermediate 56A: 5-methoxybenzofuran-2-ylboronic acid
##STR00533##
[2108] To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL)
at -78.degree. C. was added 1.6 N n-BuLi in hexanes (1.190 mL,
1.903 mmol) dropwise. The solution turned to slightly yellow. The
mixture was stirred at -78.degree. C. for 20 min, followed by
addition of triisopropyl borate (0.737 mL, 3.17 mmol). The mixture
was stirred for 30 min, and the cooling bath was removed to allow
warm up to room temperature over 1.5 h. It was diluted with EtOAc,
quenched with 3.0 mL of 1.0 N HCl. After stirring at room
temperature for 25 min, the organic layer was collected, washed
with brine, dried over sodium sulfate. After evaporation of
solvent, the crude product was dissolved in a small amount of
chloroform with a drop of MeOH, and charged to a 4 g silica gel
cartridge which was eluted with hexanes for 2 min., then a 10 min
gradient from 0% to 60% EtOAc in hexanes. The desired fractions
were combined, concentrated and lyophilized to give Intermediate
56A (170 mg, 0.886 mmol, 69.8% yield) as a white solid. .sup.1H NMR
(500 MHz, methanol-d.sub.4) .delta. 7.41 (d, J=9.1 Hz, 1H), 7.30
(s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz, 1H), 3.84
(s, 3H); LC-MS: method A, RT=1.45 min, MS (ESI) m/z: 149.0
(M-B(OH).sub.2).sup.+.
Example 56
[2109] To Intermediate I-9A (20 mg, 0.079 mmol) and Intermediate
56A (20.48 mg, 0.107 mmol) was added toluene (0.75 mL) and EtOH
(0.250 mL). The reaction mixture was stirred at room temperature
until solids are dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (5.16 mg, 6.32 .mu.mol) was added. The
flask was degassed and flushed with argon. Finally sodium carbonate
(0.079 mL, 2M, 0.158 mmol) was added dropwise. The reaction vessel
was sealed and bubbled with argon for 5 min, then placed in
microwave reactor at 120.degree. C. for 30 min. The reaction
mixture was cooled to room temperature and was diluted with EtOAc
and water, extracted with EtOAc (3.times.). The combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude material was purified via preparative LC/MS
(method D, 55-90% B over 10 min., then a 10-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to yield Example 56 (13.7 mg, 0.043
mmol, 54.1% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.47 (s, 1H), 8.06 (d, J=1.93 Hz, 1H), 7.94 (d, J=0.83 Hz, 1H),
7.56-7.65 (m, 2H), 7.41 (d, J=9.08 Hz, 1H), 7.11 (d, J=2.48 Hz,
1H), 6.90 (dd, J=2.48, 8.80 Hz, 1H), 4.09 (s, 3H), 3.85 (s, 3H),
2.59 (s, 3H). LC-MS: method C, RT=2.63 min, MS (ESI) m/z: 321
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 58
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxybenzo[d]thiazole
##STR00534##
[2111] To Intermediate 15F (15 mg, 0.075 mmol) and Intermediate I-1
(30.3 mg, 0.090 mmol) was added toluene (0.75 mL) and EtOH (0.25
mL). The mixture was stirred at room temperature until solids are
dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.36 mg, 9.02 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.056 mL, 2M, 0.113 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 30 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 65-100% B in 8 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 58 (10.5 mg, 0.028 mmol, 37.1% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.84 (d, J=1.52 Hz, 1H), 8.72 (s, 1H),
7.81-7.83 (m, 1H), 7.79 (dd, J=0.63, 8.21 Hz, 1H), 7.45-7.87 (m,
2H), 6.88 (d, J=7.83 Hz, 1H), 4.07 (s, 3H), 2.70 (s, 3H). .sup.19F
NMR (400 MHz, chloroform-d) -90.12 (s, 2F). LC-MS: method C,
RT=2.50 min, MS (ESI) m/z: 374.0 (M+H).sup.+. Analytical HPLC
purity (method A): 99%.
Example 59
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluoro-6-methoxy
benzo[d]thiazole
##STR00535##
[2112] Intermediate 59A:
4-fluoro-6-methoxybenzo[d]thiazol-2-amine
##STR00536##
[2114] To 2-fluoro-4-methoxyaniline (636 mg, 4.51 mmol) in
acetonitrile (14 mL) was added ammonium thiocyanate (515 mg, 6.76
mmol). The mixture was stirred at room temperature for 10 min. Then
it was cooled with tape water, and benzyltrimethylammonium
tribromide (1757 mg, 4.51 mmol) in acetonitrile (5.0 mL) was added
dropwise (10 min). The mixture was then stirred at room temperature
overnight. The mixture was diluted with EtOAc/saturated sodium
bicarbonate. The organic layer was collected, washed with brine,
dried over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform/a small
amount of MeOH and charged to a 40 g silica gel cartridge which was
eluted with 5% EtOAc in hexanes for 3 min., then a 12 min gradient
from 5% to 75% EtOAc in hexanes. The desired fractions were
combined and concentrated to give Intermediate 59A (0.65 g, 3.28
mmol, 72.8% yield) as a pale solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 6.84 (d, J=1.7 Hz, 1H), 6.75 (br. s., 2H),
6.55 (dd, J=12.1, 2.2 Hz, 1H), 3.74-3.72 (m, 3H); .sup.19F NMR (471
MHz, DMSO-d.sub.6) .delta. -124.96 (s, 1F); LC-MS: method A,
RT=1.17 min, MS (ESI) m/z: 199.0 (M+H).
Intermediate 59B: 2-bromo-4-fluoro-6-methoxybenzo[d]thiazole
##STR00537##
[2116] To a suspension of Intermediate 59A (0.32 g, 1.614 mmol) in
acetonitrile (15 mL) was added p-TSA monohydrate (0.983 g, 5.17
mmol). The salt formed was stirred at room temperature for 15 min,
and at 10.degree. C. (cooled with ice water) for 5 min, followed by
dropwise addition of a solution of sodium nitrite (0.223 g, 3.23
mmol) and potassium bromide (0.480 g, 4.04 mmol) in water (5 mL)
over a period of 2 min. The reaction mixture was stirred at from
10.degree. C. to room temperature overnight. The reaction was
quenched with saturated sodium bicarbonate. The insoluble material
was removed by filtration. The filtrate was extracted with EtOAc.
The organic layer was washed with brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform and charged to a 12 g silica gel
cartridge which was eluted with hexanes for 2 min., then a 15 min
gradient from 0% to 30% EtOAc in hexanes. The desired fractions
were combined and concentrated to give Intermediate 59B (0.15 g,
0.572 mmol, 35.5% yield) as a pale yellow solid. .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.07 (dd, J=2.2, 0.8 Hz, 1H), 6.84 (dd,
J=11.6, 2.2 Hz, 1H), 3.89 (s, 3H); .sup.19F NMR (471 MHz,
chloroform-d) .delta. -119.63 (s, 1F); LC-MS: method A, RT=1.87
min, MS (ESI) m/z: 262.0 and 264.0 (M+H).sup.+.
Example 59
[2117] To Intermediate 59B (15 mg, 0.057 mmol) and Intermediate I-1
(23.08 mg, 0.069 mmol) was added toluene (0.75 mL) and EtOH (0.25
mL). The mixture was stirred at room temperature until solids are
dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.61 mg, 6.87 .mu.mol) was
added. The flask was degassed and flushed with argon. Finally
sodium carbonate (0.043 mL, 2M, 0.086 mmol) was added dropwise. The
reaction vessel was sealed and bubbled with argon for 5 min, then
placed in microwave reactor at 120.degree. C. for 40 min. The
reaction mixture was cooled to room temperature and was diluted
with EtOAc and water, extracted with EtOAc (3.times.). The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 60-100% B in 8 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 59 (8.5 mg, 0.022 mmol, 37.9% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.86 (d, J=1.52 Hz, 1H), 8.70 (s, 1H), 7.81
(d, J=0.76 Hz, 1H), 7.45-7.97 (m, 1H), 7.22 (d, J=2.27 Hz, 1H),
6.88 (dd, J=2.15, 11.75 Hz, 1H), 3.92 (s, 3H), 2.69 (s, 3H).
.sup.19F NMR (376 MHz, chloroform-d) .delta. -90.22 (s, 2F),
-121.48 (br. s., 1F). LC-MS: method C, RT=2.53 min, MS (ESI) m/z:
391.9 (M+H).sup.+. Analytical HPLC purity (method A): 100%.
Example 60
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazole
##STR00538##
[2119] To 2-chloro-5-fluorobenzo[d]thiazole (15 mg, 0.080 mmol) and
Intermediate I-1 (32.2 mg, 0.096 mmol) was added toluene (0.75 mL)
and EtOH (0.25 mL). The mixture was stirred at room temperature
until solids are dissolved, then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.83 mg, 9.59 .mu.mol) was
added. The flask was degassed and flushed with Ar. Finally sodium
carbonate (2M, 0.12 mL, 0.24 mmol) was added dropwise. The reaction
vessel was sealed and bubbled with argon for 5 min, then placed in
microwave reactor at 120.degree. C. for 40 min. The reaction
mixture was cooled to room temperature and was diluted with EtOAc
and water, extracted with EtOAc (3.times.). The combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude material was purified via preparative LC/MS
(method D, 60-100% B over 10 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to yield Example 60 (18.8 mg, 0.052
mmol, 65.1% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.96 (s, 1H), 8.75 (d, J=1.65 Hz, 1H), 8.15 (dd, J=4.81, 8.94 Hz,
1H), 8.09 (dd, J=2.48, 8.53 Hz, 1H), 7.93 (s, 1H), 7.73-8.04 (m,
1H), 7.44 (dt, J=2.75, 9.08 Hz, 1H), 2.67 (s, 3H). LC-MS: method C,
a=2.54 min, MS (ESI) m/z: 361.9 (M+H).sup.+. Analytical HPLC purity
(method A): 100%.
Example 61
Methyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole-7-c-
arboxylate
##STR00539##
[2120] Intermediate 61A: methyl
2-bromobenzo[d]thiazole-7-carboxylate
##STR00540##
[2122] tert-Butyl nitrite (1.111 mL, 8.40 mmol) was added to copper
(II) bromide (1.770 g, 7.92 mmol) in dry acetonitrile (15 mL) under
argon. The mixture was stirred at room temperature for 10 min. A
suspension of methyl 2-aminobenzo[d]thiazole-7-carboxylate (1.0 g,
4.80 mmol) in dry acetonitrile (15 mL) was added dropwise. The
reaction mixture was stirred at room temperature for 1.5 h. The
mixture was heated at 50.degree. C. for 45 min. Acetonitrile was
removed under vacuum, the reaction mixture was diluted with EtOAc,
quenched with 1.0 N HCl. The organic layer was collected, washed
with 0.5 N HCl (2.times.), saturated sodium bicarbonate, brine,
dried over sodium sulfate. After evaporation of solvent,
Intermediate 61A (1.2 g, 4.41 mmol, 92% yield) was obtained as
brown solid. It was used for next step without further
purification. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.19 (dd,
J=8.0, 1.1 Hz, 1H), 8.13 (dd, J=7.7, 1.1 Hz, 1H), 7.58 (t, J=7.8
Hz, 1H), 4.05 (s, 3H); LC-MS: method A, RT=2.02 min, MS (ESI) m/z:
272.0 274.0 (M+H).sup.+.
Example 61
[2123] To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 61A
(31.6 mg, 0.116 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.83 mg, 7.14 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (0.098 mL, 2M, 0.196 mmol). The reaction mixture was
heated in a microwave reactor at 120.degree. C. for 30 min. To the
reaction mixture was added EtOAc/water. The organic layers were
collected, dried over sodium sulfate. After evaporation of solvent,
the crude product was purified via preparative LC/MS (method D,
55-95% B over 10 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to yield Example 61 (2.9 mg, 7.08 .mu.mol,
7.93%). .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta. 8.73 (s,
1H), 8.71 (d, J=1.65 Hz, 1H), 8.30 (dd, J=0.83, 7.98 Hz, 1H), 8.15
(dd, J=0.83, 7.43 Hz, 1H), 7.84 (s, 1H), 7.61 (t, J=7.70 Hz, 1H),
7.52-7.82 (m, 1H), 4.05 (s, 3H), 2.68 (s, 3H). LC-MS: method C,
RT=2.41 min, MS (ESI) m/z: 402.10 (M+H).sup.+. Analytical HPLC
purity (method B): 98%
Example 62
Methyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo-
[5,4-c]pyridine-5(4H)-carboxylate
##STR00541##
[2124] Intermediate 62A
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrothiazolo-
[5,4-c]pyridine
##STR00542##
[2126] To Example 11 (19 mg, 0.042 mmol) was added 4.0 N HCl in
dioxane (1059 .mu.l, 4.24 mmol). The mixture was aged at room
temperature for 2.0 h. Solvent was removed and the product was
lyophilized overnight to give Intermediate 62A (14 mg, 0.034 mmol,
81% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.65
(s, 1H), 8.61 (s, 1H), 7.82 (s, 1H), 7.65 (t, J.sub.HF=71.53 Hz,
1H), 4.56 (br. s., 2H), 3.77-3.73 (m, 2H), 3.72-3.68 (m, 2H), 2.66
(s, 3H); .sup.19F NMR (471 MHz, methanol-d.sub.4) .delta. -90.23
(s, 2F); LC-MS: method A, RT=1.70 min, MS (ESI) m/z: 349.0
(M+H).sup.+.
Example 62
[2127] To a solution of Intermediate 62A (9 mg, 0.026 mmol) and
DIEA (0.023 mL, 0.129 mmol) in DCM (1 mL) was added a solution of
methyl chloroformate (4.00 .mu.l, 0.052 mmol) in DCM (1 mL). The
mixture was stirred at room temperature for 1.0 h. The reaction
mixture was diluted with EtOAc and water, extracted with EtOAc. The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The crude was purified with a preparative HPLC
(method A, 60-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 62 (8 mg, 0.018 mmol, 68.6% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.63 (s, 1H), 8.55 (s, 1H), 7.74 (s, 1H),
7.40-7.97 (m, 1H), 4.82 (br. s., 2H), 3.88 (br. s., 2H), 3.79 (s,
3H), 3.05 (br. s., 2H), 2.64 (s, 3H). .sup.19F NMR (376 MHz,
chloroform-d) .delta. -90.20 (s, 2F). LC-MS: method C, RT=2.43 min,
MS (ESI) m/z: 406.9 (M+H).sup.+. Analytical HPLC purity (method A):
92%.
Example 63
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ylo-
xy)ethyl) benzenesulfonamide
##STR00543##
[2129] To a solution of Intermediate I-4 (12 mg, 0.027 mmol) and
DIEA (23.88 .mu.l, 0.137 mmol) in DCM (2 ml) was added a solution
of benzenesulfonyl chloride (9.66 mg, 0.055 mmol) in 0.2 ml of DCM.
The mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with EtOAc and water, extracted with EtOAc. The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The crude sample was purified with a preparative
HPLC (method A, 50-100% B in 6 min.). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Example 63 (10 mg, 0.018 mmol, 64.7% yield). .sup.1H NMR
(400 MHz, acetonitrile-d.sub.3) .delta. 8.90-8.58 (m, 2H), 7.95 (d,
J=8.8 Hz, 1H), 7.90-7.50 (m, 7H), 7.05 (dd, J=8.8, 2.5 Hz, 1H),
5.97 (br. s., 1H), 4.06 (t, J=5.3 Hz, 2H), 3.33 (q, J=5.6 Hz, 2H),
2.68 (s, 3H). .sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta.
-90.50 (s, 2F). LC-MS: method C, RT=2.39 min, MS (ESI) m/z: 543.0
(M+H).sup.+. Analytical HPLC purity (method A): 96%.
Example 64
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)metha-
nol
##STR00544##
[2130] Intermediate 64A: (2-bromobenzo[d]thiazol-7-yl)methanol
##STR00545##
[2132] To a solution of Intermediate 61A (0.53 g, 1.948 mmol) in
THF (10 mL) at 0.degree. C. was added 1.0 M Super-H in THF (4.28
mL, 4.28 mmol) dropwise. The mixture was stirred at 0.degree. C.
for 1.0 h. The reaction mixture was diluted with EtOAc, quenched
with saturated ammonium chloride at 0.degree. C., and then with a
few drops of 1.0 N HCl. The organic layer was washed with brine,
dried over sodium sulfate. After evaporation of solvent, the crude
product was dissolved in a small amount of chloroform and was
purified with 40 g ISCO column eluted with hexanes for 3 min, then
an 18 min gradient from 0 to 100% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 64A
(380 mg, 1.557 mmol, 80% yield) as a light yellow solid. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 7.80 (d, J=8.08 Hz, 1H),
7.44 (t, J=7.71 Hz, 1H), 7.31 (d, J=7.33 Hz, 1H), 4.83 (s, 2H).
LC-MS: method C, RT=1.58 min, MS (ESI) m/z: 243 and 245
(M+H).sup.+.
Example 64
[2133] To Intermediate I-1 (106 mg, 0.315 mmol), Intermediate 64A
(100 mg, 0.410 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (20.59 mg, 0.025 mmol) was added
toluene (7.5 mL) and EtOH (2.500 mL). The mixture was sonicated for
1 min, and flushed with argon. To this was added sodium carbonate
(0.315 mL, 2M, 0.630 mmol). The reaction mixture was heated in a
microwave reactor at 120.degree. C. for 30 min. The reaction
mixture was diluted with EtOAc and water, extracted with EtOAc
(3.times.). The combined organic layer was washed with brine, dried
with MgSO.sub.4 and concentrated. The crude sample was purified 12
g ISCO column eluted with 0-100% EtOAc in hexanes for 15 min.,
followed by a preparative HPLC (method A, 30-100% B in 8 min.). The
desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 64 (88 mg, 0.261 mmol,
83% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.76
(s, 1H), 8.02 (d, J=8.25 Hz, 1H), 7.88 (dd, J=1.10, 1.93 Hz, 1H),
7.62-7.94 (m, 1H), 7.50-7.58 (m, 1H), 7.43 (dd, J=0.96, 7.29 Hz,
1H), 4.94 (s, 2H), 2.69 (s, 3H). .sup.19F NMR (376 MHz,
methanol-d.sub.4) .delta. -91.06 (s, 2F). LC-MS: method C, RT=2.24
min, MS (ESI) m/z: 373.9 (M+H).sup.+. Analytical HPLC purity
(method A): 98%.
Example 65
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(methoxymethyl)benzo[d]t-
hiazole
##STR00546##
[2135] To a suspension of Example 64 (18 mg, 0.048 mmol) in THF (1
mL) was added NaH (3.86 mg, 0.096 mmol) and the mixture was stirred
at room temperature for 30 min Then Met (0.090 mL, 1.446 mmol) was
added. The mixture was heated up to 50.degree. C. for 2 h. The
mixture was diluted with EtOAc and water, extracted with EtOAc. The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The crude was purified with a preparative HPLC
(method A, 50-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 65 (2 mg, 5.06 .mu.mol, 10.49% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.82 (d, J=2.02 Hz, 1H), 8.75 (s, 1H),
8.13 (d, J=8.08 Hz, 1H), 7.84 (s, 1H), 7.48-7.88 (m, 2H), 7.39 (d,
J=7.33 Hz, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.70 (s, 3H). .sup.19F
NMR (376 MHz, chloroform-d) .delta. -90.20 (s, 2F). LC-MS: method
C, RT=2.45 min, MS (ESI) m/z: 387.9 (M+H).sup.+. Analytical HPLC
purity (method A): 99%.
Example 66
N-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)me-
thyl)benzenesulfonamide
##STR00547##
[2136] Intermediate 66A: tert-butyl
N-[(2-bromo-1,3-benzothiazol-7-yl)methyl]-N-[(tert-butoxy)carbonyl]carbama-
te
##STR00548##
[2138] A solution of DIAD (0.134 mL, 0.688 mmol) in THF (2 mL) was
added to a solution of di-tert-butyl iminodicarboxylate (150 mg,
0.688 mmol), Intermediate 64A (56 mg, 0.229 mmol) and
triphenylphosphine (181 mg, 0.688 mmol) in THF (2 mL). The mixture
was stirred at room temperature for 1 h, diluted with DCM and
saturated NaHCO.sub.3, extracted with DCM, the combined organic
layer was washed with brine, dried MgSO.sub.4 and concentrated. The
crude sample was purified with 40 g ISCO column eluted with 0-100%
DCM/Hex for 20 min, the desired fraction was collected to give
Intermediate 66A (55 mg, 0.124 mmol, 54.1% yield) as a yellow
solid. .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.90 (d, J=7.98
Hz, 1H), 7.45 (t, J=7.84 Hz, 1H), 7.30 (dd, J=0.83, 7.43 Hz, 1H),
4.98 (s, 2H), 1.41-1.46 (m, 18H). LC-MS: method C, RT=2.37 min, MS
(ESI) m/z: 908.9 [2M+23].sup.+.
Intermediate 66B: tert-butyl
N-[(tert-butoxy)carbonyl]-N-({2-[2-(difluoromethoxy)-7-methylquinoxalin-5--
yl]-1,3-benzothiazol-7-yl}methyl)carbamate
##STR00549##
[2140] To Intermediate I-1 (37.9 mg, 0.113 mmol), Intermediate 66A
(50 mg, 0.113 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.37 mg, 9.02 .mu.mol) was
added toluene (7.5 mL) and EtOH (2.500 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.113 mL, 2M, 0.226 mmol). The reaction mixture
was heated in a microwave reactor at 120.degree. C. for 30 min. The
reaction mixture was diluted with EtOAc and water, extracted with
EtOAc. The combined organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated. The crude sample was purified with a
preparative HPLC (method A, 70-100% B in 6 min.). The desired
fractions were placed in a SpeedVac overnight to remove solvent,
then lyophilized to give Intermediate 66B (21 mg, 0.035 mmol, 30.9%
yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.76 (s,
1H), 8.02 (d, J=8.25 Hz, 1H), 7.88 (dd, J=1.10, 1.93 Hz, 1H),
7.62-7.94 (m, 1H), 7.50-7.58 (m, 1H), 7.43 (dd, J=0.96, 7.29 Hz,
1H), 4.94 (s, 2H), 2.69 (s, 3H). .sup.19F NMR (376 MHz, methanol-d)
.delta. -90.20 (s, 2F). LC-MS: method C, RT=2.62 min, MS (ESI) m/z:
573.2 (M+H).sup.+.
Intermediate 66C: tert-butyl
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-7-yl)methylcarbamate
##STR00550##
[2142] To a solution of Intermediate 66B (17 mg, 0.030 mmol) in DCM
(1 mL) was added TFA (0.023 mL, 0.297 mmol). The mixture was
stirred at room temperature for 15 min, diluted with EtOAc and
water, extracted with EtOAc. The combined organic layer was washed
with NaHCO.sub.3 and brine, dried with MgSO.sub.4 and concentrated.
The crude sample was purified with a preparative HPLC (method A,
70-100% B in 6 min.). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Intermediate 66C (13 mg, 0.027 mmol, 92% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.83 (d, J=1.8 Hz, 1H), 8.70 (s, 1H),
8.10 (d, J=7.8 Hz, 1H), 7.84 (d, J=1.0 Hz, 1H), 7.87-7.48 (m, 3H),
7.37 (d, J=6.8 Hz, 1H), 2.70 (s, 3H), 1.52 (s, 9H). .sup.19F NMR
(376 MHz, chloroform-d) .delta. -90.20 (s, 2F). LC-MS: method C,
RT=2.44 min, MS (ESI) m/z: 472.9 (M+H).sup.+.
Intermediate 66D
(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)metha-
namine
##STR00551##
[2144] To a solution of Intermediate 66C (11 mg, 0.022 mmol, 94%
yield) in DCM was added TFA (359 .mu.l, 4.66 mmol) and the mixture
was stirred at room temperature for 15 min. The crude was purified
with a preparative HPLC (method A, 30-100% B in 6 min.). The
desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Intermediate 66D (11 mg, 0.022
mmol, 94% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.80 (d, J=1.8 Hz, 1H), 8.71 (s, 1H), 8.16 (d, J=8.1 Hz, 1H),
7.92-7.59 (m, 3H), 7.52-7.44 (m, 1H), 4.44 (s, 2H), 2.70 (s, 3H).
.sup.19F NMR (376 MHz, methanol-d.sub.4) .delta. -78.07 (s, 3F),
-92.13 (s, 2F). LC-MS: method C, RT=1.91 min, MS (ESI) m/z: 372.9
(M+H).sup.+.
Example 66
[2145] To a solution of Intermediate 66D (8 mg, 0.016 mmol) and
DIEA (0.014 mL, 0.082 mmol) in DCM (1 mL) was added a solution of
benzenesulfonyl chloride (5.81 mg, 0.033 mmol) in 0.2 ml of DCM.
The mixture was stirred at room temperature for 1.0 h. Solvent was
removed, the residual was purified with a preparative HPLC (method
A, 50-100% B in 6 min.). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Example 66 (3 mg, 5.21 .mu.mol, 31.7% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.76 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 8.06
(d, J=8.1 Hz, 1H), 7.92-7.84 (m, 3H), 7.70-7.30 (m, 6H), 4.93 (d,
J=5.8 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.70 (s, 3H). .sup.19F NMR
(376 MHz, chloroform-d) .delta. -90.22 (s, 2F). LC-MS: method C,
RT=2.30 min, MS (ESI) m/z: 513.1 (M+H).sup.+. Analytical HPLC
purity (method A): 90%
Example 67
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thia-
zol-6-yloxy) ethyl)benzenesulfonamide
##STR00552##
[2146] Intermediate 67A: 2-bromo-4-fluorobenzo[d]thiazol-6-ol
##STR00553##
[2148] Aluminum chloride (308 mg, 2.308 mmol) was added to a
solution of Intermediate 59B (220 mg, 0.839 mmol) in toluene (4
mL). The mixture was heated at 85.degree. C. for 1.5 h. The
reaction mixture was cooled to room temperature, quenched with
ice-cold 1.0 N HCl (10 mL) and EtOAc (10 mL), and stirred at room
temperature for 30 min. The organic layer was collected, washed
with water, saturated sodium bicarbonate, brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
silica gel cartridge which was eluted with hexanes for 5 min., then
an 18 min gradient from 0% to 40% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 67A
(45 mg, 0.181 mmol, 21.61% yield) as brown solid. .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. 6.98 (dd, J=2.3, 0.8 Hz, 1H), 6.71
(dd, J=11.9, 2.3 Hz, 1H). LC-MS: method C, RT=1.72 min, MS (ESI)
m/z: 247 and 249 (M+H).sup.+.
Intermediate 67B: tert-butyl
2-(2-bromo-4-fluorobenzo[d]thiazol-6-yloxy)ethylcarbamate
##STR00554##
[2150] A solution of DIAD (0.088 mL, 0.453 mmol) and tert-butyl
(2-hydroxyethyl) carbamate (0.070 mL, 0.453 mmol) in THF (1 mL) was
added to a solution of Intermediate 67A (45 mg, 0.181 mmol) and
triphenylphosphine (71.4 mg, 0.272 mmol) in THF (2 mL) at
80.degree. C. using syringe pump over 2 h. The mixture was
concentrated and redissolved in 1 ml of DCM and was purified with a
12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min, the
desired fraction was collected to give Intermediate 67B (30 mg,
0.077 mmol, 42.3% yield). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.05 (d, J=1.8 Hz, 1H), 6.82 (dd, J=11.4, 2.3 Hz, 1H),
5.13-4.95 (m, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.62-3.48 (m, 2H),
1.48-1.42 (m, 9H). LC-MS: method C, RT=2.14 min, MS (ESI) m/z: 391
and 393 (M+H).sup.+.
Intermediate 67C: tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-
-6-yloxy)ethylcarbamate
##STR00555##
[2152] To Intermediate I-1 (23 mg, 0.068 mmol), Intermediate 67B
(29.4 mg, 0.075 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (4.47 mg, 5.47 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.250 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.068 mL, 2M, 0.137 mmol). The reaction mixture
was heated in a microwave reactor at 100.degree. C. for 30 min. To
the reaction mixture was added EtOAc/water. The organic layers were
collected, dried over sodium sulfate. The crude residue was
purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes
for 15 min. The desired fraction was concentrated and further
purified with a preparative HPLC (method A, 70-100% B in 6 min.).
The desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Intermediate 67C (30 mg, 0.054
mmol, 79% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.85
(d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H),
7.95-7.41 (m, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.88 (dd, J=11.6, 2.3
Hz, 1H), 4.13 (t, J=5.1 Hz, 2H), 3.60 (br. s., 2H), 2.69 (s, 3H),
1.48 (s, 9H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -90.55
(s, 2F), -123.30 (br. s., 1F). LC-MS: method C, RT=2.47 min, MS
(ESI) m/z: 521.2 (M+H).sup.+.
Intermediate 67D
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-
-6-yloxy)ethanamine
##STR00556##
[2154] To a solution of Intermediate 67C (25 mg, 0.048 mmol) in DCM
(1 mL) was added TFA (0.920 mL, 11.94 mmol). The mixture was
stirred at room temperature for 1 h. Solvent was removed, the
residual was purified with a preparative HPLC (method A, 30-100% B
in 6 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Intermediate
67D (22 mg, 0.040 mmol, 84% yield). .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.78 (d, J=2.0 Hz, 1H), 8.74 (s, 1H),
7.87 (d, J=1.0 Hz, 1H), 8.00-7.55 (m, 1H), 7.48 (d, J=2.3 Hz, 1H),
7.04 (dd, J=11.9, 2.3 Hz, 1H), 4.43-4.30 (m, 2H), 3.52-3.41 (m,
2H), 2.69 (s, 3H). .sup.19F NMR (376 MHz, methanol-d.sub.4) .delta.
-77.57 (br. s., 3F), -84.34-98.20 (s 2F), -123.30 (br. s., 1F).
LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 421.2 (M+H).sup.+.
Example 67
[2155] To a solution of Intermediate 67D (15 mg, 0.028 mmol) and
DIEA (49.0 .mu.l, 0.281 mmol) in DCM was added a solution of
benzenesulfonyl chloride (7.20 .mu.l, 0.056 mmol) in 0.2 ml of DCM.
The mixture was stirred at room temperature for 1.0 h. The reaction
mixture was diluted with EtOAc and water, extracted with EtOAc. The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The crude sample was purified with a preparative
HPLC (method A, 50-100% B in 6 min.). The desired fractions were
placed in a SpeedVac overnight to remove solvent, then lyophilized
to give Example 67 (4 mg, 6.64 .mu.mol, 23.64% yield). .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.86 (d, J=1.8 Hz, 1H), 8.69 (s,
1H), 7.98-7.90 (m, 2H), 7.81 (s, 1H), 7.64-7.50 (m, 3H), 7.87-7.43
(m, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.77 (dd, J=11.5, 2.1 Hz, 1H),
4.96 (t, J=5.9 Hz, 1H), 4.10 (t, J=5.1 Hz, 2H), 3.47 (q, J=5.3 Hz,
2H), 2.69 (s, 3H). .sup.19F NMR (376 MHz, chloroform-d) .delta.
-90.22 (s, 2F), -120.80 (br. s., 1F). LC-MS: method C, RT=2.40 min,
MS (ESI) m/z: 560.9 (M+H).sup.+. Analytical HPLC purity (method A):
95%.
Example 68
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole
##STR00557##
[2157] To Intermediate I-1 (20 mg, 0.059 mmol),
2-chloro-5-methylbenzo[d]thiazole (14.21 mg, 0.077 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (3.89 mg, 4.76 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (0.065 mL, 2M, 0.131 mmol). The reaction mixture was
heated in a microwave reactor at 100.degree. C. for 30 min. To the
reaction mixture was added EtOAc/water. The organic layers were
collected, dried over sodium sulfate. After evaporation of solvent,
the crude was purified with a preparative HPLC (method A, 50-100% B
in 6 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Example 68
(11 mg, 0.030 mmol, 50.7% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.81 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 7.97
(s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.82 (dd, J=1.9, 0.9 Hz, 1H),
7.85-7.48 (m, 1H), 7.28 (br. s., 1H), 2.70 (s, 3H), 2.56 (s, 3H).
.sup.19F NMR (376 MHz, chloroform-d) .delta. -90.20 (s, 2F). LC-MS:
method C, RT=2.57 min, MS (ESI) m/z: 357.9 (M+H).sup.+. Analytical
HPLC purity (method A): 98%.
Example 69
Methyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-
-yloxy)ethylcarbamate
##STR00558##
[2158] Intermediate 69A: 2-chlorobenzo[d]thiazol-7-ol
##STR00559##
[2160] Aluminum chloride (184 mg, 1.377 mmol) was added to a
solution of 2-chloro-7-methoxybenzo[d]thiazole (100 mg, 0.501 mmol)
in toluene (2 mL). The mixture was heated at 85.degree. C. for 1.5
h. HPLC indicated a complete conversion of starting material. The
reaction mixture was cooled to room temperature, quenched with
ice-cold 1.0 N HCl (50 mL) and EtOAc (50 mL), and stirred at room
temperature for 30 min. The organic layer was collected, washed
with water, saturated sodium bicarbonate, brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
silica gel cartridge which was eluted with hexanes for 5 min., then
a 10 min gradient from 0% to 40% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 69A
(85 mg, 0.458 mmol, 91% yield) as brown solid. .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. 7.47-7.36 (m, 1H), 7.35-7.24 (m,
1H), 6.82 (d, J=8.1 Hz, 1H). LC-MS: method C, RT=1.72 min, MS (ESI)
m/z: 185.8 (M+H).sup.+.
Intermediate 69B: tert-butyl
2-(2-chlorobenzo[d]thiazol-7-yloxy)ethylcarbamate
##STR00560##
[2162] A solution of DIAD (0.223 mL, 1.145 mmol) and tert-butyl
(2-hydroxyethyl) carbamate (0.177 mL, 1.145 mmol) in THF (1 mL) was
added to a solution of Intermediate 69A (85 mg, 0.458 mmol) and
triphenylphosphine (180 mg, 0.687 mmol) in THF (2 mL) at 80.degree.
C. using syringe pump over 3 h. LCMS indicated a completion of the
reaction. The mixture was diluted with EtOAc and saturated
NaHCO.sub.3, extracted with EtOAc, the combined organic layer was
washed with brine, dried with MgSO.sub.4 and concentrated. The
crude was purified with a 12 g ISCO column eluted with 0-70% EtOAc
in hexanes for 15 min, the desired fraction was collected to give
Intermediate 69B (125 mg, 0.380 mmol, 83% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.58 (dd, J=8.2, 0.6 Hz, 1H), 7.41 (t,
J=8.1 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 4.21 (t, J=5.2 Hz, 2H), 3.60
(q, J=5.3 Hz, 2H), 1.51-1.44 (m, 9H). LC-MS: method C, RT=2.17 min,
MS (ESI) m/z: 329. (M+H).sup.+.
Intermediate 69C: tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-
ethylcarbamate
##STR00561##
[2164] To Intermediate I-1 (29 mg, 0.086 mmol), Intermediate 69B
(32.6 mg, 0.099 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.64 mg, 6.90 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.250 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.086 mL, 2M, 0.173 mmol). The reaction mixture
was heated in a microwave reactor at 100.degree. C. for 30 min. To
the reaction was added EtOAc/water, extracted with EtOAc. The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The crude sample was purified with a 12 g ISCO
column eluted with 0-50% EtOAc in hexane for 15 min. The desired
fraction was collected and concentrated to give Intermediate 69C
(35 mg, 0.068 mmol, 79% yield). .sup.1H NMR (400 MHz,
acetonitrile-d.sub.3) .delta. 8.79 (s, 1H), 8.77 (d, J=1.8 Hz, 1H),
7.80 (dd, J=1.9, 0.9 Hz, 1H), 7.67-7.62 (m, 1H), 7.97-7.56 (m, 1H),
7.41 (t, J=8.1 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 4.25 (t, J=5.7 Hz,
2H), 3.53 (q, J=5.8 Hz, 2H), 2.66 (d, J=13.6 Hz, 1H), 2.63 (s, 3H),
1.33 (s, 9H). .sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta.
-90.55 (s, 2F). LC-MS: method C, RT=2.49 min, MS (ESI) m/z: 503.0
(M+H).sup.+.
Intermediate 69D
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-
ethanamine
##STR00562##
[2166] To a solution of Intermediate 69C (30 mg, 0.060 mmol) in DCM
(1 mL) was added TFA (0.920 mL, 11.94 mmol). The mixture was
stirred at room temperature for 1 h. Solvent was removed, the
residual was purified with a preparative HPLC (method A, 30-100% B
in 6 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Intermediate
69D (30 mg, 0.058 mmol, 96% yield). .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.79 (d, J=1.8 Hz, 1H), 8.73 (s, 1H),
7.90 (d, J=0.8 Hz, 1H), 7.79 (s, 1H), 7.99-7.60 (m, 1H), 7.53 (t,
J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.56-4.42 (m, 2H), 3.52 (t,
J=4.9 Hz, 2H), 2.70 (s, 3H). .sup.19F NMR (376 MHz,
methanol-d.sub.4) .delta. -77.64 (br. s., 3F), -91.57 (br. s., 2F).
LC-MS: method C, RT=1.96 min, MS (ESI) m/z: 402.9 (M+H).sup.+.
Example 69
[2167] To a solution of Intermediate 69D (10 mg, 0.019 mmol) and
DIEA (0.017 mL, 0.097 mmol) in DCM (1 mL) was added a solution of
methyl chloroformate (3.00 .mu.l, 0.039 mmol) in DCM. The mixture
was stirred at room temperature for 1 hour. The reaction mixture
was diluted with EtOAc and water, and then extracted with EtOAc.
The combined organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated. The crude sample was purified with a
preparative HPLC (method A, 60-100% B in 6 min.). The desired
fractions were placed in a SpeedVac overnight to remove solvent,
then lyophilized to give Example 69 (5.5 mg, 0.011 mmol, 58.6%
yield). .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) .delta.
8.84-8.81 (m, 1H), 8.79 (s, 1H), 7.90-7.46 (m, 5H), 6.99 (d, J=7.8
Hz, 1H), 4.29 (t, J=5.4 Hz, 2H), 3.65-3.56 (m, 6H), 2.70 (s, 3H).
.sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta. -86.49-95.62
(m, 2F). LC-MS: method C, RT=2.36 min, MS (ESI) m/z: 461.0
(M+H).sup.+. Analytical HPLC purity (method A): 95%.
Example 70
Methyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]-
thiazol-7-yloxy)ethylcarbamate
##STR00563##
[2168] Intermediate 70A:
2-chloro-7-methoxy-4-methylbenzo[d]thiazole
##STR00564##
[2170] To a solution of copper (II) chloride (1.030 g, 7.66 mmol)
in acetonitrile (60 mL) at 40.degree. C. was added tert-butyl
nitrite (1.097 mL, 8.30 mmol), followed by Intermediate 12C (1.24
g, 6.38 mmol) as a solid. The mixture was stirred at 40.degree. C.
for 1.0 h, diluted with EtOAc, washed with 1.0 N HCl, water and
brine. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
silica gel cartridge which was eluted with 5% dichloromethane in
hexanes for 2 min., then a 12 min gradient from 5% to 50%
dichloromethane in hexanes. The desired fractions were combined and
concentrated to give Intermediate 70A (1.2 g, 5.62 mmol, 88% yield)
as a slightly yellow solid.
Intermediate 70B: 2-chloro-4-methylbenzo[d]thiazol-7-ol
##STR00565##
[2172] Aluminum chloride (369 mg, 2.77 mmol) was added to a
solution of Intermediate 70A (215 mg, 1.006 mmol) in toluene (4
mL). The mixture was heated at 85.degree. C. for 1.5 h. The
reaction mixture was cooled to room temperature, quenched with
ice-cold 1.0 N HCl (50 mL) and EtOAc (50 mL), and stirred at room
temperature for 30 min. The organic layer was collected, washed
with water, saturated sodium bicarbonate, brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
silica gel cartridge which was eluted with hexanes for 5 min., then
an 18 min gradient from 0% to 40% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 70B
(105 mg, 0.526 mmol, 52.3% yield) as brown solid. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 6.98 (dd, J=2.3, 0.8 Hz, 1H), 6.71
(dd, J=11.9, 2.3 Hz, 1H). LC-MS: method C, RT=2.20 min, MS (ESI)
m/z: 547.2 (M+H).sup.+. LC-MS: method C, RT=1.87 min, MS (ESI) m/z:
199.8 (M+H).sup.+.
Intermediate 70C: tert-butyl
2-(2-chloro-4-methylbenzo[d]thiazol-7-yloxy) ethylcarbamate
##STR00566##
[2174] A solution of DIAD (0.243 mL, 1.252 mmol) and Intermediate
70B (100 mg, 0.501 mmol) in THF (1 mL) was added to a solution of
tert-butyl (2-hydroxyethyl) carbamate (0.194 mL, 1.252 mmol) and
triphenylphosphine (197 mg, 0.751 mmol) in THF (2 mL) at 80.degree.
C. using a syringe pump for 2 h. The mixture was diluted with
dichloromethane and saturated NaHCO.sub.3, extracted with
dichloromethane, the combined organic layer was washed with brine,
dried with MgSO.sub.4 and concentrated. The crude sample was
purified with 40 g ISCO column eluted with 0-100% EtOAc in hexanes
for 20 min, the desired fraction was collected to give Intermediate
70C (170 mg, 0.496 mmol, 99% yield) as a yellow solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 7.17 (dd, J=8.2, 0.9 Hz, 1H), 6.74
(d, J=8.3 Hz, 1H), 5.09-4.94 (m, 1H), 4.23-4.14 (m, 2H), 3.57 (q,
J=5.1 Hz, 2H), 2.60 (d, J=0.5 Hz, 3H), 1.55-1.42 (m, 9H). LC-MS:
method C, RT=2.26 min, MS (ESI) m/z: 342.9 (M+H).sup.+.
Intermediate 70D: tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-7-yloxy)ethylcarbamate
##STR00567##
[2176] To Intermediate I-1 (33.9 mg, 0.101 mmol), Intermediate 70C
(45 mg, 0.131 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.60 mg, 8.08 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (0.111 mL, 2M, 0.222 mmol). The reaction mixture was
heated in a microwave reactor at 100.degree. C. for 30 min. To the
reaction mixture was added EtOAc/water. The organic layers were
collected, dried over sodium sulfate. After evaporation of solvent,
the crude product was purified with a 12 g ISCO column eluted with
0-70% EtOAc in hexanes for 15 min. The desired fraction was
collected to give Intermediate 70D (46 mg, 0.087 mmol, 86% yield)
was obtained as a yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.87 (d, J=1.5 Hz, 1H), 8.74 (s, 1H), 7.81 (dd, 1.0 Hz,
1H), 7.94-7.46 (m, 1H), 7.23 (dd, J=8.0, 0.9 Hz, 1H), 6.77 (d,
J=8.1 Hz, 1H), 4.25 (t, J=4.9 Hz, 2H), 3.67 (d, J=4.8 Hz, 2H), 2.81
(s, 3H), 2.71 (s, 3H), 1.48 (s, 9H). .sup.19F NMR (376 MHz,
chloroform-d) .delta. -90.17 (s, 2F). LC-MS: method C, RT=2.63 min,
MS (ESI) m/z: 517.0 (M+H).sup.+.
Intermediate 70E
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-
-7-yloxy)ethanamine
##STR00568##
[2178] To a solution of Intermediate 70D (40 mg, 0.077 mmol) in DCM
(1 mL) was added TFA (0.597 mL, 7.74 mmol). The mixture was stirred
at room temperature for 1 h. Solvent was removed, the residual was
purified with a preparative HPLC (method A, 30-100% B in 6 min.).
The desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to Intermediate 70E (35 mg, 0.065 mmol,
84% yield). .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.85
(s, 1H), 8.71 (s, 1H), 7.87 (s, 1H), 8.01-7.54 (m, 1H), 7.29 (d,
J=8.1 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 4.45 (t, J=4.9 Hz, 2H), 3.48
(t, J=4.9 Hz, 2H), 2.78 (s, 3H), 2.71 (s, 3H). .sup.19F NMR (376
MHz, Methanol-d.sub.4) .delta. -78.76 (br. s., 3F), -92.71 (s, 2F).
LC-MS: method C, RT=2.10 min, MS (ESI) m/z: 416.9 (M+H).sup.+.
Example 70
[2179] To a solution of Intermediate 70E (10 mg, 0.019 mmol) and
DIEA (0.016 mL, 0.094 mmol) in DCM (1 mL) was added a solution of
methyl chloroformate (2.92 .mu.l, 0.038 mmol) in DCM. The mixture
was stirred at room temperature for 1 h. The reaction mixture was
diluted with EtOAc and water, extracted with EtOAc. The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude was purified with a preparative HPLC
(method A, 60-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 70 (5.5 mg, 0.019 mmol, 59% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.00 (s, 1H), 8.80 (d, J=1.8 Hz, 1H), 7.93
(s, 1H), 8.11-7.68 (m, 1H), 7.42 (br. s., 1H), 7.30 (d, J=7.8 Hz,
1H), 6.98 (d, J=8.1 Hz, 1H), 4.22 (t, J=5.6 Hz, 2H), 3.50-3.38 (m,
5H), 2.71 (s, 3H), 2.69 (s, 3H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -88.27 (s, 2F). LC-MS: method C, RT=2.49 min,
MS (ESI) m/z: 475.0 (M+H).sup.+. Analytical HPLC purity (method A):
96%.
Example 71
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(thiazol-4-ylmethoxy)
benzo[d]thiazole
##STR00569##
[2180] Intermediate 71A: 2-chlorobenzo[d]thiazol-6-ol
##STR00570##
[2182] Aluminum chloride (6.01 g, 45.1 mmol) was added to a
solution of 2-chloro-6-methoxybenzo[d]thiazole (3 g, 15.03 mmol) in
toluene (80 mL). The mixture was heated at 110.degree. C. for 1.5
h. TLC indicated a complete conversion of starting material. The
reaction mixture was cooled to room temperature, quenched with
ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min.
The precipitate was collected by filtration, washed with water
(3.times.), saturated sodium bicarbonate (3.times.), water
(3.times.) and air-dried for 1.0 h under vacuum. It was further
dried under high vacuum overnight to give Intermediate 71A (2.6 g,
14.01 mmol, 93% yield) as a pale gray solid. The crude sample was
used for the next step without further purification. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 7.70 (d, J=8.8 Hz, 1H), 7.25
(s, 1H), 7.00 (dd, J=8.8, 1.5 Hz, 1H). LC-MS: method C, RT=1.65
min, MS (ESI) m/z: 185.8 (M+H).sup.+.
Intermediate 71B:
6-(tert-butyldimethylsilyloxy)-2-chlorobenzo[d]thiazole
##STR00571##
[2184] To a stirred solution of Intermediate 71A (2.6 g, 14.01
mmol) in DMF (50 mL) was added TBDMS-Cl (2.96 g, 19.61 mmol) and
imidazole (1.669 g, 24.51 mmol). The reaction mixture was left
stirring at room temperature for 1.0 h. The mixture was diluted
with EtOAc/water and extracted with EtOAc. The combined organic
layer was washed with brine, dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform and charged to a 120 g ISCO column which was
eluted with hexanes for 3 min., then a 30 min gradient from 0% to
50% EtOAc in hexanes. The desired fractions were combined and
concentrated to give Intermediate 71B (3 g, 10.00 mmol, 71.4%
yield) as clear orange oil. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.80 (s, 1H), 7.21 (s, 1H), 7.03-6.94 (m, 1H), 1.01 (s,
9H), 0.24 (s, 6H). LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 300
(M+H).sup.+.
Intermediate 71C
6-(tert-butyldimethylsilyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-
-yl)benzo[d]thiazole
##STR00572##
[2186] To Intermediate I-1 (1 g, 3.94 mmol), Intermediate 71B
(1.358 g, 4.53 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (0.161 g, 0.197 mmol) was added
toluene (9 mL), EtOH (3 mL) and sodium carbonate (3.94 mL, 2 M,
7.87 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 135.degree.
C. for 30 min. To the reaction mixture was added EtOAc/water/brine.
The insoluble was removed by filtration with a pad of celite. The
organic layers were collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of toluene/chloroform and charged to a
120 g silica gel cartridge which was eluted with hexanes for 3
min., then a 20 min gradient from 0% to 75% dichloromethane in
hexanes (flow rate 65 mL/min). The desired fractions were combined
and concentrated to give Intermediate 71C (1.6 g, 2.70 mmol, 68.6%
yield) as a bright yellow solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.75 (d, J=1.8 Hz, 1H), 8.69 (s, 1H),
8.03-7.98 (m, 1H), 7.81-7.78 (m, 1H), 7.86-7.49 (m, 1H), 7.40 (d,
J=2.5 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 2.69 (s, 3H), 1.04 (s,
9H), 0.27 (s, 6H). LC-MS: method C, gradient time 1 min, RT=2.30
min, MS (ESI) m/z: 473.9 (M+H).sup.+.
Intermediate 71D:
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
##STR00573##
[2188] To a solution of Intermediate 71C (1.75 g, 3.70 mmol) in THF
(15 mL) at room temperature was added acetic acid (0.465 mL, 8.13
mmol), followed by addition of 1.0 N TBAF in THF (4.43 mL, 4.43
mmol) dropwise. The mixture was stirred at room temperature for 20
min. The mixture was diluted with EtOAc, washed with water,
saturated sodium bicarbonate (2.times.), brine, and dried over
sodium sulfate. After evaporation of the solvent, the crude product
was triturated with EtOAc in hexanes (1:4). The precipitate was
collected by filtration to give Intermediate 71D (1 g, 2.78 mmol,
75% yield) as a yellow solid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.70 (s, 1H), 8.64 (d, J=2.0 Hz, 1H),
7.96 (s, 1H), 7.93-7.53 (m, 3H), 7.34 (d, J=2.3 Hz, 1H), 7.03 (dd,
J=8.8, 2.5 Hz, 1H), 2.67 (s, 3H). LC-MS: method C, gradient time 1
min, RT=1.45 min, MS (ESI) m/z: 359.9 (M+H).sup.+.
Example 71
[2189] A solution of DIAD (0.019 mL, 0.100 mmol) in toluene (0.5
mL) was added to a mixture of Intermediate 71D (12 mg, 0.033 mmol),
thiazol-4-ylmethanol (11.54 mg, 0.100 mmol) and triphenylphosphine
(17.52 mg, 0.067 mmol) in toluene (2 mL) at 110.degree. C. on 5
portions (0.4 ml each for 30 min). The mixture turned to a clear
solution and was stirred at 110.degree. C. for 30 min. The mixture
was concentrated and purified with a preparative HPLC (method A,
70-100% B in 6 min.). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Example 71 (5 mg, 9.86 .mu.mol, 29.5% yield). .sup.1H NMR (400 MHz,
acetonitrile-d.sub.3) .delta. 8.95 (d, J=2.0 Hz, 1H), 8.78-8.73 (m,
2H), 7.99 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.71 (d,
J=2.5 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.89-7.48 (m, 1H), 7.24 (dd,
J=9.1, 2.5 Hz, 1H), 5.35 (s, 2H), 2.68 (s, 3H). NMR (376 MHz,
acetonitrile-d.sub.3) .delta. -90.50 (s, 2F). LC-MS: method C,
RT=2.38 min, MS (ESI) m/z: 456.9 (M+H).sup.+. Analytical HPLC
purity (method A): 90%.
Example 72
N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)b-
enzenesulfonamide
##STR00574##
[2191] To a solution of Example 63 (6.9 mg, 0.013 mmol) in THF (0.5
mL) was added sodium methoxide (0.076 mL, 0.038 mmol). The mixture
was stirred at room temperature for 1 h. The reaction mixture was
diluted with EtOAc and water, extracted with EtOAc. The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a preparative HPLC
(method A, 60-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Example 72 (4 mg, 7.11 .mu.mol, 55.9% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.61 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.02
(d, J=8.8 Hz, 1H), 7.95-7.89 (m, 2H), 7.78 (dd, J=1.9, 0.9 Hz, 1H),
7.61-7.56 (m, 1H), 7.55-7.49 (m, 2H), 7.30 (d, J=2.5 Hz, 1H), 7.03
(dd, J=8.8, 2.5 Hz, 1H), 5.00 (t, J=5.9 Hz, 1H), 4.14 (s, 3H), 4.10
(t, J=5.1 Hz, 2H), 3.47 (q, J=5.7 Hz, 2H), 2.66 (s, 3H). LC-MS:
method C, RT=2.37 min, MS (ESI) m/z: 507.0 (M+H).sup.+. Analytical
HPLC purity (method A): 95%.
Example 73
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)benzenesulfonamide
##STR00575##
[2193] To a solution of Intermediate 26F (28 mg, 0.054 mmol) in DCM
(1 mL) was added DIEA (0.095 ml, 0.542 mmol) and benzenesulfonyl
chloride (19.15 mg, 0.108 mmol). The mixture was stirred at room
temperature for 1 hour. Solvent was removed under vacuum and the
residual was purified with a preparative HPLC (method A, 70-100% B
in 6 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to Example 73 (15 mg,
0.025 mmol, 46.2% yield). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.74 (d, J=1.8 Hz, 1H), 8.68 (s, 1H), 8.00-7.89 (m, 2H),
7.87-7.44 (m, 5H), 7.15 (d, J=2.3 Hz, 1H), 6.93-6.85 (m, 1H), 4.10
(t, J=5.1 Hz, 2H), 3.46 (t, J=5.1 Hz, 2H), 2.82 (s, 3H), 2.70 (s,
3H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -90.22 (s, 2F).
LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 557.0 (M+H).sup.+.
Analytical HPLC purity (method A): 96%.
Example 74
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-
ethanol
##STR00576##
[2195] A solution of DIAD (0.041 mL, 0.209 mmol) in toluene (0.5
mL) was added to a mixture of Intermediate 15J (25 mg, 0.070 mmol),
2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (20.34 mg, 0.139 mmol) and
triphenylphosphine (36.5 mg, 0.139 mmol) in toluene (2 mL) at
110.degree. C. on 5 portion of 0.4 ml each for 30 min. The mixture
turned to a clean solution and was stirred at 110.degree. C. for 30
min. The mixture was concentrated and the residual was dissolved in
1 ml of DCM and treated with 12N HCl (0.290 mL, 3.48 mmol) and the
mixture was stirred at room temperature for 1 h. The mixture was
concentrated and purified with a preparative HPLC (method A,
50-100% B in 6 min.). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Example 74 (11.5 mg, 0.027 mmol, 38.5% yield). .sup.1H NMR (400
MHz, acetonitrile-d.sub.3) .delta. 8.81 (d, J=2.0 Hz, 1H), 8.78 (s,
1H), 7.84 (dd, J=1.9, 0.9 Hz, 1H), 7.90-7.46 (m, 3H), 6.99 (d,
J=7.8 Hz, 1H), 4.33-4.25 (m, 2H), 3.99-3.92 (m, 2H), 2.69 (s, 3H).
.sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta. -90.50 (s,
2F). LC-MS: method C, RT=2.33 min, MS (ESI) m/z: 403.9 (M+H).sup.+.
Analytical HPLC purity (method A): 94%
Example 75
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d-
]thiazole
##STR00577##
[2197] A solution of DIAD (0.016 mL, 0.083 mmol) in toluene (0.5
mL) was added to a mixture of Intermediate 15J (10 mg, 0.028 mmol),
2-methoxyethanol (4.24 mg, 0.056 mmol) and triphenylphosphine
(14.60 mg, 0.056 mmol) in toluene (2 mL) at 110.degree. C. on 5
portion of 0.4 ml each for 30 min. The mixture turned to a clean
solution and was stirred at 110.degree. C. for 30 min. The mixture
was concentrated and redissolved in 1 ml of DMF and was purified
with a preparative HPLC (method A, 60-100% B in 6 min.). The
desired fractions were placed in a SpeedVac overnight to remove
solvent, then lyophilized to give Example 75 (10 mg, 0.023 mmol,
82% yield). .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) .delta.
8.81 (d, J=2.0 Hz, 1H), 8.79 (s, 1H), 7.84 (d, J=0.8 Hz, 1H),
7.90-7.43 (m, 3H), 6.99 (d, J=7.8 Hz, 1H), 4.44-4.25 (m, 2H),
3.87-3.80 (m, 2H), 3.44 (s, 3H), 2.69 (s, 3H).sup.19F NMR (376 MHz,
acetonitrile-d.sub.3) .delta. -90.22 (s, 2F). LC-MS: method C,
RT=2.46 min, MS (ESI) m/z: 418.0 (M+H).sup.+. Analytical HPLC
purity (method A): 99%.
Example 76
benzyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl-
carbamate
##STR00578##
[2199] To a solution of Intermediate 21A (15 mg, 0.042 mmol) in DCM
(1 mL) was added DIEA (0.044 mL, 0.251 mmol). After stirring at
room temperature for 2 min, benzyl carbonochloridate (0.013 mL,
0.092 mmol) was added. The mixture was heated up to 60.degree. C.
for 2 h. The mixture was concentrated and redissolved in 1 ml of
DMF and was purified with a preparative HPLC (method A, 50-100% B
in 6 min.). The desired fractions were placed in a SpeedVac
overnight to remove solvent, then lyophilized to give Example 76 (5
mg, 9.95 .mu.mol, 23.77% yield). .sup.1H NMR (400 MHz,
acetonitrile-d.sub.3) .delta. 8.80 (d, J=1.8 Hz, 1H), 8.73 (s, 1H),
7.89 (dd, J=8.1, 0.8 Hz, 1H), 7.83 (s, 1H), 7.75 (br. s., 1H), 7.60
(d, J=7.8 Hz, 1H), 7.86-7.51 (m, 1H), 7.48-7.44 (m, 2H), 7.43-7.33
(m, 3H), 5.25 (s, 2H), 2.68 (s, 3H). .sup.19F NMR (376 MHz,
acetonitrile-d.sub.3) .delta. -90.22 (s, 2F). LC-MS: method C,
RT=2.41 min, MS (ESI) m/z: 492.9 (M+H).sup.+. Analytical HPLC
purity (method A): 98%.
Example 77
2-(2-methoxy-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole
##STR00579##
[2200] Intermediate 77A
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d-
]thiazole
##STR00580##
[2202] A solution of DIAD (0.016 mL, 0.083 mmol) in toluene (0.5
mL) was added to a mixture of Intermediate 71D (10 mg, 0.028 mmol),
2-methoxyethanol (4.24 mg, 0.056 mmol) and triphenylphosphine
(14.60 mg, 0.056 mmol) in toluene (2 mL) at 110.degree. C. on 5
portion of 0.4 ml each for 30 min and then was stirred at
110.degree. C. for 30 min. The mixture was concentrated and
redissolved in 1 ml of DMF and was purified with a preparative HPLC
(method A, 60-100% B in 6 min.). The desired fractions were placed
in a SpeedVac overnight to remove solvent, then lyophilized to give
Intermediate 77A (10 mg, 0.023 mmol, 82% yield). .sup.1H NMR (400
MHz, acetonitrile-d.sub.3) .delta. 8.75 (d, J=1.8 Hz, 1H), 8.74 (s,
1H), 7.98 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.60 (d,
J=2.5 Hz, 1H), 7.88-7.50 (m, 1H), 7.16 (dd, J=8.8, 2.5 Hz, 1H),
4.27-4.08 (m, 2H), 3.82-3.67 (m, 2H), 3.40 (s, 3H), 2.68 (s, 3H).
.sup.19F NMR (376 MHz, acetonitrile-d.sub.3) .delta. -90.22 (s,
2F). LC-MS: method C, RT=2.47 min, MS (ESI) m/z: 418.1 (M+H).sup.+.
Analytical HPLC purity (method A): 95%.
Example 77
[2203] To a solution of Intermediate 77A (5 mg, 0.012 mmol) in THF
(0.5 mL) was added sodium methoxide (0.072 mL, 0.036 mmol). The
mixture was stirred at room temperature for 1 h. The reaction was
quenched by 1 drop of water and concentrated. The residual was
purified via preparative LC/MS (method C, 50-90% B over 10 min.,
then a 5-min hold at 100% B). Fractions containing the desired
product were combined and dried via centrifugal evaporation to
Example 77 (3.0 mg, 7.79 .mu.mol, 65.0% yield). .sup.1H NMR (500
MHz, methanol-d.sub.4) .delta. 8.51 (s, 1H), 8.47 (d, J=1.9 Hz,
1H), 7.95 (d, J=9.1 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.47 (s, 1H),
7.15 (dd, J=8.8, 2.5 Hz, 1H), 4.24-4.18 (m, 2H), 4.11 (s, 3H),
3.85-3.78 (m, 2H), 2.63 (s, 3H). LC-MS: method C, RT=2.41 min, MS
(ESI) m/z: 382.15 (M+H).sup.+. Analytical HPLC purity (method B):
99%.
Example 78
2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole
##STR00581##
[2205] To a solution of Example 75 (8.5 mg, 0.020 mmol) in THF (0.5
mL) was added sodium methoxide (0.122 mL, 0.061 mmol). The mixture
was stirred at room temperature for 1 h. The reaction was quenched
by 1 drop of water solvent was removed, the residual was purified
via preparative LC/MS (method C, 50-90% B over 10 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to Example 78
(6.6 mg, 0.017 mmol, 85% yield). .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.55 (s, 1H), 8.53 (d, J=1.9 Hz, 1H),
7.76 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.1 Hz, 1H), 6.90
(d, J=7.7 Hz, 1H), 4.41-4.32 (m, 2H), 4.11 (s, 3H), 3.88 (dd,
J=5.4, 3.7 Hz, 2H), 3.50 (s, 3H), 2.63 (s, 3H). LC-MS: method C,
RT=2.41 min, MS (ESI) m/z: 382.15 (M+H).sup.+. Analytical HPLC
purity (method B): 100%.
Example 79
N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylox-
y)ethyl) benzenesulfonamide
##STR00582##
[2206] Intermediate 79A
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)-2,2,2-trifluoro-N-(phenylsulfonyl)acetamide
##STR00583##
[2208] To a solution of Intermediate 26F (28 mg, 0.054 mmol) in DCM
(1 ml) was added TFA (0.418 ml, 5.42 mmol) and the mixture was
stirred at room temperature for 1 hour. Solvent was removed and the
sample was under vacuum overnight. The residual was dissolved in
DCM (1 ml) then DIEA (0.095 ml, 0.542 mmol) and benzenesulfonyl
chloride (19.15 mg, 0.108 mmol) was added. The mixture was stirred
at room temperature for 1 hour. Solvent was removed under vacuum
and the residual was purified with a preparative HPLC (method A,
70-100% B in 6 min.). The desired fractions were placed in a
SpeedVac overnight to remove solvent, then lyophilized to give
Intermediate 79A (8 mg, 0.012 mmol, 22.62% yield). LC-MS: method C,
RT=2.68 min, MS (ESI) m/z: 653 (M+H).sup.+.
Example 79
[2209] To a solution of Intermediate 79A (8 mg, 0.012 mmol) in THF
(0.5 mL) was added sodium methoxide (0.074 mL, 0.037 mmol). The
mixture was stirred at room temperature for 1 h. The reaction was
quenched by 1 drop of water and concentrated. The residual was
diluted with 1 ml of DMF and was purified via preparative LC/MS
(method C, 55-90% B over 20 min., then a 10-min hold at 90% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to Example 79 (3.9 mg, 7.49 .mu.mol,
61.1% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.55
(d, J=1.7 Hz, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.87-7.85 (m, 1H),
7.73 (s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.51-7.46 (m, 2H), 7.13 (d,
J=2.2 Hz, 1H), 6.80 (d, J=1.7 Hz, 1H), 4.10 (s, 3H), 4.03 (t, J=5.5
Hz, 2H), 3.34 (t, J=5.5 Hz, 2H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS:
method C, RT=2.48 min, MS (ESI) m/z: 521.0 (M+H).sup.+. Analytical
HPLC purity (method B): 100%.
Example 80
Methyl
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl-
carbamate
##STR00584##
[2211] To a solution of Intermediate 21A (6 mg, 0.017 mmol) in DCM
(1 mL) was added DIEA (0.058 mL, 0.335 mmol). After stirring at
room temperature for 2 min, methyl chloroformate (18.99 mg, 0.201
mmol) was added to the solution and the mixture was stirred at
60.degree. C. for 3h. Solvent was removed, the residual was
dissolved in 1 ml of DMF and purified via preparative LC/MS (method
C, 35-70% B over 10 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to afford Example 80 (3.6 mg, 8.30 .mu.mol,
49.6% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.72-8.68 (m, 2H), 7.88 (d, J=8.8 Hz, 1H), 7.84-7.52 (m, 3H),
7.51-7.45 (m, 1H), 3.82 (s, 3H), 2.67 (s, 3H). LC-MS: method C,
RT=2.24 min, MS (ESI) m/z: 416.9 (M+H).sup.+. Analytical HPLC
purity (method B): 96%
Example 81
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide
##STR00585##
[2213] To a solution of Intermediate 26F (10 mg, 0.022 mmol) and
DIEA (0.039 mL, 0.221 mmol) in DCM (1 mL) was added a solution of
4-fluorobenzene-1-sulfonyl chloride (8.59 mg, 0.044 mmol) in 0.2 ml
of DCM. The mixture was stirred at room temperature for 1 h.
Solvent was removed under vacuum and the residual was purified via
preparative LC/MS (method C, 45-85% B over 10 min., then a 7-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to Example 81 (4.4
mg, 7.66 .mu.mol, 34.7% yield). .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.71 (d, J=1.9 Hz, 1H), 8.67 (s, 1H),
7.93-7.88 (m, 2H), 7.78 (dd, 1.0 Hz, 1H), 7.83-7.51 (m, 1H),
7.23-7.12 (m, 3H), 6.80 (dd, J=2.5, 0.8 Hz, 1H), 4.05 (t, J=5.5 Hz,
2H), 3.35 (t, J=5.5 Hz, 2H), 2.76 (s, 3H), 2.67 (s, 3H). LC-MS:
method C, RT=2.50 min, MS (ESI) m/z: 575.1 (M+H).sup.+. Analytical
HPLC purity (method B): 100%.
Example 82
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-
-N-phenylacetamide
##STR00586##
[2214] Intermediate 82A: tert-butyl
2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)o-
xy)acetate
##STR00587##
[2216] To a solution of Intermediate 15J (20 mg, 0.056 mmol) in DMF
(1 mL) was added butyl 2-bromoacetate (0.041 mL, 0.278 mmol) and
NaH (4.45 mg, 0.111 mmol). The mixture was stirred at room
temperature for 30 min, diluted with EtOAc and water, extracted
with EtOAc. The combined organic layer was washed with brine, dried
with MgSO.sub.4 and concentrated. The crude sample was purified
with a 12 g ISCO column eluted with 0-50% EtOAc in hexanes for 15
min. The desired fraction was collected to give Intermediate 82A
(25 mg, 0.053 mmol, 95% yield) as a yellow solid. .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. 8.71 (s, 2H), 7.87-7.66 (m, 3H),
7.44 (t, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 4.78 (s, 2H), 2.68
(s, 3H), 1.48 (s, 9H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z:
474 (M+H).sup.+.
Intermediate 82B
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-
acetic acid
##STR00588##
[2218] To a solution of Intermediate 82A (16 mg, 0.034 mmol) in DCM
(1 mL) was added TFA (0.260 mL, 3.38 mmol). The mixture was stirred
at room temperature overnight, Solvent was removed, the residual
was dissolved in 1 ml of DMF and was purified via preparative LC/MS
(method D: 10-45% B over 10 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Intermediate 82B (14 mg, 0.034
mmol, 99% yield). LC-MS: method C, RT=2.25 min, MS (ESI) m/z:
418(M+H).sup.+.
Example 82
[2219] To a solution of Intermediate 82B (6.5 mg, 0.016 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added DIEA (27.2 .mu.L, 0.156 mmol) and
1-propanephosphonic acid cyclic anhydride, (T.sub.3P) (180 .mu.L,
50 wt % solution in ethyl acetate, 0.047 mmol) was added aniline
(5.80, 0.062 mmol). The reaction mixture was stirred at room
temperature for 2h. Solvent was removed, the residual was dissolved
in 1 ml of DMF and was purified via preparative LC/MS (method C,
50-90% B over 10 min., then a 7-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to afford Example 82 (5.0 mg, 10.15
.mu.mol, 65.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.49 (s, 1H), 8.23 (s, 1H), 7.99 (d, J=1.7 Hz, 1H), 7.36-6.91 (m,
2H), 6.82 (d, J=7.7 Hz, 2H), 6.71 (t, J=8.0 Hz, 1H), 6.52 (t, J=8.0
Hz, 2H), 6.27 (s, 1H), 6.20 (d, J=7.7 Hz, 1H), 1.87 (s, 3H),
1.73-1.57 (m, 3H). LC-MS: method C, RT=2.46 min, MS (ESI) m/z:
493.1 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 83
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)-4-(trifluoromethyl)benzenesulfonamide
##STR00589##
[2221] To a solution of Intermediate 26F (15 mg, 0.033 mmol) and
DIEA (0.058 mL, 0.331 mmol) in DCM (1 mL) was added a solution of
4-(trifluoromethyl)benzene-1-sulfonyl chloride (12.15 mg, 0.050
mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature
for 1 h. Solvent was removed, the residual was purified via
preparative LC/MS (method C, 55-95% B over 10 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 83
(6.2 mg, 9.93 .mu.mol, 30.0% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.13 (s, 1H), 7.97-7.84 (m, 1H), 7.51-7.41
(m, 1H), 7.26-7.22 (m, 2H), 7.17-7.12 (m, 2H), 7.21-6.91 (m, 2H),
6.69-6.46 (m, 1H), 6.02-5.83 (m, 1H), 3.26-3.18 (m, 2H), 2.50 (s,
2H), 1.89 (s, 3H), 1.86 (s, 3H). LC-MS: method C, RT=2.54 min, MS
(ESI) m/z: 625.1 (M+H).sup.+. Analytical HPLC purity (method B):
99%.
Example 84
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)-2,4-difluorobenzenesulfonamide
##STR00590##
[2223] To a solution of Intermediate 26F (15 mg, 0.033 mmol) and
DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of
2,4-difluorobenzene-1-sulfonyl chloride (10.56 mg, 0.050 mmol) in
0.2 ml of DCM. The mixture was stirred at room temperature for 1 h.
Solvent was removed, the residual was purified via preparative
LC/MS (method C: 0-100% B over 10 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 84 (7.8 mg, 0.013
mmol, 39.7% yield). .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta.
8.72 (s, 1H), 8.69 (s, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.79 (s, 1H),
7.84-7.52 (m, 1H), 7.15 (s, 1H), 7.01 (s, 1H), 6.96-6.88 (m, 1H),
6.75 (s, 1H), 4.07-4.03 (m, 2H), 3.73 (s, 3H), 3.46 (t, J=5.4 Hz,
2H). LC-MS: method C, RT=2.45 min, MS (ESI) m/z: 593.1 (M+H).sup.+.
Analytical HPLC purity (method B): 100%.
Example 85
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)-3,4-difluorobenzenesulfonamide
##STR00591##
[2225] To a solution of Intermediate 26F (15 mg, 0.033 mmol) and
DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of
3,4-difluorobenzene-1-sulfonyl chloride (10.56 mg, 0.050 mmol) in
0.2 ml of DCM. The mixture was stirred at room temperature for 2 h.
Solvent was removed, the residual was purified via preparative
LC/MS (method C: 0-100% B over 10 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 85 (2.3 mg, 3.88
.mu.mol, 11.72% yield). .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. 8.75-8.71 (m, 1H), 8.69-8.66 (m, 1H), 7.85-7.51 (m, 4H),
7.35-7.26 (m, 1H), 7.20-7.14 (m, 1H), 6.82-6.77 (m, 1H), 4.07 (t,
J=5.4 Hz, 2H), 3.38 (t, J=5.5 Hz, 2H), 2.77 (s, 3H), 2.68 (s, 3H).
LC-MS: method C, RT=2.51 min, MS (ESI) m/z: 593.1 (M+H).sup.+.
Analytical HPLC purity (method B): 99%.
Example 86
4-chloro N (2 (2 (2
(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylox-
y)ethyl)benzenesulfonamide
##STR00592##
[2227] To a solution of Intermediate 26F (15 mg, 0.033 mmol) and
DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of
4-chlorobenzene-1-sulfonyl chloride (10.49 mg, 0.050 mmol) in 0.2
ml of DCM. The mixture was stirred at room temperature for 1 h.
LCMS indicated a completion of the reaction. Solvent was removed
and the sample was purified via preparative LC/MS (method C,
60-100% B over 10 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to Example 86 (4.9 mg, 8.29 .mu.mol, 25.03%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.96 (s, 1H),
8.82-8.64 (m, 1H), 8.08-7.61 (m, 7H), 7.48-7.37 (m, 1H), 6.84-6.78
(m, 1H), 4.09-4.00 (m, 2H), 3.25-3.22 (m, 2H), 2.73 (s, 3H), 2.68
(s, 3H). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 591.1
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 87
N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylox-
y)ethyl)-4-methylbenzenesulfonamide
##STR00593##
[2228] Intermediate 87A
N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thia-
zol-6-yloxy) ethyl)-4-methylbenzenesulfonamide
##STR00594##
[2230] To a solution of Intermediate 26F (15 mg, 0.033 mmol) and
DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of
4-methylbenzene-1-sulfonyl chloride (9.47 mg, 0.050 mmol) in 0.2 ml
of DCM. The mixture was stirred at room temperature for 1 h. LCMS
indicated a completion of the reaction. Solvent was removed, the
residual was purified via preparative LC/MS (method C, 55-95% B
over 10 min., then a 5-min hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to give Intermediate 87A (5.5 mg, 9.64 .mu.mol, 29%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.96 (s, 1H),
8.72 (d, J=1.7 Hz, 1H), 8.04-7.74 (m, 2H), 7.72 (d, J=8.3 Hz, 2H),
7.44 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 6.88 (d, J=1.4 Hz,
1H), 4.04 (t, J=5.4 Hz, 2H), 3.17 (t, J=5.4 Hz, 2H), 2.73 (s, 3H),
2.67 (s, 3H), 2.36 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI)
m/z: 571.2 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 87
[2231] To a solution of Intermediate 87A (3.32 mg, 5.82 .mu.mol) in
DMF (0.5 mL) was added sodium methoxide in MeOH (0.035 mL, 0.5M,
0.017 mmol). The mixture was stirred at room temperature for 2 h.
LCMS indicated completion of the reaction. The reaction was
quenched by water and was purified via preparative LC/MS (method C,
55-95% B over 10 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to give Example 87 (2.7 mg, 5.05 .mu.mol,
87% yield). .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta. 8.55
(d, J=1.9 Hz, 1H), 8.51 (s, 1H), 7.74 (d, J=8.3 Hz, 3H), 7.27 (d,
J=8.3 Hz, 2H), 7.10 (d, J=2.5 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 4.22
(br. s., 2H), 4.10 (s, 3H), 4.01 (t, J=5.5 Hz, 2H), 3.35-3.33 (m,
2H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.55 min, MS
(ESI) m/z: 535.3 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 89
4-fluoro N (2 (2 (2
(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl)benzenesulfonamide
##STR00595##
[2232] Intermediate 89A:
2-chloro-6-methoxy-4-methylbenzo[d]thiazole
##STR00596##
[2234] To a solution of copper (II) chloride (1.661 g, 12.35 mmol)
in acetonitrile (8 mL) at 40.degree. C. was added tert-butyl
nitrite (1.769 mL, 13.38 mmol), followed by Intermediate I-3A (2.2
g, 11.33 mmol) as a solid. The mixture was stirring at 40.degree.
C. for 2.0 h. HPLC and LCMS indicated a complete conversion of
starting material. The mixture was diluted with EtOAc, washed with
0.5 HCl, saturated sodium bicarbonate and brine. After evaporation
of solvent, Intermediate 89A (2.4 g, 11.23 mmol, 99% yield) was
obtained as brown solid. .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.07 (d, J=2.5 Hz, 1H), 6.93-6.77 (m, 1H), 3.85 (s, 3H),
2.66 (s, 3H). LC-MS: method C, RT=2.08 min, MS (ESI) m/z: 213.9
(M+H).sup.+.
Intermediate 89B: 2-chloro-4-methylbenzo[d]thiazol-6-ol
##STR00597##
[2236] Aluminum chloride (4.49 g, 33.7 mmol) was added to a
solution of Intermediate 89A (2.4 g, 11.23 mmol) in toluene (50
mL). The mixture was heated at 110.degree. C. for 1.5 h. TLC
indicated a complete conversion of starting material. The reaction
mixture was cooled to room temperature, quenched with ice-cold 1.0
N HCl (50 mL), stirred at room temperature for 30 min. The
precipitate was collected by filtration, washed with water
(3.times.), saturated sodium bicarbonate (3.times.), water
(3.times.) and air-dried for 1.0 h under vacuum. It was further
dried under high vacuum overnight to give Intermediate 89B as brown
solid (2.2 g, 11.02 mmol, 98% yield).
Intermediate 89C:
(6-(tert-butyldimethylsilyloxy)-2-chloro-4-methylbenzo[d]thiazole
##STR00598##
[2238] To a stirred solution of Intermediate 89B (2.2 g, 11.02
mmol) in DMF (50 mL) was added TBDMS-Cl (2.325 g, 15.43 mmol) and
imidazole (1.313 g, 19.28 mmol). The reaction mixture was left
stirring at room temperature for 1.0 h. HPLC and TLC indicated a
clean reaction. The mixture was partitioned between EtOAc/water.
The organic layer was washed with brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was dissolved in a
small amount of chloroform and charged to a 120 g ISCO column which
was eluted with hexanes for 3 min., then a 30 min gradient from 0%
to 50% EtOAc in hexanes. The desired fractions were combined and
concentrated to give Intermediate 89C (1.57 g, 5.00 mmol, 45.4%
yield) as a clear orange solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.09-6.94 (m, 1H), 6.81 (dd, J=2.5, 0.8 Hz, 1H), 2.64 (s,
3H), 1.01 (s, 9H), 0.23 (s, 6H). LC-MS: method C, RT=2.74 min, MS
(ESI) m/z: 314 (M+H).sup.+.
Intermediate 89D
6-(tert-butyldimethylsilyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-y-
l)-4-methyl benzo[d]thiazole
##STR00599##
[2240] To Intermediate I-2 (28 mg, 0.121 mmol), Intermediate 89C
(37.9 mg, 0.121 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (4.93 mg, 6.03 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.121
mL, 2M, 0.241 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
135.degree. C. for 40 min. LCMS indicated a clean reaction. To the
reaction mixture was added EtOAc/water/brine. The insoluble was
removed by filtration with a pad of celite. The organic layers were
collected, washed with brine, dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform and charged to a 12 g ISCO column which was
eluted with hexanes for 3 min., then a 20 min gradient from 0% to
75% dichloromethane in hexanes The desired fractions were combined
and concentrated to give Intermediate 89D (48 mg, 0.103 mmol, 85%
yield). LC-MS: method C, gradient time 1 min, RT=2.53 min, MS (ESI)
m/z: 466.2 (M+H).sup.+.
Intermediate 89E
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
##STR00600##
[2242] To a solution of Intermediate 89D (48 mg, 0.103 mmol) in THF
(5 mL) at room temperature was added acetic acid (0.013 mL, 0.227
mmol) followed by addition of 1.0 N TBAF in THF (0.124 mL, 0.124
mmol) dropwise. The mixture was stirred at room temperature for 30
min. LCMS indicated a completion of reaction. The mixture was
diluted with EtOAc, washed with water, saturated sodium bicarbonate
(2.times.), brine, and dried over sodium sulfate. After evaporation
of the solvent, the crude product was purified with a 12 g ISCO
column eluting with 0% to 80% EtOAc in hexanes for 15 min. The
desired fraction was collected to give Intermediate 89E (36 mg,
0.102 mmol, 99% yield). .sup.1H NMR (500 MHz, chloroform-d) .delta.
9.08 (s, 1H), 8.93-8.77 (m, 1H), 7.94 (s, 1H), 7.23 (d, J=2.2 Hz,
1H), 6.86 (d, J=1.7 Hz, 1H), 4.85 (s, 2H), 3.58 (s, 3H), 2.83 (s,
3H), 2.71 (s, 3H). LC-MS: method C, RT=2.21 min, MS (ESI) (m/z) 352
[M+H].sup.+
Intermediate 89F: tert-butyl
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-
-yloxy)ethylcarbamate
##STR00601##
[2244] A solution of DIAD (0.055 mL, 0.282 mmol) in 1 ml of toluene
was added dropwise to a mixture of Intermediate 89E (33 mg, 0.094
mmol), tert-butyl (2-hydroxyethyl)carbamate (18.16 mg, 0.113 mmol)
and triphenylphosphine (49.3 mg, 0.188 mmol) in toluene (1 mL) at
110.degree. C. LCMS indicated a completion of the reaction. The
mixture was concentrated and purified with a 40 g ISCO column
eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction
was collected and concentrated to give Intermediate 89F (45 mg,
0.091 mmol, 97% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 9.05 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 7.90 (s, 1H), 7.28
(d, J=2.5 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 4.81 (s, 2H), 4.09 (t,
J=5.5 Hz, 2H), 3.56 (s, 3H), 3.50 (t, J=5.4 Hz, 2H), 2.78 (s, 3H),
2.69 (s, 3H), 1.44 (s, 9H). LC-MS: method C, RT=2.49 min, MS (ESI)
(m/z) 495.1 [M+H].sup.+.
Intermediate 89G
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-
-yloxy)ethanamine
##STR00602##
[2246] To a solution of Intermediate 89F (40 mg, 0.081 mmol) in DCM
(1 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at
room temperature for 1 h. LCMS indicated a completion of the
reaction. Solvent was removed. The crude sample was diluted with
EtOAc and water, extracted with EtOAc, the combined organic layer
was washed with saturated NaHCO.sub.3 and brine, dried with
MgSO.sub.4 and concentrated to give Intermediate 89G (30 mg, 0.076
mmol, 94% yield). .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta.
9.05 (s, 1H), 8.81 (d, J=1.7 Hz, 1H), 7.91 (s, 1H), 7.29 (d, J=2.5
Hz, 1H), 6.95 (d, J=1.4 Hz, 1H), 4.80 (s, 2H), 4.26 (t, J=5.1 Hz,
2H), 3.54 (s, 3H), 3.35 (t, J=5.0 Hz, 2H), 2.79 (s, 3H), 2.68 (s,
3H). LC-MS: method C, RT=1.91 min, MS (ESI) m/z: 395
(M+H).sup.+.
Example 89
[2247] To a solution of Intermediate 89G (15 mg, 0.038 mmol) and
4-fluorobenzene-1-sulfonyl chloride (8.88 mg, 0.046 mmol) in DMF (1
mL) was added DIEA (0.066 mL, 0.380 mmol). The mixture was stirred
at room temperature for 1 h. LCMS indicated a completion of the
reaction. Solvent was removed, the residual was dissolved purified
via preparative LC/MS (method D, 50-95% B over 10 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
89 (0.9 mg, 1.629 .mu.mol, 4.28% yield). .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. 9.06 (s, 1H), 8.80 (d, J=1.9 Hz, 1H),
7.95-7.85 (m, 3H), 7.24-7.15 (m, 3H), 6.81 (dd, J=2.2, 0.8 Hz, 1H),
4.82 (s, 2H), 4.06 (t, J=5.5 Hz, 2H), 3.57 (s, 3H), 3.35 (t, J=5.5
Hz, 2H), 2.77 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min,
MS (ESI) m/z: 553.2 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 90
4-fluoro N (2 (2 (2
methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-ylo-
xy)ethyl)benzenesulfonamide
##STR00603##
[2248] Intermediate 90A: tert-butyl
2-(4-nitro-3-(trifluoromethyl)phenoxy)ethylcarbamate
##STR00604##
[2250] DIAD (0.798 mL, 4.10 mmol) was added to a mixture of
4-nitro-3-(trifluoromethyl)phenol (0.34 g, 1.642 mmol) in THF (1.0
mL). Next, tert-butyl (2-hydroxyethyl)carbamate (0.529 g, 3.28
mmol) and triphenylphosphine (0.861 g, 3.28 mmol) in THF (10 mL)
were added to the above mixture using syringe pump in 3 h. The
reaction mixture was stirred at room temperature overnight. LCMS
indicated a completion of the reaction. The mixture was
concentrated and purified with a 40 g ISCO column eluted with 0-70%
EtOAc in hexanes for 20 min. The desired fraction was collected and
concentrated to give Intermediate 90A (1.1 g, 1.570 mmol, 96%
yield) as brown oil. .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.01 (d, J=9.0 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.13 (dd, J=9.0,
2.6 Hz, 1H), 4.18-4.13 (m, 2H), 3.58 (q, J=5.4 Hz, 2H), 1.45 (s,
9H). LC-MS: method C, RT=2.07 min, MS (ESI) m/z: 251
[M+1-Boc].sup.+.
Intermediate 90B: tert-butyl
2-(4-amino-3-(trifluoromethyl)phenoxy)ethylcarbamate
##STR00605##
[2252] To a solution of Intermediate 90A (574 mg, 1.64 mmol) in
ethyl acetate (10 mL) under argon was added 10% Pd/C (100 mg, 1.640
mmol). The mixture was stirred under an atmosphere of hydrogen
(balloon) at room temperature for 3.0 h. HPLC and TLC indicated a
completion of reaction. Pd/C was removed by filtration. The
filtrate was concentrated. The crude sample was purified with a 40
g ISCO column eluted with 0-100% EtOAc for 20 min. The desired
fraction was collected and concentrated to give Intermediate 90B
(670 mg, 1.569 mmol, 96% yield) as dark oil. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 6.98 (d, J=2.8 Hz, 1H), 6.91 (dd, J=8.7, 2.9
Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.36 (br. s., 1H), 3.96 (t, J=5.1
Hz, 2H), 3.91 (br. s., 2H), 3.50 (d, J=5.0 Hz, 2H), 1.62 (s, 3H).
LC-MS: method C, RT=1.83 min, MS (ESI) m/z: 221
(M+H-Boc).sup.+.
Intermediate 90C: tert-butyl
2-(2-amino-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)
ethylcarbamate
##STR00606##
[2254] To a solution of Intermediate 90B (180 mg, 0.562 mmol) in
acetonitrile (5 mL) was added ammonium thiocyanate (128 mg, 1.686
mmol). The mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (219 mg, 0.562 mmol) in
acetonitrile (2 mL) was added dropwise (5 min). The mixture was
stirred at room temperature overnight. The mixture was diluted with
EtOAc and NaHCO.sub.3, extracted with EtOAc. The combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a 12 g ISCO column
eluted with 0-100% EtOAc in hexanes for 15 min. The desired
fraction was collected to give Intermediate 90C (100 mg, 0.265
mmol, 47.2% yield) as a white solid. .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 7.48 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.5
Hz, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 1.44 (s,
9H). .sup.19F NMR (471 MHz, methanol-d.sub.4) .delta. -63.25 (s,
3F). LC-MS: method C, RT=1.85 min, MS (ESI) m/z: 378
(M+H).sup.+.
Intermediate 90D: tert-butyl
(2((2-bromo-4-(trifluoromethyl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
##STR00607##
[2256] tert-Butyl nitrite (0.061 mL, 0.464 mmol) was added to
copper (II) bromide (101 mg, 0.450 mmol) in dry acetonitrile (2 mL)
under argon. The mixture was stirred at room temperature for 10
min. A suspension of Intermediate 90C (100 mg, 0.265 mmol) in dry
acetonitrile (2 mL) was added dropwise. The reaction mixture was
stirred at room temperature overnight. LCMS indicated a completion
of the reaction. Acetonitrile was removed under vacuum, the
reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl.
The organic layer was collected, washed with 0.5 N HCl (2.times.),
saturated sodium bicarbonate, brine, dried over sodium sulfate.
After evaporation of solvent, the crude sample was purified with a
40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The
desired fraction was collected and concentrated to give
Intermediate 90D (92 mg, 0.208 mmol, 79% yield) as a white solid.
LC-MS: method C, RT=2.20 min, MS (ESI) m/z: 547.2 (M+H).sup.+.
Intermediate 90E: tert-butyl
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)ben-
zo[d]thiazol-6-yloxy)ethylcarbamate
##STR00608##
[2258] To Intermediate I-1 (15.24 mg, 0.045 mmol), and Intermediate
90D (20 mg, 0.045 mmol)
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (1.851 mg, 2.266 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.045
mL, 2M, 0.091 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
135.degree. C. for 40 min. To the reaction mixture was added
EtOAc/water/brine. The insoluble was removed by filtration with a
pad of celite. The organic layers were collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent, the
crude product was dissolved in a small amount of chloroform and
charged to a 12 g ISCO column which was eluted with hexanes for 3
min., then a 20 min gradient from 0% to 75% dichloromethane in
hexanes. The desired fractions were combined and concentrated to
give Intermediate 90E (25.9 mg, 0.045 mmol, 100% yield) as a bright
yellow solid. LC-MS: method C, gradient time 1 min, RT=1.67 min, MS
(ESI) m/z: 571 (M+H).sup.+.
Intermediate 90F: tert-butyl
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiaz-
ol-6-yloxy)ethylcarbamate
##STR00609##
[2260] To a solution of Intermediate 90E (25.7 mg, 0.045 mmol) in
THF (1 mL) was added sodium methoxide (0.090 mL, 0.5M, 0.045 mmol)
and the mixture was stirred at room temperature for 1 h. LCMS
indicated a completion of the reaction. The mixture was diluted
with DCM and water, extracted with DCM and the combined organic
layer was washed with brine, dried over MgSO.sub.4 and
concentrated. The crude sample was purified with a 12 g ISCO column
eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction
was collected and concentrated to give Intermediate 90F (10 mg,
0.019 mmol, 41.6% yield) as a white solid. .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. 8.63 (s, 1H), 8.51 (s, 1H), 7.75 (s, 1H),
7.65 (d, J=1.7 Hz, 1H), 7.39 (s, 1H), 4.14 (t, J=5.5 Hz, 2H), 4.11
(s, 3H), 3.52 (t, J=5.4 Hz, 2H), 2.64 (s, 3H), 1.44 (s, 9H). LC-MS:
method C, R=2.66 min, MS (ESI) m/z: 535 (M+H).sup.+.
Intermediate 90G:
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)
benzo[d]thiazol-6-yloxy)ethanamine
##STR00610##
[2262] To a solution of Intermediate 90F (7 mg, 0.013 mmol) in DCM
(1 mL) was added TFA (0.020 mL, 0.262 mmol). The mixture was
stirred at room temperature for 5 h. Solvent was removed and
Intermediate 90G was used for next step without purification.
LC-MS: method C, RT=2.15 min, MS (ESI) m/z: 435 (M+H).sup.+.
Example 90
[2263] To a solution of Intermediate 90G (5.65 mg, 0.013 mmol) and
4-fluorobenzene-1-sulfonyl chloride (3.04 mg, 0.016 mmol) in DMF (1
mL) was added DIEA (0.023 mL, 0.130 mmol). The mixture was stirred
at room temperature for 1 h. LCMS indicated a completion of the
reaction. Solvent was removed, the residual was purified via
preparative LC/MS (method D, 55-95% B over 10 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 90
(4.4 mg, 7.43 .mu.mol, 57.1% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.93 (s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.16
(d, J=2.5 Hz, 1H), 7.13-7.03 (m, 3H), 6.59-6.54 (m, 2H), 6.42 (d,
J=2.2 Hz, 1H), 3.30 (t, J=5.2 Hz, 2H), 3.26 (s, 3H), 2.45 (br. s.,
2H), 1.82 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z:
593.1 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 91
N-(2-(2-(2-cyclopropyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6--
yloxy)ethyl)-4-fluorobenzenesulfonamide
##STR00611##
[2264] Intermediate 91A: tert-butyl
(2-bromo-4-methyl-6-nitrophenyl)(2-cyclopropyl-2-oxoethyl)carbamate
##STR00612##
[2266] To Intermediate I-1B (400 mg, 1.208 mmol) in DMF (5 mL) at
room temperature was added Cs.sub.2CO.sub.3 (1181 mg, 3.62 mmol).
The brown solution was stirred at room temperature for 5 min,
followed by addition of 2-bromo-1-cyclopropylethanone (438 mg,
2.416 mmol) in acetonitrile (0.4 mL). The mixture was stirred at
room temperature for 2 h. TLC and LCMS indicated a clean reaction.
The mixture was diluted with EtOAc, washed with water, brine, dried
over sodium sulfate and concentrated. The crude sample was purified
with a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20
min. The desired fraction was collected and concentrated to give
Intermediate 91A (490 mg, 1.186 mmol, 98% yield) as yellow oil.
LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 356 and 358
[M+1-tBu].sup.+.
Intermediate 91B: 5-bromo-2-cyclopropyl-7-methylquinoxaline
##STR00613##
[2268] To Intermediate 91A (490 mg, 1.186 mmol) in DCM (4 mL) was
added 4.0 N HCl in dioxane (3.56 mL, 14.23 mmol) and the mixture
was stirred at room temperature for 1 h. TLC indicated a completion
of the reaction. Solvent was removed to give the deprotected
intermediate as yellow oil. The deprotected intermediate was
dissolved in THF (4 mL). Tin(II) chloride dihydrate (883 mg, 3.91
mmol) was added followed by concentrated HCl (0.146 mL, 1.779
mmol). The mixture was placed and stirred in an oil bath pre-heated
at 45.degree. C. for 1.0 h. TLC and LCMS indicated a clean
reaction. The reaction mixture was diluted with EtOAc/water and
neutralized with saturated sodium bicarbonate. The mixture was
stirred at room temperature for 15 min and extracted with EtOAc
(5.times.). The precipitate (tin hydroxide) was removed by a
separatory funnel. The organic layer was washed with saturated
sodium bicarbonate, brine, dried over sodium sulfate and
concentrated. The crude sample was purified with a 40 g ISCO column
eluted with 0-60% EtOAc in hexanes for 15 min. The desired fraction
was collected and concentrated to give Intermediate 91B (310 mg,
1.178 mmol, 99% yield) as a light yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.76 (s, 1H), 7.81 (d, J=1.8 Hz, 1H),
7.69 (dd, J=1.8, 0.9 Hz, 1H), 2.54 (s, 3H), 2.34-2.23 (m, 1H),
1.30-1.25 (m, 2H), 1.24-1.16 (m, 2H). LC-MS: method C, RT=2.07 min,
MS (ESI) m/z: 263 and 265. (M+H).sup.+.
Intermediate 91C
2-cyclopropyl-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quin-
oxaline
##STR00614##
[2270] A mixture of Intermediate 91B (30 mg, 0.114 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (50.7
mg, 0.200 mmol), potassium acetate (22.38 mg, 0.228 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (2.79 mg, 3.42 .mu.mol) in
dioxane (2 mL) was degassed with argon for 10 min. The reaction
vial was heated in microwave reactor at 120.degree. C. for 30 min.
LCMS indicated complete conversion of starting material and a clean
reaction. The mixture was diluted with EtOAc/water, insoluble
material was removed by filtration. The filtrate was extracted with
EtOAc, washed with brine, dried over sodium sulfate. After
evaporation of solvent, the crude sample of Intermediate 91C was
obtained and used for the next step without purification. LC-MS:
method C, RT=2.03 min, MS (ESI) m/z: 229 (M+H).sup.+ (boronic
acid).
Example 91
[2271] To Intermediate 91C (34.8 mg, 0.112 mmol), Intermediate I-5
(20 mg, 0.045 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (1.834 mg, 2.246 .mu.mol) was
added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.045 mL,
2M, 0.090 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 130.degree.
C. for 40 min. To the reaction mixture was added EtOAc/water/brine.
The insoluble was removed by filtration with a pad of celite. The
organic layers were collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
purified via preparative LC/MS (method D, 60-100% B over 20 min.,
then a 5-min hold at 100% B). Fractions containing the desired
product were combined and dried via centrifugal evaporation to give
Example 91 (6.8 mg, 0.012 mmol, 27.6% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.03 (s, 1H), 8.67 (s, 1H), 8.03 (br. s.,
1H), 7.95-7.81 (m, 3H), 7.48-7.37 (m, 3H), 6.85 (s, 1H), 4.05 (t,
J=5.0 Hz, 2H), 3.22 (br. s., 2H), 2.72 (s, 3H), 2.64 (s, 3H),
1.29-1.13 (m, 5H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z:
549.2 (M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 92
Benzyl
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]th-
iazol-6-yloxy)ethylcarbamate
##STR00615##
[2272] Intermediate 92A: tert-butyl
2-(3-methyl-4-nitrophenoxy)ethylcarbamate
##STR00616##
[2274] A solution of DIAD (7.77 mL, 40.0 mmol) in 2 ml of toluene
was added to a mixture of 3-methyl-4-nitrophenol (3.4 g, 22.20
mmol), tert-butyl (2-hydroxyethyl) carbamate (4.29 g, 26.6 mmol)
and triphenylphosphine (6.99 g, 26.6 mmol) in toluene (50 mL) at
110.degree. C. using syringe pump in 2 h. The reaction mixture was
stirred at 110.degree. C. for additional 30 min, then at room
temperature overnight. The mixture was diluted with EtOAc and
water, extracted with EtOAc, the combined organic layer was washed
with NaHCO.sub.3 and brine, dried with Na.sub.2SO.sub.4 and
concentrated. The crude sample was purified with a 120 g ISCO
column eluted with 0-70% EtOAc in hexanes for 40 min. The desired
fraction was collected and concentrated to give Intermediate 92A
(3.3 g, 11.14 mmol, 50.2% yield). .sup.1H NMR (500 MHz,
chloroform-d) .delta. 8.08 (d, J=8.8 Hz, 1H), 6.84-6.77 (m, 2H),
4.97 (br. s., 1H), 4.09 (t, J=5.1 Hz, 2H), 3.56 (q, J=5.0 Hz, 2H),
2.63 (s, 3H), 1.46 (s, 9H). LC-MS: method C, RT=2.03 min, MS (ESI)
m/z: 197 (M+H-Boc).sup.+.
Intermediate 92B: tert-butyl
2-(4-amino-3-methylphenoxy)ethylcarbamate
##STR00617##
[2276] To a solution of Intermediate 92A (3.5 g, 11.81 mmol) in
ethyl acetate (10 mL) under argon was added 10% Pd/C (200 mg, 23.62
mmol). The mixture was stirred under an atmosphere of hydrogen
(balloon) at room temperature overnight. Pd/C was removed by
filtration. The filtrate was concentrated. The crude sample was
purified with a 120 g ISCO column eluted with 0-100% EtOAc in
hexanes for 45 min. The desire fraction was collected to give
Intermediate 92B (2.5 g, 9.39 mmol, 79% yield) as a pink solid.
.sup.1H NMR (500 MHz, chloroform-d) .delta. 6.67 (s, 1H), 6.62 (d,
J=1.7 Hz, 2H), 5.00 (br. s., 1H), 3.95 (t, J=5.1 Hz, 2H), 3.49 (d,
J=5.0 Hz, 2H), 3.37 (br. s., 2H), 2.16 (d, J=0.6 Hz, 3H), 1.46 (s,
9H). LC-MS: method C, RT=1.34 min, MS (ESI) m/z: 167
[M+1-Boc].sup.+.
Intermediate 92C: tert-butyl
2-(2-amino-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
##STR00618##
[2278] To a solution of Intermediate 92B (2.5 g, 9.39 mmol) in
acetonitrile (20 mL) was added ammonium thiocyanate (1.072 g, 14.08
mmol). The mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (3.66 g, 9.39 mmol) in
acetonitrile (10 mL) was added dropwise (5 min). The mixture was
stirred at room temperature overnight. LCMS indicated a clean
reaction. The mixture was diluted with EtOAc/saturated sodium
bicarbonate. The insoluble material was removed by filtration. The
organic layer of the filtrate was collected, washed with brine,
dried over sodium sulfate. After evaporation of solvent, the
product was precipitated out from methanol, collected by
filtration, washed with acetonitrile to give Intermediate 92C (2.8
g, 8.66 mmol, 92% yield) as a slightly yellow solid. .sup.1H NMR
(500 MHz, chloroform-d) .delta. 6.97 (d, J=2.2 Hz, 1H), 6.75 (d,
J=1.9 Hz, 1H), 5.05 (s, 2H), 4.02 (t, J=5.0 Hz, 2H), 3.53 (d, J=4.7
Hz, 2H), 2.53 (s, 3H), 1.46 (s, 9H). LC-MS: method C, RT=2.57 min,
MS (ESI) m/z: 324 (M+H).sup.+.
Intermediate 92D: tert-butyl
2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
##STR00619##
[2280] To a stirred solution of Intermediate 92C (2.8 g, 8.66 mmol)
and copper (II) chloride (1.029 g, 10.39 mmol) in acetonitrile (30
mL) was added tert-butyl nitrite (1.487 mL, 11.26 mmol). The
mixture was stirred at room temperature for 2 h. Acetonitrile was
removed under vacuum, the reaction mixture was diluted with EtOAc,
quenched with 1.0 N HCl. The organic layer was collected, washed
with 0.5 N HCl (2.times.), saturated sodium bicarbonate, brine,
dried over sodium sulfate. After evaporation of solvent, the crude
dark oil was purified with a 120 g ISCO column eluted with 0-70%
EtOAc in hexanes for 40 min. The desired fraction was collected and
concentrated to give Intermediate 92D (1.75 g, 5.10 mmol, 59.0%
yield) as an off-white solid. .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.05 (d, J=2.5 Hz, 1H), 6.89 (dd, J=2.5, 0.8 Hz, 1H), 5.00
(br. s., 1H), 4.05 (t, J=5.1 Hz, 2H), 3.56 (d, J=5.0 Hz, 2H), 2.65
(s, 3H), 1.46 (s, 9H). LC-MS: method C, RT=2.21 min, MS (ESI) m/z:
343 (M+H).sup.+.
Intermediate 92E:
2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethanamine
##STR00620##
[2282] To a solution of Intermediate 92D (100 mg, 0.292 mmol) in
DCM (1.5 mL) was added TFA (1.124 mL, 14.58 mmol). The mixture was
stirred at room temperature for 1 h. LCMS indicated a completion of
the reaction. The mixture was concentrated and the residual was
diluted with EtOAc and saturated NaHCO.sub.3, extracted with EtOAc.
The combined organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated to give Intermediate 92E (70 mg, 0.288
mmol, 99% yield) as an off-white solid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.29 (d, J=2.4 Hz, 1H), 7.06-6.84 (m,
1H), 4.19 (t, J=5.2 Hz, 2H), 3.28 (br. s., 2H), 2.58 (s, 3H).
LC-MS: method C, RT=1.43 min, MS (ESI) m/z: 243 (M+H).sup.+.
Intermediate 92F: benzyl
2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
##STR00621##
[2284] To a stirred solution of Intermediate 92E (70 mg, 0.288
mmol) in THF (1 mL) at room temperature was added sodium
bicarbonate (1.154 mL, 2M, 2.307 mmol). CBz-Cl (0.049 mL, 0.346
mmol) was added dropwise. The mixture was stirred at room
temperature for 1 h, LCMS indicated a completion of the reaction.
The mixture was diluted with EtOAc and water, extracted with EtOAc.
The combined organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated. The crude sample was purified with a
12 g ISCO column eluted with 0-60% EtOAc in hexanes for 15 min. The
desired product was collected and concentrated to give Intermediate
92F (100 mg, 0.265 mmol, 92% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.38-7.35 (m, 5H), 7.04 (d, J=2.2 Hz, 1H),
6.87 (d, J=1.3 Hz, 1H), 5.25 (br. s., 1H), 5.12 (s, 2H), 4.72 (s,
1H), 4.07 (t, J=5.1 Hz, 2H), 3.64 (q, J=5.3 Hz, 2H), 2.65 (s, 3H).
LC-MS: method C, RT=2.22 min, MS (ESI) m/z: 377 (M+H).sup.+.
Example 92
[2285] To Intermediate I-2 (30 mg, 0.129 mmol), Intermediate 92F
(58.5 mg, 0.155 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.28 mg, 6.46 .mu.mol) was
added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.129 mL,
2M, 0.259 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 130.degree.
C. for 40 min. To the reaction mixture was added EtOAc/water/brine.
The insoluble was removed by filtration with a pad of celite. The
organic layers were collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
ISCO column which was eluted with hexanes for 3 min., then a 20 min
gradient from 0% to 100% EtOAc in hexanes The desired fractions
were combined and concentrated. The sample was further purified via
preparative LC/MS (method D, 50-90% B over 10 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 92
(42 mg, 0.079 mmol, 61.5% yield) as a yellow solid. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.80 (s, 1H), 8.01
(s, 1H), 7.60-7.48 (m, 2H), 7.36 (d, J=4.4 Hz, 4H), 7.33-7.28 (m,
1H), 7.00 (br. s., 1H), 5.05 (s, 2H), 4.80 (s, 2H), 4.10 (t, J=5.5
Hz, 2H), 3.48-3.41 (m, 5H), 2.74 (s, 3H), 2.70 (s, 3H). LC-MS:
method C, RT=2.50 min, MS (ESI) m/z: 529.2 (M+H).sup.+.
Example 93
4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]th-
iazole
##STR00622##
[2286] Intermediate 93A: 2-chloro-4-methoxy-1-nitrobenzene
##STR00623##
[2288] To a solution of 2-chloro-4-fluoro-1-nitrobenzene (220 mg,
1.253 mmol) in THF (2 mL) was added sodium methoxide (7.52 mL, 0.5,
3.76 mmol). The mixture was stirred at room temperature for 1.0 h.
LCMS indicated a completion of the reaction The mixture was diluted
with EtOAc, quenched with saturated ammonium chloride. The organic
layer was washed with saturated sodium bicarbonate, brine, dried
over sodium sulfate and concentrated. The crude product was
purified with flash chromatography (loading in chloroform, 0% to
30% EtOAc in hexanes over 12 min using a 12 g silica gel
cartridge). The desired fractions were combined and concentrated to
give Intermediate 93A (230 mg, 1.226 mmol, 98% yield) as a yellow
liquid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.02 (d, J=9.2
Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.89 (dd, J=9.2, 2.6 Hz, 1H), 3.90
(s, 3H). LC-MS: method C, RT=1.80 min, MS (ESI) m/z: 188
(M+H).sup.+.
Intermediate 93B: 2-chloro-4-methoxyaniline
##STR00624##
[2290] To a solution of Intermediate 93A (230 mg, 1.226 mmol) in
MeOH (6.0 mL) was added ammonium chloride (1312 mg, 24.52 mmol) and
zinc dust (802 mg, 12.26 mmol). The mixture was stirred at room
temperature for 1 h. MeOH was removed under vacuum. The residue was
diluted with EtOAc/saturated sodium bicarbonate and stirred at room
temperature for 10 min. The mixture was filtered to remove
insoluble material. The filtrate was collected, organic layer was
washed with brine, dried over sodium sulfate and concentrated. The
crude sample was purified with a 12 g ISCO column eluted with
0-100% EtOAc in hexanes for 15 min. The desired fraction was
collected and concentrated to give Intermediate 93B (193 mg, 1.225
mmol, 100% yield) as oil. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 6.86 (t, J=2.5 Hz, 1H), 6.76-6.64 (m, 2H), 3.74 (d, J=3.1
Hz, 3H). LC-MS: method C, RT=0.8 min, MS (ESI) m/z: 158
(M+H).sup.+.
Intermediate 93C: 4-chloro-6-methoxybenzo[d]thiazol-2-amine
##STR00625##
[2292] To a solution of Intermediate 93B (190 mg, 1.206 mmol) in
acetonitrile (5.0 mL) was added ammonium thiocyanate (161 mg, 2.110
mmol). The mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (635 mg, 1.628 mmol) in
acetonitrile (2.0 mL) was added dropwise (5 min). The mixture was
stirred at room temperature overnight. Acetonitrile was removed
under vacuum. The mixture was diluted with EtOAc, THF/saturated
sodium bicarbonate. The insoluble material was removed by
filtration. The organic layer of the filtrate was collected, washed
with brine, dried over sodium sulfate and concentrated to give
Intermediate 93C (250 mg, 1.165 mmol, 97% yield) as a yellow solid
that was used for the next step without further purification.
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 7.16 (d, J=2.4 Hz,
1H), 6.91 (d, J=2.4 Hz, 1H), 3.79 (s, 3H). LC-MS: method C, RT=1.38
min, MS (ESI) m/z: 215 (M+H).sup.+.
Intermediate 93D: 2-bromo-4-chloro-6-methoxybenzo[d]thiazole
##STR00626##
[2294] To a solution of copper (II) bromide (0.21 g, 1.51 mmol) in
acetonitrile (8 mL) at 40.degree. C. was added tert-butyl nitrite
(0.200 mL, 1.514 mmol) followed by Intermediate 93C (250 mg, 1.165
mmol) as a solid. The mixture was stirring at 40.degree. C. for 2.0
h. HPLC and LCMS indicated a complete conversion of starting
material. The mixture was diluted with EtOAc, washed with 0.5 HCl,
saturated sodium bicarbonate and brine. After evaporation of
solvent, Intermediate 93D (215 mg, 0.772 mmol, 66.3% yield) was
obtained as a yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.17 (d, J=2.4 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 3.87 (s,
3H). LC-MS: method C, RT=2.08 min, MS (ESI) m/z: 279.9
(M+H).sup.+.
Example 93
[2295] To Intermediate I-2 (11 mg, 0.047 mmol), Intermediate 93D
(15.85 mg, 0.057 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (1.936 mg, 2.370 .mu.mol) was
added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.047 mL,
2M, 0.095 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 130.degree.
C. for 40 min. LCMS indicated a clean reaction. To the reaction
mixture was added EtOAc/water/brine. The insoluble was removed by
filtration with a pad of celite. The organic layers were collected,
washed with brine, dried over sodium sulfate. After evaporation of
solvent, the crude product was purified via preparative LC/MS
(method D, 45-85% B over 20 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Example 93 (3.3 mg, 8.47
.mu.mol, 17.86% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.10 (s, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.07 (s, 1H), 7.77 (d, J=2.5
Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 4.82 (s, 2H), 3.89 (s, 3H), 3.47
(s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z:
386.1 (M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 94
5-(5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
##STR00627##
[2297] To Intermediate I-2E (5 mg, 0.019 mmol),
(5-methoxybenzofuran-2-yl)boronic acid (4.31 mg, 0.022 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (0.764 mg, 0.936 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.019
mL, 2M, 0.037 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
130.degree. C. for 40 min. To the reaction mixture was added
EtOAc/water/brine. The insoluble was removed by filtration with a
pad of celite. The organic layers were collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent, the
crude product was purified via preparative LC/MS (method D; 50-90%
B over 10 min., then a 5-min hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to give Example 94 (5.1 mg, 0.014 mmol, 75.0% yield).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.07 (s, 1H), 8.28 (d,
J=1.7 Hz, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.61-7.58 (m, 1H), 7.31
(d, J=2.5 Hz, 1H), 6.98-6.96 (m, 1H), 4.80 (s, 2H), 3.83 (s, 3H),
3.82 (s, 3H), 3.47 (s, 3H). LC-MS: method C, RT=2.36 min, MS (ESI)
m/z: 335.10 (M+H).sup.+. Analytical HPLC purity (method B):
92%.
Example 95
N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiaz-
ol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00628##
[2298] Intermediate 95A: tert-butyl
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol--
6-yloxy)ethylcarbamate
##STR00629##
[2300] To Intermediate I-2 (40 mg, 0.172 mmol), Intermediate 92D
(59.1 mg, 0.172 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.04 mg, 8.62 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.172
mL, 2M, 0.345 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
130.degree. C. for 40 min. LCMS indicated a clean reaction. To the
reaction mixture was added EtOAc/water/brine. The insoluble was
removed by filtration with a pad of celite. The organic layers were
collected, washed with brine, dried over sodium sulfate. After
evaporation of solvent, the crude product was dissolved in a small
amount of chloroform and charged to a 40 g ISCO column which was
eluted with hexanes for 3 min., then a 20 min gradient from 0% to
100% EtOAc in hexanes. The desired fractions were combined and
concentrated to give Intermediate 95A (80 mg, 0.162 mmol, 94%
yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 9.06 (d, J=3.5
Hz, 1H), 8.85 (d, J=3.3 Hz, 1H), 7.92 (br. s., 1H), 7.23 (t, J=2.6
Hz, 1H), 6.93 (br. s., 1H), 5.07 (br. s., 1H), 4.83 (d, J=2.4 Hz,
2H), 4.12-4.05 (m, 2H), 3.60-3.53 (m, 5H), 2.83 (s, 3H), 2.70 (d,
J=2.0 Hz, 3H), 1.48 (s, 9H). LC-MS: method C, RT=2.50 min, MS (ESI)
m/z: 495 (M+H).sup.+.
Intermediate 95B
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-
-yloxy)ethanamine
##STR00630##
[2302] To a solution of Intermediate 95A (18 mg, 0.036 mmol) in DCM
(1 mL) was added 2,6-lutidine (16.95 .mu.l, 0.146 mmol) followed by
TMS-OTf (13.15 .mu.l, 0.073 mmol) at room temperature. The mixture
was stirred at room temperature overnight. Another portion of
TMS-OTf (13.15 .mu.l, 0.073 mmol) was added to the mixture, and the
mixture was stirred at room temperature for 2 h. LCMS indicated a
completion of the reaction. The mixture was diluted with EtOAc and
NaHCO.sub.3, extracted with EtOAc. The combined organic layer was
washed with brine, dried with MgSO.sub.4 and concentrated to give
Intermediate 95B (14.2 mg, 0.036 mmol, 98% yield). The sample was
used for next step without further purification. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 9.06 (s, 1H), 8.82 (d, J=1.8 Hz,
1H), 7.93 (s, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.99 (dd, J=2.4, 0.9 Hz,
1H), 4.82-4.81 (m, 2H), 4.15 (t, J=5.2 Hz, 2H), 3.15 (t, J=5.1 Hz,
2H), 2.79 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=1.43 min, MS
(ESI) m/z: 243 (M+H).sup.+.
Example 95
[2303] To a solution of Intermediate 95B (14.20 mg, 0.036 mmol) in
DMF (1 mL) was added DIEA (0.063 mL, 0.360 mmol) and
benzenesulfonyl chloride (5.57 .mu.l, 0.043 mmol). The mixture was
stirred at room temperature for 1 h. The reaction mixture was
quenched with 0.2 ml of MeOH. Solvent was removed, the residual was
purified via preparative LC/MS (method D, 50-90% B over 12 min.,
then a 5-min hold at 100% B). Fractions containing the desired
product were combined and dried via centrifugal evaporation to give
Example 95 (3.3 mg, 6.05 .mu.mol, 16.80% yield). .sup.1H NMR (500
MHz, methanol-d.sub.4) .delta. 9.06 (s, 1H), 8.80 (d, J=1.5 Hz,
1H), 7.97-7.84 (m, 3H), 7.55 (d, J=7.4 Hz, 1H), 7.52-7.47 (m, 2H),
7.15 (d, J=2.0 Hz, 1H), 6.81 (d, J=1.5 Hz, 1H), 4.82 (s, 2H), 4.04
(t, J=5.4 Hz, 2H), 3.57 (s, 3H), 3.35 (t, J=5.7 Hz, 2H), 2.76 (s,
3H), 2.69 (s, 3H). LC-MS: method C, RT=2.43 min, MS (ESI) m/z:
535.15 (M+H).sup.+. Analytical HPLC purity (method B): 98%.
Example 96
2-fluoro N (2 (2 (2
(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl)benzenesulfonamide
##STR00631##
[2305] To a solution of Intermediate 95B (8 mg, 0.020 mmol) in DMF
(1 mL) was added DIEA (0.035 mL, 0.203 mmol) and
2-fluorobenzene-1-sulfonyl chloride (4.74 mg, 0.024 mmol). The
mixture was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. Solvent was removed, the residual was
purified via preparative LC/MS (method D, 50-90% B over 10 min.,
then a 5-min hold at 100% B). Fractions containing the desired
product were combined and dried via centrifugal evaporation to give
Example 96 (4.2 mg, 7.60 .mu.mol, 37.5% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.78 (d, J=1.9 Hz, 1H),
8.01 (d, J=0.8 Hz, 1H), 7.84 (td, J=7.6, 1.7 Hz, 1H), 7.74-7.65 (m,
1H), 7.43-7.34 (m, 3H), 6.76 (d, J=1.4 Hz, 1H), 4.80 (s, 2H), 4.05
(t, J=5.4 Hz, 2H), 3.46 (s, 3H), 3.35-3.33 (m, 2H), 2.74-2.71 (m,
3H), 2.68 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z:
553.1 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 97
3-fluoro-N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo-
[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
##STR00632##
[2307] To a solution of Intermediate 95B (8 mg, 0.020 mmol) in DMF
(1 mL) was added DIEA (0.035 mL, 0.203 mmol) and
3-fluorobenzene-1-sulfonyl chloride (4.74 mg, 0.024 mmol). The
mixture was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. Solvent was removed, the residual was
purified via preparative LC/MS (method D, 50-90% B over 10 min.,
then a 5-min hold at 100% B). Fractions containing the desired
product were combined and dried via centrifugal evaporation to give
Example 97 (4.1 mg, 7.34 .mu.mol, 36.2% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.80 (d, J=1.9 Hz, 1H),
8.14 (br. s., 1H), 8.02 (s, 1H), 7.73-7.61 (m, 3H), 7.50 (s, 1H),
7.45 (s, 1H), 6.86 (d, J=1.4 Hz, 1H), 4.81 (s, 2H), 4.06 (t, J=5.4
Hz, 2H), 3.47 (s, 3H), 3.26 (d, J=5.0 Hz, 2H), 2.74 (s, 3H), 2.69
(s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 553.1
(M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 98
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yloxy) ethyl)methanesulfonamide
##STR00633##
[2308] Intermediate 98A: tert-butyl
2-(3-chloro-4-nitrophenoxy)ethylcarbamate
##STR00634##
[2310] To a solution of tert-butyl (2-hydroxyethyl)carbamate (3.67
g, 22.79 mmol) in THF (30 mL) was added 1 N sodium
bis(trimethylsilyl)amide in THF (25.06 mL, 25.06 mmol). The mixture
was stirred at room temperature for 10 min.
2-Chloro-4-fluoro-1-nitrobenzene (2 g, 11.39 mmol) was added and
the reaction mixture was stirred at room temperature for 2 h. The
mixture was diluted with EtOAc, quenched with saturated ammonium
chloride. The organic layer was washed with saturated sodium
bicarbonate, brine, dried over sodium sulfate and concentrated. The
crude product was purified with flash chromatography (loading in
chloroform, 0% to 45% EtOAc in hexanes over 15 min using a 120 g
silica gel cartridge). The desired fractions were combined and
concentrated to yield Intermediate 98A (3.6 g, 11.37 mmol, 100%
yield) as a yellow liquid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.10-7.87 (m, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.88 (dd, J=9.0,
2.6 Hz, 1H), 4.94 (br. s., 1H), 4.11-4.02 (m, 2H), 3.57 (q, J=5.4
Hz, 2H), 1.46 (s, 9H). LC-MS: method C, RT=2.04 min, MS (ESI) m/z:
217 [M+1-Boc].sup.+.
Intermediate 98B: tert-butyl
2-(4-amino-3-chlorophenoxy)ethylcarbamate
##STR00635##
[2312] To a solution of Intermediate 98A (3.6 g, 11.37 mmol) in
MeOH (6.0 mL) was added ammonium chloride (7.30 g, 136 mmol) and
zinc dust (4.46 g, 68.2 mmol). The mixture was stirred at room
temperature overnight. MeOH was removed. The residue was diluted
with EtOAc/saturated sodium bicarbonate and stirred at room
temperature for 10 min. The mixture was filtered to remove
insoluble material. The filtrate was collected, organic layer was
washed with brine, dried over sodium sulfate and concentrated. The
crude sample was purified with a 120 g ISCO column eluted with
0-100% EtOAc in hexanes for 40 min. The desired fraction was
collected and concentrated to give Intermediate 98B (2.9 g, 10.11
mmol, 89% yield) as off-white solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 6.86 (d, J=2.4 Hz, 1H), 6.80-6.65 (m, 2H),
3.94 (t, J=5.2 Hz, 2H), 3.49 (q, J=4.9 Hz, 2H), 1.46 (s, 9H).
LC-MS: method C, RT=1.52 min, MS (ESI) m/z: 187
[M+1-B0c].sup.+.
Intermediate 98C: tert-butyl
2-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate
##STR00636##
[2314] To Intermediate 98B (2.9 g, 10.11 mmol) in acetonitrile (30
mL) was added ammonium thiocyanate (1.347 g, 17.70 mmol). The
mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (5.32 g, 13.65 mmol) in
acetonitrile (2.0 mL) was added dropwise (5 min). The mixture was
stirred at room temperature overnight. Acetonitrile was removed.
The residual was diluted with EtOAc and saturated sodium
bicarbonate, extracted with EtOAc (3.times.). The combined organic
layer was washed with brine, dried over sodium sulfate and
concentrated to give Intermediate 98C (2.8 g, 8.14 mmol, 81% yield)
as a yellow solid that was used for the next step without further
purification. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.02
(d, J=2.4 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 3.97 (t, J=5.4 Hz, 2H),
3.48-3.39 (m, 2H), 1.41 (s, 9H). LC-MS: method C, RT=1.71 min, MS
(ESI) m/z: 344 (M+H).sup.+.
Intermediate 98D: tert-butyl
2-(2-bromo-4-chlorobenzo[d]thiazol-6-yloxy) ethylcarbamate
##STR00637##
[2316] To a solution of copper (II) bromide (1.402 g, 9.77 mmol) in
acetonitrile (30 mL) at 40.degree. C. was added tert-butyl nitrite
(1.399 mL, 10.59 mmol) followed by Intermediate 98C (2.8 g, 8.14
mmol) as a solid. The mixture was stirring at 40.degree. C. for 2.0
h and then room temperature overnight. The mixture was diluted with
EtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine.
After evaporation of solvent, the crude sample was purified with a
40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The
desired fraction was collected and concentrated to give
Intermediate 98D (240 mg, 0.589 mmol, 7.23% yield). .sup.1H NMR
(400 MHz, chloroform-d) .delta. 7.15 (d, J=2.4 Hz, 1H), 7.11 (d,
J=2.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 2H), 3.56 (q, J=5.3 Hz, 2H), 1.46
(s, 9H). LC-MS: method C, RT=2.21 min, MS (ESI) m/z: 406.9 and
408.9 (M+H).sup.+.
Intermediate 98E: tert-butyl
2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yloxy)ethylcarbamate
##STR00638##
[2318] To Intermediate I-2 (40 mg, 0.172 mmol), Intermediate 98D
(70.3 mg, 0.172 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.04 mg, 8.62 .mu.mol) was
added toluene (1.5 mL), EtOH (0.5 mL) and sodium carbonate (0.172
mL, 2M, 0.345 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
120.degree. C. for 40 min. To the reaction mixture was added
EtOAc/water/brine. The insoluble was removed by filtration with a
pad of celite. The organic layers were collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent, the
crude product was dissolved in a small amount of chloroform and
charged to a 40 g ISCO column which was eluted with hexanes for 3
min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. The
desired fraction was collected and concentrated to give
Intermediate 98E (85 mg, 0.165 mmol, 96% yields). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.80 (d, J=1.7 Hz, 1H),
8.06 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.05
(br. s., 1H), 4.81 (s, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.47 (s, 3H),
3.39-3.34 (m, 2H), 2.70 (s, 3H), 1.39 (s, 9H). LC-MS: method C,
RT=2.54 min, MS (ESI) m/z: 515 (M+H).sup.+.
Intermediate 98F:
2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yloxy)ethanamine
##STR00639##
[2320] To a solution of Intermediate 98E (85 mg, 0.165 mmol) in DCM
(2 mL) was added 2,6-lutidine (0.058 mL, 0.495 mmol) followed by
TMS-OTf (0.135 mL, 0.75 mmol) at 0.degree. C. The mixture was
stirred at room temperature for 2 h. LCMS indicated a completion of
the reaction. The mixture was diluted with EtOAc and NaHCO.sub.3,
extracted with EtOAc. The combined organic layer was washed with
brine and concentrated. The residual was added 1 ml of MeOH and
stirred at room temperature for 15 min and concentrated to give
Intermediate 98F (65 mg, 0.157 mmol, 95% yield) as a yellow solid.
the crude sample was used for next step without purification.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.04 (s, 1H),
8.90-8.82 (m, 1H), 7.92 (s, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.19 (d,
J=2.2 Hz, 1H), 4.81 (s, 2H), 4.10 (t, J=5.0 Hz, 2H), 3.56 (s, 3H),
3.10 (br. s., 2H), 2.69 (s, 3H). LC-MS: method C, RT=1.91 min, MS
(ESI) m/z: 415 (M+H).sup.+.
Example 98
[2321] To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in
DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and
methanesulfonyl chloride (4.12 mg, 0.036 mmol). The mixture was
stirred at room temperature for 15 min. The reaction was quenched
with water, and the solvent was removed. The residual was purified
via preparative LC/MS (method D, 55-95% B over 10 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
98 (6.2 mg, 0.013 mmol, 41.9% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.06
(d, J=0.6 Hz, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.33 (s, 1H), 4.81 (s,
2H), 4.18 (t, J=5.5 Hz, 2H), 3.47 (s, 3H), 3.40 (d, J=5.0 Hz, 2H),
2.98 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.10 min, MS (ESI)
m/z: 493.10 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 99
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yloxy) ethyl)benzenesulfonamide
##STR00640##
[2323] To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in
DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and
benzenesulfonyl chloride (6.36 mg, 0.036 mmol). The mixture was
stirred at room temperature for 15 min. LCMS indicated a completion
of the reaction. The reaction was quenched by water and solvent was
removed. The residual was purified via preparative LC/MS (method D,
55-100% B over 11 min, then a 4-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to give Example 99 (7.0 mg, 0.012 mmol,
41.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.04 (s,
1H), 8.73 (d, J=1.4 Hz, 1H), 8.00 (s, 2H), 7.85 (d, J=7.2 Hz, 2H),
7.69-7.54 (m, 3H), 7.12 (d, J=2.2 Hz, 1H), 4.79 (s, 2H), 4.08 (t,
J=5.2 Hz, 2H), 3.47 (s, 3H), 3.22 (t, J=5.0 Hz, 2H), 2.67 (s, 3H).
LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 555.2 (M+H).sup.+.
Analytical HPLC purity (method B): 99%.
Example 100
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yloxy) ethyl)-2-fluorobenzenesulfonamide
##STR00641##
[2325] To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in
DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and
2-fluorobenzene-1-sulfonyl chloride (7.01 mg, 0.036 mmol). The
mixture was stirred at room temperature for 15 min. LCMS indicated
a completion of the reaction. The reaction was quenched by water
and solvent was removed. The residual was purified via preparative
LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 100 (7.6 mg,
0.013 mmol, 44.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.08 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.84
(td, J=7.8, 1.5 Hz, 1H), 7.71-7.64 (m, 1H), 7.62 (d, J=2.2 Hz, 1H),
7.45-7.34 (m, 2H), 7.03 (d, J=2.5 Hz, 1H), 4.81 (s, 2H), 4.09 (t,
J=5.2 Hz, 2H), 3.47 (s, 3H), 3.36 (t, J=5.2 Hz, 2H), 2.69 (s, 3H).
LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 573.1 (M+H).sup.+.
Analytical HPLC purity (method B): 100%.
Example 101
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yloxy) ethyl)-4-fluorobenzenesulfonamide
##STR00642##
[2327] To a solution of Intermediate 98F (14.52 mg, 0.035 mmol) in
DMF (1 mL) was added DIEA (0.061 mL, 0.350 mmol) and
4-fluorobenzene-1-sulfonyl chloride (8.17 mg, 0.042 mmol). The
mixture was stirred at room temperature For 15 min. LCMS indicated
a completion of the reaction. The reaction was quenched by water
and solvent was removed. The residual was purified via preparative
LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 101 (11.3 mg,
0.020 mmol, 56.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.08 (s, 1H), 8.78 (d, J=1.7 Hz, 1H), 8.05 (s, 1H),
7.96-7.84 (m, 2H), 7.66 (d, J=2.5 Hz, 1H), 7.47-7.37 (m, 2H), 7.14
(d, J=2.2 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.47 (s,
3H), 3.23 (t, J=5.2 Hz, 2H), 2.70 (s, 3H). LC-MS: method C, RT=2.38
min, MS (ESI) m/z: 573.1 (M+H).sup.+. Analytical HPLC purity
(method B): 100%.
Example 102
N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yloxy) ethyl)-3-fluorobenzenesulfonamide
##STR00643##
[2329] To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in
DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and
3-fluorobenzene-1-sulfonyl chloride (7.01 mg, 0.036 mmol). The
mixture was stirred at room temperature for 15 min. LCMS indicated
a completion of the reaction. The reaction was quenched by water
and solvent was removed. The residual was purified via preparative
LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 102 (7.5 mg,
0.013 mmol, 42.8% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.08 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.05 (d, J=0.8 Hz,
1H), 7.75-7.59 (m, 4H), 7.52-7.42 (m, 1H), 7.13 (d, J=2.5 Hz, 1H),
4.81 (s, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.27 (t, J=5.2
Hz, 2H), 2.69 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z:
573.1 (M+H).sup.+. Analytical HPLC purity (method B): 98%.
Example 103
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4--
carbonitrile
##STR00644##
[2330] Intermediate 103A: 2-bromo-4-methoxy-1-nitrobenzene
##STR00645##
[2332] To a solution of 2-bromo-4-fluoro-1-nitrobenzene (2 g, 9.09
mmol) in THF (30 mL) was added sodium methoxide (1.48 g, 27 mmol).
The mixture was stirred at room temperature overnight. Solvent was
removed under vacuum and the residual was diluted with EtOAc,
quenched with saturated ammonium chloride. The organic layer was
washed with saturated sodium bicarbonate, brine, dried over sodium
sulfate and concentrated. The crude product was purified with flash
chromatography (loading in chloroform, 0% to 50% EtOAc in hexanes
over 40 min using a 120 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 103A
(1.7 g, 7.33 mmol, 81% yield) as an off-white solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.00 (d, J=9.0 Hz, 1H), 7.23 (d,
J=2.6 Hz, 1H), 6.93 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H). LC-MS:
method C, RT=1.82 min, MS (ESI) m/z: 231.9 and 233.9
(M+H).sup.+.
Intermediate 103B: 2-bromo-4-methoxyaniline
##STR00646##
[2334] To a solution of Intermediate 103A (1.7 g, 7.33 mmol) in
MeOH (30 mL) was added ammonium chloride (7.84 g, 147 mmol) and
zinc dust (4.79 g, 73.3 mmol). The mixture was stirred at room
temperature for 1 h. LCMS indicated a clean reaction. MeOH was
removed. The residue was diluted with EtOAc/saturated sodium
bicarbonate and stirred at room temperature for 10 min. The mixture
was filtered to remove insoluble material. The filtrate was
collected, organic layer was washed with brine, dried over sodium
sulfate, concentrated. The crude sample was purified with a 120 g
ISCO column eluted with 0-100% EtOAc in hexanes for 40 min. The
desired fraction was collected and concentrated to give
Intermediate 103B (1.3 g, 6.43 mmol, 88% yield) as oil. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 7.01 (d, J=2.0 Hz, 1H), 6.76-6.70
(m, 2H), 3.79 (br. s., 2H), 3.74 (s, 3H). LC-MS: method C, RT=0.80
min, MS (ESI) m/z: 202 and 204 (M+H).sup.+.
Intermediate 103C: 4-bromo-6-methoxybenzo[d]thiazol-2-amine
##STR00647##
[2336] To a mixture of Intermediate 103B (1.3 g, 6.43 mmol) in
acetonitrile (15 mL) was added ammonium thiocyanate (0.857 g, 11.26
mmol). The mixture was stirred at room temperature for 10 min.
Benzyltrimethylammonium tribromide (3.39 g, 8.69 mmol) in
acetonitrile (10 mL) was added dropwise (5 min). The mixture was
stirred at room temperature overnight. Acetonitrile was removed.
The mixture was diluted with EtOAc, saturated sodium bicarbonate.
The insoluble material was removed by filtration. The organic layer
of the filtrate was collected, washed with brine, dried over sodium
sulfate and concentrated to give Intermediate 103C (1.5 g, 5.79
mmol, 90% yield) as a yellow solid that was used for the next step
without further purification. LC-MS: method C, RT=1.41 min, MS
(ESI) m/z: 259 and 261 (M+H).sup.+.
Intermediate 103D: tert-butyl
N-(4-bromo-6-methoxy-1,3-benzothiazol-2-yl)-N-[(tert-butoxy)carbonyl]carb-
amate
##STR00648##
[2338] To a solution of Intermediate 103C (1.2 g, 4.63 mmol) in DMF
(20 mL) was added DMAP (566 mg, 4.63 mmol) and Boc.sub.2O (3032 mg,
13.89 mmol). The mixture was stirred under argon over the weekend.
The mixture was partitioned into water (300 mL) and extracted with
ethyl acetate (2.times.200 mL). The organic layers were combined,
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified with a 40 g ISCO column
eluted with 0-50% EtOAc/hexanes for 40 min. The desired fraction
was collected and concentrated to give Intermediate 103D (400 mg,
0.871 mmol, 18.80% yield). LC-MS: method C, RT=2.40 min, MS (ESI)
m/z: 302.9 and 304.9 (M+H-Boc).sup.+.
Intermediate 103E:
2-amino-6-methoxybenzo[d]thiazole-4-carbonitrile
##STR00649##
[2340] A mixture of Intermediate 103D (100 mg, 0.218 mmol), zinc
cyanide (25.6 mg, 0.218 mmol), palladium (II) trifluoroacetate
(5.79 mg, 0.017 mmol),
racemic-2-(di-t-butylphosphino)-1,1'-binaphthyl (13.88 mg, 0.035
mmol) and zinc dust (4.27 mg, 0.065 mmol) in DMA (1.5 mL) was
degassed with argon for 5 min. The reaction mixture was heated in a
microwave reactor at 100.degree. C. for 20 min. It was diluted with
EtOAc/saturated sodium bicarbonate. The organic layer was washed
with brine, dried over sodium sulfate. After evaporation of
solvent, the crude product was purified with a 12 g ISCO column
eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction
was collected to give di-boc protected intermediate (50 mg, 0.123
mmol, 56.6% yield) as colorless oil. The intermediate was
redissolved in 1 ml of DCM and TFA (0.839 mL, 10.88 mmol) was
added. The mixture was stirred at room temperature for 1 h. LCMS
indicated a completion of the reaction. Solvent was removed and the
residual was diluted EtOAc/saturated sodium bicarbonate. The
organic layer was washed with brine, dried over sodium sulfate.
After evaporation of solvent, the crude product was purified with a
12 g ISCO column eluted with 0-100% EtOAc in hexanes for 15 min.
The desired fraction was collected and concentrated to give
Intermediate 103E (24 mg, 0.117 mmol, 53.7% yield). .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. 7.51 (d, J=2.6 Hz, 1H), 7.15
(d, J=2.6 Hz, 1H), 3.83 (s, 3H). LC-MS: method C, RT=1.42 min, MS
(ESI) m/z: 206 (M+H).sup.+.
Intermediate 103F:
2-bromo-6-methoxybenzo[d]thiazole-4-carbonitrile
##STR00650##
[2342] To a stirred solution of copper (II) bromide (20.13 mg,
0.140 mmol) and Intermediate 103E (24 mg, 0.117 mmol) in
acetonitrile (2 mL) was added tert-butyl nitrite (0.020 mL, 0.152
mmol). The mixture was stirred at 20.degree. C. for 4.0 h. TLC and
LCMS indicated a clean reaction. Acetonitrile was removed under
vacuum, the reaction mixture was diluted with EtOAc, quenched with
1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl
(2.times.), saturated sodium bicarbonate, brine, dried over sodium
sulfate. After evaporation of solvent, the crude was purified with
a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min.
Intermediate 103F (15 mg, 0.056 mmol, 47.7% yield) was obtained as
an off-white solid. .sup.1H NMR (400 MHz, chloroform-d) .delta.
7.49 (d, J=2.4 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 3.92 (s, 3H).
LC-MS: method C, RT=1.79 min, MS (ESI) m/z: 268.9 and 270.9
(M+H).sup.+.
Example 103
[2343] To Intermediate I-2 (9.5 mg, 0.041 mmol), Intermediate 103F
(11.02 mg, 0.041 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (1.672 mg, 2.047 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.041
mL, 2M, 0.082 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
120.degree. C. for 40 min. To the reaction mixture was added
EtOAc/water/brine. The insoluble was removed by filtration with a
pad of celite. The organic layers were collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent, the
crude product was purified via preparative LC/MS (method D, 45-90%
B over 20 min., then a 5-min hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to give Example 103 (1.7 mg, 4.34 .mu.mol, 10.59%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H),
8.82 (s, 1H), 8.16 (br. s., 1H), 8.09 (s, 1H), 7.75 (br. s., 1H),
4.82 (s, 2H), 3.93 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H). LC-MS:
method C, RT=2.31 min, MS (ESI) m/z: 377.1 (M+H).sup.+. Analytical
HPLC purity (method B): 96%.
Example 104
N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yloxy)ethyl)benzenesulfonamide
##STR00651##
[2344] Intermediate 104A: tert-butyl
4-bromo-6-methoxybenzo[d]thiazol-2-ylcarbamate
##STR00652##
[2346] To a solution of Intermediate 103D (300 mg, 0.653 mmol) in
DCM (3 mL) was added TFA (0.101 mL, 1.306 mmol) and the mixture was
stirred at room temperature overnight. The mixture was diluted with
EtOAc and saturated NaHCO.sub.3, extracted with EtOAc. The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated to give Intermediate 104A (235 mg, 0.654 mmol, 100%
yield) as an off white solid which was used for next step without
further purification. .sup.1H NMR (400 MHz, chloroform-d) .delta.
7.24-7.20 (m, 2H), 3.86 (s, 3H), 1.56 (s, 9H). LC-MS: method C,
RT=2.30 min, MS (ESI) m/z: 359 and 360.9 (M+H).sup.+.
Intermediate 104B: tert-butyl
4-cyclopropyl-6-methoxybenzo[d]thiazol-2-ylcarbamate
##STR00653##
[2348] A solution of Intermediate 104A (30 mg, 0.084 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.82 mg, 8.35 .mu.mol) in THF
(1 mL) was degassed for 2 min. To this solution was added
cyclopropylzinc(II) bromide (0.835 mL, 0.5 M in THF, 0.418 mmol).
The reaction tube was sealed and heated at 65.degree. C. for 1 h.
LCMS indicated a completion of the reaction. The reaction mixture
was diluted with EtOAc/water. The organic phase was washed with
brine, dried over sodium sulfate. The crude residue was purified
with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15
min. Intermediate 104B (26 mg, 0.081 mmol, 97% yield) was obtained
as colorless oil. LC-MS: method C, RT=2.33 min, MS (ESI) m/z: 321
(M+H).sup.+.
Intermediate 104C:
4-cyclopropyl-6-methoxybenzo[d]thiazol-2-amine
##STR00654##
[2350] To a solution of Intermediate 104B (125 mg, 0.390 mmol) in
DCM (1 mL) was added TFA (3.01 mL, 39.0 mmol). The mixture was
stirred at room temperature for 1 h. Solvent was removed under
vacuum and the residual was diluted with EtOAc and saturated
NaHCO.sub.3, extracted with EtOAc. The combined organic layer was
washed with brine, dried with MgSO.sub.4 and concentrated to give
Intermediate 104C (80 mg, 0.363 mmol, 93% yield) as an off-white
solid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 6.94 (d, J=2.4
Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.19 (br. s., 2H), 3.80 (s, 3H),
2.57-2.43 (m, 1H), 1.14-0.99 (m, 2H), 0.86-0.74 (m, 2H). LC-MS:
method C, RT=1.46 min, MS (ESI) m/z: 221 (M+H).sup.+.
Intermediate 104D:
2-bromo-4-cyclopropyl-6-methoxybenzo[d]thiazole
##STR00655##
[2352] To a stirred solution of copper (II) bromide (188 mg, 1.307
mmol) and Intermediate 104C (240 mg, 1.089 mmol) in acetonitrile (3
mL) was added tert-butyl nitrite (0.187 mL, 1.416 mmol). The
mixture was stirred at room temperature overnight. Acetonitrile was
removed, the reaction mixture was diluted with EtOAc, quenched with
1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl
(2.times.), saturated sodium bicarbonate, brine, dried over sodium
sulfate. After evaporation of solvent, the crude oil was purified
with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20
min. The desired fraction was collected and concentrated to give
Intermediate 104D (180 mg, 0.633 mmol, 58.1% yield) as yellow oil.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.03 (d, J=2.4 Hz, 1H),
6.49 (d, J=2.4 Hz, 1H), 3.83 (s, 3H), 2.73 (s, 1H), 1.20-1.06 (m,
2H), 0.93-0.81 (m, 2H). LC-MS: method C, RT=2.26 min, MS (ESI) m/z:
283.9 and 285.9. (M+H).sup.+.
Intermediate 104E: 2-bromo-4-cyclopropylbenzo[d]thiazol-6-ol
##STR00656##
[2354] To a solution of Intermediate 104D (150 mg, 0.528 mmol) in
DCM (3 mL) was added boron tribromide (1.056 mL, 1.0 M in DCM,
1.056 mmol) at room temperature. The mixture was stirred at room
temperature for 1 h. The mixture was diluted with EtOAc, quenched
with ice and saturated NaHCO.sub.3, extracted with EtOAc. The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The crude was purified with a 12 g ISCO column
eluted with 0-100% EtOAc in hexanes for 20 min. The desired
fraction was collected to give Intermediate 104E (100 mg, 0.37
mmol, 70.2% yield) as a white solid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.02 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.2
Hz, 1H), 2.60 (tt, J=8.5, 5.2 Hz, 1H), 1.14-1.03 (m, 2H), 0.90-0.78
(m, 2H). LC-MS: method C, RT=2.01 min, MS (ESI) m/z: 269.9 and
271.9 (M+H).sup.+.
Intermediate 104F: tert-butyl
2-(2-bromo-4-cyclopropylbenzo[d]thiazol-6-yloxy) ethylcarbamate
##STR00657##
[2356] A solution of DIAD (0.108 mL, 0.555 mmol) in toluene (1 ml)
was added dropwise to a mixture of Intermediate 104E (50 mg, 0.185
mmol), tert-butyl (2-hydroxyethyl)carbamate (35.8 mg, 0.222 mmol)
and triphenylphosphine (97 mg, 0.370 mmol) in toluene (1 mL) at
110.degree. C. The mixture was stirred at 110.degree. C. for 30
min. LCMS indicated a completion of the reaction. The mixture was
concentrated and purified with a 12 g ISCO column eluted with 0-70%
EtOAc in hexanes for 20 min. The desired fraction was collected and
concentrated to give Intermediate 104F (70 mg, 0.169 mmol, 92%
yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.02 (d, J=2.4
Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.03 (t, J=5.2 Hz, 2H), 3.55 (q,
J=5.2 Hz, 2H), 2.80-2.65 (m, 1H), 1.48-1.42 (m, 9H), 1.16-1.08 (m,
2H), 0.91-0.82 (m, 2H). LC-MS: method C, RT=2.35 min, MS (ESI) m/z:
412.9 and 414.9 (M+H).sup.+.
Intermediate 104G: tert-butyl
2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thi-
azol-6-yloxy)ethylcarbamate
##STR00658##
[2358] To Intermediate I-2 (35 mg, 0.151 mmol), Intermediate 104F
(62.3 mg, 0.151 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.16 mg, 2M, 7.54 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.151
mL, 0.302 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 120.degree.
C. for 40 min. To the reaction mixture was added EtOAc/water/brine.
The insoluble was removed by filtration with a pad of celite. The
organic layers were collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
ISCO column which was eluted with hexanes for 3 min., then a 20 min
gradient from 0% to 100% EtOAc in hexanes The desired fractions
were combined and concentrated to give Intermediate 104G (70 mg,
0.108 mmol, 71.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.09 (s, 1H), 8.82 (s, 1H), 8.02 (s, 1H), 7.49 (br. s.,
1H), 7.02 (br. s., 1H), 6.58 (br. s., 1H), 4.81 (s, 2H), 4.04 (br.
s., 2H), 3.47 (s, 3H), 3.33 (m., 2H), 3.01-2.88 (m, 1H), 2.69 (s,
3H), 1.39 (s, 9H), 1.17 (d, J=7.4 Hz, 2H), 1.00 (br. s., 2H).
LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 521 (M+H).sup.+.
[2359] Intermediate 104H:
2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yloxy)ethanamine
##STR00659##
[2361] To a solution of Intermediate 104G (65 mg, 0.125 mmol) in
DCM (1 mL) was added 2,6-lutidine (43.6 .mu.l, 0.375 mmol) followed
by TMS-OTf (90 .mu.l, 0.499 mmol) at room temperature. The mixture
was stirred at room temperature for 1 h. The mixture was diluted
with EtOAc and NaHCO.sub.3, extracted with EtOAc. The combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated to give Intermediate 104H (52.5 mg, 0.125 mmol, 100%
yield). LC-MS: method C, RT=2.01 min, MS (ESI) m/z: 421
(M+H).sup.+.
Example 104
[2362] To a solution of Intermediate 104H (14 mg, 0.033 mmol) in
DMF (1 mL) was added DIEA (0.058 mL, 0.333 mmol) and
benzenesulfonyl chloride (5.15 .mu.l, 0.040 mmol). The mixture was
stirred at room temperature for 30 min. LCMS indicated a completion
of the reaction. The reaction was quenched with 0.2 ml of MeOH.
Solvent was removed. The residual was purified via preparative
LC/MS (method D, 50-90% B over 20 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 104 (4.8 mg, 8.56
.mu.mol, 25.7% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.08 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.95 (br. s., 1H), 7.85
(d, J=7.2 Hz, 2H), 7.68-7.57 (m, 3H), 7.40 (s, 1H), 6.45 (s, 1H),
4.80 (s, 2H), 4.04 (br. s., 2H), 3.47 (s, 3H), 3.19 (br. s., 2H),
2.93 (br. s., 1H), 2.68 (s, 3H), 1.17 (d, J=8.0 Hz, 2H), 0.97 (d,
J=3.3 Hz, 2H). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 561.20
(M+H).sup.+. Analytical HPLC purity (method B): 100%
Example 105
N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
##STR00660##
[2364] To a solution of Intermediate 104H (16 mg, 0.038 mmol) in
DMF (1 mL) was added DIEA (0.066 mL, 0.380 mmol) and
4-fluorobenzene-1-sulfonyl chloride (8.89 mg, 0.046 mmol). The
mixture was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. The reaction was quenched with 0.2 ml
of MeOH. Solvent was removed, the residual was purified via
preparative LC/MS (method D, 50-90% B over 20 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 105
(8.4 mg, 0.015 mmol, 38.2% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.81 (s, 1H), 8.02 (br. s.,
2H), 7.92-7.86 (m, 2H), 7.49-7.37 (m, 3H), 6.44 (s, 1H), 4.81 (s,
2H), 4.04 (br. s., 2H), 3.47 (s, 3H), 3.21 (br. s., 2H), 2.92 (d,
J=5.2 Hz, 1H), 2.70-2.66 (m, 3H), 1.17 (d, J=7.4 Hz, 2H), 0.97 (d,
J=2.5 Hz, 2H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 579.20
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 106
N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy-
)ethyl)benzenesulfonamide
##STR00661##
[2365] Intermediate 106A: 2-chlorobenzo[d]thiazol-6-ol
##STR00662##
[2367] Aluminum chloride (7.01 g, 52.6 mmol) was added to a
solution of 2-chloro-6-methoxybenzo[d]thiazole (3.5 g, 17.53 mmol)
in toluene (80 mL). The mixture was heated at 110.degree. C. for
1.5 h. TLC indicated a complete conversion of starting material.
The reaction mixture was cooled to room temperature, quenched with
ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min.
The precipitate was collected by filtration, washed with water
(3.times.), saturated sodium bicarbonate (3.times.), water
(3.times.) and air-dried for 1.0 h under vacuum. It was further
dried under high vacuum overnight to give Intermediate 106A (2.9 g,
15.62 mmol, 89% yield) as a pale gray solid. The crude sample was
used for the next step without purification. .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.70 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.4
Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H). LC-MS: method C, RT=1.65
min, MS (ESI) m/z: 185.8 (M+H).sup.+.
Intermediate 106B: tert-butyl
2-(2-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate
##STR00663##
[2369] A solution of DIAD (0.943 mL, 4.85 mmol) in toluene (4 mL)
was added dropwise to a mixture of Intermediate 106A (300 mg, 1.616
mmol), tert-butyl (2-hydroxyethyl)carbamate (313 mg, 1.939 mmol)
and triphenylphosphine (848 mg, 3.23 mmol) in toluene (10 mL) at
110.degree. C. The mixture turned to a clean solution and was
stirred at 110.degree. C. for 30 min. LCMS indicated a completion
of the reaction. The mixture was concentrated and purified with a
40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The
desired fraction was collected and concentrated to give
Intermediate 106B (620 mg, 1.508 mmol, 93% yield). .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.83 (d, J=9.0 Hz, 1H), 7.23 (d, J=2.4
Hz, 1H), 7.07 (dd, J=8.9, 2.5 Hz, 1H), 5.12-4.94 (m, 2H), 4.11-4.05
(m, 2H), 3.57 (q, J=5.1 Hz, 2H), 1.51-1.42 (m, 9H). LC-MS: method
C, RT=2.49 min, MS (ESI) m/z: 329 (M+H).sup.+.
Intermediate 106C: tert-butyl
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)e-
thylcarbamate
##STR00664##
[2371] To Intermediate I-2 (35 mg, 0.151 mmol), Intermediate 106B
(62.0 mg, 0.151 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (6.16 mg, 7.54 .mu.mol) was
added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.151
mL, 2M, 0.302 mmol). The mixture was degassed with argon for 5 min.
The reaction mixture was heated in a microwave reactor at
120.degree. C. for 30 min. To the reaction mixture was added
EtOAc/water/brine. The insoluble was removed by filtration with a
pad of celite. The organic layers were collected, washed with
brine, dried over sodium sulfate. After evaporation of solvent, the
crude product was dissolved in a small amount of chloroform and
charged to a 40 g ISCO column which was eluted with hexanes for 3
min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. The
desired fractions were combined and concentrated to give
Intermediate 106C (63 mg, 0.119 mmol, 79% yield) as a yellow solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (br. s., 1H), 8.80
(br. s., 1H), 8.05-7.99 (m, 2H), 7.74 (br. s., 1H), 7.16 (d, J=8.8
Hz, 1H), 7.05 (br. s., 1H), 4.81 (br. s., 2H), 4.08 (br. s., 2H),
3.47 (br. s., 3H), 3.36 (br. s., 2H), 2.68 (br. s., 3H), 1.39 (br.
s., 9H). LC-MS: method C, RT=2.40 min, MS (ESI) m/z: 481
(M+H).sup.+.
Intermediate 106D
2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)et-
hanamine
##STR00665##
[2373] To a mixture of Intermediate 106C (60 mg, 0.125 mmol) in DCM
(2 ml) was added 2,6-lutidine (43.6 .mu.l, 0.375 mmol) followed by
TMS-OTf (90 .mu.l, 0.499 mmol). The mixture was stirred at room
temperature for 1 h. LCMS indicated a completion of the reaction.
The mixture was diluted with EtOAc and NaHCO.sub.3, extracted with
EtOAc. The combined organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated to give Intermediate 106D (45 mg, 0.118
mmol, 95% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 9.09
(s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.95 (s,
1H), 7.45 (d, J=2.4 Hz, 1H), 7.15 (dd, J=9.0, 2.4 Hz, 1H), 4.85 (s,
2H), 4.11 (t, J=4.8 Hz, 2H), 3.58 (s, 3H), 3.17 (br. s., 2H), 2.70
(s, 3H). LC-MS: method C, RT=1.74 min, MS (ESI) m/z: 381
(M+H).sup.+.
Example 106
[2374] To a solution of Intermediate 106D (14 mg, 0.037 mmol) in
DMF (1 mL) was added DIEA (0.064 mL, 0.368 mmol) and
benzenesulfonyl chloride (5.69 .mu.l, 0.044 mmol). The mixture was
stirred at room temperature for 30 min. LCMS indicated a completion
of the reaction. The reaction mixture was quenched with 0.2 ml of
MeOH. Solvent was removed, the residual was purified via
preparative LC/MS (method D, 40-80% B over 10 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 106
(10.7 mg, 0.021 mmol, 55.9% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.09 (br. s., 1H), 8.79 (br. s., 1H),
8.12-7.94 (m, 3H), 7.85 (d, J=6.9 Hz, 2H), 7.69-7.53 (m, 4H), 7.08
(d, J=8.5 Hz, 1H), 4.81 (br. s., 2H), 4.08 (br. s., 2H), 3.47 (br.
s., 3H), 3.22 (br. s., 2H), 2.68 (br. s., 3H). LC-MS: method C,
RT=2.25 min, MS (ESI) m/z: 521.15 (M+H).sup.+. Analytical HPLC
purity (method B): 100%.
Example 107
4-fluoro N (2 (2 (2
(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)ben-
zenesulfonamide
##STR00666##
[2376] To a solution of Intermediate 106D (16 mg, 0.042 mmol) in
DMF (1 mL) was added DIEA (0.073 mL, 0.421 mmol) and
4-fluorobenzene-1-sulfonyl chloride (9.82 mg, 0.050 mmol). The
mixture was stirred at room temperature for 30 min. LCMS indicated
a completion of the reaction. The reaction mixture was quenched
with 0.2 ml of MeOH. Solvent was removed, the residual was purified
via preparative LC/MS (method D, 40-80% B over 10 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
107 (16.3 mg, 0.030 mmol, 70.5% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.09 (br. s., 1H), 8.79 (br. s., 1H),
8.09-7.97 (m, 3H), 7.90 (br. s., 2H), 7.66 (br. s., 1H), 7.42 (t,
J=8.4 Hz, 2H), 7.07 (d, J=9.1 Hz, 1H), 4.81 (br. s., 2H), 4.08 (br.
s., 2H), 3.47 (m, 3H), 3.23 (br. s., 2H), 2.68 (br. s., 3H). LC-MS:
method C, RT=2.25 min, MS (ESI) m/z: 539.15 (M+H).sup.+. Analytical
HPLC purity (method B): 98%.
Example 108
4-fluoro N (2 (2 (2 (1
fluoroethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)eth-
yl)benzenesulfonamide
##STR00667##
[2377] Intermediate 108A:
1-(5-bromo-7-methylquinoxalin-2-yl)ethanone
##STR00668##
[2379] To a suspension of methyl
5-bromo-7-methylquinoxaline-2-carboxylate (300 mg, 1.067 mmol) in
toluene (5 mL) was added N.sub.1,N.sub.2-dimethylethane-1,2-diamine
(DMEDA) (0.126 mL, 1.174 mmol) and trimethylaluminum (1.601 mL,
3.20 mmol) dropwise under argon at room temperature. The mixture
was stirred at room temperature over the weekend. The mixture was
diluted with EtOAc and water, extracted with EtOAc. The combined
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried with MgSO.sub.4 and concentrated. The crude sample was
purified with a 40 g ISCO column eluted with 0-80% EtOAc in hexanes
for 20 min. The desired fraction was collected to give Intermediate
108A (250 mg, 0.943 mmol, 88% yield) as a yellow solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. 9.50 (s, 1H), 8.07 (d, J=1.8 Hz,
1H), 7.96 (dd, J=1.7, 1.0 Hz, 1H), 2.85 (s, 3H), 2.63 (s, 3H).
LC-MS: method C, RT=1.99 min, MS (ESI) m/z: 265 and 267
(M+H).sup.+.
Intermediate 108B: 2-acetyl-7-methylquinoxalin-5-ylboronic acid
##STR00669##
[2381] A mixture of Intermediate 108A (80 mg, 0.302 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (123
mg, 0.483 mmol), potassium acetate (59.2 mg, 0.604 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (9.86 mg, 0.012 mmol) in dioxane
(1 ml) was degassed with argon for 10 min. The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. The
mixture was diluted with EtOAc/water, insoluble material was
removed by filtration. The filtrate was extracted with EtOAc,
washed with brine, dried over sodium sulfate, concentrated to give
Intermediate 108B (69.0 mg, 0.3 mmol) which was used for next step
without purification. LC-MS: method C, RT=1.94 min, MS (ESI) m/z:
231 (M+H).sup.+ (boronic acid).
Intermediate 108C:
N-(2-(2-(2-acetyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ylox-
y)ethyl)-4-fluorobenzenesulfonamide
##STR00670##
[2383] To Intermediate 108B (69.0 mg, 0.3 mmol), Intermediate I-5
(111 mg, 0.250 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (10.21 mg, 0.013 mmol) was added
toluene (1.5 mL), EtOH (0.5 mL) and sodium carbonate (0.250 mL, 2M,
0.500 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 130.degree.
C. for 30 min. To the reaction mixture was added EtOAc/water/brine.
The insoluble was removed by filtration with a pad of celite. The
organic layers were collected, washed with brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 12 g
ISCO column which was eluted with hexanes for 3 min., then a 15 min
gradient from 0% to 100% EtOAc in hexanes. The desired fractions
were combined and concentrated to give Intermediate 108C (20 mg,
0.036 mmol, 14.53% yield) as a yellow solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 9.57 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.08
(dd, J=2.0, 0.9 Hz, 1H), 7.97-7.90 (m, 2H), 7.24-7.16 (m, 3H), 6.85
(d, J=1.5 Hz, 1H), 5.04-4.90 (m, 1H), 4.15-4.09 (m, 2H), 3.48-3.40
(m, 2H), 2.88 (s, 3H), 2.83 (s, 3H), 2.77 (s, 3H). LC-MS: method C,
RT=2.50 min, MS (ESI) m/z: 551 (M+H).sup.+.
Intermediate 108D
4-fluoro N (2 (2 (2 (1
hydroxyethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)et-
hyl)benzenesulfonamide
##STR00671##
[2385] To a solution of Intermediate 108C (20 mg, 0.036 mmol) in
MeOH (1.5 ml) and THF (0.5 mL) was added CeCl.sub.3 (13.53 mg,
0.036 mmol) and NaBH.sub.4 (5.50 mg, 0.145 mmol) at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 1 h. TLC and
LCMS indicated a completion of the reaction. The reaction mixture
was diluted with saturated NH.sub.4Cl solution and EtOAc. The
combined organic layer was washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure to give
Intermediate 108D (20 mg, 0.036 mmol, 100% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.21 (br. s., 1H), 8.78 (br. s., 1H),
8.06 (br. s., 1H), 8.02-7.94 (m, 1H), 7.90 (br. s., 2H), 7.45 (d,
J=16.8 Hz, 3H), 6.86 (br. s., 1H), 5.86 (br. s., 1H), 5.03 (br. s.,
1H), 4.05 (d, J=3.0 Hz, 2H), 3.21 (d, J=3.0 Hz, 2H), 2.73 (br. s.,
3H), 2.68 (br. s., 3H). LC-MS: method C, RT=2.33 min, MS (ESI) m/z:
553 (M+H).sup.+.
Example 108
[2386] To a solution of Intermediate 108D (15 mg, 0.027 mmol) in
DCM (1 ml) was added diethylaminosulfur trifluoride (7.17 .mu.l,
0.054 mmol) dropwise at -78.degree. C. The mixture was stirred from
-78.degree. C. to room temperature for 30 min. LCMS indicated a
completion of the reaction. The reaction was quenched with water,
extracted with EtOAc, the combined organic layer was washed with
NaHCO.sub.3, brine and concentrated. The crude sample was purified
via preparative LC/MS (method D, 50-90% B over 20 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
108 (5.3 mg, 9.46 .mu.mol, 34.9% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (br. s., 1H), 8.83 (br. s., 1H), 8.06
(br. s., 2H), 7.90 (br. s., 2H), 7.44 (d, J=13.5 Hz, 3H), 6.86 (br.
s., 1H), 6.19-5.98 (m, 1H), 4.05 (br. s., 2H), 3.22 (br. s., 2H),
2.73 (br. s., 3H), 2.69 (br. s., 3H), 1.85-1.75 (m, 3H). LC-MS:
method C, RT=2.70 min, MS (ESI) m/z: 555.10 (M+H).sup.+. Analytical
HPLC purity (method B): 99%.
Example 109
N-(2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
##STR00672##
[2387] Intermediate 109A: tert-butyl
2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-
-yloxy)ethylcarbamate
##STR00673##
[2389] A mixture of Intermediate 98E (60 mg, 0.116 mmol), zinc
cyanide (27.36 mg, 0.232 mmol), palladium (II) trifluoroacetate
(6.20 mg, 18.64 .mu.mol),
racemic-2-(di-t-butylphosphino)-1,1'-binaphthyl (14.86 mg, 0.019
mmol) and zinc dust (4.57 mg, 0.070 mmol) in DMA (2 mL) was
degassed with argon for 5 min. The reaction mixture was heated in a
microwave reactor at 130.degree. C. for 1 h. The mixture was
diluted with EtOAc/saturated sodium bicarbonate. The organic layer
was washed with brine, dried over sodium sulfate. After evaporation
of solvent, the crude product was purified with a 40 g ISCO column
eluted with 0-100% EtOAc in hexanes for 20 min. The desired
fraction was collected and concentrated to give Intermediate 109A
(10 mg, 0.020 mmol, 16.98% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 9.09 (s, 1H), 9.04 (d, J=2.0 Hz, 1H), 7.95
(s, 1H), 7.66 (dd, J=4.2, 2.4 Hz, 1H), 7.43 (t, J=2.3 Hz, 1H), 4.86
(s, 2H), 4.19-4.14 (m, 2H), 3.62 (d, J=5.5 Hz, 2H), 3.59 (s, 3H),
2.73 (s, 3H), 1.48 (s, 9H). LC-MS: method C, RT=2.54 min, MS (ESI)
m/z: 506 (M+H).sup.+.
Intermediate 109B
6-(2-aminoethoxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thi-
azole-4-carbonitrile
##STR00674##
[2391] To a mixture of Intermediate 109A (10 mg, 0.020 mmol) in DCM
(1 mL) was added 2,6-lutidine (6.91 .mu.l, 0.059 mmol) followed by
TMS-OTf (14.30 .mu.l, 0.079 mmol) at room temperature. The mixture
was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. The mixture was diluted with EtOAc and
saturated NaHCO.sub.3, extracted with EtOAc. The combined organic
layer was washed with brine, dried with MgSO.sub.4 and concentrated
to give Intermediate 109B which was used for next step without
purification. LC-MS: method C, RT=1.83 min, MS (ESI) m/z: 406
(M+H).sup.+.
Example 109
[2392] To a solution of Intermediate 109B in DMF (1 mL) was added
DIEA (0.034 mL, 0.197 mmol) and 4-fluorobenzene-1-sulfonyl chloride
(4.61 mg, 0.024 mmol). The mixture was stirred at room temperature
for 30 min. LCMS indicated a completion of the reaction. The
reaction was quenched with 0.2 ml of MeOH. Solvent was removed, the
residual was purified via preparative LC/MS (method D, 45-85% B
over 18 min., then a 5-min hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to give Example 109 (0.7 mg, 0.621 .mu.mol, 3.15%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.00 (s, 1H),
8.76 (d, J=1.7 Hz, 1H), 8.06 (d, J=2.5 Hz, 1H), 8.03 (d, J=0.5 Hz,
1H), 7.89 (dd, J=8.8, 5.2 Hz, 2H), 7.59 (dd, J=3.2, 2.6 Hz, 1H),
7.41 (t, J=8.8 Hz, 2H), 4.82 (s, 2H), 4.13 (td, J=5.1, 2.5 Hz, 2H),
3.47 (s, 3H), 3.24 (t, J=5.2 Hz, 2H), 2.78 (s, 3H). LC-MS: method
C, RT=2.20 min, MS (ESI) m/z: 564.20 (M+H).sup.+. Analytical HPLC
purity (method B): 97%.
Example 110
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thylphenylcarbamate
##STR00675##
[2393] Intermediate 110A
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thyl acetate
##STR00676##
[2395] To a solution of Intermediate 35B (125 mg, 0.370 mmol) in
DMF (4 mL) was added cesium carbonate (362 mg, 1.111 mmol), then
2-bromoethyl acetate (0.049 mL, 0.445 mmol) was added dropwise. The
reaction mixture was stirred at room temperature overnight. LCMS
indicated a completion of the reaction. The reaction mixture was
diluted with EtOAc and water, extracted with EtOAc, the combined
organic layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was purified with a 12 g ISCO
column, eluted with 0-100% EtOAc in hexane for 15 min. The desired
fraction was collected and concentrated to give Intermediate 110A
(150 mg, 0.354 mmol, 96% yield) as a yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.65 (d, J=1.5 Hz, 1H), 8.54 (s, 1H),
7.73 (dd, J=1.8, 0.9 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.95 (dd,
J=2.4, 0.9 Hz, 1H), 4.53-4.43 (m, 2H), 4.30-4.21 (m, 2H), 4.12 (s,
3H), 2.19-2.09 (m, 3H). LC-MS: method C, RT=2.58 min, MS (ESI) m/z:
424 (M+H).sup.+.
Intermediate 110B
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thanol
##STR00677##
[2397] To a suspension of Intermediate 110A (190 mg, 0.449 mmol) in
THF (3 mL) and MeOH (1 mL) was added 1 N NaOH (1.346 mL, 1.346
mmol) at room temperature. The mixture was stirred at room
temperature for 1 h. LCMS indicated a completion of the reaction.
The mixture was diluted with EtOAc and 1N HCl, extracted with
EtOAc, the combined organic layer was washed with water and brine,
dried with MgSO.sub.4 and concentrated to Intermediate 110B (155
mg, 0.394 mmol, 88% yield) as a yellow solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.69 (s, 1H), 8.56 (s, 1H), 7.78 (s, 1H),
7.50 (s, 1H), 6.99 (s, 1H), 4.91 (br. s., 1H), 4.07 (m, 5H), 3.76
(d, J=4.1 Hz, 2H), 2.73 (s, 3H), 2.62 (s, 3H). LC-MS: method C,
RT=2.41 min, MS (ESI) m/z: 382 (M+H).sup.+.
Intermediate 110C
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thyl carbonochloridate
##STR00678##
[2399] To a solution of Intermediate 110B (150 mg, 0.393 mmol) in
THF (5 mL) at room temperature was added 15% phosgene in toluene
(1.387 mL, 1.966 mmol), and the mixture was stirred at room
temperature for 5 h. LCMS indicated the reaction was complete.
Solvent was removed and the sample was dried under vacuum overnight
to give Intermediate 110C (175 mg, 0.394 mmol, 100% yield) as a
yellow solid. It was used for the next step without any
purification. LC-MS: method C, RT=2.73 min, MS (ESI) m/z: 444
(M+H).sup.+.
Example 110
[2400] To a solution of Intermediate 110C (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added aniline (14.69 mg, 0.158
mmol), followed by DIEA (0.079 mL, 0.451 mmol). The mixture was
stirred at room temperature for 0.5 h. LCMS indicated a completion
of reaction. The reaction mixture was quenched by addition of a
small amount of MeOH/water/0.1% TFA (HPLC solvent) and diluted with
EtOAc and water, extracted with EtOAc. The combined organic layer
was washed with brine, dried over MgSO.sub.4 and concentrated. The
crude sample was purified via preparative LC/MS (method D, 70-100%
B over 10 min., then a 5-min hold at 100% B). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to give Example 110 (8.6 mg, 0.017 mmol, 37.8% yield).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.79 (br. s., 1H), 8.71
(s, 1H), 8.57 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.48 (d, J=8.0
Hz, 2H), 7.27 (t, J=7.6 Hz, 2H), 7.03 (s, 1H), 6.99 (t, J=7.4 Hz,
1H), 4.47 (br. s., 2H), 4.33 (br. s., 2H), 4.07 (s, 3H), 2.74 (s,
3H), 2.63 (s, 3H). LC-MS: method C, RT=2.80 min, MS (ESI) m/z:
501.20 (M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 111
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thylpyridin-3-ylcarbamate
##STR00679##
[2402] To a solution of Intermediate 110C (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added pyridin-3-amine (14.84 mg,
0.158 mmol) followed by DIEA (0.079 mL, 0.451 mmol). The mixture
was stirred at room temperature overnight. The reaction was
quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC
solvent). Solvent was removed under vacuum. The crude was purified
via preparative LC/MS (method D, 55-100% B over 10 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
111 (4.1 mg, 8.17 .mu.mol, 18.14% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.05 (br. s., 1H), 8.65 (br. s., 1H), 8.58
(s, 1H), 8.22 (d, J=3.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.80 (s,
1H), 7.57 (s, 1H), 7.42-7.29 (m, 1H), 7.03 (s, 1H), 4.50 (br. s.,
2H), 4.34 (br. s., 2H), 4.08 (s, 3H), 2.78-2.69 (m, 3H), 2.63 (s,
3H). LC-MS: method C, RT=2.09 min, MS (ESI) m/z: 502.10
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 112
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thyl 6-methoxypyridin-3-ylcarbamate
##STR00680##
[2404] To a solution of Intermediate 110C (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added 6-methoxypyridin-3-amine
(19.58 mg, 0.158 mmol) followed by DIEA (0.079 mL, 0.451 mmol). The
mixture was stirred at room temperature for 0.5 h. LCMS indicated a
completion of reaction. The reaction was quenched by addition of a
small amount of MeOH/water/0.1% TFA (HPLC solvent). Solvent was
removed under vacuum. The crude sample was purified via preparative
LC/MS (method D, 70-100% B over 10 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 112 (8.6 mg,
0.016 mmol, 35.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.77 (br. s., 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.24 (br.
s., 1H), 7.81 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.03
(s, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.47 (br. s., 2H), 4.33 (br. s.,
2H), 4.08 (s, 3H), 3.80 (s, 3H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS:
method C, RT=2.52 min, MS (ESI) m/z: 532.25 (M+H).sup.+. Analytical
HPLC purity (method B): 98%.
Example 113
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thylpyridin-4-ylcarbamate
##STR00681##
[2406] To a solution of Intermediate 110C (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added pyridin-4-amine (14.84 mg,
0.158 mmol) followed by DIEA (0.079 mL, 0.451 mmol). The mixture
was stirred at room temperature overnight. The reaction was
quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC
solvent). The reaction mixture was diluted with EtOAc and water,
extracted with EtOAc. The combined organic layer was washed with
brine, dried with MgSO.sub.4 and concentrated. The crude sample was
purified via preparative LC/MS (method D, 55-95% B over 15 min.,
then a 6-min hold at 100% B). Fractions containing the desired
product were combined and dried via centrifugal evaporation to give
Example 113 (2.6 mg, 4.98 .mu.mol, 11.05% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.29 (s, 1H), 8.73 (s, 1H), 8.59 (s,
1H), 8.38 (d, J=4.7 Hz, 2H), 7.82 (s, 1H), 7.57 (s, 1H), 7.45 (d,
J=5.0 Hz, 2H), 7.04 (s, 1H), 4.51 (br. s., 2H), 4.35 (br. s., 2H),
4.08 (s, 3H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.11
min, MS (ESI) m/z: 502.15 (M+H).sup.+. Analytical HPLC purity
(method B): 96%.
Example 114
N-(2-(2-(2-((difluoromethoxy)methyl)-7-methylquinoxalin-5-yl)-4-methylbenz-
o[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
##STR00682##
[2407] Intermediate 114A: methyl
7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-2-car-
boxylate
##STR00683##
[2409] A mixture of methyl
5-bromo-7-methylquinoxaline-2-carboxylate (225 mg, 0.800 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (447
mg, 1.761 mmol), potassium acetate (196 mg, 2.001 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (26.1 mg, 0.032 mmol) in dioxane
(3.0 mL) was degassed with argon for 10 min. The reaction mixture
was heated in a microwave reactor at 120.degree. C. for 30 min.
LCMS indicated a complete conversion of starting material. The
mixture was diluted with EtOAc/water, insoluble material was
removed by filtration. The filtrate was extracted with EtOAc,
washed with brine, dried over sodium sulfate. The crude product was
purified with flash chromatography (loading in chloroform, 5% to
75% EtOAc in hexanes over 12 min using a 12 g silica gel
cartridge). The desired fractions were combined and concentrated to
yield Intermediate 114A (225 mg, 0.686 mmol, 86% yield) as brown
solid. LC-MS: method C, RT=1.48 min, MS (ESI) m/z: 247 (M+H).sup.+
(boronic acid).
Intermediate 114B: ethyl
5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)--
7-methylquinoxaline-2-carboxylate
##STR00684##
[2411] To Intermediate 114A (89 mg, 0.271 mmol), Intermediate I-5
(115 mg, 0.258 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (10.54 mg, 0.013 mmol) was added
toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.258 mL, 2M,
0.516 mmol). The mixture was degassed with argon for 5 min. The
reaction mixture was heated in a microwave reactor at 130.degree.
C. for 30 min. The mixture was diluted with EtOAc and water,
extracted with EtOAc. The combined organic layer was washed with
brine, dried with MgSO.sub.4 and concentrated. The crude sample was
purified with a 12 g ISCO column eluted with EtOAc in hexanes for
15 min. The desired fraction was collected and concentrated to give
Intermediate 114B (45 mg, 0.039 mmol, 15.01% yield) as a yellow
solid [Note: Transesterification with the EtOH solvent occurred
under these reaction conditions]. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 9.62 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.84
(s, 1H), 8.17 (dd, J=1.8, 0.9 Hz, 1H), 8.00-7.76 (m, 2H), 7.23-7.07
(m, 2H), 6.84 (dd, J=2.4, 0.9 Hz 1H), 4.63 (q, J=7.3 Hz, 2H),
4.12-4.03 (m, 2H), 3.48-3.39 (m, 2H), 1.93 (s, 3H), 1.59 (s, 3H),
1.54 (t, J=7.2 Hz, 3H). LC-MS: method C, RT=2.44 min, MS (ESI) m/z:
581 (M+H).sup.+.
Intermediate 114C
4-fluoro N (2 (2 (2
(hydroxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)-
ethyl)benzenesulfonamide
##STR00685##
[2413] NaBH.sub.4 (2.93 mg, 0.077 mmol) and calcium chloride (4.30
mg, 0.039 mmol) was dissolved in THF (2 ml) and the mixture was
stirred at room temperature for 1.5 h, followed by addition of a
solution of Intermediate 114B (45 mg, 0.039 mmol) in THF (1 mL).
The mixture was stirred at room temperature for 1.5 h. LCMS
indicated a completion of the reaction. The mixture was diluted
with water and EtOAc. The organic layer was washed with brine,
dried with sodium sulfate, and concentrated. The crude sample was
purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes
for 20 min. The desired fraction was collected and concentrated to
give Intermediate 114C (20 mg, 0.037 mmol, 96% yield) as a yellow
solid. LC-MS: method C, RT=2.23 min, MS (ESI) m/z: 539
(M+H).sup.+.
Example 114
[2414] To a heated suspension of Intermediate 114C (20 mg, 0.037
mmol) and sodium sulfate (1.319 mg, 9.28 .mu.mol) in acetonitrile
(2.0 mL) at 65.degree. C. was added
2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.76 .mu.l, 0.056 mmol)
in acetonitrile (0.5 mL) dropwise over 40 min, The mixture was
stirred at 65.degree. C. for 0.5 h. After the mixture was cooled to
room temperature, it was diluted with EtOAc and quenched with
NaHCO.sub.3, extracted with EtOAc. The combined organic layer was
washed with NaHCO.sub.3 and brine, dried over MgSO.sub.4 and
concentrated. The crude sample was purified via preparative LC/MS
(method D, 40-80% B over 10 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Example 114 (0.4 mg, 0.584
.mu.mol, 1.259% yield). LC-MS: method C, RT=2.48 min, MS (ESI) m/z:
589.20 (M+H).sup.+. Analytical HPLC purity (method B): 86%.
Example 115
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl
6-methoxypyridin-3-ylcarbamate
##STR00686##
[2415] Intermediate 115A:
2-(2-chlorobenzo[d]thiazol-6-yloxy)ethanol
##STR00687##
[2417] To a solution of Intermediate I-4A (500 mg, 2.69 mmol) in
DMF (10 mL) was added cesium carbonate (1755 mg, 5.39 mmol), then
2-bromoethyl acetate (0.356 mL, 3.23 mmol) was added dropwise. The
reaction mixture was stirred at room temperature overnight, diluted
with EtOAc and water, extracted with EtOAc. The combined organic
layer was washed with brine, dried with MgSO.sub.4 and
concentrated. The crude sample was dissolved in 10 ml of THF
followed by addition of NaOH (5.39 mL, 1M, 5.39 mmol). The mixture
was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. The reaction mixture was diluted with
EtOAc and water, extracted with EtOAc. The combined organic layer
was washed with brine, dried with MgSO.sub.4 and concentrated. The
crude sample was purified with a 40 g ISCO column eluted with
0-100% EtOAc in hexanes for 20 min. The desired fraction was
collected and concentrated to give Intermediate 115A (550 mg, 2.395
mmol, 89% yield) as off-white solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.73 (d, J=8.8 Hz, 1H), 7.14 (d, J=2.4 Hz,
1H), 6.99 (dd, J=8.9, 2.5 Hz, 1H), 4.10-4.04 (m, 2H), 4.01-3.91 (m,
2H). LC-MS: method C, RT=1.64 min, MS (ESI) m/z: 230
(M+H).sup.+.
Intermediate 115B
2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)-
ethanol
##STR00688##
[2419] To Intermediate I-1 (512 mg, 1.524 mmol), Intermediate 115A
(350 mg, 1.524 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (49.8 mg, 0.061 mmol) was added
toluene (3 mL) and EtOH (1). The mixture was sonicated for 1 min,
and flushed with argon. To this was added sodium carbonate (1.524
mL, 2M, 3.05 mmol). The reaction mixture was heated in a microwave
reactor at 130.degree. C. for 30 min. The reaction mixture was
diluted with EtOAc and water, extracted with EtOAc (3.times.). The
combined organic layer was washed with brine, dried with MgSO.sub.4
and concentrated. The residual was dissolved in 1 ml DMSO and DCM
and was loaded to a 40 g ISCO column eluted with 0-100% EtOAc in
hexanes for 20 min. The desired fractions were combined and
concentrated to yield Intermediate 115B (550 mg, 1.363 mmol, 89%
yield) as a brown-yellow solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.75 (d, J=1.8 Hz, 1H), 8.67 (s, 1H), 8.03 (d, J=8.8 Hz,
1H), 7.77 (s, 1H), 7.86-7.46 (m, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.15
(dd, J=9.0, 2.4 Hz, 1H), 4.23-4.16 (m, 2H), 4.04 (d, J=4.6 Hz, 2H),
2.67 (s, 3H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -89.73
(s, 2F). LC-MS: method C, RT=2.31 min, MS (ESI) m/z: 404
(M+H).sup.+.
Intermediate 115C
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanol
##STR00689##
[2421] To a solution of Intermediate 115B (550 mg, 1.363 mmol) in
THF (10 mL) was added NaOMe in MeOH (4.3 M, 0.936 mL, 4.09 mmol).
The mixture was stirred at room temperature for 1 h. LCMS indicated
a completion of the reaction. The reaction was quenched by 1N HCl
(12 ml) and extracted with DCM (3.times.). The combined organic
layer was washed with brine, dried with MgSO.sub.4 and concentrated
to give Intermediate 115C (400 mg, 1.089 mmol, 80% yield) as a
yellow solid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.63 (d,
J=1.5 Hz, 1H), 8.57 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.76 (dd,
J=2.0, 0.9 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.9, 2.5
Hz, 1H), 4.27-4.18 (m, 2H), 4.14 (s, 3H), 4.08-4.01 (m, 2H), 2.66
(s, 3H). LC-MS: method C, RT=2.31 min, MS (ESI) m/z: 368
(M+H).sup.+.
Intermediate 115D
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl
carbonochloridate
##STR00690##
[2423] To a suspension of Intermediate 115C (150 mg, 0.408 mmol) in
THF (3 mL) at room temperature was added 15% phosgene in toluene
(1.440 mL, 2.041 mmol). The mixture was stirred at room temperature
overnight. Solvent was removed under vacuum and Intermediate 115D
(175 mg, 0.407 mmol, 100% yield) was obtained as a yellow solid. It
was used for the next step without any purification. LC-MS: method
C, RT=2.56 min, MS (ESI) m/z: 430 (M+H).sup.+.
Example 115
[2424] To a solution of 6-methoxypyridin-3-amine (15.16 mg, 0.122
mmol) in DCM (0.5 mL) was added Intermediate 115D (15 mg, 0.035
mmol) in THF (0.5 mL), followed by DIEA (0.061 mL, 0.349 mmol). The
mixture was stirred at room temperature for 1 h. The reaction was
quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC
solvent) and concentrated. The residual was purified via
preparative LC/MS (method D, 50-100% B over 12 min., then a 7-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 115
(5.0 mg, 9.56 .mu.mol, 27.4% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.82 (br. s., 1H), 8.73 (s, 1H), 8.57 (d,
J=1.4 Hz, 1H), 8.24 (br. s., 1H), 8.01 (d, J=9.1 Hz, 1H), 7.86-7.72
(m, 3H), 7.19 (dd, J=8.8, 2.5 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H),
4.54-4.42 (m, 2H), 4.38-4.29 (m, 2H), 4.07 (s, 3H), 3.79 (s, 3H),
2.62 (s, 3H). LC-MS: method C, RT=2.23 min, MS (ESI) m/z: 518.20
(M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 116
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)e-
thyl 5-cyanopyridin-3-ylcarbamate
##STR00691##
[2426] To a solution of Intermediate 110B in THF (0.5 mL) was added
a suspension of (5-cyanopyridin-3-yl)carbamic chloride (21.42 mg,
0.118 mmol) (23.80 mg, 0.131 mmol) in DCM and toluene, followed by
DIEA (0.046 ml, 0.262 mmol). The mixture was stirred at room
temperature for 30 min. LCMS indicated a completion of the
reaction. The mixture was quenched by 10% water/acetonitrile with
01% TFA. Solvent was removed and the crude was purified via
preparative LC/MS (method D, 50-85% B over 20 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 116
(9.0 mg, 0.016 mmol, 61.9% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.51 (br. s., 1H), 8.85 (d, J=2.5 Hz, 1H),
8.72 (s, 1H), 8.65 (d, J=1.7 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.29
(s, 1H), 7.80 (s, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.03 (d, J=1.7 Hz,
1H), 4.57-4.49 (m, 2H), 4.38-4.31 (m, 2H), 4.07 (s, 3H), 2.74 (s,
3H), 2.63 (s, 3H). LC-MS: method C, RT=2.52 min, MS (ESI) m/z:
527.15 (M+H).sup.+. Analytical HPLC purity (method B): 95%.
Example 117
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)ethyl (6-cyanopyridin-3-yl)carbamate
##STR00692##
[2428] To Intermediate 110B (15 mg, 0.039 mmol) in THF (0.5 mL) was
added (6-cyanopyridin-3-yl)carbamic chloride (21.42 mg, 0.118 mmol)
(21.42 mg, 0.118 mmol) in DCM (1 ml) followed by DIEA (0.069 ml,
0.393 mmol). The mixture was stirred at room temperature for 30
min. LCMS indicated a completion of the reaction. The mixture was
quenched by 10% water/acetonitrile with 01% TFA. Solvent was
removed, the residual was purified via preparative LC/MS (method D,
55-95% B over 10 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to give Example 117 (13.1 mg, 0.025 mmol,
63.3% yield). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 527.20
(M+H).sup.+. Analytical HPLC purity (method B): 98%.
Example 118
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl
(3-cyanophenyl)carbamate
##STR00693##
[2430] To a solution of 3-aminobenzonitrile (14.43 mg, 0.122 mmol)
in DCM (0.5 mL) was added Intermediate 115D (15 mg, 0.035 mmol) in
THF (1 mL) followed by DIEA (0.061 mL, 0.349 mmol). The mixture was
stirred at room temperature overnight. The reaction was quenched by
addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent)
and concentrated. The residual was dissolved in DMSO and purified
via preparative LC/MS (method D, 60-100% B over 20 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
118 (2.1 mg, 3.94 .mu.mol, 11.29% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.26 (br. s., 1H), 8.74 (s, 1H), 8.58 (d,
J=1.4 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 7.90 (s, 1H), 7.82 (s, 1H),
7.78 (d, J=2.2 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.54-7.48 (m, 1H),
7.48-7.44 (m, 1H), 7.20 (dd, J=8.8, 2.5 Hz, 1H), 4.52 (d, J=4.4 Hz,
2H), 4.37 (d, J=3.9 Hz, 2H), 4.08 (s, 3H), 2.63 (s, 3H). LC-MS:
method C, RT=2.43 min, MS (ESI) m/z: 512.20 (M+H).sup.+. Analytical
HPLC purity (method B): 96%.
Example 119
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)ethyl (2-chloropyrimidin-5-yl)carbamate
##STR00694##
[2432] To a solution of Intermediate 110B (15.5 mg, 0.041 mmol) in
THF (1 mL) was added (2-chloropyrimidin-5-yl)carbamic chloride
(39.0 mg, 0.203 mmol) in DCM (1 ml) followed by DIEA (0.071 ml,
0.406 mmol). The mixture was stirred at room temperature overnight,
quenched by a drop of 10% water/acetonitrile with 0.1% TFA. Solvent
was removed, the residual was dissolved in DMSO and purified via
preparative LC/MS (method C, 55-100% B over 15 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 119
(3.7 mg, 6.61 .mu.mol, 16.28% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.82 (s, 2H), 8.73 (s, 1H), 8.59 (s, 1H),
7.82 (s, 1H), 7.57 (s, 1H), 7.03 (s, 1H), 4.53 (br. s., 2H), 4.35
(br. s., 2H), 4.07 (s, 3H), 2.74 (s, 3H), 2.64 (s, 3H). LC-MS:
method C, RT=2.54 min, MS (ESI) m/z: 537.15 (M+H).sup.+. Analytical
HPLC purity (method B): 96%.
Example 120
5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline
##STR00695##
[2433] Intermediate 120A:
4-fluoro-2-hydroxy-5-methoxybenzaldehyde
##STR00696##
[2435] To a solution of 3-fluoro-4-methoxyphenol (200 mg, 1.407
mmol) in THF (8 ml) was added magnesium chloride (260 mg, 2.81
mmol), triethylamine (0.981 mL, 7.04 mmol) and paraformaldehyde
(211 mg, 7.04 mmol). The reaction mixture was heated to reflux at
80.degree. C. under argon for 3.0 h. TLC and LCMS indicated a
complete conversion of starting material. The reaction mixture was
cooled to room temperature, diluted with EtOAc, quenched with 1.0 N
HCl (8.0 mL)/water and stirred at room temperature for 15 min until
the cloudy solution turned to a clear solution. The mixture was
passed through a pad of wet celite. The organic layer was
collected, washed with brine, dried over sodium sulfate and
concentrated. The crude product was purified with flash
chromatography (loading in chloroform, 0% to 30% EtOAc in hexanes
over 15 min using a 12 g silica gel cartridge). The desired
fractions were combined and concentrated to yield Intermediate 120A
(235 mg, 1.381 mmol, 98% yield) as a white solid. .sup.19F NMR (376
MHz, Chloroform-d) .delta. -117.87 (s, 1F). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 11.09 (d, J=1.8 Hz, 1H), 9.81 (s, 1H), 7.09
(d, J=9.0 Hz, 1H), 6.75 (d, J=11.9 Hz, 1H), 3.91 (s, 3H). LC-MS:
method C, RT=1.45 min, MS (ESI) m/z: No (M+H).sup.+.
Intermediate 120B: ethyl
6-fluoro-5-methoxybenzofuran-2-carboxylate
##STR00697##
[2437] To a mixture of Intermediate 120A (1.7 g, 9.99 mmol) and
Cs.sub.2CO.sub.3 (3.91 g, 11.99 mmol) in acetonitrile (50 mL) was
added ethyl bromoacetate (1.266 mL, 10.99 mmol). The mixture was
stirred at room temperature over weekend. The mixture was filtered
and the filter cake was rinse with EtOAc. The combined filtrate was
concentrated to a white solid of ethyl
2-(5-fluoro-2-formyl-4-methoxyphenoxy)acetate. The crude sample was
added to a solution of
2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane
(0.864 g, 4.00 mmol) in EtOH (10 mL). The mixture was heated at
70.degree. C. for 2 h. TLC and LCMS indicated a completion of the
reaction. The mixture was concentrated and the residual was
purified with a 120 g ISCO column eluted with 0-100% EtOAc in
hexanes for 40 min. The desired fraction was collected and
concentrated to give Intermediate 120B (1.6 g, 6.72 mmol, 67.2%
yield) as a white solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.47 (d, J=0.9 Hz, 1H), 7.35 (dd, J=10.5, 0.8 Hz, 1H), 7.16
(d, J=8.1 Hz, 1H), 4.44 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 1.43 (t,
J=7.2 Hz, 3H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -130.18
(s, 1F). LC-MS: method C, RT=1.93 min, MS (ESI) m/z: 239.1
(M+H).sup.+.
Intermediate 120C: 6-fluoro-5-methoxybenzofuran
##STR00698##
[2439] To a solution of Intermediate 120B (1.6 g, 6.72 mmol) in THF
(25 mL) and MeOH (5 mL) was added NaOH (0.806 g, 20.15 mmol) in
water (10 mL). The mixture was stirred at room temperature for 1 h.
LCMS indicated the reaction was complete. The mixture was diluted
with EtOAc and 1N HCl (pH<2), extracted with EtOAc. The combined
organic layer was washed with brine, dried over MgSO.sub.4 and
concentrated to 6-fluoro-5-methoxybenzofuran-2-carboxylic acid as a
white solid. LC-MS: method C, RT=1.59 min, MS (ESI) m/z: 211
(M+H).sup.+. The crude acid was redissolved in DMSO (25 mL), then
silver carbonate (0.740 g, 1.35 mmol) and AcOH (0.038 mL, 0.672
mmol) was added. The mixture was heated at 120.degree. C.
overnight. LCMS indicated a completion of the reaction. The mixture
was filtered and the filter cake was washed with EtOAc. The
filtrate was concentrated and purified with a 120 g ISCO column
eluted with 0-50% EtOAc in hexanes for 40 min. The desired fraction
was collected and concentrated to give Intermediate 120C (0.97 g,
5.84 mmol, 87% yield) as a yellow solid. .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.71 (d, J=2.2 Hz, 1H), 7.30 (dd, J=10.9,
0.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.79 (dd, J=2.2, 1.1 Hz, 1H).
.sup.19F NMR (376 MHz, methanol-d.sub.4) .delta. -138.84 (s, 1F).
LC-MS: method C, RT=1.74 min, MS (ESI) m/z: No (M+H).sup.+.
Intermediate 120D: 6-fluorobenzofuran-5-ol
##STR00699##
[2441] To a mixture of Intermediate 120C (0.73 g, 4.39 mmol) and
tetrabutylammonium iodide (1.704 g, 4.61 mmol) in DCM (4 ml) at
-78.degree. C. was added boron trichloride in heptane (10.33 ml,
1.0 M, 10.33 mmol) dropwise. The mixture was stirred at -78.degree.
C. for 45 min. The cooling bath was removed and the mixture was
stirred at room temperature for 3.0 h. HPLC and TLC indicated a
clean reaction. The mixture was poured into 1.5M K.sub.2HPO.sub.4
with ice, stirred for 20 min, extracted with EtOAc. The organic
layers were collected, washed with 10% Na.sub.2S.sub.2O.sub.3,
water, brine, dried over sodium sulfate. After evaporation of
solvent, the crude product was dissolved in a small amount of
chloroform and charged to a 40 g ISCO column eluted with hexanes
for 1 min., then a 15 min gradient from 0% to 50% EtOAc in hexanes.
The desired fractions were combined and concentrated to give
Intermediate 120D (650 mg, 4.27 mmol, 97% yield) as off-white
solid. .sup.19F NMR (376 MHz, chloroform-d) .delta. -142.05 (s,
1F). .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.59 (d, J=2.2 Hz,
1H), 7.29-7.26 (d, Hz 1H), 7.17 (d, J=8.6 Hz, 1H), 6.73-6.64 (m,
1H), 5.00 (d, J=4.8 Hz, 1H). LC-MS: method C, RT=1.37 min, MS (ESI)
m/z: No (M+H).sup.+.
Intermediate 120E:
tert-butyl(6-fluorobenzofuran-5-yloxy)dimethylsilane
##STR00700##
[2443] To a stirred solution of Intermediate 120D (0.65 g, 4.27
mmol) in DMF (15 mL) was added TBDMS-Cl (0.966 g, 6.41 mmol) and
imidazole (0.524 g, 7.69 mmol). The reaction mixture was stirred at
room temperature for 1.0 h. TLC and LCMS indicated a clean
reaction. The mixture was partitioned between EtOAc/water. The
organic layer was washed with water, brine, dried over sodium
sulfate. After evaporation of solvent, the crude product was
dissolved in a small amount of chloroform and charged to a 40 g
silica gel cartridge which was eluted with hexanes for 3 min., then
15 min gradient from 0% to 15% EtOAc in hexanes. The desired
fractions were combined and concentrated to give Intermediate 120E
(1 g, 3.75 mmol, 88% yield) as clear oil. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.58 (d, J=2.2 Hz, 1H), 7.24 (dd, J=10.0, 0.8
Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.66 (dd, J=2.1, 1.0 Hz, 1H),
1.08-1.00 (m, 9H), 0.26-0.16 (m, 6H). .sup.19F NMR (376 MHz,
chloroform-d) .delta. -133.00 (s, 1F). LC-MS: method C, RT=2.53
min, MS (ESI) m/z: 267 (M+H).sup.+.
Intermediate 120F:
tert-butyl(6-fluoro-7-(trimethylsilyl)benzofuran-5-yloxy)
dimethylsilane
##STR00701##
[2445] To diisopropylamine (0.594 mL, 4.17 mmol) in THF (10 mL) at
-78.degree. C. was added 1.6 N n-BuLi in hexanes (2.083 mL, 3.33
mmol). The mixture was stirred at -78.degree. C. for 0.5 h. Then
Intermediate 120E (740 mg, 2.78 mmol) in THF (2 mL) was added, the
mixture was stirred at -78.degree. C. for 0.5 h. TMS-Cl in DCM
(3.61 mL, 3.61 mmol) was added, and the reaction mixture was warmed
up to room temperature over 0.5 h. The reaction mixture was diluted
with EtOAc, quenched with saturated ammonium chloride. The organic
layer was washed with Na.sub.2CO.sub.3, brine, dried over sodium
sulfate. After evaporation of solvent, the crude was purified with
a 40 g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min.
The desired fraction was collected and concentrated to give
Intermediate 120F (840 mg, 2.481 mmol, 89% yield) as colorless oil.
.sup.19F NMR (376 MHz, chloroform-d) .delta. -121.09 (s, 1F).
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.57 (d, J=2.2 Hz, 1H),
7.08 (d, J=8.8 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 1.03 (s, 9H), 0.46
(d, J=1.1 Hz, 9H), 0.20 (d, J=1.1 Hz, 6H). LC-MS: method C, RT=2.24
min, MS (ESI) m/z: 339 (M+H).sup.+.
Intermediate 120G
tert-butyl(6-fluoro-2-iodo-7-(trimethylsilyl)benzofuran-5-yloxy)dimethylsi-
lane
##STR00702##
[2447] To a solution of Intermediate 120F (840 mg, 2.481 mmol) in
THF (10 mL) at -78.degree. C. was added 1.6 N n-BuLi in hexanes
(2.016 mL, 3.23 mmol). The mixture was stirred at -78.degree. C.
for 0.5 h. Then iodine (945 mg, 3.72 mmol) in THF (2 mL) was added,
the mixture was stirred at -78.degree. C. for 0.5 h. LCMS indicated
a completion of the reaction. The reaction mixture was diluted with
EtOAc, quenched with saturated ammonium chloride. The organic layer
was washed with Na.sub.2S.sub.2O.sub.3 and brine, dried over sodium
sulfate. After evaporation of solvent, the crude was purified with
a 40 g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min.
The desired fraction was collected and concentrated to give
Intermediate 120G (880 mg, 1.895 mmol, 76% yield) as colorless oil.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.00 (d, J=8.6 Hz, 1H),
6.81 (s, 1H), 1.03 (s, 9H), 0.45 (d, J=1.1 Hz, 9H), 0.18 (d, J=1.1
Hz, 6H). .sup.19F NMR (376 MHz, chloroform-d) .delta. -120.92 (s,
1F). LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 465
(M+H).sup.+.
Intermediate 120H:
5-(5-(tert-butyldimethylsilyloxy)-6-fluoro-7-(trimethylsilyl)
benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
##STR00703##
[2449] To Intermediate I-1 (57.9 mg, 0.172 mmol), Intermediate 120G
(80 mg, 0.172 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (7.03 mg, 8.61 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To the above mixture
was added sodium carbonate (0.172 mL, 2M, 0.344 mmol). The reaction
mixture was heated in a microwave reactor at 120.degree. C. for 30
min. The crude reaction mixture was directly loaded onto a 40 g
ISCO column, eluted with 0-20% EtOAc in hexanes for 20 min. The
desired fractions were combined and concentrated to yield
Intermediate 120H (100 mg, 0.128 mmol, 74.3% yield) as a yellow
oil. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.63 (s, 1H), 8.12
(d, J=1.8 Hz, 1H), 7.97 (s, 1H), 7.63 (dd, J=1.9, 1.0 Hz, 1H),
7.86-7.47 (m, 1H), 7.17 (d, J=8.6 Hz, 1H), 2.64 (s, 3H), 1.05 (s,
9H), 0.57 (d, J=1.1 Hz, 9H), 0.21 (d, J=0.9 Hz, 6H). .sup.19F NMR
(376 MHz, chloroform-d) .delta. -89.68 (s, 2F). LC-MS: method C,
RT=4.63 min, MS (ESI) m/z: 547 (M+H).sup.+.
Intermediate 120I
6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(trimethylsilyl)benzofura-
n-5-ol
##STR00704##
[2451] To solution of Intermediate 120H (100 mg, 0.128 mmol) in THF
(3 mL) at room temperature was added sodium methoxide in MeOH
(0.095 mL, 4.37M, 0.448 mmol). The reaction mixture was stirred at
room temperature for 30 min. TLC and LCMS indicated a completion of
the reaction. The reaction mixture was quenched with saturated
NH.sub.4Cl, diluted with EtOAc. The organic layer was washed with
saturated sodium bicarbonate, brine, dried over MgSO.sub.4 and
concentrated. The crude was purified with a 12 g ISCO column eluted
with 0-50% EtOAc in hexanes for 15 min. The desired fraction was
collected and concentrated to give Intermediate 120I (69 mg, 0.122
mmol, 95% yield) as a yellow solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.51 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.97
(s, 1H), 7.62 (dd, J=1.8, 0.9 Hz, 1H), 7.23 (d, J=9.2 Hz, 1H), 4.12
(s, 3H), 0.58 (s, 9H). LC-MS: method C, RT=2.77 min, MS (ESI) m/z:
397 (M+H).sup.+.
Intermediate 120J:
6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol
##STR00705##
[2453] To a solution of Intermediate 120I (69 mg, 0.122 mmol) in
THF (2 mL) was added AcOH (0.021 mL, 0.365 mmol) followed by TBAF
(0.488 mL, 0.488 mmol). The mixture was stirred at room temperature
for 3 h. LCMS indicated a completion of the reaction. Solvent was
removed and the residual was purified with a 12 g ISCO column
eluted with 0-70% EtOAc/hexanes for 20 min. The desired fraction
was collected and concentrated to give Intermediate 120J (30 mg,
0.093 mmol, 76% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.48 (s, 1H), 8.42-8.38 (m, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.50
(s, 1H), 7.16 (d, J=10.6 Hz, 1H), 7.12-7.06 (m, 1H), 4.07-3.98 (m,
3H), 2.51 (s, 3H). .sup.19F NMR (376 MHz, chloroform-d) .delta.
-137.18 (s, 1F). LC-MS: method C, RT=2.42 min, MS (ESI) m/z: 325
(M+H).sup.+.
Example 120
[2454] To a solution of Intermediate 120J (15 mg, 0.046 mmol) in
DMF (1 mL) was added Cs.sub.2CO.sub.3 (45.2 mg, 0.139 mmol) and Met
(0.014 mL, 0.231 mmol). The mixture was stirred at room temperature
for 2 h. LCMS indicated a completion of the reaction. The mixture
was filtered. The filtrate was purified via preparative LC/MS
(method D, 65-100% B over 20 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Example 120 (2.6 mg, 7.45
.mu.mol, 16.12% yield). .sup.1H NMR (500 MHz, chloroform-d) .delta.
8.51 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.33 (d,
J=10.5 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.12 (s, 3H), 3.96 (s, 3H),
2.62 (s, 3H). LC-MS: method C, RT=2.59 min, MS (ESI) m/z: 338.9
(M+H).sup.+. Analytical HPLC purity (method B): 97%.
Example 121
5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylq-
uinoxaline
##STR00706##
[2455] Intermediate 121A: 7-chloro-6-fluoro-5-methoxybenzofuran
##STR00707##
[2457] To diisopropylamine (0.270 mL, 1.896 mmol) in THF (5 mL) at
-78.degree. C. was added 1.6 N n-BuLi in hexanes (0.948 mL, 1.517
mmol). The mixture was stirred at -78.degree. C. for 0.5 h.
Intermediate 120C (210 mg, 1.264 mmol) in THF (1 mL) was added, the
mixture was stirred at -78.degree. C. for 0.5 h. Hexachloroethane
(449 mg, 1.896 mmol) in THF (1 mL) was added, and the reaction
mixture was stirred at -78.degree. C. for 0.5 h. The reaction
mixture was diluted with EtOAc, quenched with saturated ammonium
chloride. The organic layer was washed with Na.sub.2SO.sub.3,
brine, dried over sodium sulfate and concentrated. The crude sample
was purified with a 40 g ISCO column eluted with 0-70% EtOAc in
hexanes for 20 min. The desired fraction was collected and
concentrated to give Intermediate 121A (240 mg, 1.196 mmol, 95%
yield) as a white solid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.67 (d, J=2.0 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.76 (d,
J=2.2 Hz, 1H), 3.94 (s, 3H). .sup.19F NMR (376 MHz, chloroform-d)
.delta. -140.56 (s, 1F). LC-MS: method C, RT=2.01 min, MS (ESI)
m/z: No (M+H).sup.+.
Intermediate 121B: 7-chloro-6-fluoro-2-iodo-5-methoxybenzofuran
##STR00708##
[2459] To a solution of Intermediate 121A (240 mg, 1.196 mmol) in
THF (5 mL) at -78.degree. C. was added 1.6 N n-BuLi in hexanes
(0.972 mL, 1.555 mmol). The mixture was stirred at -78.degree. C.
for 0.5 h. Iodine (456 mg, 1.795 mmol) in THF (2 mL) was added, and
the mixture was stirred at -78.degree. C. for 0.5 h. The mixture
was warmed up to room temperature and continued stirring for 1 h.
The reaction mixture was diluted with EtOAc, quenched with
saturated ammonium chloride. The organic layer was washed with
Na.sub.2S.sub.2O.sub.3, brine, dried over sodium sulfate. The crude
sample was purified with a 12 g ISCO column eluted with 0-20% EtOAc
in hexanes for 20 min. The desired fraction was collected and
concentrated to give Intermediate 121B (280 mg, 0.686 mmol, 57.3%
yield) as colorless oil. .sup.19F NMR (376 MHz, chloroform-d)
.delta. -140.34 (s, 1F). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 6.96 (d, J=7.3 Hz, 1H), 6.92 (s, 1H), 3.93 (s, 3H). LC-MS:
method C, RT=2.24 min, MS (ESI) m/z: No (M+H).sup.+.
Example 121
[2460] To Intermediate I-2 (11.37 mg, 0.049 mmol), Intermediate
121B (20 mg, 0.049 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (2.001 mg, 2.450 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this mixture was
added Na.sub.2CO.sub.3 (0.049 mL, 2M, 0.098 mmol). The reaction
mixture was heated in a microwave reactor at 120.degree. C. for 30
min. The crude reaction mixture was directly loaded onto a 12 g
ISCO column, eluted with 0-50% EtOAc in hexanes for 20 min. The
desired fractions were combined and concentrated. The sample was
redissolved in DMSO and further purified via preparative LC/MS
(method D, 65-100% B over 15 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Example 121 (4.7 mg, 0.012
mmol, 24.55% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.05 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.56 (d,
J=7.7 Hz, 1H), 4.79 (s, 2H), 3.93 (s, 3H), 3.46 (s, 3H), 2.66 (s,
3H). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 387.1 (M+H).sup.+.
Analytical HPLC purity (method B): 99%.
Example 122
5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxali-
ne
##STR00709##
[2462] To Intermediate I-1 (16.47 mg, 0.049 mmol), Intermediate
121B (20 mg, 0.049 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (2.001 mg, 2.450 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.049 mL, 2M, 0.098 mmol). The reaction mixture
was heated in a microwave reactor at 120.degree. C. for 30 min. The
crude reaction mixture was directly loaded onto a 12 g ISCO column,
eluted with 0-20% EtOAc in hexane for 20 min. The desired fractions
were combined and concentrated to yield
5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(difluoromethoxy)-7-meth-
ylquinoxaline as a yellow oil. LC-MS: method C, RT=2.81 min, MS
(ESI) m/z: 409 (M+H).sup.+. The above sample was dissolved in THF
(1 ml) and sodium methoxide (0.036 mL, 4.37M, 0.172 mmol) was
added. The mixture was stirred at room temperature for 30 min,
quenched with a drop of 10% water/MeOH with 0.1% TFA (HPLC solvent)
and concentrated. The crude was redissolved in DMSO and purified
via preparative LC/MS (method C, 60-100% B over 20 min., then a
5-min hold at 100% B). Fractions containing the desired product
were combined and dried via centrifugal evaporation to give Example
122 (0.8 mg, 2.146 .mu.mol, 4.38% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.13 (s, 1H), 8.07 (s, 1H),
7.74 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 4.09 (s, 3H), 3.95 (s, 3H),
2.63 (s, 3H). LC-MS: method C, RT=2.76 min, MS (ESI) m/z: 373.05
(M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 123
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethy-
l (2-methylpyridin-4-yl)carbamate
##STR00710##
[2463] Intermediate 123A: 6-fluoro-2-iodobenzofuran-5-ol
##STR00711##
[2465] To a solution of Intermediate 120G (64 mg, 0.138 mmol) in
THF (1 mL) was added TBAF (0.413 mL, 0.413 mmol). The mixture was
stirred at room temperature for 1 h. Solvent was removed under
vacuum and the residual was purified with a 12 g ISCO column eluted
with 0-70% EtOAc in hexanes for 15 min. The desired fraction was
collected and concentrated to give Intermediate 123A (38 mg, 0.137
mmol, 99% yield) as white solid. .sup.19F NMR (376 MHz,
chloroform-d) .delta. -141.74 (s, 1F). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.27-7.23 (m, 1H), 7.10 (d, J=8.6 Hz, 1H),
6.86 (d, J=0.9 Hz, 1H), 5.10-4.99 (m, 1H). LC-MS: method C, RT=1.84
min, MS (ESI) m/z: No (M+H).sup.+.
Intermediate 123B:
6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol
##STR00712##
[2467] To Intermediate I-1 (45.9 mg, 0.137 mmol), Intermediate 123A
(38 mg, 0.137 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (5.58 mg, 6.83 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.137 mL, 2M, 0.273 mmol). The reaction mixture
was heated in a microwave reactor at 120.degree. C. for 30 min. The
crude reaction mixture was directly loaded onto a 12 g ISCO column,
eluted with 0-50% EtOAc in hexanes for 15 min. The desired
fractions were combined and concentrated to yield Intermediate 123B
(78 mg, 0.130 mmol, 95% yield) as a yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.65 (s, 1H), 8.20 (s, 1H), 8.01 (s,
1H), 7.66 (s, 1H), 7.33 (d, J=10.1 Hz, 1H), 2.65 (s, 3H). .sup.19F
NMR (376 MHz, chloroform-d) .delta. -89.71 (s, 2F), -140.50 (s,
1F). LC-MS: method C, RT=2.37 min, MS (ESI) m/z: 361
(M+H).sup.+.
Intermediate 123C
2-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethano-
l
##STR00713##
[2469] To a solution of Intermediate 123B (49.4 mg, 0.137 mmol) in
DMF (2 mL) was added Cs.sub.2CO.sub.3 (134 mg, 0.411 mmol) and
2-bromoethyl acetate (0.031 mL, 0.274 mmol). The mixture was
stirred at room temperature for 1 h. LCMS indicated a completion of
the reaction. The mixture was diluted with EtOAc and water,
extracted with EtOAc. The combined organic layer was washed with
brine, dried with MgSO.sub.4 and concentrated. LC-MS: method C,
RT=2.53 min, MS (ESI) m/z: 447 (M+H).sup.+. The crude sample was
redissolved in THF (1 ml) and sodium methoxide (0.094 mL, 4.37M,
0.411 mmol) was added. The mixture was stirred at room temperature
for 30 min, diluted with EtOAc and saturated NH.sub.4Cl, extracted
with EtOAc. The combined organic layer was washed with saturated
NaHCO.sub.3, brine, dried over MgSO.sub.4 and concentrated. The
crude sample was dissolved in DMF and load on a 40 g ISCO column,
eluted with 0-100% EtOAc in hexanes for 20 min. The desired
fraction was collected and concentrated to give Intermediate 123C
(50 mg, 0.136 mmol, 99% yield) as a yellow solid. .sup.19F NMR (376
MHz, methanol-d.sub.4) .delta. -136.00 (s, 1F). .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. 8.51 (s, 1H), 8.07 (d, J=1.8 Hz,
1H), 8.02 (d, J=0.9 Hz, 1H), 7.62 (dd, J=1.8, 0.9 Hz, 1H), 7.38
(dd, J=10.8, 0.9 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.19-4.16 (m,
2H), 4.11 (s, 3H), 3.97-3.92 (m, 2H), 2.61 (s, 3H). LC-MS: method
C, RT=2.39 min, MS (ESI) m/z: 369 (M+H).sup.+.
Intermediate 123D
2-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethyl
carbonochloridate
##STR00714##
[2471] To a solution of Intermediate 123C (45 mg, 0.122 mmol) in
THF (2 mL) was added 15% phosgene in toluene (0.431 mL, 0.611
mmol), and the mixture was stirred at room temperature overnight.
Solvent was removed under vacuum to give Intermediate 123D as a
yellow solid. It was used for the next step without any
purification. LC-MS: method C, RT=2.63 min, MS (ESI) m/z: 431
(M+H).sup.+.
Example 123
[2472] To a solution of Intermediate 123D (10 mg, 0.023 mmol) in
THF (1 mL) was added 2-methylpyridin-4-amine (7.53 mg, 0.070 mmol)
in DCM (0.5 mL) followed by DIEA (0.041 mL, 0.232 mmol). The
mixture was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. The reaction was quenched by addition
of a small amount of 10% MeOH/water/0.1% TFA (HPLC solvent).
Solvent was removed under vacuum. The residual was dissolved in
DMSO and purified via preparative LC/MS (method C, 40-80% B over 20
min., then a 5-min hold at 100% B). Fractions containing the
desired product were combined and dried via centrifugal evaporation
to give Example 123 (2.7 mg, 5.37 .mu.mol, 23.15% yield). .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.20 (br. s., 1H), 8.67 (s,
1H), 8.50 (d, J=6.6 Hz, 1H), 8.03 (s, 2H), 7.76-7.65 (m, 4H), 7.57
(d, J=8.5 Hz, 1H), 4.60 (br. s., 2H), 4.41 (br. s., 2H), 4.06 (s,
3H), 2.58 (br. s., 6H). LC-MS: method C, RT=1.99 min, MS (ESI) m/z:
503.15 (M+H).sup.+. Analytical HPLC purity (method B): 100%.
Example 124
(8-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)m-
ethanol
##STR00715##
[2474] To Intermediate I-27 (14.22 mg, 0.035 mmol), Intermediate
121B (14.22 mg, 0.035 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (1.423 mg, 1.742 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this mixture was
added sodium carbonate (0.035 mL, 2M, 0.070 mmol). The reaction
mixture was heated in a microwave reactor at 120.degree. C. for 30
min. The crude reaction mixture was directly loaded onto a 12 g
ISCO column and eluted with 0-20% EtOAc in hexanes for 20 min. The
desired fractions were combined and concentrated to yield
7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(7-chloro-6-fluoro-5-methoxybe-
nzofuran-2-yl)-2-methoxyquinoxaline as an off-white solid. The
sample was dissolved in 2 ml of DCM and TFA (0.013 mL, 0.174 mmol)
was added. The mixture was stirred at room temperature for 1 h. TLC
indicated a small conversion. TBAF (0.070 mL, 0.070 mmol) was added
to the mixture and stirred at room temperature overnight. LCMS
indicate a completion of the reaction. Solvent was completely
removed and the residual was purified via preparative LC/MS (method
C, 45-90% B over 20 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to give Example 124 (3.0 mg, 7.33 .mu.mol,
21.04% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.69 (s,
1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.79 (s, 1H), 7.52 (d, J=7.4 Hz,
1H), 5.60 (t, J=5.2 Hz, 1H), 4.80 (d, J=5.5 Hz, 2H), 4.07 (s, 3H),
3.93 (s, 3H). LC-MS: method C, RT=2.20 min, MS (ESI) m/z: 388.90
(M+H).sup.+. Analytical HPLC purity (method B): 95%.
Example 125
(8-(6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol
##STR00716##
[2475] Intermediate 125A
2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluo-
robenzofuran-5-ol
##STR00717##
[2477] To Intermediate I-27 (90 mg, 0.209 mmol), Intermediate 123A
(58.1 mg, 0.209 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (8.54 mg, 10.45 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.209 mL, 2M, 0.418 mmol). The reaction mixture
was heated in a microwave reactor at 120.degree. C. for 30 min. The
crude reaction mixture was directly loaded onto a 40 g ISCO column
which was eluted with 0-50% EtOAc in hexanes for 20 min. The
desired fractions were combined and concentrated to yield
Intermediate 125A (105 mg, 0.185 mmol, 88% yield) as a yellow oil.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 8.55 (s, 1H), 8.18 (d,
J=2.0 Hz, 1H), 8.00 (d, J=0.9 Hz, 1H), 7.82-7.77 (m, 1H), 7.31 (dd,
J=10.0, 0.8 Hz, 1H), 7.25-7.22 (m, 1H), 5.00 (s, 2H), 4.14 (s, 3H),
1.02 (d, J=5.7 Hz, 9H), 0.19 (s, 6H). LC-MS: method C, RT=2.97 min,
MS (ESI) m/z: 455 (M+H).sup.+.
Example 125
[2478] To a solution of Intermediate 125A (14 mg, 0.031 mmol) in
DMF (1 mL) was added Cs.sub.2CO.sub.3 (30.1 mg, 0.092 mmol) and MeI
(9.63 .mu.l, 0.154 mmol). The mixture was stirred at room
temperature for 2 h. LCMS indicated a completion of the reaction.
The mixture was loaded to 12 g ISCO column which was eluted with
0-50% EtOAc in hexanes for 15 min. The desired fraction was
combined and concentrated to give
7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(6-fluoro-5-methoxybenzofuran--
2-yl)-2-methoxyquinoxaline as a light yellow solid. The
intermediate was dissolved in THF (2 ml), and TBAF (0.062 mL, 0.062
mmol) was added. The mixture was stirred at room temperature for 1
h. LCMS indicated a completion of the reaction. Solvent was
removed, the residual was purified via preparative LC/MS (method D,
35-75% B over 15 min., then a 5-min hold at 100% B). Fractions
containing the desired product were combined and dried via
centrifugal evaporation to give Example 125 (3.3 mg, 9.13 .mu.mol,
29.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.18 (d, J=1.7 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.78 (d, J=1.7
Hz, 1H), 7.70 (d, J=11.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 5.57 (t,
J=5.8 Hz, 1H), 4.78 (d, J=5.5 Hz, 2H), 4.08 (s, 3H), 3.90 (s, 3H).
LC-MS: method C, RT=1.95 min, MS (ESI) m/z: 355.15 (M+H).sup.+.
Analytical HPLC purity (method B): 98%.
Example 126
2-((6-fluoro-2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)benzofuran-5-yl-
)oxy)ethyl (2-methylpyridin-4-yl)carbamate
##STR00718##
[2479] Intermediate 126A
2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-f-
luorobenzofuran-5-yloxy)ethanol
##STR00719##
[2481] To a solution of Intermediate 125A (90 mg, 0.158 mmol) in
DMF (2 mL) was added Cs.sub.2CO.sub.3 (155 mg, 0.475 mmol) and
2-bromoethyl acetate (0.035 mL, 0.317 mmol). The mixture was
stirred at room temperature overnight. LCMS indicated a completion
of the reaction. The mixture was diluted with EtOAc and water,
extracted with EtOAc. The combined organic layer was washed with
brine, dried over MgSO.sub.4 and concentrated. The crude sample was
dissolved in THF (2 ml) and NaOMe (0.109 mL, 4.37M, 0.475 mmol) was
added. The mixture was stirred at room temperature for 30 min. LCMS
indicated a completion of the reaction. The mixture was diluted
with EtOAc and saturate NH.sub.4Cl, extracted with EtOAc. The
combined organic layer was washed with NaHCO.sub.3, brine, dried
over MgSO.sub.4 and concentrated. The crude sample was dissolved in
a small amount of DMF, loaded on a 40 g ISCO column, eluted with
0-100% EtOAc in hexanes for 20 min. The desired fraction was
collected and concentrated to give Intermediate 126A (47 mg, 0.075
mmol, 47.6% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.53 (s, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H),
7.83-7.76 (m, 1H), 7.32 (dd, J=10.5, 0.8 Hz, 1H), 7.23 (d, J=8.4
Hz, 1H), 5.00 (s, 2H), 4.23-4.16 (m, 2H), 4.14 (s, 3H), 4.01 (dt,
J=8.9, 4.3 Hz, 2H), 1.05-1.01 (m, 9H), 0.19 (s, 6H). LC-MS: method
C, RT=2.98 min, MS (ESI) m/z: 499 (M+H).sup.+.
Intermediate 126B
2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-f-
luorobenzofuran-5-yloxy)ethyl carbonochloridate
##STR00720##
[2483] To the solution of Intermediate 126A (47 mg, 0.075 mmol) and
DIEA (0.066 ml, 0.377 mmol) in THF (1 mL) was added to 15% phosgene
in toluene (0.160 ml, 0.226 mmol). The mixture was stirred at room
temperature for 3 h. Solvent was removed under vacuum to give
Intermediate 126B as a yellow solid. It was used for the next step
without any purification. LC-MS: method C, RT=3.46 min, MS (ESI)
m/z: 561 (M+H).sup.+.
Example 126
[2484] To a solution of Intermediate 126B (10 mg, 0.018 mmol) in
THF (1 mL) was added 2-methylpyridin-4-amine (5.78 mg, 0.053 mmol)
in DCM (0.5 mL) followed by DIEA (0.031 mL, 0.178 mmol). The
mixture was stirred at room temperature for 1 h. LCMS indicated a
completion of the reaction. TBAF (0.071 mL, 0.071 mmol) was added,
and the mixture was stirred at room temperature overnight. The
reaction mixture was quenched by addition of a small amount of
MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed under
vacuum. The residual was dissolved in DMSO and purified via
preparative LC/MS (method D, 30-70% B over 20 min., then a 5-min
hold at 100% B). Fractions containing the desired product were
combined and dried via centrifugal evaporation to give Example 126
(2.3 mg, 4.26 .mu.mol, 23.89% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.35 (s, 1H), 8.70 (s, 1H), 8.28 (d, J=5.8
Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.73
(d, J=10.7 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.37 (s, 1H), 7.33 (d,
J=5.5 Hz, 1H), 5.57 (s, 1H), 4.78 (d, J=5.0 Hz, 2H), 4.57-4.45 (m,
2H), 4.42-4.32 (m, 2H), 4.07 (s, 3H), 2.41 (s, 3H). LC-MS: method
C, RT=1.48 min, MS (ESI) m/z: 519.20 (M+H).sup.+. Analytical HPLC
purity (method B): 96%.
Example 127
3-methoxy-8-(6-methoxybenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol
##STR00721##
[2486] To Intermediate I-27 (10.6 mg, 0.025 mmol),
2-bromo-6-methoxybenzo[d]thiazole (6.01 mg, 0.025 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (1.006 mg, 1.231 .mu.mol) was
added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was
sonicated for 1 min, and flushed with argon. To this was added
sodium carbonate (0.025 mL, 2M, 0.049 mmol). The reaction mixture
was heated in a microwave reactor at 120.degree. C. for 30 min. The
crude reaction mixture was directly loaded on a 12 g ISCO column,
eluted with 0-50% EtOAc in hexanes for 15 min. The desired fraction
was collected and concentrated to yield
2-(7-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxyquinoxalin-5-yl)-6-m-
ethoxybenzo[d]thiazole. LC-MS: method C, RT=3.4 min, MS (ESI) m/z:
468 (M+H).sup.+. The sample was redissolved in THF (1 ml) and TBAF
(0.074 mL, 0.074 mmol) was added. The mixture was stirred at room
temperature for 30 min. LCMS indicated a completion of the
reaction. The mixture was concentrated and purified via preparative
LC/MS (method C, 30-70% B over 20 min., then a 5-min hold at 100%
B). Fractions containing the desired product were combined and
dried via centrifugal evaporation to give Example 127 (1.4 mg, 3.80
.mu.mol, 15.44% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.75 (s, 1H), 8.72 (s, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.91 (s, 1H),
7.72 (d, J=2.4 Hz, 1H), 7.16 (dd, J=9.0, 2.3 Hz, 1H), 4.82 (d,
J=5.5 Hz, 2H), 4.09 (s, 3H). LC-MS: method C, RT=1.82 min, MS (ESI)
m/z: 345.10 (M+H).sup.+. Analytical HPLC purity (method B):
100%.
Example 128
2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol--
6-yloxy)ethyl 6-methylpyridin-3-ylcarbamate
##STR00722##
[2487] Intermediate 128A:
2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethanol
##STR00723##
[2489] To a suspension of Intermediate 89B (500 mg, 2.504 mmol) in
DMF (10 mL) was added cesium carbonate (1.63 g, 5.01 mmol). Then
2-bromoethyl acetate (0.331 mL, 3.01 mmol) was added dropwise. The
reaction mixture was stirred at room temperature overnight. LCMS
indicated a completion of the reaction. NaOH (2.504 mL, 2M, 5.01
mmol) was added to the reaction mixture, followed by MeOH (1 ml).
The mixture was stirred at room temperature for 1 h. LCMS indicated
a completion of the reaction. The reaction mixture was diluted with
EtOAc and water, extracted with EtOAc, the combined organic layer
was washed with brine, dried with MgSO.sub.4 and concentrated. The
crude sample was purified with a 40 g ISCO column eluted with
0-100% EtOAc in hexane for 20 min. The desired fraction was
collected and concentrated to give Intermediate 128A (600 mg, 2.462
mmol, 98% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.09
(d, J=2.2 Hz, 1H), 6.97-6.85 (m, 1H), 4.24-4.09 (m, 2H), 4.00 (d,
J=3.7 Hz, 2H), 2.66 (s, 3H). LC-MS: method C, RT=1.82 min, MS (ESI)
m/z: 244 (M+H).sup.+.
Intermediate 128B
2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-m-
ethylbenzo[d]thiazol-6-yloxy)ethanol
##STR00724##
[2491] To Intermediate 124E (50 mg, 0.116 mmol), Intermediate 128A
(28.3 mg, 0.116 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (4.74 mg, 5.81 .mu.mol) was
added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated
for 1 min, and flushed with argon. To this was added sodium
carbonate (0.116 mL, 2M, 0.232 mmol). The reaction mixture was
heated in a microwave reactor at 130.degree. C. for 30 min. The
crude reaction mixture was directly loaded to 12 g ISCO column
eluted with 0% to 100% EtOAc in hexanes over 15 min. The desired
fractions were combined and concentrated to yield Intermediate 128B
(80 mg, 0.109 mmol, 94% yield) as a yellow solid. .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.80 (d, J=2.0 Hz, 1H), 8.58 (s, 1H),
7.94-7.90 (m, 1H), 7.27 (s, 1H), 6.96 (dd, J=2.4, 0.9 Hz, 1H), 5.05
(s, 2H), 4.20-4.16 (m, 2H), 4.15 (s, 3H), 4.05-3.98 (m, 2H), 2.82
(s, 3H), 1.04 (s, 9H), 0.21-0.20 (m, 6H). LC-MS: method C, RT=3.07
min, MS (ESI) m/z: 512 (M+H).sup.+.
Intermediate 128C
2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-m-
ethylbenzo[d]thiazol-6-yloxy)ethyl carbonochloridate
##STR00725##
[2493] To a solution of Intermediate 128B (110 mg, 0.193 mmol) and
DIEA (0.169 ml, 0.967 mmol) in THF (2 ml) was added 15% phosgene in
toluene (0.409 ml, 0.580 mmol). The reaction mixture was stirred at
room temperature overnight and then concentrated to give
Intermediate 128C which was used for next step without
purification. LC-MS: method C, RT=3.64 min, MS (ESI) m/z: 574
(M+H).sup.+.
Intermediate 128D
2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-m-
ethylbenzo[d]thiazol-6-yloxy)ethyl
6-methylpyridin-3-ylcarbamate
##STR00726##
[2495] To a solution of Intermediate 128C (16.5 mg, 0.029 mmol) in
DCM (1 mL) was added 6-methylpyridin-3-amine (9.32 mg, 0.086 mmol)
in DCM (0.5 mL) and DIEA (0.050 mL, 0.287 mmol). The mixture was
stirred at room temperature for 1 h. The reaction mixture was
loaded to a 12 g ISCO column, eluted with 0-100% EtOAc in hexane
for 15 min. The desired fraction was collected and concentrated to
give Intermediate 128D (18 mg, 0.028 mmol, 97% yield). .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.81 (d, J=2.0 Hz, 1H), 8.58 (s,
1H), 8.39 (d, J=2.4 Hz, 1H), 7.92-7.90 (m, 1H), 7.85 (br. s., 1H),
7.26 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (dd, J=2.4, 0.9 Hz, 1H),
6.82-6.69 (m, 1H), 5.05 (s, 2H), 4.62-4.54 (m, 2H), 4.34-4.28 (m,
2H), 4.15 (s, 3H), 2.82 (s, 3H), 2.52 (s, 3H), 1.07-1.01 (m, 9H),
0.22-0.18 (m, 6H). LC-MS: method C, RT=2.48 min, MS (ESI) m/z: 646
(M+H).sup.+.
Example 128
[2496] To a solution of Intermediate 128D (18 mg, 0.028 mmol) in
DCM (1 mL) was added TBAF (0.139 mL, 0.139 mmol), the mixture was
stirred at room temperature for 1 h. Solvent was removed, the
residual was dissolved in DMSO and purified via preparative LC/MS
(method D, 30-70% B over 20 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Example 128 (3.0 mg, 5.53
.mu.mol, 19.84% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.05 (br. s., 1H), 8.73 (s, 1H), 8.71 (br. s., 1H), 8.55 (br. s.,
1H), 7.92 (d, J=15.3 Hz, 1H), 7.86 (br. s., 1H), 7.55 (br. s., 1H),
7.32 (br. s., 1H), 7.02 (br. s., 1H), 4.81 (br. s., 2H), 4.48 (br.
s., 2H), 4.33 (br. s., 2H), 4.08 (s, 3H), 2.88 (s, 3H), 2.43 (br.
s., 3H). LC-MS: method C, RT=1.49 min, MS (ESI) m/z: 532.20
(M+H).sup.+. Analytical HPLC purity (method B): 98%.
Example 129
2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol--
6-yloxy)ethyl 2-methylpyridin-4-ylcarbamate
##STR00727##
[2497] Intermediate 129A
2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-m-
ethylbenzo[d]thiazol-6-yloxy)ethyl
2-methylpyridin-4-ylcarbamate
##STR00728##
[2499] To a solution of Intermediate 128C (16.5 mg, 0.029 mmol) in
DCM (1 mL) was added 2-methylpyridin-4-amine (9.32 mg, 0.086 mmol)
in DCM (0.5 mL) and DIEA (0.050 mL, 0.287 mmol). The mixture was
stirred at room temperature for 1 h. LCMS indicated a completion of
reaction. The reaction mixture was loaded to a 12 g ISCO column,
eluted with 0-100% EtOAc in hexanes for 15 min. The desired
fraction was collected and concentrated to give Intermediate 129A
(17 mg, 0.026 mmol, 92% yield). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.81 (d, J=2.0 Hz, 1H), 8.59 (s, 1H), 8.37 (d, J=4.2 Hz,
1H), 7.94-7.90 (m, 1H), 7.29-7.22 (m, 1H), 7.14 (d, J=4.2 Hz, 1H),
6.97 (dd, J=2.4, 0.9 Hz, 1H), 6.87 (br. s., 1H), 5.05 (s, 2H),
4.64-4.56 (m, 2H), 4.35-4.29 (m, 2H), 4.15 (s, 3H), 2.82 (s, 3H),
2.53 (s, 3H), 1.06-1.01 (m, 10H), 0.23-0.18 (m, 6H). LC-MS: method
C, RT=2.46 min, MS (ESI) m/z: 646 (M+H).sup.+.
Example 129
[2500] To a solution of Intermediate 129A (17 mg, 0.026 mmol) in
DCM (1 mL) was added TBAF (0.132 mL, 0.132 mmol), the mixture was
stirred at room temperature for 1 h. Solvent was removed and the
residual was dissolved in DMSO and purified via preparative LC/MS
(method D, 30-70% B over 25 min., then a 5-min hold at 100% B).
Fractions containing the desired product were combined and dried
via centrifugal evaporation to give Example 129 (2.9 mg, 5.40
.mu.mol, 20.52% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.70 (d, J=9.2 Hz, 2H), 8.25 (br. s., 1H), 7.88 (s, 1H), 7.53 (s,
1H), 7.31 (d, J=16.2 Hz, 2H), 7.01 (s, 1H), 4.81 (d, J=4.3 Hz, 2H),
4.50 (br. s., 2H), LC-MS: method C, RT=1.55 min, MS (ESI) m/z:
532.20 (M+H).sup.+. Analytical HPLC purity (method B): 99%.
Example 130
5-(benzofuran-2-yl)-2-methoxy-7-methyl-1,6-naphthyridine
##STR00729##
[2501] Intermediate 130A:
(E)-2-(2-(dimethylamino)prop-1-en-1-yl)-6-methoxynicotinonitrile
##STR00730##
[2503] 6-methoxy-2-methylnicotinonitrile (200 mg, 1.350 mmol) was
dissolved in DMF (1350 .mu.L) and N,N-dimethylacetamide dimethyl
acetal (987 .mu.L, 6.75 mmol) and heated to 150.degree. C. for 24
hours. The reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 12 g silica gel column, 17 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 130A (177.9
mg, 0.819 mmol, 60.7%) as a yellow solid: LC-MS: Ketone product
mass observed, Method H, RT=0.72 min, MS (ESI) m/z: 191.2
(M+H).sup.+.
Intermediate 130B: 2-methoxy-7-methyl-1,6-naphthyridin-5-ol
##STR00731##
[2505] Intermediate 130A (178 mg, 0.819 mmol) was dissolved in
CHCl.sub.3 (6145 .mu.L), AcOH (1024 .mu.L), and HBr (1024 .mu.L)
and stirred for 18 hours. The reaction mixture was diluted with 1 N
NaOH and extracted thrice with EtOAc. The combined organic layers
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 24 g silica gel column, 19 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 130B (51.6
mg, 0.271, 33.1%) as a white solid: .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.34 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.8
Hz, 1H), 6.44 (br. s., 1H), 4.02 (d, J=2.8 Hz, 3H), 2.33 (s, 3H);
LC-MS: Method H, RT=0.7 min, MS (ESI) m/z: 191.2 (M+H).sup.+.
Intermediate 130C: 2-methoxy-7-methyl-1,6-naphthyridin-5-yl
trifluoromethanesulfonate
##STR00732##
[2507] Intermediate 130B (0.0516 g, 0.271 mmol), pyridine (0.055
mL, 0.678 mmol), and DIEA (0.104 mL, 0.597 mmol) were dissolved in
DCM (13.56 mL). Triflic anhydride (0.092 mL, 0.543 mmol) was added
and the reaction mixture stirred for 1.5 hours. The reaction
mixture was concentrated in vacuo. 2D TLC was used to determine if
the triflate product was unstable to silica gel and there was a
slight bit of decomposition observed. Therefore, the reaction
mixture was filtered through a pad of silica gel in a fritted
funnel with rapid DCM elution and concentrated in vacuo to give
Intermediate 130C (77.5 mg, 0.240 mmol, 89%) as a red oil: .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 8.14 (d, J=9.0 Hz, 1H), 7.52
(s, 1H), 7.00 (d, J=9.0 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H); LC-MS:
Method H, RT=1.10 min, MS (ESI) m/z: 323.0 (M+H).sup.+.
Example 130
[2508] Intermediate 130C (30 mg, 0.093 mmol) and
benzofuran-2-ylboronic acid (22.61 mg, 0.140 mmol) were dissolved
in toluene (698 .mu.L) and EtOH (233 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (4.56 mg, 5.59 .mu.mol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 55.9 .mu.L, 0.112 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 90.degree. C. in the microwave for 30 minutes. The
reaction mixture was purified by preparative HPLC (Method D, 30 to
80% B in 10 minutes) to give Example 130 (9.8 mg, 0.033 mmol,
35.2%): .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.95 (d,
J=9.4 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.57
(s, 1H), 7.51 (s, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.35-7.29 (m, 1H),
7.02 (d, J=9.4 Hz, 1H), 4.11 (s, 3H), 2.73 (s, 3H); LC-MS: Method
H, RT=0.88 min, MS (ESI) m/z: 291.2 (M+H).sup.+. Analytical HPLC
Method B: 97.2% purity.
Example 131
5-(benzofuran-2-yl)-7-methyl-2-vinylquinoxaline
##STR00733##
[2509] Intermediate 131A:
2-(benzyloxy)-5-iodo-7-methylquinoxaline
##STR00734##
[2511] Intermediate I-14 (200 mg, 0.699 mmol) was suspended in
toluene (4661 .mu.L). Silver oxide (405 mg, 1.748 mmol) then benzyl
bromide (83 .mu.L, 0.699 mmol) were added and the reaction mixture
was stirred for 1 week. The reaction mixture was filtered to remove
the silver salts and concentrated in vacuo. The material was
purified by column chromatography (ISCO, 12 g silica gel column, 15
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 131A (78.8 mg, 0.209 mmol, 30%) as an off-white solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.47 (s, 1H), 8.01 (d,
J=1.5 Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 7.52 (d, J=6.8 Hz, 2H),
7.45-7.32 (m, 3H), 5.54 (s, 2H), 2.52 (s, 3H); LC-MS: Method H,
RT=1.22 min, MS (ESI) m/z: 377.0 (M+H).sup.+.
Intermediate 131B:
5-(benzofuran-2-yl)-2-(benzyloxy)-7-methylquinoxaline
##STR00735##
[2513] Intermediate 131A (78.8 mg, 0.209 mmol) and
benzofuran-2-ylboronic acid (50.9 mg, 0.314 mmol) were dissolved in
toluene (1571 .mu.L) and EtOH (524 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (10.26 mg, 0.013 mmol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 126 .mu.L, 0.251 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 90.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with EtOAc and filtered through a
micron filter and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 131B (67.7 mg, 0.185 mmol, 88%) as a yellow solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.56 (s, 1H), 8.15 (d,
J=2.0 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.69-7.63 (m, 2H), 7.58-7.53
(m, 3H), 7.45-7.40 (m, 2H), 7.39-7.28 (m, 3H), 5.56 (s, 2H), 2.63
(s, 3H); LC-MS: Method H, compound did not ionize.
Intermediate 131C:
5-(benzofuran-2-yl)-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
##STR00736##
[2515] Intermediate 131B (67.7 mg, 0.185 mmol) was partially
dissolved in MeOH (1848 .mu.L) and EtOAc (1848 .mu.L). Palladium on
carbon (19.66 mg, 0.018 mmol) was added. The reaction mixture was
purged with hydrogen for 5 minutes and sealed under a hydrogen
balloon for 2.5 hours. The reaction mixture was diluted with EtOAc,
filtered through a micron filter, and concentrated in vacuo to give
Intermediate 131C, which was used directly in the subsequent step:
LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 279.1 (M+H).sup.+.
Intermediate 131D:
5-(benzofuran-2-yl)-7-methylquinoxalin-2(1H)-one
##STR00737##
[2517] Intermediate 131C (51 mg, 0.183 mmol) was suspended in MeOH
(533 .mu.L). NaOH (550 .mu.L, 0.550 mmol) then H.sub.2O.sub.2 (96
.mu.L, 1.100 mmol) were added and the reaction mixture was stirred
for 18 hours. More H.sub.2O.sub.2 (96 .mu.L, 1.100 mmol) was added
and the reaction mixture was stirred for 24 hours. The reaction
mixture was diluted with water and extracted with EtOAc. The
organic layer was further washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 131D (34.6 mg, 0.125 mmol, 68.3%) as a yellow solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.41 (br. s., 1H),
8.40 (s, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.92 (d, J=1.3 Hz, 1H), 7.67
(d, J=7.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.37-7.32 (m, 2H), 7.00
(s, 1H), 2.57 (s, 3H); LC-MS: Method H, RT=1.01 min, MS (ESI) m/z:
277.3 (M+H).sup.+.
Intermediate 131E: 5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl
trifluoromethanesulfonate
##STR00738##
[2519] Intermediate 131D (26 mg, 0.094 mmol), pyridine (19.03
.mu.L, 0.235 mmol), and DIEA (36.2 .mu.L, 0.207 mmol) were
dissolved in DCM (4705 .mu.L). Triflic anhydride (31.8 .mu.L, 0.188
mmol) was added and the reaction mixture was stirred for 2 hours.
The reaction mixture was concentrated in vacuo. The reaction
mixture was filtered through a pad of silica gel in a fritted
funnel with rapid DCM elution to give Intermediate 131E (24.8 mg,
0.061 mmol, 64.5%) as an orange solid: LC-MS: Method H, RT=1.28
min, MS (ESI) m/z: 409.0 (M+H).sup.+.
Example 131
[2520] Intermediate 131E (24.8 mg, 0.061 mmol) and vinylboronic
acid pinacol ester (21.09 .mu.L, 0.121 mmol) were dissolved in
toluene (455 .mu.L) and EtOH (152 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (2.98 mg, 3.64 .mu.mol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 36.4 .mu.L, 0.073 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 90.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with EtOAc and filtered through a
micron filter and concentrated in vacuo. The crude material was
purified by preparative HPLC (Method D, 45-75% B in 10 minutes) to
give Example 131 (2.6 mg, 0.00874 mmol, 14%): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 9.11 (s, 1H), 8.28 (d, J=1.7 Hz, 1H),
8.11 (s, 1H), 7.77 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.3
Hz, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.27-7.21 (m, 1H), 7.05 (dd,
J=17.9, 11.0 Hz, 1H), 6.51 (d, J=17.9 Hz, 1H), 5.85 (d, J=11.3 Hz,
1H), 2.66 (s, 3H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z:
287.2 (M+H).sup.+. Analytical HPLC Method B: 97.3% purity.
Example 132
5-(benzofuran-2-yl)-2-ethyl-7-methylquinoxaline
##STR00739##
[2522] Example 131 (1.4 mg, 4.89 .mu.mol) (92793-013-01) was
dissolved in MeOH (244 .mu.L). Palladium on carbon (0.520 mg, 0.489
.mu.mol) was added and the reaction mixture was sealed under an
atmosphere of hydrogen for 30 minutes. The reaction mixture was
filtered and concentrated in vacuo. The crude material was purified
by preparative HPLC (Method A, 30 to 100% B in 20 minutes; with a
flow rate of 40 mL/min). The desired fractions were concentrated
and lyophilized to give Example 132 (0.69 mg, 0.00235 mmol, 48.2%
yield) as a yellow solid: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 8.87 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.15 (d, J=0.8 Hz,
1H), 7.85 (d, J=0.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.60-7.55 (m,
1H), 7.37-7.31 (m, 1H), 7.29-7.23 (m, 1H), 3.12 (q, J=7.7 Hz, 2H),
2.67 (s, 3H), 1.47 (t, J=7.7 Hz, 3H); LC-MS: Method H, RT=1.25 min,
MS (ESI) m/z: 289.2 (M+H).sup.+. Analytical HPLC Method A: 98.4%
purity.
Example 133
5-(benzofuran-2-yl)-2-(difluoromethoxy)-8-methylquinoxaline
##STR00740##
[2523] Intermediate 133A: 6-bromo-3-methyl-2-nitroaniline
##STR00741##
[2525] 3-Methyl-2-nitroaniline (250 mg, 1.643 mmol) and NBS (292
mg, 1.643 mmol) were dissolved in AcOH (8216 .mu.L) and heated to
120.degree. C. for 4 hours. The reaction mixture was cooled to
ambient temperature and diluted with H.sub.2O (50 mL). The material
was extracted with EtOAc. The organic layer was washed twice with
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 40 g silica gel column, 19
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 133A (302.8 mg, 1.311 mmol, 80%) as an orange solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.43 (d, J=9.0 Hz, 1H),
6.59 (d, J=8.8 Hz, 1H), 4.77 (br. s., 2H), 2.47 (s, 3H); LC-MS:
Method H, RT=0.94 min, MS (ESI) m/z: 231/233 (M+H).sup.+.
Intermediate 133B: 3-bromo-6-methylbenzene-1,2-diamine
##STR00742##
[2527] Intermediate 133A (302.8 mg, 1.311 mmol) was dissolved in
MeOH (8961 .mu.L) and THF (1120 .mu.L). Ammonium chloride (1402 mg,
26.2 mmol) and zinc (857 mg, 13.11 mmol) were added and the
reaction mixture was heated to 40.degree. C. for 1 hour. The
reaction mixture was cooled to ambient temperature and concentrated
in vacuo. The crude material was redissolved in EtOAc/saturated
Sodium carbonate and allowed to stir vigorously for 15 minutes. The
mixture was filtered through a sintered glass funnel. The organic
layer was washed twice with water then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 133B (257.8 mg, 1.282 mmol, 98%): .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 6.91 (d, J=8.2 Hz, 1H), 6.49 (d, J=8.8
Hz, 1H), 3.53 (br. s., 2H), 3.29 (br. s., 2H), 2.30 (s, 3H); LC-MS:
Method H, RT=0.54 min, MS (ESI) m/z: 201/203 (M+H).sup.+.
Intermediate 133C:
3-(benzofuran-2-yl)-6-methylbenzene-1,2-diamine
##STR00743##
[2529] Intermediate 133B (257.8 mg, 1.282 mmol) and
benzofuran-2-ylboronic acid (311 mg, 1.923 mmol) were dissolved in
toluene (9616 .mu.L) and EtOH (3205 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (62.8 mg, 0.077 mmol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 769 .mu.L, 1.539 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 90.degree. C. in the microwave for 60 minutes. The
reaction mixture was diluted with EtOAc and filtered through a
micron filter and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 40 g silica gel column, 19
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 133C (237.8 mg, 0.998 mmol, 78%) as a brown oil:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.59-7.55 (m, 1H),
7.52-7.47 (m, 1H), 7.29-7.18 (m, 2H), 7.10 (d, J=8.3 Hz, 1H),
6.73-6.65 (m, 2H), 3.51 (br. s., 4H), 2.36 (s, 3H); LC-MS: Method
H, The compound did not ionize.
Intermediate 133D:
5-(benzofuran-2-yl)-8-methylquinoxalin-2(1H)-one
##STR00744##
[2531] Intermediate 133C (237.8 mg, 0.998 mmol) was dissolved in
EtOH (2697 .mu.L). Ethyl glyoxalate solution (50 wt %, 297 .mu.L,
1.497 mmol) was added and the reaction mixture was heated to
80.degree. C. and allowed to stir overnight. The reaction mixture
was cooled to ambient temperature and filtered to collect the solid
precipitate, which was washed with EtOH and collected to give
Intermediate 133D (63.8 mg, 0.231 mmol, 23.1%) as an off-white
solid mixture of regioisomers. The material was used as-is for the
subsequent step: LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 277.1
(M+H).sup.+.
Example 133
[2532] Intermediate 133D (30 mg, 0.109 mmol) and K.sub.2CO.sub.3
(300 mg, 2.172 mmol) were dissolved in DMF (1086 .mu.L) and heated
to 100.degree. C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate
(66.2 mg, 0.434 mmol) was added and the reaction mixture was heated
for 2.5 hours. The reaction mixture was diluted with water and
extracted thrice with DCM. The combined organic extracts were
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 60 to 90% B in 25 minutes) then
repurified by preparative HPLC (Method D, 55-80% B in 15 minutes)
to give Example 133 (1.4 mg, 0.00417 mmol, 3.84%): .sup.1H NMR (500
MHz, METHANOL-d.sub.4) .delta. 8.62 (s, 1H), 8.24 (d, J=8.8 Hz,
1H), 8.02 (d, J=8.8 Hz, 1H), 7.91-7.59 (m, 3H), 7.36 (t, J=7.6 Hz,
1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 2.97 (s, 3H); LC-MS: Method
H, RT=1.17 min, MS (ESI) m/z: 327.1 (M+H).sup.+. Analytical HPLC
Method B: 97.3% purity.
Example 134
8-(benzofuran-2-yl)-3-methoxy-6-methyl-1,7-naphthyridine\
##STR00745##
[2533] Intermediate 134A: 5-methoxy-3-methylpicolinonitrile
##STR00746##
[2535] 5-Hydroxy-3-methylpicolinonitrile (0.25 g, 1.864 mmol) was
suspended in DMF (12.43 mL). Cesium carbonate (1.518 g, 4.66 mmol)
then iodomethane (0.146 mL, 2.330 mmol) were added and stirred for
3 hours. The reaction mixture was diluted with water and extracted
with EtOAc. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 134A (252.7 mg, 1.706 mmol, 92%) as a light brown
solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.21 (d, J=2.5
Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3H); LC-MS:
Method H, RT=0.71 min, MS (ESI) m/z: 149.2 (M+H).sup.+.
Intermediate 134B: 5-methoxy-3-(2-oxopropyl)picolinonitrile
##STR00747##
[2537] Intermediate 134A (252.7 mg, 1.706 mmol) was dissolved in
DMF (1706 .mu.L) and N,N-dimethylacetamide dimethyl acetal (1247
.mu.L, 8.53 mmol) and heated to 150.degree. C. for 18 hours. More
N,N-dimethylacetamide dimethylacetal (0.5 mL) was added and heating
continued for 24 hours. The reaction mixture was cooled to ambient
temperature and concentrated in vacuo. The crude material was
purified by preparative HPLC (Method A, 20 to 100% B in 17 minutes)
to give Intermediate 134B (81.8 mg, 0.430 mmol, 25.2%) as a brown
oil: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.30 (d, J=2.8 Hz,
1H), 7.11 (d, J=2.8 Hz, 1H), 3.98 (s, 2H), 3.92 (s, 3H), 2.35 (s,
3H); LC-MS: Method H, RT=0.64 min, MS (ESI) m/z: 191.2
(M+H).sup.+.
Intermediate 134C: 3-methoxy-6-methyl-1,7-naphthyridin-8-ol
##STR00748##
[2539] Intermediate 134B (81.8 mg, 0.430 mmol) was dissolved in
CHCl.sub.3 (3226 .mu.L), AcOH (538 .mu.L), and HBr (538 .mu.L) at
and stirred overnight. The reaction mixture was diluted with 1 N
NaOH and extracted thrice with EtOAc. The combined organic layers
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method A, 20 to 100% B in 17 minutes) to give
Intermediate 134C (7.6 mg, 0.040 mmol, 9.3%) as a brown solid:
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.34 (d, J=8.8 Hz,
1H), 6.80 (d, J=8.8 Hz, 1H), 6.44 (br. s., 1H), 4.02 (d, J=2.8 Hz,
3H), 2.33 (s, 3H); LC-MS: Method H, RT=0.55 min, MS (ESI) m/z:
191.2 (M+H).sup.+.
Intermediate 134D:
3-methoxy-6-methyl-1,7-naphthyridin-8-yltrifluoromethanesulfonate
##STR00749##
[2541] Intermediate 134C (10.1 mg, 0.053 mmol), pyridine (21.47
.mu.L, 0.266 mmol), and DIEA (20.40 .mu.L, 0.117 mmol) were
dissolved in DCM (2655 .mu.L). Triflic anhydride (35.9 .mu.L, 0.212
mmol) was added and the reaction mixture was stirred for 45
minutes. More triflic anhydride (35.9 .mu.L, 0.212 mmol) was added
and stirring continued for 30 minutes. The reaction mixture was
filtered through a pad of silica gel in a fritted funnel with rapid
DCM elution to give Intermediate 134D (11.8 mg, 0.037 mmol, 69%) as
a red oil: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 323.0
(M+H).sup.+.
Example 134
[2542] Intermediate 134D (11.8 mg, 0.037 mmol) and
benzofuran-2-ylboronic acid (7.12 mg, 0.044 mmol) were dissolved in
DMF (366 .mu.L). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.794 mg, 2.197
.mu.mol) was added and the reaction mixture was degassed by
bubbling with argon for 15 minutes. Sodium carbonate (2 M, 21.97
.mu.L, 0.044 mmol) was added and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction mixture was diluted with
EtOAc and filtered through a micron filter and concentrated in
vacuo. The crude material was purified by preparative HPLC (Method
D, 0 to 40% B in 10 minutes) to give Example 134 (2.0 mg, 0.00675
mmol, 18.4%): .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.82
(d, J=2.8 Hz, 1H), 8.57 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.69 (d,
J=8.3 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=2.8 Hz, 1H), 7.47 (t, J=7.7
Hz, 1H), 7.37-7.30 (m, 1H), 4.07 (s, 3H), 2.82 (s, 3H); LC-MS:
Method H, RT=0.78 min, MS (ESI) m/z: 291.1 (M+H).sup.+. Analytical
HPLC Method B: 98% purity.
Example 135
5-(benzofuran-2-yl)-2-(furan-3-yl)-7-methylquinoxaline
##STR00750##
[2543] Intermediate 135A: 5-bromo-7-methylquinoxalin-2-yl
trifluoromethanesulfonate
##STR00751##
[2545] Intermediate I-1F (0.2 g, 0.837 mmol), pyridine (0.338 mL,
4.18 mmol), and DIEA (0.321 mL, 1.840 mmol) were dissolved in DCM
(41.8 mL). Triflic anhydride (0.565 mL, 3.35 mmol) was added and
the reaction mixture was stirred for 1.5 hours. The reaction
mixture was concentrated in vacuo. The reaction mixture was
filtered through a pad of silica gel in a fritted funnel with rapid
DCM elution to give Intermediate 135A (137.3 mg, 0.370 mmol, 44.2%)
as a red oil: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.78 (s,
1H), 8.04 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 2.62 (s, 3H); LC-MS:
Method H, RT=1.10 min, The compound did not ionize.
Intermediate 135B: 5-bromo-2-(furan-3-yl)-7-methylquinoxaline
##STR00752##
[2547] Intermediate 135A (34.3 mg, 0.092 mmol) and
furan-3-ylboronic acid (10.34 mg, 0.092 mmol) were dissolved in DMF
(924 .mu.L). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (4.53 mg, 5.55
.mu.mol) was added and the reaction mixture was degassed by
bubbling with argon for 15 minutes. Sodium carbonate (2 M, 55.5
.mu.L, 0.111 mmol) was added and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction mixture was diluted with
EtOAc and filtered through a micron filter and concentrated in
vacuo. The crude material was purified by preparative HPLC (Method
A, 20 to 100% B in 15 minutes), to give Intermediate 135B (2.9 mg,
0.010 mmol, 10.9%) as a brown solid: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.07 (s, 1H), 8.24 (s, 1H), 7.87 (d, J=1.5
Hz, 1H), 7.83 (s, 1H), 7.59 (t, J=1.6 Hz, 1H), 7.15-7.11 (m, 1H),
2.58 (s, 3H); LC-MS: Method H, The compound did not ionize.
Example 135
[2548] Intermediate 135B (2.9 mg, 10.03 .mu.mol) and
benzofuran-2-ylboronic acid (2.437 mg, 0.015 mmol) were dissolved
in toluene (752 .mu.L) and EtOH (251 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.491 mg, 0.602 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 6.02 .mu.L, 0.012 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
The reaction mixture was diluted with EtOAc and filtered through a
micron filter and concentrated in vacuo. The crude material was
purified by preparative HPLC (Method D, 55 to 90% B in 10 minutes)
to give 135 (1.1 mg, 0.0032 mmol, 31.9%): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 9.19 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H),
8.13 (s, 1H), 7.82 (s, 1H), 7.71-7.64 (m, 2H), 7.57 (d, J=8.3 Hz,
1H), 7.33 (t, J=7.6 Hz, 1H), 7.28-7.23 (m, 1H), 7.20 (s, 1H), 2.67
(s, 3H); LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 327.1
(M+H).sup.+. Analytical HPLC Method B: 95% purity.
Example 136
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[-
d]thiazole
##STR00753##
[2549] Intermediate 136A:
2-bromo-5,6-dihydro-4H-cyclopenta[d]thiazole
##STR00754##
[2551] 5,6-Dihydro-4H-cyclopenta[d]thiazol-2-amine, HCl (50 mg,
0.283 mmol) and isoamyl nitrite (41.9 .mu.L, 0.311 mmol) were
dissolved in MeCN (1132 .mu.L). Copper(II) bromide (60.9 mg, 0.425
mmol) was added portionwise over 1 hour. After an additional hour,
the reaction mixture was diluted with water and extracted with DCM.
The DCM layer was washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 136A,
which was volatile and was used as-is for the next reaction: LC-MS:
Method H, RT=0.99 min, MS (ESI) m/z: 204/206 (M+H).sup.+.
Example 136
[2552] Intermediate I-1 (15 mg, 0.045 mmol) and Intermediate 136A
(13.66 mg, 0.067 mmol) were dissolved in DMF (446 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (2.187 mg, 2.68 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 26.8 .mu.L, 0.054 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. More PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (2.187 mg, 2.68
.mu.mol) and Sodium carbonate (2 M, 26.8 .mu.L, 0.054 mmol) were
added and the reaction mixture was heated to 120.degree. C. in the
microwave for 30 minutes. The compound was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 35 to 80% B
in 10 minutes) then repurified by preparative HPLC (Method D, 45 to
80% B in 20 minutes) to give Example 136 (1.4 mg, 0.00403 mmol,
9.0%): .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.64 (s,
1H), 8.42 (d, J=1.9 Hz, 1H), 7.83-7.51 (m, 2H), 3.03 (t, J=7.2 Hz,
2H), 2.95 (t, J=7.4 Hz, 2H), 2.63 (s, 3H), 2.62-2.53 (m, 2H);
LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 333.9 (M+H).sup.+;
Analytical HPLC Method B: 96% purity.
Example 137
2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]t-
hiazole
##STR00755##
[2554] Intermediate I-12 (10 mg, 0.043 mmol) and
2-chlorocycloheptanone (6.28 mg, 0.043 mmol) were dissolved in
dioxane (857 .mu.L) and heated to 80.degree. C. for 18 hours. More
2-chlorocycloheptanone (6.28 mg, 0.043 mmol) was added and the
reaction mixture was heated to 110.degree. C. for 24 hours. The
reaction mixture was concentrated in vacuo, diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 55 to 95% B
in 10 minutes) to give Example 137 (2.9 mg, 0.00873 mmol, 20.4%):
.sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.48 (s, 1H), 8.26
(d, J=1.7 Hz, 1H), 7.66 (s, 1H), 4.11 (s, 3H), 3.08-3.01 (m, 2H),
2.95-2.89 (m, 2H), 2.60 (s, 3H), 1.98-1.87 (m, 2H), 1.83-1.71 (m,
4H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 326.1 (M+H).sup.+;
Analytical HPLC Method B: 98% purity.
Example 138
2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7--
ol
##STR00756##
[2555] Intermediate 138A
2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydrobenzo[d]thiazol-7(4H)-one
##STR00757##
[2557] Intermediate I-12 (15 mg, 0.064 mmol) and
2-chlorocyclohexane-1,3-dione (18.85 mg, 0.129 mmol) were dissolved
in 1,4-dioxane (1286 .mu.L) and heated to 100.degree. C. for 18
hours. The reaction mixture was concentrated in vacuo, diluted with
DMF, filtered, and purified by preparative HPLC (Method D, 35 to
75% B in 10 minutes) to give Intermediate 138A (4.6 mg, 0.014 mmol,
21.6%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (s, 1H),
8.53 (s, 1H), 7.86 (s, 1H), 4.08 (s, 3H), 3.10 (t, J=6.1 Hz, 2H),
2.67-2.58 (m, 5H), 2.24-2.15 (m, 2H); LC-MS: Method H, RT=1.12 min,
MS (ESI) m/z: 326.1 (M+H).sup.+; Analytical HPLC Method B: 98%
purity.
Example 138
[2558] Intermediate 138A (3.68 mg, 0.011 mmol) was dissolved in
MeOH (565 .mu.L) and cooled to 0.degree. C. Sodium borohydride
(0.642 mg, 0.017 mmol) was added and the reaction mixture was
allowed to slowly warm to ambient temperature and stir for 20
hours. The reaction mixture was diluted with water and extracted
with EtOAc. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was diluted with DMF, filtered, and purified by
preparative HPLC (Method D, 25 to 65% B in 10 minutes) to give
Example 138 (2.3 mg, 0.00703 mmol, 62.1%): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 8.49 (s, 1H), 8.30 (d, J=1.7 Hz, 1H),
7.70 (d, J=0.8 Hz, 1H), 5.03 (br. s., 1H), 4.24 (br. s., 1H), 4.11
(s, 3H), 2.96-2.88 (m, 1H), 2.87-2.78 (m, 1H), 2.61 (s, 3H), 2.13
(d, J=9.9 Hz, 2H), 1.95-1.86 (m, 2H); LC-MS: Method H, RT=0.94 min,
MS (ESI) m/z: 328.2 (M+H).sup.+; Analytical HPLC Method B: 100%
purity.
Example 139
7-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]-
thiazole
##STR00758##
[2560] Example 138 (9.9 mg, 0.030 mmol) was dissolved in THF (605
.mu.L). Sodium hydride (1.330 mg, 0.033 mmol) was added and the
reaction mixture was stirred for 30 minutes. Iodomethane (3.78
.mu.L, 0.060 mmol) was added and the reaction mixture was stirred
for 2 hours. The reaction mixture was diluted with EtOAc and washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 40 to 80% B
in 10 minutes) to give Example 139 (6.4 mg, 0.018 mmol, 60.8%):
.sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.51 (s, 1H), 8.33
(d, J=1.7 Hz, 1H), 7.71 (dd, J=1.9, 0.8 Hz, 1H), 7.62 (dd, J=3.0,
1.7 Hz, 1H), 4.12 (s, 3H), 3.54 (s, 3H), 3.00-2.90 (m, 1H),
2.87-2.78 (m, 1H), 2.61 (s, 3H), 2.16-2.00 (m, 3H), 1.96-1.86 (m,
1H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 342.2 (M+H).sup.+;
Analytical HPLC Method B: 98% purity.
Example 140
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]-
thiazole
##STR00759##
[2561] Intermediate 140A:
4-((tert-butyldimethylsilyl)oxy)cyclohexanone
##STR00760##
[2563] 4-hydroxycyclohexanone (500 mg, 4.38 mmol), TBS-Cl (792 mg,
5.26 mmol), and imidazole (447 mg, 6.57 mmol) were dissolved in DCM
(8761 .mu.L) for 3 hours. The reaction mixture was diluted with
DCM, washed with water, 1 N HCl, saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 140A as a light yellow oil: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 4.09 (tt, J=5.1, 2.7 Hz, 1H), 2.69-2.56 (m,
2H), 2.24-2.14 (m, 2H), 1.99-1.77 (m, 4H), 0.88 (s, 9H), 0.06 (s,
6H).
Intermediate 140B
2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6--
ol
##STR00761##
[2565] Intermediate 140A (9.79 mg, 0.043 mmol), magnesium chloride
(4.08 mg, 0.043 mmol), and NBS (7.63 mg, 0.043 mmol) were dissolved
in dioxane (429 .mu.L) and heated to 70.degree. C. for 1 hour.
Intermediate I-12 (10 mg, 0.043 mmol) was added and the reaction
mixture was stirred for 18 hours. The reaction mixture was heated
to 110.degree. C. for 4 hours. The reaction mixture was diluted
with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was dissolved in 90:10:0.1 MeOH:H.sub.2O:TFA (ca 1 mL) and
allowed to stir overnight. The reaction mixture was concentrated in
vacuo. The crude material was dissolved in DMF, filtered, and
purified by preparative HPLC (Method D, 20 to 60% B in 10 minutes)
to give Intermediate 140B (2.7 mg, 0.00825 mmol, 19.2%): .sup.1H
NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.48 (s, 1H), 8.27 (d,
J=1.9 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 4.26-4.19 (m, 1H), 4.11 (s,
3H), 3.18 (dd, J=16.1, 4.8 Hz, 1H), 3.09-3.00 (m, 1H), 2.95-2.87
(m, 1H), 2.83 (dd, J=16.2, 7.2 Hz, 1H), 2.61 (s, 3H), 2.17-2.09 (m,
1H), 2.04-1.95 (m, 1H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z:
328.3 (M+H).sup.+; Analytical HPLC Method B: 100% purity.
Example 140
[2566] Intermediate 140B (1.78 mg, 5.44 .mu.mol) was dissolved in
THF (109 .mu.L). Sodium hydride (0.239 mg, 5.98 .mu.mol) was added
and the reaction mixture was stirred for 30 minutes. Iodomethane
(0.680 .mu.L, 10.87 .mu.mol) was added and the reaction mixture was
stirred for 2 hours. The reaction mixture was diluted with EtOAc
and washed with water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 45
to 90% B in 10 minutes) to give Example 140 (0.9 mg, 0.00264 mmol,
48.5%): .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.48 (s,
1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 4.11 (s, 3H),
3.88-3.82 (m, 1H), 3.20 (dd, J=16.4, 5.4 Hz, 1H), 3.06-2.97 (m,
1H), 2.94-2.86 (m, 2H), 2.61 (s, 3H), 2.18-2.03 (m, 2H); LC-MS:
Method H, RT=1.19 min, MS (ESI) m/z: 342.2 (M+H).sup.+; Analytical
HPLC Method B: 100% purity.
Example 141
2-(2-methoxy-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo-
[d]thiazole
##STR00762##
[2568] 4,4-Dimethylcyclohexanone (6.49 mg, 0.051 mmol), magnesium
chloride (4.08 mg, 0.043 mmol), and NBS (9.16 mg, 0.051 mmol) were
dissolved in dioxane (429 .mu.L) and heated to 70.degree. C. for 1
hour. Intermediate I-12 (10 mg, 0.043 mmol) was added and the
reaction mixture was heated to 110.degree. C. for 18 hours. The
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was dissolved in DMF, filtered, and
purified by preparative HPLC (Method D, 55 to 100% B in 10 minutes)
to give Example 141 (3.3 mg, 0.00943 mmol, 22%): .sup.1H NMR (500
MHz, METHANOL-d.sub.4) .delta. 8.48 (s, 1H), 8.27 (d, J=1.9 Hz,
1H), 7.68 (dd, J=1.9, 0.8 Hz, 1H), 4.11 (s, 3H), 2.88 (t, J=6.6 Hz,
2H), 2.66 (s, 2H), 2.61 (s, 3H), 1.72 (t, J=6.5 Hz, 2H), 1.08 (s,
6H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 340.0 (M+H).sup.+;
Analytical HPLC Method B: 97% purity.
Example 142
2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiaz-
ol-5-yl) ethanol
##STR00763##
[2569] Intermediate 142A:
3-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopentanone
##STR00764##
[2571] 3-(2-hydroxyethyl)cyclopentanone (500 mg, 3.90 mmol), TBS-Cl
(706 mg, 4.68 mmol), and imidazole (398 mg, 5.85 mmol) were
dissolved in DCM (7802 .mu.L) for 3.5 hours. The reaction mixture
was diluted with DCM, washed with water, 1 N HCl, saturated
NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 142A as a light yellow
oil: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 3.63-3.52 (m, 2H),
2.35-2.26 (m, 1H), 2.25-2.13 (m, 2H), 2.12-1.99 (m, 2H), 1.73 (ddd,
J=17.9, 10.0, 1.3 Hz, 1H), 1.65-1.40 (m, 3H), 0.80 (s, 9H), -0.05
(s, 6H).
Example 142
[2572] Intermediate 142A (18.71 mg, 0.077 mmol), magnesium chloride
(6.12 mg, 0.064 mmol), and NBS (13.73 mg, 0.077 mmol) were
dissolved in dioxane (643 .mu.L) and heated to 70.degree. C. for 1
hour. 2-Methoxy-7-methylquinoxaline-5-carbothioamide (15 mg, 0.064
mmol) was added and the reaction mixture was heated to 110.degree.
C. for 18 hours. The reaction mixture was diluted with EtOAc,
washed with water, then brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The crude material was dissolved in
90:10:0.1 MeOH:H.sub.2O:TFA (ca 1 mL) for 18 hours. The reaction
mixture was concentrated in vacuo. The crude material was dissolved
in DMF, filtered, and purified by preparative HPLC (Method D, 35 to
80% B in 10 minutes) to give Example 142 (2.9 mg, 0.00790 mmol,
12.3%): LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 342.0
(M+H).sup.+; Analytical HPLC Method B: 93% purity.
Example 143
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]th-
iazol-7-ol
##STR00765##
[2573] Intermediate 143A:
2-amino-5,6-dihydrobenzo[d]thiazol-7(4H)-one, HCl
##STR00766##
[2575] 2-chlorocyclohexane-1,3-dione (1 g, 6.82 mmol) and thiourea
(0.519 g, 6.82 mmol) were dissolved in EtOH (13.65 mL) and heated
to 80.degree. C. for 3 days. The reaction mixture was cooled to
ambient temperature and the solid collected by suction filtration,
washing with EtOH to give Intermediate 143A (790 mg, 3.86 mmol,
56.6%) as a white solid: .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 2.80 (t, J=6.2 Hz, 2H), 2.51 (dd, J=7.2, 5.8 Hz, 2H), 2.15
(quin, J=6.4 Hz, 2H); LC-MS: Method H, RT=0.63 min, MS (ESI) m/z:
169.0 (M+H).sup.+.
Intermediate 143B: 2-bromo-5,6-dihydrobenzo[d]thiazol-7(4H)-one
##STR00767##
[2577] Copper(II) bromide (1.466 g, 6.56 mmol) and t-butyl nitrite
(0.780 mL, 6.56 mmol) were dissolved in MeCN (15.44 mL) and allowed
to stir 10 minutes. Intermediate 143A (0.79 g, 3.86 mmol) was
dissolved in MeCN (23.16 mL) and the copper solution was added and
the reaction mixture was stirred for 1.5 hours. The reaction
mixture was concentrated in vacuo. The residue was dissolved in
EtOAc, washed twice with 1 N HCl, saturated NaHCO.sub.3, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 143B (817.9 mg, 3.52 mmol, 91%) as an
orange solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 3.07 (t,
J=6.2 Hz, 2H), 2.64 (dd, 5.7 Hz, 2H), 2.24 (quin, J=6.4 Hz, 2H);
LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 232/234
(M+H).sup.+.
Intermediate 143C:
2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
##STR00768##
[2579] Intermediate 143B (500 mg, 2.154 mmol) was dissolved in MeOH
(10.8 mL) and cooled to 0.degree. C. Sodium borohydride (163 mg,
4.31 mmol) was added and stirred for 1.5 hours. The reaction
mixture was quenched with saturated ammonium chloride and extracted
with EtOAc. The organic layer was washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 143C (488 mg, 2.084 mmol, 97%) as an orange oil:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.93 (br. s., 1H),
2.89-2.79 (m, 1H), 2.79-2.69 (m, 1H), 2.17-2.07 (m, 1H), 2.06-1.98
(m, 1H), 1.92-1.80 (m, 2H); LC-MS: Method H, RT=0.88 min, MS (ESI)
m/z: 234/236 (M+H).sup.+.
Example 143
[2580] Intermediate I-2 was purified by column chromatography
(ISCO, 12 g silica gel column, 17 minute gradient from 0 to 20%
MeOH in DCM) to give dimethyl
(2-(methoxymethyl)-7-methylquinoxalin-5-yl)boronate (25 mg, 0.096
mmol), Intermediate 143C (27.0 mg, 0.115 mmol), and potassium
phosphate tribasic (40.8 mg, 0.192 mmol) were dissolved in DMF (961
.mu.L) and degassed by bubbling with argon for 15 minutes.
Palladium tetrakistriphenylphosphine (11.11 mg, 9.61 .mu.mol) was
added and degassing continued for 5 minutes. The reaction mixture
was heated to 85.degree. C. at for 18 hours. The reaction mixture
was diluted with DMF, filtered, and purified by preparative HPLC
(Method D, 20 to 60% B in 20 minutes) to give Example 143 (5.4 mg,
0.015 mmol, 15.1%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.06 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 5.56 (d, J=6.3 Hz, 1H),
4.92 (br. s., 1H), 4.80 (s, 2H), 3.47 (s, 3H), 2.87-2.73 (m, 2H),
2.65 (s, 3H), 2.07-1.99 (m, 2H), 1.84-1.70 (m, 2H); LC-MS: Method
H, RT=1.02 min, MS (ESI) m/z: 342.2 (M+H).sup.+; Analytical HPLC
Method B: 92% purity.
Example 144
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]th-
iazole
##STR00769##
[2581] Intermediate 144A:
2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole
##STR00770##
[2583] 2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (25 mg, 0.115
mmol) was dissolved in Et.sub.2O (458 .mu.L) and cooled to
-78.degree. C. BuLi (60.0 .mu.L, 0.126 mmol) was added and the
reaction mixture was stirred for 30 minutes. Tributylchlorostannane
(31.1 .mu.L, 0.115 mmol) was added and stirred for 40 minutes. The
reaction mixture was warmed to ambient temperature and concentrated
in vacuo. The crude material was suspended in hexanes and filtered
through dry celite. The residue was concentrated in vacuo to give
Intermediate 144A, which was used directly in the subsequent
reaction.
Example 144
[2584] Intermediate I-2E (15 mg, 0.056 mmol), Intermediate 144A
(30.1 mg, 0.070 mmol), and potassium acetate (11.02 mg, 0.112 mmol)
were dissolved in dioxane (814 .mu.L) and degassed by bubbling with
argon for 15 minutes. Palladium tetrakistriphenylphosphine (3.24
mg, 2.81 .mu.mol) was added and the reaction mixture was sealed and
heated to 120.degree. C. in the microwave for 2 hours. The reaction
mixture was diluted with EtOAc, washed with water, 1 N HCl, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 40 to 80% B in 20 minutes)
and repurified by preparative HPLC (Method D, 50 to 85% B in 20
minutes) to give Example 144 (1.9 mg, 0.00584 mmol, 10.4%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.03 (s, 1H), 8.59 (s, 1H),
7.92 (s, 1H), 4.79 (s, 2H), 3.46 (s, 3H), 2.88 (br. s., 2H), 2.82
(br. s., 2H), 2.64 (s, 3H), 1.87 (br. s., 4H); LC-MS: Method H,
RT=1.23 min, MS (ESI) m/z: 326.3 (M+H).sup.+; Analytical HPLC
Method B: 100% purity.
Example 145
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahy-
drobenzo[d]thiazol-7-ol
##STR00771##
[2585] Intermediate 145A:
2-amino-6,6-dimethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one, HCl
##STR00772##
[2587] 2-bromo-4,4-dimethylcyclohexane-1,3-dione (0.5 g, 2.282
mmol) and thiourea (0.174 g, 2.282 mmol) were dissolved in EtOH
(4.56 mL) and heated to 75.degree. C. for 18 hours. The reaction
mixture was cooled to ambient temperature then to 0.degree. C. and
the solid was collected by suction filtration, washing with cold
EtOH to give Intermediate 145A (128.3 mg, 0.551 mmol, 24.2%) as an
off-white solid: .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
2.90 (t, J=6.2 Hz, 2H), 2.08 (t, J=6.2 Hz, 2H), 1.20 (s, 6H);
LC-MS: Method H, RT=0.85 min, MS (ESI) m/z: 197.1 (M+H).sup.+.
Intermediate 145B:
2-bromo-6,6-dimethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one
##STR00773##
[2589] Copper(II) bromide (248 mg, 1.111 mmol) and t-butyl nitrite
(132 .mu.L, 1.111 mmol) were dissolved in MeCN (2615 .mu.L) and
allowed to stir 10 minutes. Intermediate 145A (128.3 mg, 0.654
mmol) was dissolved in MeCN (3922 .mu.L) and the copper solution
was added and stirring continued for 1.5 hours. The reaction
mixture was diluted with EtOAc, washed with 1 N HCl, saturated
NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 145B (110 mg, 0.423
mmol, 64.7%): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 3.08 (t,
J=6.2 Hz, 2H), 2.06 (t, J=6.2 Hz, 2H), 1.25 (s, 6H); LC-MS: Method
H, RT=1.21 min, MS (ESI) m/z: 260/262 (M+H).sup.+.
Intermediate 145C:
2-bromo-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
##STR00774##
[2591] Intermediate 145B (110 mg, 0.423 mmol) was dissolved in MeOH
(2114 .mu.L) and cooled to 0.degree. C. Sodium borohydride (32.0
mg, 0.846 mmol) was added and the reaction mixture stirred for 40
minutes. The reaction mixture was quenched with saturated ammonium
chloride and extracted with EtOAc. The organic layer was washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 145C (107 mg, 0.408
mmol, 97%) as a yellow oil: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 4.45 (d, J=6.4 Hz, 1H), 2.88-2.68 (m, 2H), 1.93 (d, J=7.5
Hz, 1H), 1.82 (dt, J=13.8, 5.9 Hz, 1H), 1.70-1.63 (m, 1H), 1.07 (s,
3H), 1.02 (s, 3H); LC-MS: Method H, RT=1.12 min, MS (ESI) m/z:
263.9 (M+H).sup.+.
Example 145
[2592] Intermediate I-2 was purified by column chromatography
(ISCO, 12 g silica gel column, 17 minute gradient from 0 to 20%
MeOH in DCM) to give dimethyl
(2-(methoxymethyl)-7-methylquinoxalin-5-yl)boronate (20 mg, 0.077
mmol), Intermediate 145C (24.19 mg, 0.092 mmol), and potassium
phosphate tribasic (32.6 mg, 0.154 mmol) were dissolved in DMF
(7694) and degassed by bubbling with argon for 15 minutes.
Palladium tetrakistriphenylphosphine (8.89 mg, 7.69 .mu.mol) was
added and degassing continued for 5 minutes. The reaction mixture
was heated to 85.degree. C. for 18 hours. The reaction mixture was
diluted with DMF, filtered, and purified by preparative HPLC
(Method D, 40 to 80% B in 20 minutes) to give Example 145 (5.6 mg,
0.015 mmol, 18.9%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.06 (s, 1H), 8.60 (d, J=1.4 Hz, 1H), 7.94 (s, 1H), 5.58 (d, J=6.9
Hz, 1H), 4.80 (s, 2H), 4.48 (d, J=6.3 Hz, 1H), 3.47 (s, 3H),
2.82-2.74 (m, 2H), 2.65 (s, 3H), 1.86-1.78 (m, 1H), 1.70-1.62 (m,
1H), 1.03 (s, 3H), 0.91 (s, 3H); LC-MS: Method H, RT=1.22 min, MS
(ESI) m/z: 370.1 (M+H).sup.+; Analytical HPLC Method B: 96%
purity.
Example 146
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine
##STR00775##
[2593] Intermediate 146A: 2-bromothiazolo[4,5-c]pyridine
##STR00776##
[2595] Copper(II) bromide (71.6 mg, 0.320 mmol) and t-butyl nitrite
(38.1 .mu.L, 0.320 mmol) were dissolved in MeCN (754 .mu.L) and
allowed to stir 10 minutes. Thiazolo[4,5-c]pyridin-2-amine, TFA (50
mg, 0.189 mmol) was dissolved in MeCN (1131 .mu.L) and the copper
solution was added and the reaction mixture was stirred for 2
hours. The reaction mixture was diluted with EtOAc, washed with
saturated NaHCO.sub.3, water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 146A (12.5
mg, 0.058 mmol, 30.8%) as a brown solid: LC-MS: Method H, RT=0.68
min, MS (ESI) m/z: 215/217 (M+H).sup.+.
Example 146
[2596] Intermediate I-2 (10 mg, 0.032 mmol) and Intermediate 146A
(10.27 mg, 0.048 mmol) were dissolved in DMF (318 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.560 mg, 1.910 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 19.10 .mu.L, 0.038 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 25 to 65% B in 20 minutes)
to give Example 146 (3.0 mg, 0.00893 mmol, 28.1%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.43 (br. s., 1H), 9.14 (br. s., 1H),
8.92 (br. s., 1H), 8.57 (br. s., 1H), 8.30 (br. s., 1H), 8.14 (br.
s., 1H), 4.84 (br. s., 2H), 3.49 (br. s., 3H), 2.72 (br. s., 3H);
LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 323.3 (M+H).sup.+;
Analytical HPLC Method B: 96% purity.
Example 147
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
##STR00777##
[2597] Intermediate 147A:
2-bromo-5-methoxythiazolo[5,4-b]pyridine
##STR00778##
[2599] Copper(II) bromide (64.3 mg, 0.288 mmol) and t-butyl nitrite
(34.2 .mu.L, 0.288 mmol) were dissolved in MeCN (677 .mu.L) and
allowed to stir 10 minutes.
5-methoxythiazolo[5,4-b]pyridin-2-amine, TFA (50 mg, 0.169 mmol)
was dissolved in MeCN (1016 .mu.L) and the copper solution was
added and the reaction mixture was stirred for 1.5 hours. The
reaction mixture was diluted with EtOAc, washed with saturated
NaHCO.sub.3, water, then brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo to give Intermediate 147A as a tan solid:
.sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.08 (d, J=8.8 Hz, 1H),
6.86 (d, J=8.8 Hz, 1H), 4.02 (s, 3H); LC-MS: Method H, RT=1.21 min,
MS (ESI) m/z: 245/247 (M+H).sup.+.
Example 147
[2600] Intermediate I-2 (10 mg, 0.032 mmol) and Intermediate 147A
(11.70 mg, 0.048 mmol) were dissolved in DMF (318 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.560 mg, 1.910 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 19.10 .mu.L, 0.038 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 45 to 85% B in 20 minutes)
to give Example 147 (3.1 mg, 0.00862 mmol, 27.1%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.14 (br. s., 1H), 8.81 (br. s., 1H),
8.43 (d, J=8.0 Hz, 1H), 8.08 (br. s., 1H), 7.08 (d, J=8.8 Hz, 1H),
4.84 (br. s., 2H), 4.02 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br.
s., 3H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 353.2
(M+H).sup.+; Analytical HPLC Method B: 98% purity.
Example 148
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
##STR00779##
[2602] Intermediate I-2 (10 mg, 0.032 mmol) and
2-bromothiazolo[5,4-b]pyridine (10.27 mg, 0.048 mmol) (10.27 mg,
0.048 mmol) were dissolved in DMF (318 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.560 mg, 1.910 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 19.10 .mu.L, 0.038 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 30 to 70% B in 20 minutes)
to give Example 148 (3.0 mg, 0.00893 mmol, 28.1%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.17 (br. s., 1H), 8.89 (br. s., 1H),
8.70 (br. s., 1H), 8.54 (d, J=8.3 Hz, 1H), 8.14 (br. s., 1H), 7.66
(br. s., 1H), 4.84 (br. s., 2H), 3.49 (br. s., 3H), 2.72 (br. s.,
3H); LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 323.2 (M+H).sup.+;
Analytical HPLC Method B: 96% purity.
Example 149
7-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyrid-
ine
##STR00780##
[2604] Intermediate I-2 (10 mg, 0.032 mmol) and
2-bromo-7-chlorothiazolo[5,4-c]pyridine (11.91 mg, 0.048 mmol) were
dissolved in DMF (318 .mu.L). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
(1.560 mg, 1.910 .mu.mol) was added and the reaction mixture was
degassed by bubbling with argon for 15 minutes. Sodium carbonate (2
M, 19.10 .mu.L, 0.038 mmol) was added and the reaction mixture was
degassed for 5 minutes, then sealed and heated to 100.degree. C. in
the microwave for 30 minutes. The reaction mixture was diluted with
DMF, filtered, and purified by preparative HPLC (Method D, 45 to
85% B in 12 minutes) to give Example 149 (3.1 mg, 0.00834 mmol,
26.2%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.46 (s, 1H),
9.17 (s, 1H), 8.96 (d, J=1.9 Hz, 1H), 8.75 (s, 1H), 8.21 (s, 1H),
4.86 (s, 2H), 3.49 (s, 3H), 2.75 (s, 3H); LC-MS: Method H, RT=1.28
min, MS (ESI) m/z: 357.1 (M+H).sup.+; Analytical HPLC Method B: 96%
purity.
Example 150
5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
##STR00781##
[2606] Intermediate I-9 (10 mg, 0.033 mmol),
2-bromo-5-methoxythiazolo[5,4-b]pyridine (9.80 mg, 0.040 mmol), and
potassium phosphate tribasic (14.14 mg, 0.067 mmol) were dissolved
in DMF (333 .mu.L) and degassed by bubbling with argon for 15
minutes. Palladium tetrakistriphenylphosphine (3.85 mg, 3.33
.mu.mol) was added and degassing continued for 5 minutes. The
reaction mixture was heated to 85.degree. C. for 18 hours. The
reaction mixture was diluted with DMF, filtered, and purified by
preparative HPLC (Method D, 60 to 100% B in 20 minutes) to give
Example 150 (1.1 mg, 0.00325 mmol, 9.8%): LC-MS: Method H, RT=1.50
min, MS (ESI) m/z: 339.1 (M+H).sup.+; Analytical HPLC Method B:
100% purity.
Example 151
7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine
##STR00782##
[2608] Intermediate I-9 (10 mg, 0.033 mmol),
2-bromo-7-chlorothiazolo[5,4-c]pyridine (9.98 mg, 0.040 mmol), and
potassium phosphate tribasic (14.14 mg, 0.067 mmol) were dissolved
in DMF (333 .mu.L) and degassed by bubbling with argon for 15
minutes. Palladium tetrakistriphenylphosphine (3.85 mg, 3.33
.mu.mol) was added and degassing continued for 5 minutes. The
reaction mixture was heated to 85.degree. C. for 24 hours. The
reaction mixture was diluted with DMF, filtered, and purified by
preparative HPLC (Method D, 50 to 100% B in 20 minutes) then
repurified by preparative (Method D, 45 to 85% B in 20 minutes) to
give Example 151 (0.9 mg, 0.00252 mmol, 7.6%): .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta. 9.17 (br. s., 1H), 8.88 (br. s., 1H),
8.68 (br. s., 1H), 8.62 (br. s., 1H), 7.89 (br. s., 1H), 4.18 (br.
s., 3H), 2.73 (br. s., 3H); LC-MS: Method H, RT=1.40 min, MS (ESI)
m/z: 343.1 (M+H).sup.+; Analytical HPLC Method B: 96% purity.
Example 152
methyl
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-c-
arboxylate
##STR00783##
[2610] Intermediate I-9 (99 mg, 0.331 mmol), Intermediate I-20C
(100 mg, 0.331 mmol), and potassium phosphate tribasic (141 mg,
0.662 mmol) were dissolved in DMF (3310 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (38.2 mg, 0.033 mmol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with water and extracted thrice with EtOAc. The combined organic
layers were washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The crude material was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 60 to 100% B
in 15 minutes) to give Example 152 (2.7 mg, 0.00676 mmol, 2%) as a
yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (br.
s., 1H), 8.61 (br. s., 1H), 8.04 (br. s., 1H), 7.87 (br. s., 1H),
7.57 (br. s., 1H), 4.10 (br. s., 3H), 4.01 (br. s., 3H), 3.93 (br.
s., 3H), 2.67 (br. s., 3H); LC-MS: Method H, RT=1.40 min, MS (ESI)
m/z: 396.1 (M+H).sup.+; Analytical HPLC Method B: 99% purity.
Example 153
6-methoxy-2-(3-(methoxymethyl)-6-methyl-1,7-naphthyridin-8-yl)-4-methylben-
zo[d]thiazole
##STR00784##
[2611] Intermediate 153A: 2-nitroacetamide
##STR00785##
[2613] Ethyl 2-nitroacetate (1 g, 7.51 mmol) was dissolved in
NH.sub.3 in MeOH (7 M, 16.10 mL, 113 mmol) and heated to 65.degree.
C. in a sealed tube at for 5 hours. The reaction mixture was cooled
to ambient temperature and concentrated in vacuo to give
Intermediate 153A, which was used directly in the subsequent
reaction.
Intermediate 153B: ethyl
6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-4-carboxylate
##STR00786##
[2615] Intermediate 153A (782 mg, 7.51 mmol), ethyl
2,4-dioxovalerate (1161 .mu.L, 8.27 mmol), and piperidinium acetate
(1091 mg, 7.51 mmol) were dissolved in water (37.6 mL) and stirred
for 18 hours. The reaction mixture was concentrated in vacuo. The
crude material was dissolved in DCM, filtered and purified by
column chromatography (ISCO, 80 g silica gel column, 29 minute
gradient from 0 to 20% MeOH in DCM) to give Intermediate 153B (890
mg, 3.93 mmol, 52.4%) as an orange solid: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.49 (d, J=0.7 Hz, 1H), 4.40 (q, J=7.0 Hz,
2H), 2.49 (d, J=0.7 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H); LC-MS: Method
H, RT=0.90 min, MS (ESI) m/z: 227.2 (M+H).sup.+.
Intermediate 153C: ethyl
2-(benzyloxy)-6-methyl-3-nitroisonicotinate
##STR00787##
[2617] Intermediate 153B (400 mg, 1.768 mmol) was suspended in
toluene (11.8 mL). Silver oxide (1025 mg, 4.42 mmol) then benzyl
bromide (210 .mu.L, 1.768 mmol) were added and the reaction mixture
was heated to 40.degree. C. for 4 days. The reaction mixture was
diluted with EtOAc and filtered through a micron filter. The
residue was concentrated in vacuo. The crude material was purified
by column chromatography (ISCO, 40 g silica gel column, 29 minute
gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 153C
(260 mg, 0.822 mmol, 46.5%) as a white solid: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.49-7.30 (m, 5H), 7.22 (d, J=0.4 Hz, 1H),
5.53 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.57 (d, J=0.4 Hz, 3H), 1.37
(t, J=7.2 Hz, 3H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z:
317.1 (M+H).sup.+.
Intermediate 153D:
(2-(benzyloxy)-6-methyl-3-nitropyridin-4-yl)methanol
##STR00788##
[2619] Sodium borohydride (93 mg, 2.466 mmol) and calcium chloride
(137 mg, 1.233 mmol) were dissolved in THF (3288 .mu.L). After 1
hour, a solution of Intermediate 153C (260 mg, 0.822 mmol) in THF
(822 .mu.L) was added dropwise. After 18 hours, the reaction
mixture was diluted with EtOAc, washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 153D (169 mg, 0.616 mmol, 75%) as a yellow oil:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.49-7.44 (m, 2H),
7.42-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.04 (s, 1H), 5.53 (s, 2H),
4.75 (s, 2H), 2.54 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI)
m/z: 275.1 (M+H).sup.+.
Intermediate 153E:
(3-amino-2-(benzyloxy)-6-methylpyridin-4-yl)methanol
##STR00789##
[2621] Intermediate 153D (169 mg, 0.616 mmol) was dissolved in MeOH
(4213 .mu.L) and THF (527 .mu.L). Ammonium chloride (659 mg, 12.32
mmol) and zinc (403 mg, 6.16 mmol) were added and the reaction
mixture was heated to 40.degree. C. for 1.5 hours. The reaction
mixture was concentrated in vacuo. The crude material was
redissolved in EtOAc/saturated sodium carbonate and allowed to stir
vigorously for 15 minutes. The mixture was filtered through a
sintered glass funnel. The organic layer was washed with water then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 153E (146.7 mg, 0.601 mmol, 97%) as a
yellow oil: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.52-7.47
(m, 2H), 7.44-7.31 (m, 4H), 6.55 (s, 1H), 5.44 (s, 2H), 4.66 (s,
2H), 4.10 (br. s., 2H), 2.39 (d, J=0.4 Hz, 3H); LC-MS: Method H,
RT=0.93 min, MS (ESI) m/z: 245.2 (M+H).sup.+.
Intermediate 153F:
3-amino-2-(benzyloxy)-6-methylisonicotinaldehyde
##STR00790##
[2623] Intermediate 153E (146 mg, 0.598 mmol) was dissolved in
CHCl.sub.3 (3984 .mu.L). Manganese dioxide (312 mg, 3.59 mmol) was
added. After 2.5 hours, the reaction mixture was filtered through
celite and concentrated in vacuo to give Intermediate 153F (125.7
mg, 0.519 mmol, 87%) as an orange oil: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.81 (s, 1H), 7.43-7.37 (m, 2H), 7.35-7.23
(m, 3H), 6.75 (s, 1H), 6.08 (br. s., 2H), 5.36 (s, 2H), 2.33 (d,
J=0.7 Hz, 3H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 243.3
(M+H).sup.+.
Intermediate 153G:
8-(benzyloxy)-3-(methoxymethyl)-6-methyl-1,7-naphthyridine
##STR00791##
[2625] Intermediate 153F (125 mg, 0.516 mmol), 3-methoxypropanal
(50.0 mg, 0.568 mmol), and sodium methoxide (0.5 M, 1135 .mu.L,
0.568 mmol) were dissolved in MeOH (5159 .mu.L) and heated to
reflux for 3.5 hours. The reaction mixture was diluted with
saturated NH.sub.4Cl and EtOAc. The layers were separated and the
organic layer was washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 24 g silica gel column, 19
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 153G (47 mg, 0.160 mmol, 30.9%) as a yellow oil:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.85 (d, J=2.0 Hz, 1H),
7.96-7.91 (m, 1H), 7.65-7.59 (m, 2H), 7.41-7.34 (m, 2H), 7.33-7.29
(m, 1H), 7.03 (d, J=0.7 Hz, 1H), 7.04-7.00 (m, 1H), 5.74 (s, 2H),
4.66 (d, J=0.7 Hz, 2H), 3.49 (s, 3H), 2.57 (d, J=0.7 Hz, 3H);
LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 295.3 (M+H).sup.+.
Intermediate 153H:
3-(methoxymethyl)-6-methyl-1,7-naphthyridin-8-ol
##STR00792##
[2627] Intermediate 153G (47 mg, 0.160 mmol) was dissolved in MeOH
(1597 .mu.L). Palladium on carbon (16.99 mg, 0.016 mmol) was added
and the reaction mixture was sealed under a balloon of hydrogen for
30 minutes. The reaction mixture was filtered through a micron
filter and concentrated in vacuo to give Intermediate 153H (29.6
mg, 0.145 mmol, 91%) as a yellow solid: LC-MS: Method H, RT=0.71
min, MS (ESI) m/z: 205.2 (M+H).sup.+.
Intermediate 153I:
8-chloro-3-(methoxymethyl)-6-methyl-1,7-naphthyridine
##STR00793##
[2629] Intermediate 153H (29.6 mg, 0.145 mmol) was dissolved in
POCl.sub.3 (675 .mu.L, 7.25 mmol) and heated to 90.degree. C. for 5
hours. The reaction mixture was diluted with EtOAc and quenched
with water. The organic layer was washed with saturated
NaHCO.sub.3, brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 153I (24.3 mg, 0.109
mmol, 75%) as a brown solid: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 8.99 (d, J=2.0 Hz, 1H), 8.09-8.04 (m, 1H), 7.44 (s, 1H),
4.72 (d, J=0.9 Hz, 2H), 3.53 (s, 3H), 2.72 (s, 3H); LC-MS: Method
H, RT=0.83 min, MS (ESI) m/z: 223.2 (M+H).sup.+.
Intermediate 153J:
6-methoxy-4-methyl-2-(tributylstannyl)benzo[d]thiazole
##STR00794##
[2631] Intermediate I-3 (20 mg, 0.077 mmol) was dissolved in
Et.sub.2O (310 .mu.L) and cooled to -78.degree. C. BuLi (2.5 M,
34.1 .mu.L, 0.085 mmol) was added. After 30 minutes,
tributylchlorostannane (21.02 .mu.L, 0.077 mmol) was added. After
45 minutes, the reaction mixture was warmed to ambient temperature
and concentrated in vacuo. The crude material was suspended in
hexanes and filtered through dry celite. The residue was
concentrated in vacuo to give Intermediate 153J, which was used
directly in the next reaction.
Example 153
[2632] Intermediate 153I (10 mg, 0.045 mmol), Intermediate 153J
(30.5 mg, 0.065 mmol), and potassium acetate (8.82 mg, 0.090 mmol)
were dissolved in dioxane (449 .mu.L) and degassed by bubbling with
argon for 15 minutes. Palladium tetrakistriphenylphosphine (2.59
mg, 2.245 .mu.mol) was added and the reaction mixture was sealed
and heated to 120.degree. C. in the microwave for 2 hours. The
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 20 to 60% B in 15 minutes)
to give Example 153 (6 mg, 0.016 mmol, 35.8%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.06 (d, J=2.2 Hz, 1H), 8.39-8.34 (m,
1H), 7.91 (s, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.07-6.99 (m, 1H), 4.75
(s, 2H), 3.88 (s, 3H), 3.44 (s, 3H), 2.78 (s, 3H), 2.76 (s, 3H);
LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 366.1 (M+H).sup.+;
Analytical HPLC Method B: 98% purity.
Example 154
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)metha-
nol
##STR00795##
[2634] Intermediate I-9 (12.77 mg, 0.043 mmol), Intermediate I-20D
(14 mg, 0.051 mmol), and potassium phosphate tribasic (18.07 mg,
0.085 mmol) were dissolved in DMF (426 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.92 mg, 4.26 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 45
to 90% B in 10 minutes) to give Example 154 (4.5 mg, 0.011 mmol,
26.5%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H),
8.59 (s, 1H), 7.82 (s, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.22 (d, J=1.7
Hz, 1H), 5.38 (t, J=5.8 Hz, 1H), 5.13 (d, J=5.5 Hz, 2H), 4.09 (s,
3H), 3.89 (s, 3H), 2.65 (s, 3H); LC-MS: Method H, RT=1.26 min, MS
(ESI) m/z: 368.2 (M+H).sup.+; Analytical HPLC Method B: 92%
purity.
Example 155
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4--
yl) methanol
##STR00796##
[2636] Intermediate I-2 (13.37 mg, 0.043 mmol), Intermediate I-20D
(14 mg, 0.051 mmol), and potassium phosphate tribasic (18.07 mg,
0.085 mmol) were dissolved in DMF (426 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.92 mg, 4.26 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 30
to 70% B in 12 minutes) to give Example 155 (3.9 mg, 0.01012 mmol,
23.8%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H),
8.81 (s, 1H), 8.04 (s, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.22 (d, J=1.4
Hz, 1H), 5.40 (t, J=5.6 Hz, 1H), 5.14 (d, J=5.5 Hz, 2H), 4.82 (s,
2H), 3.90 (s, 3H), 3.49 (s, 3H), 2.71 (s, 3H); LC-MS: Method H,
RT=1.17 min, MS (ESI) m/z: 382.1 (M+H).sup.+; Analytical HPLC
Method B: 99% purity.
Example 156
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl) ethanol
##STR00797##
[2637] Intermediate 156A:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)ethanol
##STR00798##
[2639] Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF
(294 .mu.L) and cooled to -78.degree. C. Methylmagnesium bromide
(61.2 .mu.L, 0.184 mmol) was added. After 1 hour, the reaction
mixture was warmed to 0.degree. C. and stirred for 18 hours. The
reaction mixture was quenched with saturated NH.sub.4Cl and
extracted with EtOAc. The organic layer was washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 156A (26.8 mg, 0.093 mmol,
63.3%) as a clear oil: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.17-7.11 (m, 1H), 7.08-7.04 (m, 1H), 5.41-5.31 (m, 1H), 3.87 (s,
3H), 3.44-3.34 (m, 1H), 1.66-1.60 (m, 3H); LC-MS: Method H, RT=1.06
min, MS (ESI) m/z: 288/290 (M+H).sup.+.
Example 156
[2640] Intermediate I-2 (12.18 mg, 0.039 mmol), Intermediate 156A
(13.4 mg, 0.047 mmol), and potassium phosphate tribasic (16.45 mg,
0.078 mmol) were dissolved in DMF (388 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.48 mg, 3.88 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 30
to 70% B in 20 minutes) to give Example 156 (5.1 mg, 0.012 mmol,
31.9%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (br. s.,
1H), 8.80 (br. s., 1H), 8.05 (br. s., 1H), 7.61 (br. s., 1H), 7.25
(br. s., 1H), 5.68 (d, J=4.7 Hz, 1H), 4.83 (br. s., 2H), 3.89 (br.
s., 3H), 3.49 (br. s., 3H), 2.71 (br. s., 3H), 1.57 (d, J=5.0 Hz,
3H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 396.2 (M+H).sup.+;
Analytical HPLC Method B: 96% purity.
Example 157
2-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl) propan-2-ol
##STR00799##
[2641] Intermediate 157A:
2-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)propan-2-ol
##STR00800##
[2643] Intermediate I-20C (50 mg, 0.165 mmol) was dissolved in THF
(331 .mu.L) and cooled to -78.degree. C. Methylmagnesium bromide
(124 .mu.L, 0.372 mmol) was added and the reaction mixture warmed
to 0.degree. C. for 18 hours. The reaction mixture was quenched
with saturated NH.sub.4Cl and extracted with EtOAc. The organic
layer was washed with water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 157A (13.6 mg, 0.045 mmol, 27.2%) as a clear oil:
LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 302/304
(M+H).sup.+.
Example 157
[2644] Intermediate I-2 (11.78 mg, 0.038 mmol), Intermediate 157A
(13.6 mg, 0.045 mmol), and potassium phosphate tribasic (15.92 mg,
0.075 mmol) were dissolved in DMF (375 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.33 mg, 3.75 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 40
to 80% B in 15 minutes) to give Example 157 (8.1 mg, 0.020 mmol,
52.2%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (s, 1H),
8.73 (d, J=1.9 Hz, 1H), 8.07-8.02 (m, 1H), 7.62 (d, J=2.5 Hz, 1H),
7.36 (d, J=2.8 Hz, 1H), 5.42 (s, 1H), 4.83 (s, 2H), 3.89 (s, 3H),
3.49 (s, 3H), 2.71 (s, 3H), 1.84 (s, 6H); LC-MS: Method H, RT=1.12
min, MS (ESI) m/z: 410.2 (M+H).sup.+; Analytical HPLC Method B: 99%
purity.
Example 158
Cyclopropyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-4-yl)methanol
##STR00801##
[2645] Intermediate 158A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclopropyl)methanol
##STR00802##
[2647] Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF
(294 .mu.L) and cooled to -78.degree. C. Cyclopropylmagnesium
bromide (367 .mu.L, 0.184 mmol) was added and the reaction mixture
was warmed to 0.degree. C. for 18 hours. The reaction mixture was
quenched with saturated NH.sub.4Cl and extracted with EtOAc. The
organic layer was washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 158A (24.5 mg, 0.078 mmol, 53%) as a yellow oil,
which was used directly in the subsequent reaction.
Example 158
[2648] Intermediate I-2 (14.40 mg, 0.046 mmol), Intermediate 158A
(12 mg, 0.038 mmol), and potassium phosphate tribasic (16.21 mg,
0.076 mmol) were dissolved in DMF (382 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.41 mg, 3.82 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 35
to 75% B in 15 minutes) to give Example 158 (9.2 mg, 0.022 mmol,
57.1%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (s, 1H),
8.78 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.25
(d, J=2.5 Hz, 1H), 5.35 (d, J=4.7 Hz, 1H), 5.14 (dd, J=6.5, 5.1 Hz,
1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H),
1.36-1.27 (m, 1H), 0.62 (dt, J=9.1, 4.5 Hz, 1H), 0.54 (td, J=9.1,
5.1 Hz, 1H), 0.49-0.42 (m, 1H), 0.42-0.34 (m, 1H); LC-MS: Method H,
RT=1.11 min, MS (ESI) m/z: 421.8 (M+H).sup.+; Analytical HPLC
Method B: 100% purity.
Example 159
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl)-N,N-dimethylmethanamine
##STR00803##
[2649] Intermediate 159A: methyl 5-methoxy-2-nitrobenzoate
##STR00804##
[2651] 5-methoxy-2-nitrobenzoic acid (2 g, 10.14 mmol) was
dissolved in MeOH (50.7 mL). SOCl.sub.2 (2.96 mL, 40.6 mmol) was
added and the reaction mixture was heated to reflux for 20 hours.
The reaction mixture was concentrated in vacuo. The crude material
was dissolved in EtOAc and washed with 1 N NaOH, then water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 159A (1.7786 g, 8.42 mmol, 83%) as a
brown oil: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.04 (d,
J=9.0 Hz, 1H), 7.07-6.99 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H);
LC-MS: Method H, The compound did not ionize.
Intermediate 159B: (5-methoxy-2-nitrophenyl)methanol
##STR00805##
[2653] Intermediate 159A (1.676 g, 7.94 mmol) was dissolved in
toluene (52.9 mL) and THF (26.5 mL) and cooled to -78.degree. C.
DIBAL-H (17.46 mL, 17.46 mmol) was added for 30 minutes. The
reaction mixture was warmed to ambient temperature for 2 hours. The
reaction was quenched with 1 N HCl and stirred for 18 hours. The
reaction mixture was diluted with EtOAc, filtered through celite,
washed with water, then brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The crude material was purified by
column chromatography (ISCO, 80 g silica gel column, 29 minute
gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 159B
(1.21 g, 6.61 mmol, 83%) as a yellow solid: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.18 (d, J=9.0 Hz, 1H), 7.22 (d, J=2.9 Hz,
1H), 6.90 (dd, J=9.0, 2.9 Hz, 1H), 5.00 (d, J=6.4 Hz, 2H), 3.92 (s,
3H), 2.55 (t, J=6.6 Hz, 1H); LC-MS: Method H, The compound did not
ionize.
Intermediate 159C: 5-methoxy-2-nitrobenzyl methanesulfonate
##STR00806##
[2655] Intermediate 159B (0.2 g, 1.092 mmol) and TEA (0.457 mL,
3.28 mmol) were dissolved in DCM (21.84 mL). Methanesulfonic
anhydride (0.228 g, 1.310 mmol) was added for 45 minutes. The
reaction mixture was diluted with DCM and washed with saturated
NaHCO.sub.3, dried (Na.sub.2SO.sub.4), filtered, and concentrated
in vacuo to give Intermediate 159C. The material was used crude in
the next step.
Intermediate 159D:
1-(5-methoxy-2-nitrophenyl)-N,N-dimethylmethanamine
##STR00807##
[2657] Intermediate 159C (0.285 g, 1.091 mmol), DIEA (0.286 mL,
1.636 mmol), and dimethylamine (1.091 mL, 2.182 mmol) were
dissolved in THF (10.91 mL) for 18 hours. The reaction mixture was
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 40 g silica gel column, 19 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 159D (66.4
mg, 0.316 mmol, 29%) as a yellow oil: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.99 (d, J=9.0 Hz, 1H), 7.24 (d, J=2.9 Hz,
1H), 6.83 (dd, J=9.0, 2.9 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 2H), 2.27
(s, 6H); LC-MS: Method H, RT=0.54 min, MS (ESI) m/z: 211.2
(M+H).sup.+.
Intermediate 159E: 2-((dimethylamino)methyl)-4-methoxyaniline,
TFA
##STR00808##
[2659] Intermediate 159D (66 mg, 0.314 mmol) was dissolved in MeOH
(2147 .mu.L) and THF (268 .mu.L). Ammonium chloride (336 mg, 6.28
mmol) and zinc (205 mg, 3.14 mmol) were added and the reaction
mixture was heated to 40.degree. C. for 4.5 hours. The reaction
mixture was diluted with EtOAc and saturated sodium carbonate and
allowed to stir vigorously for 15 minutes. The mixture was filtered
through a sintered glass funnel. The organic layer was washed with
water then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method A, 20 to 100% B in 12 minutes) to give
Intermediate 159E (34.3 mg, 0.117 mmol, 37.1%) as a brown oil:
.sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 6.99-6.94 (m, 2H),
6.93-6.89 (m, 1H), 4.30 (s, 2H), 3.77 (s, 3H), 2.87 (s, 6H); LC-MS:
Method H, RT=0.55 min, MS (ESI) m/z: 181.2 (M+H).sup.+.
Intermediate 159F:
4-((dimethylamino)methyl)-6-methoxybenzo[d]thiazol-2-amine
##STR00809##
[2661] Intermediate 159E (34.3 mg, 0.117 mmol) was dissolved in
MeCN (583 .mu.L). Ammonium thiocyanate (13.31 mg, 0.175 mmol) was
added, followed by benzyltrimethylammonium tribromide (45.5 mg,
0.117 mmol) for 18 hours. The reaction mixture was diluted with
EtOAc, washed with saturated NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 159F (10.3 mg, 0.043 mmol, 37.2%) as a yellow oil:
LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 238.1 (M+H).sup.+.
Intermediate 159G:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-N,N-dimethylmethanamine
##STR00810##
[2663] Copper(II) bromide (16.00 mg, 0.072 mmol) and t-butyl
nitrite (8.52 .mu.L, 0.072 mmol) were dissolved in MeCN (1694) and
allowed to stir 10 minutes. Intermediate 159F (10 mg, 0.042 mmol)
was dissolved in MeCN (2534) and the copper solution was added at
and the reaction mixture was stirred for 75 minutes. The reaction
mixture was diluted with EtOAc, washed with 1 N HCl, saturated
NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 159G (9.8 mg, 0.033
mmol, 77%), which was used as-is for the subsequent step: LC-MS:
Method H, RT=1.017 min, MS (ESI) m/z: 301/303 (M+H).sup.+.
Example 159
[2664] Intermediate I-2 (12.27 mg, 0.039 mmol), Intermediate 159G
(9.8 mg, 0.033 mmol), and potassium phosphate tribasic (13.81 mg,
0.065 mmol) were dissolved in DMF (325 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (3.76 mg, 3.25 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 20
to 60% B in 20 minutes) then repurified by preparative HPLC (Method
D, 20 to 60% B in 15 minutes) to give Example 159 (2.8 mg, 0.00651
mmol, 20%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (s,
1H), 8.90 (d, J=1.7 Hz, 1H), 8.08 (s, 1H), 7.82 (d, J=1.9 Hz, 1H),
7.32 (d, J=1.9 Hz, 1H), 4.82 (s, 2H), 4.59 (br. s., 2H), 3.91 (s,
3H), 3.48 (s, 3H), 2.72 (s, 6H) (1 methyl group buried under the
water peak); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 408.8
(M+H).sup.+; Analytical HPLC Method B: 95% purity.
Example 160
Cyclopropyl(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl) methanol
##STR00811##
[2666] Intermediate I-9 (13.76 mg, 0.046 mmol), Intermediate 158A
(12 mg, 0.038 mmol), and potassium phosphate tribasic (16.21 mg,
0.076 mmol) were dissolved in DMF (382 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.41 mg, 3.82 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 45
to 85% B in 15 minutes) to give Example 160 (4.2 mg, 0.0103 mmol,
27%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H),
8.55 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.24
(d, J=2.5 Hz, 1H), 5.35 (d, J=5.0 Hz, 1H), 5.13 (dd, J=6.5, 5.1 Hz,
1H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H), 1.34-1.27 (m, 1H),
0.61 (dt, J=9.0, 4.4 Hz, 1H), 0.57-0.50 (m, 1H), 0.49-0.42 (m, 1H),
0.42-0.34 (m, 1H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z:
407.8 (M+H).sup.+; Analytical HPLC Method B: 98% purity.
Example 161
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4--
yl) (phenyl)methanol
##STR00812##
[2667] Intermediate 161A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(phenyl)methanol
##STR00813##
[2669] Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF
(294 .mu.L) and cooled to -78.degree. C. Phenylmagnesium bromide
(61.2 .mu.L, 0.184 mmol) was added and the reaction mixture was
warmed to 0.degree. C. for 18 hours. The reaction mixture was
quenched with saturated NH.sub.4Cl and extracted with EtOAc. The
organic layer was washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 161A (33.6 mg, 0.096 mmol, 65.3%) as a white
solid: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 350/352
(M+H).sup.+.
Example 161
[2670] Intermediate I-2 (14.80 mg, 0.047 mmol), Intermediate 161A
(16.5 mg, 0.047 mmol), and potassium phosphate tribasic (20.00 mg,
0.094 mmol) were dissolved in DMF (471 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (5.44 mg, 4.71 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 40
to 75% B in 15 minutes) to give Example 161 (11 mg, 0.024 mmol,
50%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H),
8.83 (d, J=1.7 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.65-7.57 (m, 3H),
7.35-7.27 (m, 3H), 7.23-7.16 (m, 1H), 6.72 (d, J=4.1 Hz, 1H), 6.10
(d, J=4.4 Hz, 1H), 4.82 (s, 2H), 3.87 (s, 3H), 3.48 (s, 3H), 2.74
(s, 3H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 457.8
(M+H).sup.+; Analytical HPLC Method B: 98% purity.
Example 162
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4--
carboxylic acid
##STR00814##
[2671] Intermediate 162A: 5-methoxy-2-nitrobenzoyl chloride
##STR00815##
[2673] 5-Methoxy-2-nitrobenzoic acid (1 g, 5.07 mmol) was dissolved
in DCM (50.7 mL). Oxalyl chloride (0.958 mL, 11.16 mmol) then DMF
(0.039 mL, 0.507 mmol) was added at ambient temperature and the
reaction mixture was stirred for 2.5 hours. The reaction mixture
was concentrated in vacuo and stored on HIVAC to give Intermediate
162A, which was used directly in the subsequent reaction.
Intermediate 162B: tert-butyl 5-methoxy-2-nitrobenzoate
##STR00816##
[2675] Intermediate 162A (1.094 g, 5.07 mmol) was dissolved in THF
(50.7 mL). Potassium tert-butoxide (0.854 g, 7.61 mmol) was added
and the reaction mixture was stirred for 18 hours. The reaction
mixture was diluted with EtOAc and washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 162B (910 mg, 3.59 mmol, 70.8%) as a brown oil:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.98 (d, J=9.0 Hz, 1H),
7.03 (d, J=2.9 Hz, 1H), 6.98 (dd, J=9.0, 2.6 Hz, 1H), 3.91 (s, 3H),
1.58 (s, 9H); LC-MS: Method H, the compound did not ionize.
Intermediate 162C: tert-butyl 2-amino-5-methoxybenzoate
##STR00817##
[2677] Intermediate 162B (0.910 g, 3.59 mmol) was dissolved in EtOH
(5.13 mL). Palladium on carbon (0.076 g, 0.072 mmol) then ammonium
formate (1.133 g, 17.97 mmol) was added and the reaction mixture
was heated to reflux for 1.5 hours. The reaction mixture was
filtered through celite and concentrated in vacuo to give
Intermediate 162C (795 mg, 3.56 mmol, 99%) as a brown oil: .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 7.33 (d, J=2.9 Hz, 1H), 6.92
(dd, J=8.8, 3.1 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 5.36 (br. s., 2H),
3.76-3.74 (m, 3H), 1.59 (s, 9H); LC-MS: Method H, The compound did
not ionize.
Intermediate 162D: tert-butyl
2-amino-6-methoxybenzo[d]thiazole-4-carboxylate
##STR00818##
[2679] Intermediate 162C (0.795 g, 3.56 mmol) was dissolved in MeCN
(17.80 mL). Ammonium thiocyanate (0.407 g, 5.34 mmol) was added,
followed by benzyltrimethylammonium tribromide (1.389 g, 3.56 mmol)
for 18 hours. The reaction mixture was diluted with EtOAc, washed
with saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 80 g silica gel column, 29
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 162D (685.8 mg, 2.446 mmol, 68.7%) as a yellow solid:
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.46 (d, J=2.6 Hz, 1H),
7.29 (d, J=2.6 Hz, 1H), 5.71 (br. s., 2H), 3.85 (s, 3H), 1.63 (s,
9H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z: 282.1
(M+H).sup.+.
Intermediate 162E: tert-butyl
2-bromo-6-methoxybenzo[d]thiazole-4-carboxylate
##STR00819##
[2681] Copper(II) bromide (0.928 g, 4.15 mmol) and t-butyl nitrite
(0.494 mL, 4.15 mmol) were dissolved in MeCN (9.77 mL) and allowed
to stir 10 minutes. Intermediate 162D (0.685 g, 2.443 mmol) was
dissolved in MeCN (14.66 mL) and the copper solution was added for
2.5 hours. The reaction mixture was diluted with EtOAc, washed with
1 N HCl, saturated NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 80 g silica
gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 162E (323.8 mg, 0.941 mmol, 38.5%) as a white
solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.59 (d, J=2.6
Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 3.90 (s, 3H), 1.65 (s, 9H); LC-MS:
The compound did not ionize.
Intermediate 162F: tert-butyl
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-
-carboxylate
##STR00820##
[2683] Intermediate I-2 (22.82 mg, 0.073 mmol), Intermediate 162E
(25 mg, 0.073 mmol), and potassium phosphate tribasic (30.8 mg,
0.145 mmol) were dissolved in DMF (726 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (8.39 mg, 7.26 .mu.mol) was added and
degassing continued for 5 minutes. The reaction mixture was heated
to 85.degree. C. for 18 hours. The reaction mixture was diluted
with water and extracted thrice with EtOAc. The combined organic
layers were washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The crude material was purified by
column chromatography (ISCO, 12 g silica gel column, 17 minute
gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 162F
(14.7 mg, 0.033 mmol, 44.8%) as an orange solid: LC-MS: Method H,
RT=1.22 min, MS (ESI) m/z: 452.2 (M+H).sup.+.
Example 162
[2684] Intermediate 162F (14.7 mg, 0.033 mmol) was dissolved in DCM
(1085 .mu.L) and cooled to 0.degree. C. 2,6-Lutidine (11.38 .mu.L,
0.098 mmol) and TMS-OTf (17.65 .mu.L, 0.098 mmol) were added and
the reaction mixture was warmed to ambient temperature for 45
minutes. The reaction mixture was diluted with water and extracted
with DCM. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was dissolved in DMF, filtered, and purified by
preparative HPLC (Method D, 20 to 60% B in 12 minutes) to give
Example 162 (5.5 mg, 0.014 mmol, 42.3%): LC-MS: Method H, RT=1.07
min, MS (ESI) m/z: 396.1 (M+H).sup.+; Analytical HPLC Method B: 99%
purity.
Example 163
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4--
yl)(phenyl)methanol
##STR00821##
[2686] Example 161 (8 mg, 0.017 mmol) was purified by SFC
chromatography (Berger Multigram II SFC, Chiralpak OJ-H,
21.times.250 mm, 5 micron, 25% MeOH/75% CO.sub.2, 45 mL/min flow
rate) to give Enantiomer 1 (1.54 mg, 0.0032 mmol, 19%) and Example
163 (Enantiomer 2, 3.4 mg, 0.00706 mmol, 40.4%) as a yellow solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.08 (s, 1H), 8.75 (d,
J=1.5 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J=7.5 Hz, 2H), 7.39-7.33 (m,
2H), 7.32 (d, J=2.4 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 6.86 (d, J=2.0
Hz, 1H), 6.40 (d, J=5.7 Hz, 1H), 5.78 (d, J=6.2 Hz, 1H), 4.84 (s,
2H), 3.86 (s, 3H), 3.58 (s, 3H), 2.70 (s, 3H); LC-MS: Method H,
RT=1.11 min, MS (ESI) m/z: 458.3 (M+H).sup.+; 95% purity.
Example 164
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl)-2,2-dimethylpropan-1-ol
##STR00822##
[2687] Intermediate 164A:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
##STR00823##
[2689] Intermediate I-20 (100 mg, 0.367 mmol) was dissolved in THF
(3675 .mu.L) and cooled to -78.degree. C. tert-Butylmagnesium
chloride (1 M, 735 .mu.l, 0.735 mmol) was added and warmed to
0.degree. C. for 2 hours. The reaction was quenched with saturated
NH.sub.4Cl and extracted with EtOAc. The organic layer was washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 24 g silica gel column, 17 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 164A (74.2
mg, 0.225 mmol, 61.1%) as a yellow solid: LC-MS: Method H, RT=1.07
min, MS (ESI) m/z: 330/332 (M+H).sup.+.
Intermediate 164B:
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
##STR00824##
[2691] Intermediate I-2 (58.8 mg, 0.187 mmol) and Intermediate 164A
(74.2 mg, 0.225 mmol) were dissolved in DMF (1872 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (9.17 mg, 0.011 mmol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 112 .mu.L, 0.225 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 100.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 164B (45 mg, 0.103 mmol,
54.9%) as a yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65
(d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.45 (d, J=4.7 Hz, 1H),
5.34 (d, J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H),
2.72 (s, 3H), 0.97 (s, 9H); LC-MS: Method H, RT=1.19 min, MS (ESI)
m/z: 438.2 (M+H).sup.+.
Example 164
[2692] Intermediate 164B (62 mg, 0.017 mmol) was purified by SFC
chromatography (Berger Multigram II SFC, Chiralpak OJ-H,
21.times.250 mm, 5 micron, 25% MeOH/75% CO.sub.2, 45 mL/min flow
rate) to give Enantiomer 1 (15.2 mg, 0.034 mmol, 24.3%) and Example
164 (Enantiomer 2, 18.3 mg, 0.040 mmol, 28%) as a yellow solid:
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (s, 1H), 8.77 (d,
J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5
Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d, J=4.7 Hz, 1H), 4.83 (s,
2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H), 0.97 (s, 9H); LC-MS:
Method H, RT=1.19 min, MS (ESI) m/z: 438.2 (M+H).sup.+; 95%
purity.
Example 165
Cyclohexyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-4-yl)-methanol
##STR00825##
[2693] Intermediate 165A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclohexyl)methanol
##STR00826##
[2695] Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF
(735 .mu.L) and cooled to -78.degree. C. Cyclohexylmagnesium
bromide (1 M, 147 .mu.L, 0.147 mmol) was added and the reaction
mixture was warmed to 0.degree. C. for 5 hours. The reaction was
quenched with saturated NH.sub.4Cl and extracted with EtOAc. The
organic layer was washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 165A (5.3 mg, 0.015 mmol, 20.2%) as a clear oil:
LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 356/358
(M+H).sup.+.
Example 165
[2696] Intermediate I-2 (5.61 mg, 0.018 mmol) and Intermediate 165A
(5.3 mg, 0.015 mmol) were dissolved in DMF (149 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.729 mg, 0.893 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 8.93 .mu.L, 0.018 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 70 to 100% B in 20 minutes)
to give Example 165 (2.9 mg, 0.00626 mmol, 42.1%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.75 (d, J=1.7 Hz, 1H),
8.04 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.37
(t, J=5.6 Hz, 1H), 5.22 (d, J=5.2 Hz, 1H), 4.82 (s, 2H), 3.88 (s,
3H), 3.48 (s, 3H), 2.71 (s, 3H), 1.89 (br. s., 1H), 1.81 (d, J=5.8
Hz, 1H), 1.70 (br. s., 1H), 1.66 (d, J=3.6 Hz, 1H), 1.59 (br. s.,
1H), 1.44 (d, J=9.4 Hz, 1H), 1.21-1.09 (m, 5H); LC-MS: Method H,
RT=1.24 min, MS (ESI) m/z: 464.3 (M+H).sup.+; Analytical HPLC
Method B: 100% purity.
Example 166
Cyclobutyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-4-yl)methanol
##STR00827##
[2697] Intermediate 166A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclobutyl)methanol
##STR00828##
[2699] Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF
(735 .mu.L) and cooled to -78.degree. C. Cyclobutylmagnesium
bromide (0.25 M, 588 .mu.L, 0.147 mmol) was added and the reaction
mixture was warmed to 0.degree. C. for 18 hours. The reaction was
quenched with saturated NH.sub.4Cl and extracted with EtOAc. The
organic layer was washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 166A (4 mg, 0.012 mmol, 16.6%): LC-MS: Method H,
RT=0.82 min, MS (ESI) m/z: 328/330 (M+H).sup.+.
Example 166
[2700] Intermediate I-2 (4.59 mg, 0.015 mmol) and Intermediate 166A
(4 mg, 0.012 mmol) were dissolved in DMF (122 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.597 mg, 0.731 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 7.31 .mu.L, 0.015 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 50 to 100% B in 23 minutes)
to give Example 166 (2.7 mg, 0.00595 mmol, 48.8%): .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta. 9.01 (s, 1H), 8.67 (d, J=1.4 Hz, 1H),
7.89 (s, 1H), 7.25 (d, J=2.2 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 4.95
(d, J=8.0 Hz, 1H), 4.77 (s, 2H), 3.87-3.82 (m, 3H), 3.51 (s, 3H),
2.92-2.84 (m, 1H), 2.65 (s, 3H), 2.18-2.06 (m, 2H), 1.91 (br. s.,
1H), 1.86-1.75 (m, 3H); LC-MS: Method H, RT=1.15 min, MS (ESI) m/z:
436.2 (M+H).sup.+; Analytical HPLC Method B: 96% purity.
Example 167
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4--
yl)(pyridin-2-yl)methanol
##STR00829##
[2701] Intermediate 167A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(pyridin-2-yl)methanol
##STR00830##
[2703] Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF
(735 .mu.L) and cooled to -78.degree. C. Pyridin-2-ylmagnesium
bromide (0.25 M, 588 .mu.L, 0.147 mmol) was added and the reaction
mixture was warmed to 0.degree. C. for 18 hours. The reaction was
quenched with saturated NH.sub.4Cl and extracted with EtOAc. The
organic layer was washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 167A (9.1 mg, 0.026 mmol, 35.3%) as a yellow oil:
LC-MS: Method H, RT=0.66 min, MS (ESI) m/z: 351/353
(M+H).sup.+.
Example 167
[2704] Intermediate I-2 (9.77 mg, 0.031 mmol) and Intermediate 167A
(9.1 mg, 0.026 mmol) were dissolved in DMF (259 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.270 mg, 1.555 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 15.55 .mu.L, 0.031 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 40 to 80% B in 20 minutes)
to give Example 167 (2.7 mg, 0.00548 mmol, 21.1%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.72 (d, J=1.4 Hz, 1H),
8.48 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.90-7.80 (m, 1H), 7.76 (d,
J=7.7 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.31-7.22 (m, 1H), 7.14 (d,
J=2.2 Hz, 1H), 6.72 (s, 1H), 6.22 (br. s., 1H), 4.82 (s, 2H), 3.86
(s, 3H), 3.48 (s, 3H), 2.71 (s, 3H); LC-MS: Method H, RT=0.80 min,
MS (ESI) m/z: 459.2 (M+H).sup.+; Analytical HPLC Method B: 93%
purity.
Example 168
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4--
yl) (pyridin-3-yl)methanol
##STR00831##
[2705] Intermediate 168A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(pyridin-3-yl)methanol
##STR00832##
[2707] Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF
(735 .mu.L) and cooled to -78.degree. C. Pyridin-3-ylmagnesium
bromide (0.25 M, 588 .mu.L, 0.147 mmol) was added and the reaction
mixture was warmed to 0.degree. C. for 18 hours. The reaction was
quenched with saturated NH.sub.4Cl and extracted with EtOAc. The
organic layer was washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 168A (14.6 mg, 0.042 mmol, 56.6%) as a white
solid: LC-MS: Method H, RT=0.65 min, MS (ESI) m/z: 351/353
(M+H).sup.+.
Example 168
[2708] Intermediate I-2 (15.67 mg, 0.050 mmol) and Intermediate
168A (14.6 mg, 0.042 mmol) were dissolved in DMF (416 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (2.037 mg, 2.494 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 24.94 .mu.L, 0.050 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 35 to 75% B in 20 minutes)
to give Example 168 (10 mg, 0.022 mmol, 51.9%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.86 (s, 1H), 8.80 (s,
1H), 8.41 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.93 (d, J=8.0 Hz, 1H),
7.65 (d, J=2.5 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.34 (dd, J=8.0,
4.7 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 6.29 (d, J=4.4 Hz, 1H), 4.82
(s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.73 (s, 3H); LC-MS: Method H,
RT=0.79 min, MS (ESI) m/z: 459.2 (M+H).sup.+; Analytical HPLC
Method B: 99% purity.
Example 169
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl)-2,2-dimethylpropan-1-ol-1-d.sub.1
##STR00833##
[2709] Intermediate 169A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)methanol-d.sub.2
##STR00834##
[2711] Intermediate I-20C (370 mg, 1.225 mmol) was dissolved in
toluene (8164 .mu.L) and THF (4082 .mu.L) and cooled to -78.degree.
C. DIBAL-D (3849 .mu.L, 2.69 mmol) was added and the reaction
mixture was stirred for 30 minutes. The reaction mixture was warmed
to ambient temperature. After 1.5 hours, the reaction was quenched
with 1 N HCl, stirred for 1 hour, and extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 40 g
silica gel column, 19 minute gradient from 0 to 100% EtOAc in
hexanes) to give Intermediate 169A (76.5 mg, 0.277 mmol, 22.5%) as
a white solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.17
(dd, J=7.7, 2.4 Hz, 1H), 7.05 (dd, 2.5 Hz, 1H), 3.87 (s, 3H), 2.95
(d, J=15.0 Hz, 1H); LC-MS: Method H, RT=0.83 min, MS (ESI) m/z:
276/278 (M+H).sup.+.
Intermediate 169B:
2-bromo-6-methoxybenzo[d]thiazole-4-carbaldehyde-d.sub.1
##STR00835##
[2713] Intermediate 169A (76 mg, 0.275 mmol) was dissolved in
CHCl.sub.3 (1835 .mu.L). Manganese dioxide (144 mg, 1.651 mmol) was
added and the reaction mixture was heated to 40.degree. C. for 18
hours. More manganese dioxide (144 mg, 1.651 mmol) was added and
heating continued for 36 hours. The reaction mixture was filtered
through celite and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 24 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 169B (35.7 mg, 0.131 mmol, 47.5%) as a white solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.62 (dd, J=5.1, 2.6
Hz, 1H), 7.54 (dd, J=8.1, 2.6 Hz, 1H), 3.93 (s, 3H); LC-MS: Method
H, RT=0.95 min, MS (ESI) m/z: 275/277 (M+H).sup.+.
Intermediate 169C:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d.sub-
.1
##STR00836##
[2715] Intermediate 169B (35 mg, 0.128 mmol) was dissolved in THF
(1281 .mu.L) and cooled to -78.degree. C. tert-Butylmagnesium
chloride (384 .mu.L, 0.384 mmol) was added and the reaction mixture
was warmed to 0.degree. C. for 18 hours. The reaction was quenched
with saturated NH.sub.4Cl and extracted with EtOAc. The organic
layer was washed with water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 169C (27.1 mg, 0.082 mmol, 63.8%) as a white solid:
LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 331/333
(M+H).sup.+.
Intermediate 169D:
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d.sub.1
##STR00837##
[2717] Intermediate I-2 (30.8 mg, 0.098 mmol) and Intermediate 169C
(27.1 mg, 0.082 mmol) were dissolved in DMF (818 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (4.01 mg, 4.91 .mu.mol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 49.1 .mu.L, 0.098 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 100.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 12 g silica gel column, 19 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 169D (17.3 mg, 0.039 mmol,
48.2%) as a yellow solid: LC-MS: Method H, RT=1.18 min, MS (ESI)
m/z: 439.3 (M+H).sup.+.
Example 169
[2718] Intermediate 169D (17.3 mg, 0.039 mmol) was purified by SFC
chromatography (Berger Multigram II SFC, Chiralpak OJ-H,
21.times.250 mm, 5 micron, 25% MeOH/75% CO.sub.2, 45 mL/min flow
rate) to give Enantiomer 1 (6.5 mg, 0.014 mmol, 35.7%) and Example
169 (Enantiomer 2, 6.5 mg, 0.014 mmol, 35.7%) as a yellow solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.08 (s, 1H), 8.69 (d,
J=1.8 Hz, 1H), 7.96 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 6.93 (d, J=2.4
Hz, 1H), 5.71 (s, 1H), 4.85 (s, 2H), 3.92 (s, 3H), 3.58 (s, 3H),
2.72 (s, 3H), 1.05 (s, 9H); LC-MS: Method H, RT=1.18 min, MS (ESI)
m/z: 439.3 (M+H).sup.+; 95% purity.
Example 170
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl)-2,2-dimethylpropan-1-ol-d.sub.5
##STR00838##
[2719] Intermediate 170A:
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-2,2-dimethylpropan-1-ol-d.sub.5
##STR00839##
[2721] Intermediate I-25 (39.6 mg, 0.124 mmol) and Intermediate
164A (41 mg, 0.124 mmol) were dissolved in DMF (1242 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (6.08 mg, 7.45 .mu.mol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 74.5 .mu.L, 0.149 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 100.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 12 g silica gel column, 19 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 170A (17.8 mg, 0.040 mmol,
32.4%) as a yellow solid: LC-MS: Method H, RT=1.18 min, MS (ESI)
m/z: 443.3 (M+H).sup.+.
Example 170
[2722] Intermediate 170A (19.8 mg, 0.045 mmol) was purified by SFC
chromatography (Berger Multigram II SFC, Chiralpak OJ-H,
21.times.250 mm, 5 micron, 25% MeOH/75% CO.sub.2, 45 mL/min flow
rate) to give Enantiomer 1 (7.7 mg, 0.017 mmol, 36.9%) and Example
170 (Enantiomer 2, 7.8 mg, 0.017 mmol, 37.4%) as a yellow solid:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.08 (s, 1H), 8.69 (d,
J=1.8 Hz, 1H), 7.96 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 6.93 (d, J=2.4
Hz, 1H), 5.74 (br. s., 1H), 4.77 (br. s., 1H), 3.92 (s, 3H), 2.72
(s, 3H), 1.05 (s, 9H); LC-MS: Method H, RT=1.18 min, MS (ESI) m/z:
443.3 (M+H).sup.+; 95% purity.
Example 171
2,2,2-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-
benzo[d]thiazol-4-yl)ethanol
##STR00840##
[2723] Intermediate 171A:
2-chloro-6-methoxybenzo[d]thiazole-4-carbaldehyde
##STR00841##
[2725] Intermediate I-20 (250 mg, 0.919 mmol) was dissolved in THF
(8352 .mu.L) and concentrated HCl (835 .mu.L) for 2.5 hours. The
reaction mixture was diluted with EtOAc, washed with water,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 171A (207
mg, 0.909 mmol, 99%) as an off-white solid: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 10.85 (s, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.53
(d, J=2.6 Hz, 1H), 3.93 (s, 3H); LC-MS: Method H, RT=1.02 min, MS
(ESI) m/z: 242.1 (M+Na).sup.+.
Intermediate 171B:
1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2,2-trifluoroethanol
##STR00842##
[2727] Intermediate 171A (207 mg, 0.909 mmol) was dissolved in THF
(18.2 mL). (Trifluoromethyl)trimethylsilane (161 .mu.L, 1.091 mmol)
then TBAF (1091 .mu.L, 1.091 mmol) were added and the reaction
mixture was stirred for 18 hours. The reaction mixture was diluted
with EtOAc and washed with water, saturated NaHCO.sub.3, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 171B (70.8 mg, 0.238 mmol,
26.2%) as a white solid: LC-MS: Method H, RT=0.98 min, MS (ESI)
m/z: 298.1 (M+H).sup.+.
Example 171
[2728] Intermediate I-2 (30.0 mg, 0.096 mmol) and Intermediate 171B
(23.7 mg, 0.080 mmol) were dissolved in DMF (796 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (3.90 mg, 4.78 .mu.mol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 47.8 .mu.L, 0.096 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 100.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with DMF, filtered, and purified by
preparative HPLC (Method D, 45 to 95% B in 20 minutes) to give
Example 171 (9.8 mg, 0.021 mmol, 26.6%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.83 (br. s., 1H), 8.07 (br.
s., 1H), 7.84 (br. s., 1H), 7.33 (br. s., 1H), 7.07 (d, J=5.8 Hz,
1H), 6.22 (br. s., 1H), 4.83 (s, 2H), 3.92 (s, 3H), 3.49 (s, 3H),
2.72 (s, 3H); LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 450.2
(M+H).sup.+; Analytical HPLC Method B: 97% purity.
Example 172
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4--
yl)(pyridin-4-yl)methanol
##STR00843##
[2729] Intermediate 172A:
(2-amino-6-methoxybenzo[d]thiazol-4-yl)(pyridin-4-yl)methanol
##STR00844##
[2731] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1930 .mu.L). Sodium hydride (8.49 mg, 0.212 mmol) was added and
the reaction mixture was stirred for 10 minutes. The reaction
mixture was cooled to -78.degree. C. and BuLi (2.3 M, 101 .mu.L,
0.232 mmol) was added, and the reaction mixture was stirred for 1
hour. Isonicotinaldehyde (41.3 mg, 0.386 mmol) was added and the
reaction mixture was allowed to warm to ambient temperature. After
1 hour, the reaction mixture was diluted with EtOAc and washed with
water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 172A, which was used
directly in the subsequent reaction: LC-MS: Method H, RT=0.47 min,
MS (ESI) m/z: 288.2 (M+H).sup.+.
Intermediate 172B:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(pyridin-4-yl)methanol
##STR00845##
[2733] Copper(II) chloride (36.0 mg, 0.268 mmol) and t-butyl
nitrite (34.1 .mu.L, 0.287 mmol) were dissolved in MeCN (766 .mu.L)
and allowed to stir 10 minutes. Intermediate 172A (55 mg, 0.191
mmol) was dissolved in MeCN (1148 .mu.L) and the copper solution
was added and the reaction mixture was heated to 60.degree. C. for
2 hours. The reaction mixture was diluted with EtOAc, washed with
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The reaction mixture was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 20% MeOH in DCM) to give Intermediate
172B (11.5 mg, 0.037 mmol, 19.6%) as a yellow solid: LC-MS: Method
H, RT=0.63 min, MS (ESI) m/z: 307.1 (M+H).sup.+.
Example 172
[2734] Intermediate I-2 (14.13 mg, 0.045 mmol) and Intermediate
172B (11.5 mg, 0.037 mmol) were dissolved in DMF (375 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.837 mg, 2.249 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 22.49 .mu.L, 0.045 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with DMF, filtered, and
purified by preparative HPLC (Method D, 35 to 75% B in 20 minutes)
to give Example 172 (6 mg, 0.013 mmol, 34.9%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.83 (s, 1H), 8.57 (br.
s., 2H), 8.06 (s, 1H), 7.70 (br. s., 2H), 7.67 (d, J=2.1 Hz, 1H),
7.26 (s, 2H), 6.75 (s, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 2.74 (s,
3H); LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: 459.3 (M+H).sup.+;
Analytical HPLC Method B: 100% purity.
Example 173
3,3,3-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-
benzo[d]thiazol-4-yl)propan-1-ol
##STR00846##
[2735] Intermediate 173A:
1-(2-amino-6-methoxybenzo[d]thiazol-4-yl)-3,3,3-trifluoropropan-1-ol
##STR00847##
[2737] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1930 .mu.L). Sodium hydride (8.49 mg, 0.212 mmol) was added and
the reaction mixture was stirred for 15 minutes. The reaction
mixture was cooled to -78.degree. C. and BuLi (2.3 M, 101 .mu.L,
0.232 mmol) was added and the reaction mixture was stirred for 30
minutes. 3,3,3-Trifluoropropanal (43.2 mg, 0.386 mmol) was added
and the reaction mixture was allowed to warm to ambient temperature
and stir for 1 hour. The reaction mixture was diluted with EtOAc
and washed with water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 173A,
which was used directly in the subsequent step: LC-MS: Method H,
RT=0.65 min, MS (ESI) m/z: 293.2 (M+H).sup.+.
Intermediate 173B:
1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-3,3,3-trifluoropropan-1-ol
##STR00848##
[2739] Copper(II) chloride (36.3 mg, 0.270 mmol) and t-butyl
nitrite (34.4 .mu.L, 0.289 mmol) were dissolved in MeCN (772 .mu.L)
and allowed to stir 10 minutes. Intermediate 173A (56.4 mg, 0.193
mmol) was dissolved in MeCN (1158 .mu.L) and the copper solution
was added and the reaction mixture was heated to 60.degree. C.
After 3 hours, the reaction mixture was diluted with EtOAc, washed
with 1 N HCl, saturated NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 173B (9.4 mg, 0.030 mmol, 15.6%) as a yellow oil:
LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 312.1 (M+H).sup.+.
Example 173
[2740] Intermediate I-2 (11.37 mg, 0.036 mmol) and Intermediate
173B (9.4 mg, 0.030 mmol) were dissolved in DMF (302 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.478 mg, 1.809 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 18.09 .mu.L, 0.036 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. More PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.478 mg, 1.809
.mu.mol) was added and the reaction mixture was heated to
100.degree. C. for 30 minutes in the microwave. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 45 to 85% B in 25 minutes) to give Example 173 (2.5
mg, 0.00523 mmol, 17.4%): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.10 (s, 1H), 8.75 (s, 1H), 8.05 (s, 1H), 7.68 (d, J=2.1
Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 5.93 (d, J=5.5 Hz, 1H), 5.85 (br.
s., 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.02-2.90 (m, 1H), 2.84-2.73
(m, 1H), 2.69 (s, 3H) (1 methyl group under DMSO); LC-MS: Method H,
RT=1.10 min, MS (ESI) m/z: 464.2 (M+H).sup.+; Analytical HPLC
Method B: 97% purity.
Example 174
2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-4-yl)ethanol
##STR00849##
[2742] Intermediate I-9 (20.09 mg, 0.067 mmol) and Intermediate
171B (16.6 mg, 0.056 mmol) were dissolved in DMF (558 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (2.73 mg, 3.35 .mu.mol) was added
and the reaction mixture was degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 33.5 .mu.L, 0.067 mmol) was added
and the reaction mixture was degassed for 5 minutes, then sealed
and heated to 100.degree. C. in the microwave for 30 minutes. The
reaction mixture was diluted with DMF, filtered, and purified by
preparative HPLC (Method D, 40 to 80% B in 25 minutes) to give
Example 174 (4.6 mg, 0.0104 mmol, 18.6%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.57 (s, 1H), 7.82 (s, 1H),
7.78 (s, 1H), 7.31 (s, 1H), 7.16 (d, J=6.1 Hz, 1H), 6.24-6.15 (m,
1H), 4.08 (s, 3H), 3.90 (s, 3H), 2.64 (s, 3H); LC-MS: Method H,
RT=1.17 min, MS (ESI) m/z: 436.2 (M+H).sup.+; Analytical HPLC
Method B: 98% purity.
Example 175
5-(benzofuran-2-yl)-2-methoxy-7-methylquinoxaline
##STR00850##
[2744] Intermediate I-9A (0.053 g, 0.209 mmol) and
benzofuran-2-ylboronic acid (0.051 g, 0.314 mmol) were dissolved in
toluene (3.14 mL) and EtOH (1.047 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (10.26 mg, 0.013 mmol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. 2 M aqueous Na.sub.2CO.sub.3 (0.126 mL, 0.251 mmol)
was added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 120.degree. C. in the microwave for 30
minutes. The reaction mixture was diluted with EtOAc, filtered
through a micron filter, and concentrated in vacuo. The reaction
mixture was purified on Prep HPLC using Method A to yield Example
175 (2.57 mg, 8.41 .mu.mol, 4.02% yield). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.52 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.08
(s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.63 (d, J=0.8 Hz, 1H), 7.56 (d,
J=8.0 Hz, 1H), 7.32 (td, J=7.7, 1.3 Hz, 1H), 7.25-7.22 (m, 1H),
4.14-4.10 (m, 3H), 2.63 (s, 3H). LC-MS: method H, RT=1.27 min, MS
(ESI) m/z: 291.1 (M+H).sup.+. Analytical HPLC: Method A, 94.5%
purity.
Example 176
Methyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
##STR00851##
[2745] Intermediate 176A: ethyl
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
##STR00852##
[2747] Intermediate I-15B (0.250 g, 0.847 mmol) and
benzofuran-2-ylboronic acid (0.137 g, 0.847 mmol) were dissolved in
DMF (20 mL). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.042 g,
0.051 mmol) was added and the reaction mixture was degassed by
bubbling with argon for 15 minutes. Na.sub.2CO.sub.3 (3 mL, 6.00
mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with EtOAc and
filtered through a micron filter and concentrated in vacuo. The
reaction mixture was purified by ISCO to remove any Pd or ligand
based impurities. 40 g column with a 0-100% gradient of EtOAc in
hexanes was used. Fractions pooled and the residue was purified on
Prep HPLC using Method A to yield Intermediate 176A (0.074 g, 0.223
mmol, 26.3% yield) LC-MS: method H, RT=1.20 min, MS (ESI) m/z:
333.0 (M+H).sup.+.
Intermediate 176B:
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylic acid
##STR00853##
[2749] Intermediate 176A (0.050 g, 0.150 mmol) was dissolved in THF
(3 mL) and MeOH (0.300 mL). NaOH, 1 N in water (0.500 mL, 0.500
mmol) was added and the reaction mixture was allowed to stir at
room temperature for 18 h. Diluted with 1 N HCl and EtOAc. The
layers were separated and the aqueous layer was back extracted with
EtOAc (.times.3). The organic layer was washed with brine, dried
with sodium sulfate, and concentrated under reduced pressure to
yield Intermediate 176B (0.046 g, 0.151 mmol, 100% yield) as a
yellow solid. Used without further purification in the next step.
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.50 (s, 1H), 8.44 (s, 2H),
8.00 (s, 1H), 7.82 (d, J=7.4 Hz, 1H), 7.72 (dd, J=8.3, 0.8 Hz, 1H),
7.43 (td, J=7.7, 1.4 Hz, 1H), 7.36-7.30 (m, 1H), 2.71 (s, 3H).
LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 305.1 (M+H).sup.+.
Intermediate 176C:
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carbonyl chloride
##STR00854##
[2751] Intermediate 176B (0.046 g, 0.151 mmol) was dissolved in DCM
(3 mL) and oxalyl chloride (0.013 mL, 0.151 mmol) was added. DMF
(1.170 .mu.l, 0.015 mmol) was added and the reaction mixture was
allowed to stir at room temperature for 30 min. The reaction
mixture was concentrated and stored under vacuum for 1 h. Used
without further purification in the next step. LC-MS: method H,
RT=1.15 min, MS (ESI) m/z: 319.0 (M+H).sup.+. Methyl ester mass
observed by LC/MS.
Example 176
[2752] Intermediate 176C (0.0125 g, 0.039 mmol) was dissolved in
DCM (3 mL). DMAP (0.473 mg, 3.87 .mu.mol), TEA (10.80 .mu.l, 0.077
mmol), and methanol (1.241 mg, 0.039 mmol) were added and the
reaction mixture was allowed to stir at room temperature over the
weekend. The reaction mixture was concentrated. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 50 to 90% B in 10 minutes) to give Example 176
(0.0057 g, 0.017 mmol, 44.8% yield): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4)) .delta. 9.53 (s, 1H), 8.44 (s, 1H), 8.17 (s,
1H), 7.97 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H),
7.35 (t, J=7.7 Hz, 1H), 7.29-7.22 (m, 1H), 3.37 (s, 3H), 2.69 (s,
3H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 319.1 (M+H).sup.+.
Analytical HPLC Method B: 97.0% purity.
Example 177
8-(benzofuran-2-yl)-3-methoxy-6-methylquinoline
##STR00855##
[2753] Intermediate 177A:
(Z)-3-((2-bromo-4-methylphenyl)amino)-2-nitroacrylaldehyde
##STR00856##
[2755] 2-Bromo-4-methylaniline (0.380 g, 2.044 mmol) was dissolved
in hydrochloric acid, 2 N in water (1 mL) and sodium
(Z)-2-nitro-3-oxoprop-1-en-1-olate hydrate (0.321 g, 2.044 mmol) in
water (2.5 mL) was added to the reaction mixture. The reaction
mixture was allowed to stir for 30 min and the solid was collected
to yield Intermediate 177A (0.537 g, 1.884 mmol, 92%). Material
carried on without further purification in the next step. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 12.46 (br. s., 1H), 10.17 (s,
1H), 8.32 (d, J=14.6 Hz, 1H), 7.45 (s, 1H), 7.25-7.22 (m, 2H), 2.34
(s, 3H). LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 285.0
(M+H).sup.+.
Intermediate 177B: 8-bromo-6-methyl-3-nitroquinoline
##STR00857##
[2757] Intermediate 177A (0.537 g, 1.884 mmol) and
2-bromo-4-methylaniline hydrochloride (0.419 g, 1.884 mmol) were
dissolved in acetic acid (3 mL) and allowed to reflux for 18 h. The
reaction mixture was diluted with 1 N NaOH, until basic, and EtOAc.
The layers were separated and the aqueous layer was back extracted
with EtOAc (.times.3). The combined organic layer was washed with
brine, dried with sodium sulfate, and concentrated under reduced
pressure and was purified on ISCO, 40 g column 0-100% EtOAc in
hexanes to yield Intermediate 177B (0.188 g, 0.704 mmol, 37.4%
yield) as a yellow solid. LC-MS: method H, RT=0.99 min, MS (ESI)
m/z: 267.0 (M+H).sup.+.
Intermediate 177C:
8-(benzofuran-2-yl)-6-methyl-3-nitroquinoline
##STR00858##
[2759] Intermediate 177B (0.070 g, 0.262 mmol) and
benzofuran-2-ylboronic acid (0.042 g, 0.262 mmol) were dissolved in
DMF (20 mL). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.013 g,
0.016 mmol) was added and the reaction mixture was degassed by
bubbling with argon for 15 minutes. Na.sub.2CO.sub.3 (0.175 mL,
0.524 mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with EtOAc and
filtered through a micron filter and concentrated in vacuo. The
reaction mixture was purified by ISCO 40 g column with a 0-100%
gradient of EtOAc in hexanes was used. Combined impure fractions
were diluted with DMF, filtered, and purified by preparative HPLC
(Method D, 55 to 90% B in 10 minutes) to yield Intermediate 177C
(0.0364 g, 0.120 mmol, 45.6% yield): .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.97 (d, J=2.5 Hz, 1H), 8.54 (d, J=1.8 Hz,
1H), 8.29 (d, J=0.8 Hz, 1H), 7.75 (s, 1H), 7.73-7.70 (m, 1H), 7.58
(dd, J=8.3, 0.8 Hz, 1H), 7.36 (td, J=7.7, 1.4 Hz, 1H), 7.30-7.27
(m, 1H), 2.69 (s, 3H). LC-MS: method H, RT=1.31 min, MS (ESI) m/z:
304.9 (M+H).sup.+. Analytical HPLC Method B: 100% purity.
Intermediate 177D: 8-(benzofuran-2-yl)-6-methylquinolin-3-amine
##STR00859##
[2761] Intermediate 177C (0.031 g, 0.102 mmol) was dissolved in
MeOH (5 mL) and Pd/C (1.084 mg, 10.19 .mu.mol) was added. The
reaction mixture was evacuated and back filled with argon
(.times.3). The reaction mixture was then evacuated and back filled
with hydrogen (0.205 mg, 0.102 mmol) (.times.3). The reaction
mixture was allowed to stir at room temperature for 3 hours. The
reaction mixture was filtered to remove the Pd/C and concentrated
under reduced pressure to yield Intermediate 177D (0.022 g, 0.080
mmol, 79% yield). Used without further purification. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.56 (d, J=2.8 Hz, 1H), 8.17 (d,
J=0.8 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.55 (dd,
J=8.2, 0.6 Hz, 1H), 7.36 (s, 1H), 7.32-7.27 (m, 1H), 7.24 (dd,
J=7.5, 1.0 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H), 3.91 (s, 2H), 2.56 (s,
3H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z: 275.3
(M+H).sup.+.
Intermediate 177E: 8-(benzofuran-2-yl)-6-methylquinolin-3-ol
##STR00860##
[2763] Intermediate 177D (0.0178 g, 0.065 mmol) was dissolved in
MeCN (0.468 mL) and cooled to 0.degree. C. Tetrafluoroboric acid
(9.84 .mu.l, 0.071 mmol) was added and stirring continued for 10
minutes. After this time, a solution of tert-butyl nitrite (8.49
.mu.l, 0.071 mmol) in MeCN (0.047 mL) was added dropwise and
stirring continued for 10 minutes. After this time, the reaction
mixture was cooled to -15.degree. C. and water (0.936 mL) was
added. This cooled solution was added into a solution of copper(II)
nitrate, trihydrate (3.14 g, 12.98 mmol) and copper(I) oxide (0.418
g, 2.92 mmol) in water (9.36 mL), precooled to 0.degree. C.
Stirring was continued at the same temperature for 18 h. The
reaction mixture was then extracted thrice with EtOAc. The combined
organic extracts were washed with brine, dried with sodium sulfate,
filtered through Celite, and concentrated in vacuo. The reaction
mixture was purified on Prep HPLC Method A to yield Intermediate
177E 0.018 g, 0.065 mmol, 60%, 65% purity) Used in the next step
without further purification. LC-MS: method H, RT=1.14 min, MS
(ESI) m/z: 276.1 (M+H).sup.+.
Example 177
[2764] Intermediate 177E (0.018 g, 0.065 mmol) was dissolved in
acetone (3 mL) and K.sub.2CO.sub.3 (0.018 g, 0.131 mmol) was added.
MeI (8.18 .mu.l, 0.131 mmol) was added and the reaction mixture was
allowed to stir at room temperature for 5h. The reaction mixture
was diluted with water and EtOAc. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure. The reaction mixture was
diluted with DMF, filtered, and purified by preparative HPLC
(Method D, 35 to 85% B in 10 minutes) to give Example 177 (0.0032
g, 10.95 .mu.ma 16.75% yield): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 8.68 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.7
Hz, 1H), 8.08 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.56-7.53 (m, 2H),
7.46 (d, J=3.0 Hz, 1H), 7.32-7.27 (m, 1H), 7.26-7.19 (m, 1H), 3.98
(s, 3H), 2.59 (s, 3H)). LC-MS: method H, RT=1.31 min, MS (ESI) m/z:
290.2 (M+H).sup.+. Analytical HPLC Method B: 99% purity.
Example 178
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]-
thiazole
##STR00861##
[2766] Intermediate I-1 (0.007 g, 0.028 mmol) and
2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (6.01 mg, 0.028 mmol)
were dissolved in DMF (3 mL). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (1.350 mg, 1.654 mmol) was added and the reaction mixture
was degassed by bubbling with argon for 15 minutes.
Na.sub.2CO.sub.3 (0.018 mL, 0.055 mmol) was added and the reaction
mixture was degassed for 5 minutes, then sealed and heated to
90.degree. C. in the microwave for 30 minutes. The reaction mixture
was diluted with EtOAc and filtered through a micron filter and
concentrated in vacuo. The reaction mixture was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 50 to 85% B
in 10 minutes) to yield Example 178 (0.0052 g, 0.015 mmol, 54.0%
yield): .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.64 (s,
1H), 8.43 (d, J=1.7 Hz, 1H), 7.84-7.53 (m, 2H), 2.89 (d, J=5.8 Hz,
4H), 2.64 (s, 3H), 2.00-1.87 (m, 4H). LC-MS: method H, RT=1.26 min,
MS (ESI) m/z: 348.0 (M+H).sup.+. Analytical HPLC Method B: 99%
purity.
Example 179
5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyr-
idine
##STR00862##
[2768] Intermediate I-9 (10 mg, 0.033 mmol),
2-bromo-5-methoxy-7-methylthiazolo[5,4-b]pyridine (10.36 mg, 0.040
mmol), and phosphoric acid, potassium salt (14.14 mg, 0.067 mmol)
were dissolved in DMF (333 .mu.l) and degassed by bubbling with
argon for 15 minutes. Pd(Ph.sub.3P).sub.4 (3.85 mg, 3.33 .mu.mol)
was added and degassing continued for 5 minutes. The reaction
mixture was heated to 85.degree. C. for 18 h. The reaction mixture
was diluted with DMF, filtered, and purified by preparative HPLC
(Method D, 60% to 100% B in 20 minutes) to yield Example 179
(0.0014 g, 3.89 .mu.mol, 11.69% yield): .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. 8.62 (br. s., 1H), 8.56 (br. s., 1H), 7.76
(br. s., 1H), 6.72 (br. s., 1H), 4.15 (br. s., 3H), 4.05 (br. s.,
3H), 2.81 (br. s., 3H), 2.69 (br. s., 3H). LC-MS: method H, RT=1.57
min, MS (ESI) m/z: 353.0 (M+H).sup.+. Analytical HPLC Method B: 98%
purity.
Example 180
6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5-
,4-b]pyridine
##STR00863##
[2770] Intermediate I-2 (955 .mu.l, 0.048 mmol), Intermediate I-17
(15.07 mg, 0.057 mmol), and phosphoric acid, potassium salt (20.27
mg, 0.095 mmol) were dissolved in DMF (477 .mu.l) and degassed by
bubbling with argon for 15 minutes. Pd(Ph.sub.3).sub.4 (5.52 mg,
4.77 .mu.mol) was added and degassing continued for 5 minutes. The
reaction mixture was heated to 85.degree. C. for 18 h. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 45% to 75% B in 22 minutes) to yield Example 180
(2.0 mg, 4.91 .mu.mol, 10.29% yield): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.13 (s, 1H), 8.79 (s, 1H), 8.48 (d, J=10.7
Hz, 1H), 8.09 (s, 1H), 4.83 (s, 2H), 4.12 (s, 3H), 3.49 (s, 3H),
2.70 (s, 3H). LC-MS: method H, RT=1.39 min, MS (ESI) m/z: 371.1
(M+H).sup.+. Analytical HPLC Method B: 91% purity.
Example 181
5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5-
,4-b]pyridine
##STR00864##
[2772] Intermediate I-2 (1273 .mu.l, 0.064 mmol), Intermediate I-16
(19.79 mg, 0.076 mmol), and phosphoric acid, potassium salt (27.0
mg, 0.127 mmol) were dissolved in DMF (637 .mu.l) and degassed by
bubbling with argon for 15 minutes. Pd(PPh.sub.3).sub.4 (7.36 mg,
6.37 .mu.mol) was added and degassing continued for 5 minutes. The
reaction mixture was heated to 85.degree. C. for 18 h. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 60% to 100% B in 20 minutes) to yield Example 181
(11 mg, 0.029 mmol, 45.7% yield): .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. 9.06 (s, 1H), 8.82 (d, J=1.7 Hz, 1H), 7.94
(d, J=0.8 Hz, 1H), 6.71 (d, J=0.8 Hz, 1H), 4.84 (s, 2H), 4.03 (s,
3H), 3.58 (s, 3H), 2.79 (d, J=0.6 Hz, 3H), 2.71 (s, 3H) LC-MS:
method H, RT=1.43 min, MS (ESI) m/z: 367.1 (M+H).sup.+. Analytical
HPLC Method B: 97% purity.
Example 182
6-fluoro-5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyr-
idine
##STR00865##
[2774] Intermediate I-1 (0.020 g, 0.067 mmol) and Intermediate I-17
(0.018 g, 0.067 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.26 mg, 4.00 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was filtered and the solid was
collected. Recrystallized from DMSO to yield Example 182 (0.0024 g,
6.13 .mu.mol, 9.20% yield) as a yellow solid: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.57 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.98
(d, J=10.6 Hz, 1H), 7.77 (s, 1H), 4.15 (s, 3H), 4.13 (s, 3H), 2.65
(s, 3H). LC-MS: method H, RT=1.52 min, MS (ESI) m/z: 357.1
(M+H).sup.+. Analytical HPLC Method A: 91% purity.
Example 183
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]th-
iazole
##STR00866##
[2776] Intermediate I-2 (0.025 g, 0.080 mmol) and Intermediate I-3
(0.021 g, 0.080 mmol) were dissolved in DMF (3 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.90 mg, 4.77 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aq. solution (0.100 mL,
0.300 mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with EtOAc and
water. The layers were separated and the organic layer was washed
with brine, dried with sodium sulfate, and concentrated under
reduced pressure. The reaction mixture was purified on Prep HPLC
using Method A yield Example 183 (0.021 g, 0.057 mmol, 72.2%
yield): .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.08 (s, 1H),
8.88 (s, 1H), 7.93 (s, 1H), 7.27-7.26 (m, 1H), 6.94 (s, 1H), 4.84
(s, 2H), 3.90 (s, 3H), 3.57 (d, J=0.6 Hz, 3H), 2.84 (s, 3H), 2.71
(s, 3H). LC-MS: method H, RT=1.40 min, MS (ESI) m/z: 366.2
(M+H).sup.+. Analytical HPLC: Method A, 92.3% purity.
Example 184
5-(benzofuran-2-yl)-2-(1-methoxyethyl)-7-methylquinoxaline
##STR00867##
[2777] Intermediate 184A: ethyl
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
##STR00868##
[2779] Intermediate I-15 (0.650 g, 2.202 mmol) and
benzofuran-2-ylboronic acid (0.357 g, 2.202 mmol) were dissolved in
DMF (20 mL). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.108 g,
0.132 mmol) was added and the reaction mixture was degassed by
bubbling with argon for 15 minutes. 3 M Na.sub.2CO.sub.3 (1.468 mL,
4.40 mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with EtOAc and
filtered through a micron filter and concentrated in vacuo.
Purified by ISCO to remove any Pd or ligand based impurities using
a 40 g column with a 0-100% gradient of EtOAc in hexanes. Fractions
pooled and the residue was purified on Prep HPLC Method A to yield
Intermediate 184A (0.117 g, 0.352 mmol, 15.98% yield). LC-MS:
method H, RT=1.21 min, MS (ESI) m/z: 333.1 (M+H).
Intermediate 184B:
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylic acid
##STR00869##
[2781] Intermediate 184A (0.020 g, 0.060 mmol) was dissolved in THF
(3 mL) and MeOH. NaOH, 1 N in water (0.500 mL, 0.500 mmol) was
added and the reaction mixture was allowed to stir at room
temperature for 18 h. Diluted with 1 N HCl and EtOAc. The layers
were separated and the aqueous layer was back extracted with EtOAc
(.times.3). The organic layer was washed with brine, dried with
sodium sulfate, and concentrated under reduced pressure to yield
Intermediate 184B (0.017 g, 0.060 mmol, 99% yield) as a yellow
solid. Used without further purification in the next step. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.49 (s, 1H), 8.42 (d, J=1.4
Hz, 1H), 8.23 (s, 1H), 8.03 (br. s., 1H), 7.81 (d, J=7.4 Hz, 1H),
7.71 (d, J=8.0 Hz, 1H), 7.41 (td, J=7.7, 1.4 Hz, 1H), 7.35-7.29 (m,
1H), 2.69 (s, 3H). LC-MS: method H, RT=1.05 min, MS (ESI) m/z:
305.0 (M+H).sup.+.
Intermediate 184C:
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carbonyl chloride
##STR00870##
[2783] Intermediate 184B (0.018 g, 0.059 mmol) was dissolved in DCM
(3 mL) and oxalyl chloride (5.18 .mu.l, 0.059 mmol) was added. DMF
(0.458 .mu.l, 5.92 .mu.mol) was added and the reaction mixture was
allowed to stir at room temperature for 30 min. The reaction was
concentrated and stored under vacuum for 1 h to yield Intermediate
184C (0.019 g, 0.059 mmol, 100% yield). Used without further
purification in the next step. LC-MS: method H, RT=1.16 min, MS
(ESI) m/z: 319.1 (M+H).sup.+. Observed mass of the methyl ether in
the LC/MS.
Intermediate 184D:
5-(benzofuran-2-yl)-N-methoxy-N,7-dimethylquinoxaline-2-carboxamide
##STR00871##
[2785] Intermediate 184C (0.019 g, 0.059 mmol) was dissolved in DCM
(3 mL). DMAP (0.719 mg, 5.89 .mu.mol), TEA (0.016 mL, 0.118 mmol),
and N,O-dimethylhydroxylamine hydrochloride (5.74 mg, 0.059 mmol)
were added and the reaction mixture was allowed to stir at room
temperature for 18 h. The reaction mixture was diluted with water
and EtOAc. The layers were extracted and the aqueous layer was back
extracted with EtOAc (.times.3). The combined organic layer was
washed with brine, dried with sodium sulfate, and concentrated
under reduced pressure to yield Intermediate 184D (0.021 g, 0.060
mmol, 100% yield) as a yellow solid. Used without further
purification in the next step. NMR (400 MHz, CHLOROFORM-d) .delta.
8.41 (d, J=1.8 Hz, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=7.5
Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.40-7.33 (m, 1H), 7.31-7.25 (m,
2H), 3.83 (br. s., 3H), 3.48 (d, J=15.6 Hz, 3H), 2.74-2.64 (m, 3H).
LC-MS: method H, RT=1.13 min, MS (ESI) m/z: 348.1 (M+H).sup.+.
Intermediate 184E:
5-(benzofuran-2-yl)-N-methoxy-N,7-dimethylquinoxaline-2-carboxamide
##STR00872##
[2787] Intermediate 184D (0.0698 g, 0.201 mmol) was dissolved in
THF (2.009 mL) and cooled to 0.degree. C. methylmagnesium bromide
(0.067 mL, 0.201 mmol) was added and the reaction mixture was
allowed to slowly warm to room temperature over 3 h. The reaction
mixture was diluted with EtOAc and 1 N aqueous HCl. The mixture was
allowed to stir for 30 min. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure. The reaction mixture was
purified on Prep HPLC using Method A to yield Intermediate 184E
(0.0087 g, 0.029 mmol, 14.32% yield) as a yellow solid. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.54 (s, 1H), 8.46 (d, J=1.8 Hz,
1H), 8.23 (d, J=0.8 Hz, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.71 (d, J=7.8
Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.35 (td, J=7.7, 1.3 Hz, 1H),
7.31-7.29 (m, 1H), 2.87 (s, 3H), 2.71 (s, 3H). LC-MS: method H,
RT=1.25 min, MS (ESI) m/z: 303.1 (M+H).sup.+.
Intermediate 184F:
1-(5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl)ethanol
##STR00873##
[2789] Intermediate 184E (0.010 g, 0.033 mmol) was dissolved in
MeOH (1 mL) and cooled to 0.degree. C. CeCl.sub.3 (0.012 g, 0.033
mmol) was added to the reaction mixture followed by NaBH.sub.4
(5.01 mg, 0.132 mmol). The reaction mixture was allowed to stir for
1 h. The reaction mixture was diluted with saturated NH.sub.4Cl
solution and EtOAc. The layers were separated and the aqueous layer
was back extracted with EtOAc (.times.3). The combined organic
layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate 184F
(0.009 g, 0.030 mmol, 89% yield). Will be used without further
purification. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 305.1
(M+H).sup.+.
Example 184
[2790] Intermediate 184F (0.0069 g, 0.023 mmol) was dissolved in
DMF and NaH (0.907 mg, 0.023 mmol) was added. The reaction mixture
was allowed to stir at room temperature for 10 min and MeI (1.418
.mu.l, 0.023 mmol) was added. The reaction mixture was stirred at
room temperature for 3h. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with brine, dried with sodium sulfate and concentrated
under reduced pressure to yield a yellow oil. The reaction mixture
was diluted with DMF, filtered, and purified by preparative HPLC
(Method D, 55% to 95% B in 10 minutes) to yield Example 184 (0.0005
g, 1.571 .mu.mol, 6.93% yield): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 9.07 (s, 1H), 8.34 (d, J=1.7 Hz, 1H),
8.16 (s, 1H), 7.82 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.3
Hz, 1H), 7.36-7.31 (m, 1H), 7.27-7.23 (m, 1H), 4.69 (q, J=6.8 Hz,
1H), 3.42 (s, 3H), 2.68 (s, 3H), 1.62 (d, J=6.6 Hz, 3H). LC-MS:
method H, RT=1.30 min, MS (ESI) m/z: 319.1 (M+H).sup.+. Analytical
HPLC Method B: 100% purity.
Example 185
6-methoxy-2-(3-(methoxymethyl)-6-methylquinolin-8-yl)-4-methylbenzo[d]thia-
zole
##STR00874##
[2791] Intermediate 185A: methyl
8-bromo-6-methylquinoline-3-carboxylate
##STR00875##
[2793] 8-bromo-6-methylquinoline-3-carboxylic acid (250 mg, 0.940
mmol) was dissolved in MeOH (3758 .mu.l). Thionyl chloride (206
.mu.l, 2.82 mmol) was added and the reaction mixture was heated to
reflux for 4h. The reaction mixture was cooled to ambient
temperature and concentrated in vacuo to yield Intermediate 185A
(0.263 g, 0.940 mmol, 100% yield): .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.52 (d, J=2.0 Hz, 1H), 8.80 (d, J=1.8 Hz,
1H), 8.06 (d, J=1.5 Hz, 1H), 7.70 (s, 1H), 4.06 (s, 3H), 2.59 (s,
3H). LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 280/282
(M+H).sup.+.
Intermediate 185B: (8-bromo-6-methylquinolin-3-yl)methanol
##STR00876##
[2795] NaBH.sub.4 (70.2 mg, 1.856 mmol) and calcium chloride (103
mg, 0.928 mmol) were dissolved in THF (2750 .mu.l). A solution of
Intermediate 185A (260 mg, 0.928 mmol) in THF (688 .mu.l) was added
dropwise. The reaction mixture was allowed to stir for 18 h. The
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried sodium sulfate, filtered, and concentrated in vacuo.
The crude material was purified by column chromatography (ISCO, 40
g silica gel column, 19 minute gradient from 0 to 100% EtOAc in
hexanes) to yield Intermediate 185B (0.146 g, 0.579 mmol, 62%
yield): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.97 (d, J=1.8
Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 4.97 (d, J=5.5
Hz, 2H), 2.55 (s, 3H), 1.93 (t, J=5.7 Hz, 1H). LC-MS: method H,
RT=0.85 min, MS (ESI) m/z: 252/254 (M+H).sup.+.
Intermediate 185C: (8-bromo-6-methylquinolin-3-yl)methyl
methanesulfonate
##STR00877##
[2797] Intermediate 185B (146 mg, 0.579 mmol) and TEA (242 .mu.l,
1.737 mmol) were dissolved in DCM (16 mL). Methanesulfonic
anhydride (121 mg, 0.695 mmol) was added and the reaction mixture
was allowed to stir at room temperature for 3h. The reaction
mixture was diluted with DCM and washed with saturated NaHCO.sub.3,
dried sodium sulfate, filtered, and concentrated in vacuo to yield
Intermediate 185C (0.191 g, 0.579 mmol, 100% yield). The material
will be used crude in the next step. LC-MS: method H, RT=1.03 min,
MS (ESI) m/z: 330.0 (M+H).sup.+.
Intermediate 185D: 8-bromo-3-(methoxymethyl)-6-methylquinoline
##STR00878##
[2799] Intermediate 185C (190 mg, 0.575 mmol) was dissolved in THF
(12 mL). 0.5 M sodium methoxide (2302 .mu.l, 1.151 mmol) and the
reaction mixture was allowed to stir for 18 h. The reaction mixture
was concentrated in vacuo to remove the THF, diluted with EtOAc and
washed with 0.5 N HCl, then brine, dried sodium sulfate, filtered,
and concentrated in vacuo to yield Intermediate 185D (0.100 g,
0.376 mmol, 65% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.94 (d, J=2.0 Hz, 1H), 8.07-8.03 (m, 1H), 7.93 (d, J=1.8 Hz, 1H),
7.57 (s, 1H), 4.69 (s, 2H), 3.49 (s, 3H), 2.55 (s, 3H). LC-MS:
method H, RT=1.00 min, MS (ESI) m/z: 266.0 (M+H).sup.+.
Intermediate 185E: (3-(methoxymethyl)-6-methylquinolin-8-yl)boronic
acid
##STR00879##
[2801] Intermediate 185D (100 mg, 0.376 mmol),
bis(pinacolato)diboron (143 mg, 0.564 mmol), and potassium acetate
(92 mg, 0.939 mmol) were dissolved in dioxane (2099 .mu.l) and
degassed for 5 minutes by bubbling with argon.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (24.55 mg, 0.030 mmol) was
added and the reaction mixture was degassed for an additional 10
minutes. The reaction mixture was heated to 130.degree. C. in the
microwave for 45 minutes. The reaction mixture was then diluted
with EtOAc and water. The reaction mixture was further extracted
twice with EtOAc. The combined organic layers were washed with
brine, dried sodium sulfate, filtered, and concentrated in vacuo.
The crude material was purified by Prep LC (Axia Luna 5 u C18
30.times.100 mm column, 12 minute gradient from 30 to 100% B in A,
A=10:90:0.1 MeOH:H.sub.2O:TFA, B=90:10:0.1 MeOH:H.sub.2O:TFA) to
yield Intermediate 185E (0.063 g, 0.240 mmol, 64% yield): LC-MS:
method H, RT=0.75 min, MS (ESI) m/z: 232.1 (M+H).sup.+ (see mass of
methyl boronic ester in the LC/MS).
Example 185
[2802] Intermediate 185E (0.025 g, 0.096 mmol) and Intermediate I-3
(0.025 g, 0.096 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (4.73 mg, 5.79 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aq. solution (0.030 mL,
0.090 mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 30% to 70% B
in 10 minutes) to yield Example 185 (0.0097 g, 0.026 mmol, 27.0%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.00 (d, J=1.9
Hz, 1H), 8.80 (d, J=1.4 Hz, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.54
(d, J=2.2 Hz, 1H), 7.00 (d, J=1.4 Hz, 1H), 4.71 (s, 2H), 3.86 (s,
3H), 3.42 (s, 3H), 2.76 (s, 3H), 2.65 (s, 3H). LC-MS: method H,
RT=1.22 min, MS (ESI) m/z: 365.3 (M+H).sup.+. Analytical HPLC
Method B: 98% purity.
Example 186
2-(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methyl-
benzo[d]thiazole
##STR00880##
[2803] Intermediate 186A: O-methyl
5-bromo-7-methylquinoxaline-2-carbothioate
##STR00881##
[2805] Methyl 5-bromo-7-methylquinoxaline-2-carboxylate (0.200 g,
0.711 mmol) was dissolved in o-xylenes (2.85 mL) and Lawesson's
Reagent (0.576 g, 1.423 mmol) was added. The reaction mixture was
heated to reflux for 18 h. The reaction mixture was filtered and
the filter cake washed with o-xylenes. o-Xylenes solution was
loaded directly on the ISCO column. The reaction mixture was
purified on ISCO 40 g column 0-50% EtOAc in hexanes gradient to
yield Intermediate 186A (0.005 g, 0.017 mmol, 2.365% yield) as a
yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.78 (s,
1H), 8.07 (d, J=1.8 Hz, 1H), 8.04 (d, J=0.9 Hz, 1H), 4.49 (s, 3H),
2.64 (s, 3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 296.9
(M+H).sup.+.
Intermediate 186B:
5-bromo-2-(difluoro(methoxy)methyl)-7-methylquinoxaline
##STR00882##
[2807] Intermediate 186A (0.068 g, 0.229 mmol) was dissolved in
CH.sub.2Cl.sub.2. Bis-(2-methoxyethyl)aminosulfur trifluoride
(0.084 mL, 0.458 mmol) was added and the reaction mixture was
allowed to stir at room temperature for 48h. The reaction mixture
was diluted with EtOAc and water. The organic layer was washed with
sodium bicarbonate, washed with brine, dried with sodium sulfate,
and concentrated under reduced pressure to yield Intermediate 186B
(0.065 g, 0.214 mmol, 94% yield) a yellow oil. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.21 (s, 1H), 8.08 (d, J=1.8 Hz, 1H),
8.01 (s, 1H), 3.91 (s, 3H), 2.64 (s, 3H). LC-MS: method H, RT=1.29
min, MS (ESI) m/z: 302.9 (M+H).sup.+.
Intermediate 186C:
(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)boronic
acid
##STR00883##
[2809] A mixture of Intermediate 186B (0.070 g, 0.231 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.088
g, 0.346 mmol), potassium acetate (0.057 g, 0.577 mmol) in dioxane
(2.309 mL) were degassed by bubbling argon for 5 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (9.43 mg, 0.012 mmol) was
added and the mixture was sealed and heated in microwave at
130.degree. C. for 30 min. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with water, washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure. The reaction
mixture was purified on Prep HPLC using Method A to yield
Intermediate 186C (0.010 g, 0.037 mmol, 16.16% yield) as a brown
solid. LC-MS: method H, RT=0.88 min, MS (ESI) m/z: 269.1
(M+H).sup.+.
Example 186
[2810] Intermediate 186C (0.010 g, 0.029 mmol) and Intermediate I-3
(7.37 mg, 0.029 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.399 mg, 1.713 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.050
mL, 0.150 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 55% to 100% B
in 20 minutes) to yield Example 186 (0.0064 g, 0.016 mmol, 55.8%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.36 (s, 1H),
8.93 (s, 1H), 8.17 (s, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.02 (d, J=1.1
Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.76 (s, 3H), 2.73 (s, 3H).
LC-MS: method H, RT=1.50 min, M/S (ESI) m/z: 402.1 (M+H).sup.+.
Analytical HPLC Method B: 100% purity.
Example 187
6-methoxy-4-methyl-2-(7-methyl-2-(phenoxymethyl)quinoxalin-5-yl)benzo[d]th-
iazole
##STR00884##
[2811] Intermediate 187A: 1-diazo-3-phenoxypropan-2-one
##STR00885##
[2813] To 2-phenoxyacetyl chloride (0.250 g, 1.465 mmol) in MeCN
cooled with ice-bath was added (diazomethyl)trimethylsilane 2.0 M
in diethyl ether (1.282 mL, 2.56 mmol). The mixture was allowed to
stir at room temperature for 3h. Solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(loading in chloroform, 0% to 50% EtOAc in hexane over 18 min using
a 40 g silica gel cartridge). The desired fractions were combined
and concentrated (bath temp below 35.degree. C.) to yield
Intermediate 187A (0.215 g, 1.220 mmol, 83% yield) as a pale yellow
oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.32 (t, J=8.0 Hz,
2H), 7.03 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H), 5.82 (s, 1H),
4.55 (s, 2H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 177.1
(M+H).sup.+.
Intermediate 187B: 1-bromo-3-phenoxypropan-2-one
##STR00886##
[2815] Intermediate 187A (0.215 g, 1.220 mmol) was dissolved in
Et.sub.2O (4.88 mL) and the mixture was cooled to 0.degree. C. and
HBr (0.242 mL, 2.136 mmol) was added dropwise. After 5 min at
0.degree. C., the reaction mixture was allowed to stir at room
temperature for 10 min. The reaction mixture was diluted with
ether, washed with saturated aqueous sodium bicarbonate, washed
with brine, and dried over sodium sulfate. The organic layer was
concentrated (kept bath below 30.degree. C.) and the product was
used immediately without further purification. Intermediate 187B
(0.224 g, 0.978 mmol, 80% yield). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.33 (t, J=7.9 Hz, 2H), 7.03 (t, J=7.4 Hz,
1H), 6.91 (d, J=8.1 Hz, 2H), 4.79 (s, 2H), 4.18 (s, 2H). LC-MS:
method H, RT=1.09 min, Compound does not ionize well.
Intermediate 187C:
5-bromo-7-methyl-2-(phenoxymethyl)quinoxaline
##STR00887##
[2817] To Intermediate I-1B (0.300 g, 0.906 mmol) in anhydrous DMF
(30 mL) at 0.degree. C. was added cesium carbonate (0.516 g, 1.585
mmol) in several portions. The brown solution was stirred at
0.degree. C. for 10 min, followed by addition of Intermediate 187B
(0.249 g, 1.087 mmol) in DMF (5.0 mL). The brown solution turned
yellow. The mixture was stirred at room temperature for 18 h. The
mixture was diluted with EtOAc, washed with water, brine, dried
over sodium sulfate and concentrated. The residue was dissolved in
ethyl acetate (8 mL) and 4.0 N HCl in dioxane (1.170 mL, 4.68 mmol)
was added. The mixture was stirred at room temperature for 45 min.
Solvent was removed under vacuum to give the deprotected
intermediate as a yellow oil. The deprotected intermediate was
dissolved in THF (20 mL). Tin(II) chloride dihydrate (0.290 g,
1.287 mmol) was added, followed by concentrated HCl (0.048 mL,
0.585 mmol). The mixture was placed and stirred in an oil bath
pre-heated at 45.degree. C. for 18 h. The reaction mixture was
diluted with EtOAc/water and neutralized with saturated sodium
bicarbonate. The mixture was stirred at room temperature for 15
min, the precipitate was removed by filtration. The organic layer
was washed with saturated sodium bicarbonate, washed with brine,
dried over sodium sulfate, and concentrated. The reaction mixture
was purified on ISCO, 24 g column 0-100% EtOAc in hexanes to give
Intermediate 187C (0.093 g, 0.254 mmol, 65.2% yield) as a light
yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.13 (s,
1H), 7.95 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 7.36-7.28 (m, 2H),
7.06-6.95 (m, 3H), 5.44 (s, 2H), 2.60 (s, 3H). LC-MS: method H,
RT=1.30 min, MS (ESI) m/z: 329.1 (M+H).sup.+.
Intermediate 187D:
7-methyl-2-(phenoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)quinoxaline
##STR00888##
[2819] A mixture of Intermediate 187C (0.093 g, 0.283 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.108
g, 0.424 mmol), potassium acetate (0.069 g, 0.706 mmol) in dioxane
(2.83 mL) were degassed by bubbling argon for 5 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.012 g, 0.014 mmol) was
added and the mixture was sealed and heated in microwave at
130.degree. C. for 30 min. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with water, washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure to yield
Intermediate 187D (0.100 g, 0.266 mmol, 94% yield). Used without
further purification. LC-MS: method H, RT=1.21 min, MS (ESI) m/z:
295.2 (M+H)+(Mass of the boronic acid was observed in LC/MS).
Example 187
[2820] Intermediate 187D (0.025 g, 0.066 mmol) and
2-bromo-6-methoxy-4-methylbenzo[d]thiazole (0.017 g, 0.066 mmol)
were dissolved in DMF (1 mL). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (3.26 mg, 3.99 .mu.mol) was added and the reaction mixture
was degassed by bubbling with argon for 15 minutes. 3 M aqueous
sodium bicarbonate solution (0.022 mL, 0.066 mmol) was added and
the reaction mixture was degassed for 5 minutes, then sealed and
heated to 90.degree. C. in the microwave for 30 minutes. The
reaction mixture was filtered and concentrated. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 55% to 100% B in 20 minutes) to yield Example 187
(0.0084 g, 0.019 mmol, 28.7% yield): .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. 9.22 (s, 1H), 8.93 (s, 1H), 7.97 (s, 1H),
7.36 (t, J=7.8 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 7.10 (d, J=8.3 Hz,
2H), 7.05 (t, J=7.3 Hz, 1H), 6.97 (s, 1H), 5.49 (s, 2H), 3.93 (s,
3H), 2.87 (s, 3H), 2.76 (s, 3H). LC-MS: method H, RT=1.53 min, MS
(ESI) m/z: 428.2 (M+H).sup.+. Analytical HPLC Method B: 97%
purity.
Example 188
1-(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)-N,N-
-dimethylmethanamine
##STR00889##
[2821] Intermediate 188A: Ethyl
5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxyl-
ate
##STR00890##
[2823] Intermediate I-15 (0.030 g, 0.104 mmol) and Intermediate I-3
(0.027 g, 0.104 mmol) were dissolved in DMF (3 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (5.10 mg, 6.25 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with water and
EtOAc. The layers were separated and the organic layer was washed
with brine, dried with sodium sulfate, and concentrated under
reduced pressure to yield a black oil. The reaction mixture was
purified on ISCO 12 g column 0-100% EtOAc in hexanes to yield
Intermediate 188A (0.026 g, 0.066 mmol, 63.5% yield) as a yellow
solid. .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.62 (s, 1H),
9.02 (s, 1H), 8.16 (s, 1H), 7.28-7.27 (m, 1H), 6.95 (s, 1H), 4.62
(q, J=7.2 Hz, 2H), 3.91 (s, 3H), 2.84 (s, 3H), 2.74 (s, 3H), 1.51
(br. s., 3H), 1.53-1.51 (m, 3H). LC-MS: method H, RT=1.41 min, MS
(ESI) m/z: 394.1 (M+H).sup.+.
Intermediate 188B:
(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)metha-
nol
##STR00891##
[2825] Sodium borohydride (4.92 mg, 0.130 mmol) and calcium
chloride (7.22 mg, 0.065 mmol) were dissolved in tetrahydrofuran (2
mL) and allowed to stir for 1 h. To this suspension was added
Intermediate 188A (0.0256 g, 0.065 mmol) and the reaction mixture
was allowed to stir at room temperature for 18 h. The reaction
mixture diluted with water and EtOAc. The layer were separated and
the organic layer was washed with brine, dried with sodium sulfate,
and concentrated under reduced pressure to yield Intermediate 188B
(0.025 g, 0.071 mmol, 109% yield) as a yellow oil. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.94 (s, 1H), 8.91 (d, J=1.8 Hz, 1H),
7.98 (d, J=0.9 Hz, 1H), 7.31-7.30 (m, 1H), 6.97 (dd, J=2.5, 0.8 Hz,
1H), 5.10 (s, 2H), 3.93 (s, 3H), 2.87 (s, 3H), 2.75 (s, 3H). LC-MS:
method H, RT=1.29 min, MS (ESI) m/z: 352.1 (M+H).sup.+.
Intermediate 188C:
(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)methy-
l methanesulfonate
##STR00892##
[2827] Intermediate 188B (0.025 g, 0.071 mmol) was dissolved in DCM
(3 mL) and treated with TEA (0.030 mL, 0.213 mmol). To this
solution was added methanesulfonic anhydride (0.015 g, 0.085 mmol)
and the reaction mixture was allowed to stir at room temperature
for 1 h. The reaction mixture was diluted with EtOAc and saturated
sodium bicarbonate. The layers were separated and the organic layer
was washed with brine, dried with sodium sulfate and concentrated
under reduced pressure to yield Intermediate 188C (0.027 g, 0.063
mmol, 88% yield). Used in next step to without further
purification. LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 430.1
(M+H).sup.+.
Example 188
[2828] Intermediate 188C (0.0125 g, 0.029 mmol) was dissolved in
tetrahydrofuran (0.291 mL) and DIEA (7.62 .mu.l, 0.044 mmol) was
added. To the stirred reaction mixture was added dimethylamine
(7.37 .mu.l, 0.146 mmol) and the reaction mixture was allowed to
stir at room temperature for 18 h. The reaction mixture was diluted
with DMF, filtered, and purified by preparative HPLC (Method D, 45%
to 85% B in 18 minutes) to yield Example 188 (1.7 mg, 4.22 .mu.mol,
14.51% yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s,
1H), 8.79 (d, J=1.7 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.56 (d, J=2.5
Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 3.86 (s, 3H), 3.35 (s, 2H), 2.76
(s, 3H), 2.69 (s, 3H), 2.33 (s, 6H). LC-MS: method H, RT=1.10 min,
MS (ESI) m/z: 379.2 (M+H).sup.+. Analytical HPLC Method B: 94%
purity.
Example 189
2-(2-(ethoxymethyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thi-
azole
##STR00893##
[2829] Intermediate 189A: 1-diazo-3-ethoxypropan-2-one
##STR00894##
[2831] To 2-ethoxyacetyl chloride (0.250 g, 2.040 mmol) in MeCN
cooled with ice-bath was added (diazomethyl)trimethylsilane 2.0 M
in diethyl ether (1.785 mL, 3.57 mmol). The mixture was allowed to
stir at room temperature for 3h. Solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(loading in chloroform, 0% to 50% EtOAc in hexane over 18 min using
a 40 g silica gel cartridge). The desired fractions were combined
and concentrated (bath temp below 35.degree. C.) to yield
Intermediate 189A (0.181 g, 1.413 mmol, 69.2% yield) as a pale
yellow oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 5.77 (s,
1H), 3.99 (s, 2H), 3.56 (q, J=6.9 Hz, 2H), 1.25 (t, J=7.0 Hz,
3H).
Intermediate 189B: 1-diazo-3-ethoxypropan-2-one
##STR00895##
[2833] Intermediate 189A (0.145 g, 1.132 mmol) was dissolved in
Et.sub.2O (4.53 mL) and cooled to 0.degree. C. and HBr (0.224 mL,
1.980 mmol) was added dropwise. After 5 min at 0.degree. C., the
reaction mixture was allowed to stir at room temperature for 10
min. The reaction mixture was diluted with ether, washed with
saturated sodium bicarbonate, washed with brine, and dried over
sodium sulfate. The organic layer was concentrated (kept bath below
30.degree. C.) and the product was used immediately without further
purification. Intermediate 189B (0.148 g, 0.818 mmol, 72.2% yield).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.26 (s, 2H), 4.07 (s,
2H), 3.59 (q, J=6.9 Hz, 2H), 1.27 (t, J=6.9 Hz, 3H).
Intermediate 189C: tert-butyl
(2-bromo-4-methyl-6-nitrophenyl)(3-ethoxy-2-oxopropyl)carbamate
##STR00896##
[2835] To Intermediate I-1B (0.226 g, 0.681 mmol) in anhydrous DMF
(30 mL) at 0.degree. C. was added cesium carbonate (0.388 g, 1.192
mmol) in several parts. The brown solution was stirred at 0.degree.
C. for 10 min, followed by addition of Intermediate 189B (0.148 g,
0.818 mmol) in DMF (5.0 mL). The brown solution turned yellow. The
mixture was stirred at room temperature for 18 h. The mixture was
diluted with EtOAc, washed with water, brine, dried over sodium
sulfate and concentrated. The crude product was purified by ISCO
(40 g silica gel column, (0% to 60% EtOAc/Hexane over 18 min) to
yield Intermediate 189C (0.197 g, 0.457 mmol, 67.0% yield) as a
yellow solid. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 431.0
(M+H).sup.+.
Intermediate 189D: 5-bromo-2-(ethoxymethyl)-7-methylquinoxaline
##STR00897##
[2837] To Intermediate 189C (0.187 g, 0.434 mmol) in Ethyl acetate
(8 mL) was added 4.0 N HCl in dioxane (1.301 mL, 5.20 mmol) and the
mixture was stirred at room temperature for 45 min. Solvent was
removed under vacuum to give the deprotected intermediate as a
yellow oil. The deprotected intermediate was dissolved in THF (20
mL). Tin(II) chloride dihydrate (0.323 g, 1.431 mmol) was added,
followed by concentrated HCl (0.053 mL, 0.650 mmol). The mixture
was placed and stirred in an oil bath pre-heated at 45.degree. C.
for 18 h. The reaction mixture was diluted with EtOAc/water and
neutralized with saturated sodium bicarbonate. The mixture was
stirred at room temperature for 15 min, the precipitate was removed
by a separatory funnel. The organic layer was washed with saturated
sodium bicarbonate, washed with brine, dried over sodium sulfate
and concentrated. The reaction mixture was purified on ISCO 24 g
column 0-100% EtOAc in hexanes to yield Intermediate 189D (0.056 g,
0.199 mmol, 45.9% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.05 (s, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.81 (s, 1H), 4.86
(s, 2H), 3.68 (q, J=7.0 Hz, 2H), 2.58 (s, 3H), 1.31 (t, J=6.9 Hz,
3H). LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 281.1
(M+H).sup.+.
Intermediate 189E:
2-(ethoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
quinoxaline
##STR00898##
[2839] A mixture of Intermediate 189D (0.056 g, 0.199 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.076
g, 0.299 mmol), potassium acetate (0.049 g, 0.498 mmol) in dioxane
(1.992 mL) were degassed by bubbling argon for 5 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (8.13 mg, 9.96 .mu.mol)
was added and the mixture was sealed and heated in microwave at
130.degree. C. for 30 min. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with water, washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure to yield
Intermediate 189E (0.050 g, 0.152 mmol, 76% yield) as a brown oil
Used without further purification in the next step. LC-MS: method
H, RT=1.06 min, MS (ESI) m/z: 247.2 (M+H).sup.+. Mass of the
boronic acid seen in LC/MS.
Example 189
[2840] Intermediate 189E (0.025 g, 0.076 mmol) and Intermediate I-3
(0.020 g, 0.076 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.73 mg, 4.57 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. 3 M sodium carbonate solution (0.025 mL,
0.076 mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was filtered and concentrated.
The reaction mixture was diluted with DMF, filtered, and purified
by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to
yield Example 189 (0.0003 g, 0.759 .mu.mol, 0.996% yield): .sup.1H
NMR (500 MHz, CHLOROFORM-d) .delta. 9.15 (s, 1H), 8.90 (d, J=1.4
Hz, 1H), 7.95 (s, 1H), 7.31-7.30 (m, 1H), 6.97 (s, 1H), 4.91 (s,
2H), 3.93 (s, 3H), 3.76 (q, J=6.9 Hz, 2H), 2.87 (s, 3H), 2.74 (s,
3H), 1.37 (t, J=6.9 Hz, 3H). LC-MS: method H, RT=1.49 min, MS (ESI)
m/z: 380.2 (M+H).sup.+. Analytical HPLC Method B: 96% purity.
Example 190
6-methoxy-2-(4-methoxy-3-(methoxymethyl)-6-methylquinolin-8-yl)-4-methylbe-
nzo[d]thiazole
##STR00899##
[2841] Intermediate 190A: diethyl
2-(((2-bromo-4-methylphenyl)amino)methylene)malonate
##STR00900##
[2843] 2-bromo-4-methylaniline (0.667 mL, 5.37 mmol) and diethyl
2-(ethoxy methylene)malonate (1.184 mL, 5.91 mmol) were heated to
100.degree. C. under a stream of argon. The reaction mixture
stirred for 2h and was cooled to ambient temperature, diluted with
hexanes, heated gently to break up the material, and the solid
collected by suction filtration Intermediate 190A (1.80 g, 5.05
mmol, 94% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 11.22
(d, J=12.8 Hz, 1H), 8.48 (d, J=13.4 Hz, 1H), 7.42 (s, 1H),
7.21-7.11 (m, 2H), 4.35 (q, J=7.3 Hz, 2H), 4.26 (q, J=7.0 Hz, 2H),
1.39 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H).
Intermediate 190B: ethyl
8-bromo-4-hydroxy-6-methylquinoline-3-carboxylate
##STR00901##
[2845] Intermediate 190A (0.250 g, 0.702 mmol) was dissolved in
biphenyl ether (12.5 mL) was added. The reaction mixture was
stirred at 250.degree. C. for 18 h. The reaction mixture was cooled
to ambient temperature. The reaction mixture was filtered and
washed with Et.sub.2O to yield Intermediate 190B (0.187 g, 0.603
mmol, 86% yield) as a white solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 12.33 (s, 1H), 9.19 (s, 1H), 8.09 (s, 1H),
7.99 (d, J=1.5 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 2.54 (s, 3H), 1.48
(t, J=7.0 Hz, 3H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z:
310.0 (M+H).sup.+.
Intermediate 190C: ethyl
8-bromo-4-chloro-6-methylquinoline-3-carboxylate
##STR00902##
[2847] Intermediate 190B (0.100 g, 0.322 mmol) was dissolved in
POCl.sub.3 (0.150 mL, 1.612 mmol) and heated to reflux for 3h. The
reaction mixture was carefully diluted with water and ice. The
layers were separated and the organic layer was washed with aqueous
saturated NaHCO.sub.3, brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate 190C
(0.048 g, 0.146 mmol, 45.3% yield) as a pale yellow solid. Used
without further purification in the next step. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.61 (s, 1H), 8.44 (s, 1H), 8.33 (s,
1H), 4.60 (q, J=7.2 Hz, 2H), 2.75 (s, 3H), 1.51 (t, J=7.2 Hz, 3H).
LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 328.0 (M+H).sup.+.
Intermediate 190D: methyl
8-bromo-4-methoxy-6-methylquinoline-3-carboxylate
##STR00903##
[2849] Intermediate 190C (0.480 g, 1.461 mmol) was dissolved in THF
(10 mL) and sodium methoxide (8.76 mL, 4.38 mmol) was added. The
reaction mixture was allowed to stir at room temperature for 30
min. The reaction mixture was diluted with water and EtOAc. The
layers were separated and the organic layer was washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure
to yield Intermediate 190D (0.454 g, 1.464 mmol, 100% yield) as a
white solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.21 (s,
1H), 8.02 (dd, J=1.8, 0.9 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 4.14 (s,
3H), 4.01 (s, 3H), 2.55 (s, 3H). LC-MS: method H, RT=1.16 min, MS
(ESI) m/z: 310.0 (M+H).sup.+.
Intermediate 190E:
(8-bromo-4-methoxy-6-methylquinolin-3-yl)methanol
##STR00904##
[2851] Calcium chloride (0.072 g, 0.645 mmol) and sodium
borohydride (0.049 g, 1.290 mmol) were suspended in tetrahydrofuran
and allowed to stir for 1 h. To the stirred reaction mixture was
added Intermediate 190D (0.200 g, 0.645 mmol) in tetrahydrofuran
(25 mL) and the reaction mixture was allowed to stir for 3 days.
The reaction mixture was diluted with water and EtOAc. The layers
were separated and the organic layer was washed with brine, dried
with sodium sulfate, and concentrated under reduced pressure. The
reaction mixture was purified by ISCO 24 g column 0-100% EtOAc in
hexanes to yield Intermediate 190E (0.050 g, 0.177 mmol, 27.5%
yield) as a white solid. .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. 8.96 (s, 1H), 7.91 (d, J=1.4 Hz, 1H), 7.85 (d, J=0.8 Hz,
1H), 4.94 (d, J=5.8 Hz, 2H), 4.11 (d, J=0.8 Hz, 3H), 2.55 (s, 3H).
LC-MS: method H, RT=0.84 min, MS (ESI) m/z: 282.1 (M+H).sup.+.
Intermediate 190F: (8-bromo-4-methoxy-6-methylquinolin-3-yl)methyl
methanesulfonate
##STR00905##
[2853] Intermediate 190E (0.050 g, 0.177 mmol) was dissolved in DCM
(3 mL) and treated with TEA (0.074 mL, 0.532 mmol). To this
solution was added methanesulfonic acid (0.037 g, 0.213 mmol), and
the reaction mixture was allowed to stir at room temperature for 1
h. The reaction mixture was diluted with EtOAc and saturated sodium
bicarbonate. The layers were separated and the organic layer was
washed with brine, dried with sodium sulfate and concentrated under
reduced pressure to yield Intermediate 190F (0.027 g, 0.073 mmol,
53%). Used without further purification in the next step. LC-MS:
method H, RT=0.96 min, MS (ESI) m/z: 296.1 (M+H).sup.+ Observed the
methyl ether in LC/MS.
Intermediate 190G:
8-bromo-4-methoxy-3-(methoxymethyl)-6-methylquinoline
##STR00906##
[2855] Intermediate 190F (0.180 g, 0.500 mmol) was dissolved in THF
(5.00 ml) and DIPEA (0.131 ml, 0.750 mmol) was added. To the
stirred reaction was added sodium methoxide (5.00 ml, 2.498 mmol),
and the reaction was allowed to stir at room temperature overnight.
The reaction was diluted with water and EtOAc. The layers were
separated, and the organic layer was washed with brine, dried with
sodium sulfate, and concentrated under reduced pressure to yield
Intermediate 190G (0.068 g, 0.230 mmol, 46%) as a yellow solid.
Used without further purification in the next step. LC-MS: method
H, RT=0.97 min, MS (ESI) m/z: 298.1 (M+H).sup.+.
Intermediate 190H:
4-methoxy-3-(methoxymethyl)-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)quinoline
##STR00907##
[2857] A mixture of Intermediate 190G (0.027 g, 0.091 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.035
g, 0.137 mmol), potassium acetate (0.022 g, 0.228 mmol) in dioxane
(0.912 mL) were degassed by bubbling argon for 5 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.72 mg, 4.56 .mu.mol)
was added and the mixture was sealed and heated in microwave at
130.degree. C. for 30 min. The reaction mixture was diluted with
water and EtOAc. The layers were separated and the organic layer
was washed with brine, dried with sodium sulfate, and concentrated
under reduced pressure to yield Intermediate 190H (0.040, 0.058,
64%) as a brown oil. Used in the next step without further
purification. LC-MS: method H, RT=0.98 min, MS (ESI) m/z: 262.2
(M+H).sup.+. Mass of the boronic acid was seen in LC/MS.
Example 190
[2858] Intermediate 190H (0.031 g, 0.090 mmol) and Intermediate I-3
(0.023 g, 0.090 mmol) were dissolved in DMF (3 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (4.43 mg, 5.42 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was filtered and concentrated.
The reaction mixture was diluted with DMF, filtered, and purified
by preparative HPLC (Method D, 55% to 100% B in 22 minutes) to
yield Example 190 (0.0036 g, 8.58 .mu.mol, 9.50% yield): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.98 (s, 1H), 8.82 (s, 1H),
8.10 (s, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.00 (s, 1H), 4.73 (s, 2H),
4.12 (s, 3H), 3.86 (s, 3H), 3.42 (s, 3H), 2.76 (s, 3H), 2.68 (s,
3H). LC-MS: method H, RT=1.10 min, MS (ESI) m/z: 395.2 (M+H).sup.+.
Analytical HPLC Method B: 94% purity.
Example 191
5-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,-
4-b]pyridine
##STR00908##
[2859] Intermediate 191A:
5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine
##STR00909##
[2861] Potassium thiocyanate (0.682 g, 7.01 mmol) was dissolved in
acetic acid (10 mL) and cooled to 0.degree. C.
6-chloro-4-methylpyridin-3-amine (1.00 g, 7.01 mmol) was dissolved
in acetic acid (3.33 mL) and added dropwise. Bromine (0.361 mL,
7.01 mmol) was dissolved in acetic acid (3.33 mL) and added
dropwise to the reaction mixture. The reaction mixture was allowed
to warm to room temperature for 18 h. The reaction mixture was
concentrated under reduced pressure. The resultant residue was
diluted with water and neutralized with 1 N NaOH. The aqueous
solution was extracted with EtOAc (.times.3). The combined organic
layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure. The reaction mixture was
purified on Prep HPLC using Method A to yield Intermediate 191A
(0.890 g, 4.46 mmol, 63.6% yield) as a white solid. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.08 (d, J=0.7 Hz, 1H), 3.39 (dt,
J=3.2, 1.6 Hz, 2H), 2.50 (d, J=0.7 Hz, 3H). LC-MS: method H,
RT=0.92 min, MS (ESI) m/z: 200.1 (M+H).sup.+.
Intermediate 191B:
2-bromo-5-chloro-7-methylthiazolo[5,4-b]pyridine
##STR00910##
[2863] Copper(II) bromide (0.295 g, 1.320 mmol) and t-butyl nitrite
(0.157 mL, 1.320 mmol) were dissolved in MeCN (3.11 mL) and allowed
to stir 10 minutes. Intermediate 191A (0.155 g, 0.776 mmol) was
dissolved in MeCN (4.66 mL) and the copper solution was added. The
reaction mixture was stirred for 30 min. The reaction mixture was
diluted with EtOAc, washed with 1 N HCl, washed with saturated
NaHCO.sub.3, washed with brine, dried with sodium sulfate,
filtered, and concentrated in vacuo to yield Intermediate 191B
(0.163 g, 0.618 mmol, 80% yield). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.43 (d, J=0.9 Hz, 1H), 2.68 (d, J=0.9
Hz, 3H). LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 263.0
(M+H).sup.+.
Example 191
[2864] Intermediate 191B (0.025 g, 0.095 mmol) was dissolved in
Et.sub.2O (0.379 mL) and cooled to -78.degree. C. BuLi (0.042 mL,
0.104 mmol) was added and allowed to stir for 15 min.
Tributylchlorostannane (0.026 mL, 0.095 mmol) was added and allowed
to stir for 30 min. The reaction mixture was warmed to ambient
temperature and concentrated in vacuo. The crude material was
suspended in hexanes and filtered through dry celite. Used
immediately without further purification. Intermediate I-2E (0.015
g, 0.056 mmol), stannane, and potassium acetate (0.011 g, 0.112
mmol) were dissolved in dioxane (0.562 mL) and degassed by bubbling
with argon for 15 minutes. Pd(Ph.sub.3P).sub.4 (3.24 mg, 2.81
.mu.mol) was added and the reaction mixture was sealed and heated
to 120.degree. C. in the microwave for 2 hours. The reaction
mixture was diluted with EtOAc and water. The layers were separated
and the organic layer was washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 65% to 100% B in 12 minutes) to yield Example 191
(0.0023 g, 6.08 .mu.mol, 10.82% yield): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.17 (s, 1H), 8.88 (s, 1H), 8.14 (s, 1H),
7.62 (s, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.84 (s, 3H), 2.73 (s,
3H). LC-MS: method H, RT=1.11 min, MS (ESI) m/z: 371.2 (M+H).sup.+.
Analytical HPLC Method B: 98% purity.
Example 192
(5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyr-
idin-7-yl) methanol
##STR00911##
[2865] Intermediate 192A: 2-methoxy-5-nitroisonicotinic acid
##STR00912##
[2867] 2-chloro-5-nitroisonicotinic acid (0.100 g, 0.494 mmol) was
dissolved in DCM (4.94 mL) and oxalyl chloride (0.043 mL, 0.494
mmol) was added. To the stirred reaction mixture was added 2 drops
of DMF. The reaction mixture was stirred for 30 min and
concentrated under reduced pressure. The compound was used without
further purification in the next step. The residue was dissolved in
tetrahydrofuran (4.98 mL) and sodium methoxide (3.98 mL, 1.991
mmol) was added. The reaction mixture was allowed to stir at room
temperature for 18 h. The reaction mixture was diluted with water
and EtOAc. 1 N HCl was added and the layers were separated. The
organic layer was washed brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate 192A
(0.078 g, 0.394 mmol, 79% yield) as a white solid. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.97 (s, 1H), 6.95 (s, 1H), 4.08 (s,
3H). LC-MS: method H, RT=0.82 min, MS (ESI) m/z: 198.9
(M+H).sup.+.
Intermediate 192B: methyl 2-methoxy-5-nitroisonicotinate
##STR00913##
[2869] Intermediate 192A (0.085 g, 0.429 mmol) was dissolved in DCM
(4.29 mL) and oxalyl chloride (0.038 mL, 0.429 mmol) was added. To
the stirred reaction mixture was added 2 drops of DMF. The reaction
mixture was stirred for 30 min and concentrated under reduced
pressure. The compound was used without further purification in the
next step. The residue dissolved in MeOH (4.16 mL) and sodium
methoxide (0.831 mL, 0.416 mmol) was added. The reaction mixture
was stirred at room temperature for 18 h. The reaction mixture was
diluted with water and EtOAc. The layers were separated and the
organic layer was washed with water, brine, dried with sodium
sulfate, and concentrated under reduced pressure to yield
Intermediate 192B (0.060 g, 0.283 mmol, 68.1% yield) as a white
solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.96 (s, 1H),
6.86 (s, 1H), 4.06 (s, 3H), 3.96 (s, 3H). LC-MS: method H, RT=0.83
min, MS (ESI) m/z: 213.1 (M+H).sup.+.
Intermediate 192C: methyl 5-amino-2-methoxyisonicotinate
##STR00914##
[2871] Intermediate 192B (60 mg, 0.283 mmol) was dissolved in EtOH
(1.131 mL). Pd/C (6.02 mg, 5.66 .mu.mol) then ammonium formate (89
mg, 1.414 mmol) were added and the reaction mixture was heated to
reflux for 1 h. The reaction mixture was filtered through celite
and concentrated in vacuo to yield Intermediate 192C (47.5 mg,
0.261 mmol, 92% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.80 (s, 1H), 7.15 (s, 1H), 5.09 (br. s., 2H), 3.91 (s, 3H), 3.87
(s, 3H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 183.1
(M+H).sup.+.
Intermediate 192D: methyl
2-amino-5-methoxythiazolo[5,4-b]pyridine-7-carboxylate, 2 AcOH
##STR00915##
[2873] Potassium thiocyanate (0.029 g, 0.299 mmol) was dissolved in
acetic acid (10 mL) and cooled to 0.degree. C. Intermediate 192C
(0.0545 g, 0.299 mmol) was dissolved in acetic acid (3.33 mL) and
added dropwise. Bromine (0.015 mL, 0.299 mmol) was dissolved in
acetic acid (3.33 mL) and added dropwise to the reaction mixture.
The reaction mixture was allowed to warm to room temperature and
stir for 18 h. The reaction mixture was concentrated under reduced
pressure. The resultant residue was diluted with water and
neutralized with 1 N NaOH. The aqueous solution was extracted with
EtOAc (.times.3). The combined organic layer was washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure
to yield Intermediate 192D (0.100 g, 0.278 mmol, 93% yield).
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.10 (s, 1H), 3.94
(s, 3H), 3.93 (s, 3H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z:
240.1 (M+H).sup.+.
Intermediate 192E: methyl
2-bromo-5-methoxythiazolo[5,4-b]pyridine-7-carboxylate
##STR00916##
[2875] Copper(II) bromide (0.106 g, 0.473 mmol) and t-butyl nitrite
(0.056 mL, 0.473 mmol) were dissolved in MeCN (1.113 mL) and
allowed to stir 10 minutes. Intermediate 192D (0.100 g, 0.278 mmol)
was dissolved in MeCN (1.670 mL) and the copper solution was added.
The reaction mixture was stirred for 1 h. The reaction mixture was
diluted with EtOAc, washed with 1 N HCl, washed with saturated
NaHCO.sub.3, washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo to yield Intermediate 192E (0.025 g,
0.082 mmol, 29.6% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.31 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H). LC-MS: method H,
RT=0.96 min, MS (ESI) m/z: 303.0 (M+H).sup.+.
Intermediate 192F:
(2-bromo-5-methoxythiazolo[5,4-b]pyridin-7-yl)methanol
##STR00917##
[2877] Intermediate 192E (25 mg, 0.082 mmol) was dissolved in
toluene (550 .mu.l) and THF (275 .mu.l) and cooled to -78.degree.
C. 1 M DIBAL-H (181 .mu.l, 0.181 mmol) was added, and the reaction
mixture was allowed to stir for 18 h. The reaction mixture was
quenched with 1 N HCl (1 mL), diluted with EtOAc. The layers were
separated and the organic layer was washed with brine, dried with
sodium sulfate, and concentrated under reduced pressure to yield
Intermediate 192F (0.02 g, 0.029 mmol, 35.3% yield). Used without
further purification in the next step. LC-MS: method H, RT=0.96
min, MS (ESI) m/z: 275.0 (M+H).sup.+.
Example 192
[2878] Intermediate I-2 (0.020 g, 0.064 mmol) and Intermediate 192E
(0.018 g, 0.064 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.12 mg, 3.82 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 25% to 55% B
in 20 minutes) to yield Example 192 (0.0012 g, 3.01 .mu.mol, 4.73%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.13 (s, 1H),
8.78 (d, J=1.9 Hz, 1H), 8.07 (s, 1H), 7.05 (s, 1H), 5.64 (t, J=5.6
Hz, 1H), 5.13 (d, J=5.2 Hz, 2H), 4.83 (s, 2H), 4.01 (s, 3H), 3.49
(s, 3H), 2.71 (s, 3H). LC-MS: method H, RT=1.02 min, MS (ESI) m/z:
383.1 (M+H).sup.+. Analytical HPLC Method B: 98% purity.
Example 193
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthia-
zolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide
##STR00918##
[2879] Intermediate 193A:
2-amino-7-methylthiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
##STR00919##
[2881] Intermediate I-16 (0.750 g, 3.84 mmol) was dissolved HBr in
acetic acid (2.61 mL, 23.05 mmol) and the reaction mixture was
stirred at 130.degree. C. for 3h. The reaction mixture was
concentrated under reduced pressure to yield Intermediate 193A
(1.48 g, 4.31 mmol, 100%) as a tan solid. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 6.66 (d, J=0.9 Hz, 1H), 2.48 (d, J=0.7
Hz, 3H) LC-MS: method H, RT=0.47 min, MS (ESI) m/z: 182.1
(M+H).sup.+.
Intermediate 193B: tert-butyl
(2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
##STR00920##
[2883] Intermediate 193A (0.100 g, 0.332 mmol) was dissolved in DMF
(3.32 mL). t-Butyl (2-bromoethyl)carbamate (0.089 g, 0.398 mmol)
and Cs.sub.2CO.sub.3 (0.541 g, 1.659 mmol) were added and the
reaction mixture was stirred at 40.degree. C. for 3h. The reaction
mixture was diluted with water and EtOAc. The layers were
separated. The organic layer was washed with brine dried with
sodium sulfate, and concentrated under reduced pressure. The
reaction mixture was purified on ISCO using a 24 g column with a
0-100% gradient of EtOAc in hexanes to yield Intermediate 193B
(0.038 g, 0.117 mmol, 35.3% yield) a brown solid. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 6.53 (s, 1H), 5.14 (br. s., 2H), 4.33
(t, J=5.2 Hz, 2H), 3.71 (t, J=5.0 Hz, 1H), 3.52 (d, J=5.1 Hz, 2H),
2.49 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=0.77 min, MS (ESI) m/z:
325.2 (M+H).sup.+.
Intermediate 193C: tert-butyl
(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
##STR00921##
[2885] Copper(II) bromide (0.044 g, 0.199 mmol) and t-butyl nitrite
(0.024 mL, 0.199 mmol) were dissolved in MeCN (0.469 mL) and
allowed to stir 10 minutes. Intermediate 193B (0.038 g, 0.117 mmol)
was dissolved in MeCN (0.703 mL) and the copper solution was added.
The reaction mixture was diluted with EtOAc, washed with 1 N HCl,
washed with saturated NaHCO.sub.3, washed with brine, dried with
sodium sulfate, filtered, and concentrated in vacuo to yield
Intermediate 193C (0.042 g, 0.108 mmol, 92% yield). LC-MS: method
H, RT=1.12 min, MS (ESI) m/z: 390.0 (M+H).sup.+.
Intermediate 193D:
2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanamine
##STR00922##
[2887] To a mixture of Intermediate 193C (0.042 g, 0.108 mmol) in
DCM (1) was added 2,6-lutidine (0.038 mL, 0.325 mmol) followed by
TMS-OTf (0.078 mL, 0.433 mmol) at room temperature. The mixture was
stirred at room temperature for 1 h. The mixture was diluted by
EtOAc and NaHCO.sub.3. The organic layer was washed by brine, dried
by sodium sulfate and concentrated to Intermediate 193D (0.0185 g,
0.064 mmol, 59.4% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 6.68 (d, J=0.9 Hz, 1H), 4.37 (t, J=5.3 Hz, 2H), 3.11 (t,
J=5.3 Hz, 2H), 2.63 (d, J=0.9 Hz, 3H), 2.53 (s, 1H). LC-MS: method
H, RT=0.68 min, MS (ESI) m/z: 290.1 (M+H).sup.+.
Intermediate 193E:
N-(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)-4-fluoroben-
zenesulfonamide
##STR00923##
[2889] To a solution of Intermediate 193D (0.018 g, 0.062 mmol) in
DMF (1 mL) was added DIEA (0.109 mL, 0.625 mmol) and
4-fluorobenzene-1-sulfonyl chloride (0.015 g, 0.075 mmol). The
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with water and EtOAc. The layers were separated
and the organic layer was washed with brine, dried with sodium
sulfate and concentrated under reduced pressure to yield
Intermediate 193E (0.028 g, 0.063 mmol, 100% yield) as a yellow
glass. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.89-7.84 (m,
2H), 7.15 (t, J=8.7 Hz, 2H), 6.55 (d, J=0.9 Hz, 1H), 4.97 (br. s.,
1H), 4.43-4.32 (m, 2H), 3.47-3.37 (m, 2H), 2.63 (d, J=0.9 Hz, 3H).
LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 446.0 (M+H).sup.+.
Example 193
[2890] Intermediate I-2 (0.010, 0.032 mmol) and Intermediate 193E
(0.014 g, 0.032 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.560 mg, 1.910 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 45% to 90% B
in 20 minutes) to yield Example 193 (0.0053 g, 9.48 .mu.mol, 29.8%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H),
8.76 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.92-7.88 (m, 2H), 7.44-7.39
(m, 2H), 6.73 (s, 1H), 4.82 (s, 2H), 4.34 (t, J=5.5 Hz, 2H), 3.49
(s, 3H), 3.26 (q, J=5.6 Hz, 2H), 2.73 (s, 3H), 2.69 (s, 3H). LC-MS:
method H, RT=1.15 min, MS (ESI) m/z: 554.1 (M+H).sup.+. Analytical
HPLC Method B: 99% purity.
Example 194
4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-
-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide
##STR00924##
[2892] Intermediate I-2 (0.010, 0.032 mmol) and Example 193E (0.015
g, 0.032 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.560 mg, 1.910 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with DMF,
filtered, and purified by preparative HPLC (Method D, 60% to 90% B
in 20 minutes) to yield Example 194 (0.0043 g, 7.65 .mu.mol, 23%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H),
8.55 (d, J=1.4 Hz, 1H), 8.01 (t, J=5.8 Hz, 1H), 7.89 (dd, J=8.8,
5.2 Hz, 2H), 7.83 (s, 1H), 7.41 (t, J=8.8 Hz, 2H), 6.72 (s, 1H),
4.33 (t, J=5.5 Hz, 2H), 4.09 (s, 3H), 3.26 (d, J=5.8 Hz, 2H), 2.72
(s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z:
540.1 (M+H).sup.+. Analytical HPLC Method B: 96% purity.
Example 195
5-(benzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
##STR00925##
[2893] Intermediate 195A: ethyl
5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
##STR00926##
[2895] Intermediate I-15 (0.250 g, 0.847 mmol) and
benzofuran-2-ylboronic acid (0.137 g, 0.847 mmol) were dissolved in
DMF (20 mL). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.042 g,
0.051 mmol) was added and the reaction mixture was degassed by
bubbling with argon for 15 minutes. Na.sub.2CO.sub.3 (3 mL, 6.00
mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with EtOAc and
filtered through a micron filter and concentrated in vacuo.
Purified by ISCO to remove any Pd or ligand based impurities. 40 g
column with a 0-100% gradient of EtOAc in hexanes was used.
Fractions pooled and the residue was purified on Prep HPLC using
Method A to yield Intermediate 195A (0.074 g, 0.223 mmol, 26.3%
yield) LC-MS: method H, RT=1.19 min, MS (ESI) m/z: 333.0
(M+H).sup.+.
Intermediate 195B:
(5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl)methanol
##STR00927##
[2897] Intermediate 195A (0.010 g, 0.030 mmol) was dissolved in THF
(1 mL). LiBH.sub.4 (1.311 mg, 0.060 mmol) was added and the
reaction mixture was allowed to stir at room temperature for 18 h.
The reaction mixture was diluted with water and EtOAc. The layers
were separated and the organic layer was washed with brine, dried
with sodium sulfate, and concentrated under reduced pressure to
yield Intermediate 195B. LC-MS: method H, RT=1.07 min, MS (ESI)
m/z: 291.1 (M+H).sup.+. Used without further purification in the
next step.
Example 195
[2898] Intermediate 195B (0.0087 g, 0.030 mmol), Cs.sub.2CO.sub.3
(0.024 g, 0.075 mmol), and MeI (1.874 .mu.l, 0.030 mmol) were
dissolved in DMF (1 mL) and allowed to stir at 50.degree. C. for
over the weekend. The reaction mixture was diluted with water and
EtOAc. The aqueous layer was back extracted with EtOAc and the
combined organic layer was washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure. The reaction
mixture was diluted with DMF, filtered, and purified by preparative
HPLC (Method D, 45% to 80% B in 20 minutes) to yield Example 195
(0.0006 g, 1.932 .mu.mol, 6.45% yield): .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 9.05 (s, 1H), 8.34 (d, J=1.7 Hz, 1H),
8.15 (d, J=0.8 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 7.68 (d, J=7.4 Hz,
1H), 7.58-7.55 (m, 1H), 7.33 (td, J=7.7, 1.1 Hz, 1H), 7.28-7.22 (m,
1H), 4.82 (s, 2H), 3.58 (s, 3H), 2.68 (s, 3H). LC-MS: method H,
RT=1.17 min, MS (ESI) m/z: 305.3 (M+H).sup.+. Analytical HPLC
Method B: 99% purity.
Example 196
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-
-yl)oxy)ethyl pyridin-3-ylcarbamate
##STR00928##
[2899] Intermediate 196A:
2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR00929##
[2901] Example 193A (0.050 g, 0.146 mmol) was dissolved in DMF.
2-Bromomethyl acetate (0.058 g, 0.350 mmol) and Cs.sub.2CO.sub.3
(0.237 g, 0.729 mmol) were added and the reaction mixture was
stirred at 40.degree. C. for 18 h. The reaction mixture was diluted
with EtOAc and water. The layers were separated. The organic layer
was washed with brine dried with sodium sulfate, and concentrated
under reduced pressure. The reaction mixture was purified on ISCO
using a 24 g column with a 0-100% EtOAc in hexanes gradient to
yield Intermediate 196A (0.044 g, 0.165 mmol, 56.5% yield) as a
pale yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
6.53-6.53 (m, 1H), 5.01 (br. s., 2H), 4.52-4.48 (m, 2H), 4.44-4.39
(m, 2H), 2.49 (d, J=0.7 Hz, 3H), 2.09 (s, 3H). LC-MS: method H,
RT=0.72 min, MS (ESI) m/z: 268.2 (M+H).sup.+.
Intermediate 196B:
2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR00930##
[2903] Copper(II) bromide (0.063 g, 0.280 mmol) and t-butyl nitrite
(0.033 mL, 0.280 mmol) were dissolved in MeCN (0.658 mL) and
allowed to stir 10 minutes. Intermediate 196A (0.044 g, 0.165 mmol)
was dissolved in MeCN (0.988 mL) and the copper solution was added.
The reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to yield Intermediate 196B
(0.046 g, 0.139 mmol, 84% yield): .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.69 (d, J=0.9 Hz, 1H), 4.57-4.53 (m, 2H),
4.44-4.41 (m, 2H), 2.63 (d, J=0.9 Hz, 3H), 2.09 (s, 3H). LC-MS:
method H, RT=1.07 min, MS (ESI) m/z: 331.0 (M+H).sup.+.
Intermediate 196C:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl acetate
##STR00931##
[2905] Intermediate I-9 (0.042 g, 0.140 mmol) and Intermediate 196B
(0.046 g, 0.140 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (6.86 mg, 8.40 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
mL, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was purified on ISCO using 24
g column with a 0-100% EtOAc in hexanes gradient to yield
Intermediate 196C (0.021 g, 0.049 mmol, 35.4% yield) as an off
white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.60 (d,
J=2.0 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H), 6.74 (s, 1H), 4.63 (dd,
J=5.8, 3.6 Hz, 2H), 4.51-4.43 (m, 2H), 4.13 (s, 3H), 2.79 (s, 3H),
2.66 (s, 3H), 2.11 (s, 3H). LC-MS: method H, RT=1.34 min, MS (ESI)
m/z: 425.1 (M+H).sup.+.
Intermediate 196D:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethanol
##STR00932##
[2907] To a suspension of Intermediate 196C (0.143 g, 0.337 mmol)
in THF (3 mL) and MeOH (1 mL) was added NaOH (1.011 mL, 1.011 mmol)
at room temperature. The mixture was stirred at room temperature
for 1 h. The mixture was diluted by EtOAc and 1N HCl, extracted by
EtOAc, the combined organic layer was washed by water and brine and
dried by sodium sulfate, and concentrated to yield Intermediate
196D (0.120 g, 0.314 mmol, 93% yield) as a tan solid. .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.61 (s, 1H), 8.58 (s, 1H),
7.78 (s, 1H), 6.82 (s, 1H), 4.48-4.45 (m, 2H), 4.40-4.36 (m, 1H),
4.13 (s, 3H), 3.94-3.90 (m, 2H), 2.77 (s, 3H), 2.66 (s, 3H). LC-MS:
method H, RT=1.15 min, MS (ESI) m/z: 383.9 (M+H).sup.+.
Intermediate 196E:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl carbonochloridate
##STR00933##
[2909] To a solution of Intermediate 196D (0.025 g, 0.065 mmol) in
THF (3 mL) at room temperature was added 15% phosgene in toluene
(0.231 mL, 0.327 mmol) and the mixture was stirred at room
temperature for 1 h. The reaction mixture was concentrated under
vacuum to give Intermediate 196E (0.030 g, 0.067 mmol, 100% yield)
as an yellow solid. It was used for the next step without any
purification. LC-MS: method H, RT=1.35 min, MS (ESI) m/z: 444.7
(M+H).sup.+.
Example 196
[2910] To a solution of Intermediate 196E (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added pyridin-3-amine (14.81 mg,
0.157 mmol) followed by DIEA (0.079 mL, 0.450 mmol). The mixture
was stirred at room temperature for 1 h. The reaction mixture was
diluted with EtOAc and water. The combined organic layer was washed
by brine and concentrated under vacuum. The reaction mixture was
diluted with DMSO, filtered, and purified by preparative HPLC
(Method D, 55% to 100% B in 20 minutes) to yield Example 196 (0.003
g, 5.61 .mu.mol, 12.48% yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.05 (br. s., 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.56 (d,
J=1.4 Hz, 1H), 8.22 (d, J=4.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.84
(s, 1H), 7.34 (dd, J=8.3, 4.7 Hz, 1H), 6.93 (s, 1H), 4.67-4.63 (m,
2H), 4.55-4.48 (m, 2H), 4.09 (s, 3H), 2.75 (s, 3H), 2.65 (s, 3H).
LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 503.9 (M+H).sup.+.
Analytical HPLC Method B: 94% purity.
Example 197
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-
-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate
##STR00934##
[2912] To a solution of Intermediate 196E (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added 5-aminopicolinonitrile (18.74
mg, 0.157 mmol) followed by DIEA (0.079 mL, 0.450 mmol). The
mixture was stirred at room temperature for 0.5 h. The reaction
mixture was allowed to stir for 18 h at 40.degree. C. The reaction
mixture was diluted with EtOAc and water. The combined organic
layer was washed by brine and concentrated under vacuum. The
reaction mixture was diluted with DMSO, filtered, and purified by
preparative HPLC (Method D, 50% to 85% B in 20 minutes) to yield
Example 197 (3.2 mg, 5.88 .mu.mol, 13% yield): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.57 (s, 1H), 8.73 (d, J=2.2 Hz, 1H),
8.71 (s, 1H), 8.55 (s, 1H), 8.11 (dd, J=8.7, 2.3 Hz, 1H), 7.98 (d,
J=8.5 Hz, 1H), 7.84 (s, 1H), 6.92 (s, 1H), 4.71-4.66 (m, 2H),
4.58-4.53 (m, 2H), 4.09 (s, 3H), 2.74 (s, 3H), 2.65 (s, 3H). LC-MS:
method H, RT=1.24 min, MS (ESI) m/z: 527.8 (M+H).sup.+. Analytical
HPLC Method B: 97% purity.
Example 198
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-
-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate
##STR00935##
[2913] Intermediate 198A:
2-amino-6-fluorothiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
##STR00936##
[2915] Intermediate I-17 (0.500 g, 2.510 mmol) was dissolved HBr in
acetic acid (1.704 mL, 15.06 mmol), and the reaction was stirred at
130.degree. C. for 3 h. The reaction was concentrated under reduced
pressure to yield Intermediate 198A (0.422 g, 1.216 mmol, 48.5%
yield) as a tan solid. .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.67 (d, J=9.7 Hz, 1H). LC-MS: method H, RT=0.44 min, MS
(ESI) m/z: 186.1 (M+H).sup.+.
Intermediate 198B:
2-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR00937##
[2917] Intermediate 198A (0.100 g, 0.288 mmol) was dissolved in DMF
(2.88 ml) and Cs.sub.2CO.sub.3 (0.376 g, 1.153 mmol) was added
followed by 2-bromoethyl acetate (0.058 g, 0.346 mmol). The
reaction was stirred at room temperature for 3 h. Reaction was
diluted with water and EtOAc. The layers were separated, and the
aqueous layer was washed with EtOAc thrice. The combined organic
layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate 198B
(0.079 g, 0.291 mmol, 101% yield) as a brown solid. Will be used
without further purification in the next step. (0.079 g, 0.291
mmol, 100% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d.sub.6)
.delta. 7.46 (d, J=10.6 Hz, 1H), 4.65-4.54 (m, 2H), 4.49-4.43 (m,
2H), 2.10 (s, 4H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z:
272.1 (M+H).sup.+.
Intermediate 198C:
2-((2-bromo-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR00938##
[2919] Copper(II) bromide (0.078 g, 0.347 mmol) and t-butyl nitrite
(0.041 ml, 0.347 mmol) were dissolved in MeCN (0.818 ml) and
allowed to stir for 10 minutes. Intermediate 198B (0.080 g, 0.204
mmol) was dissolved in MeCN (1.226 ml), and the copper solution was
added. The reaction was stirred for 1 h. The reaction was diluted
with EtOAc, washed with 1 N HCl, washed with saturated NaHCO.sub.3,
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to yield Intermediate 198C (0.069 g, 0.206
mmol, 100%). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.89 (d,
J=9.7 Hz, 1H), 4.69-4.65 (m, 2H), 4.51-4.46 (m, 2H), 2.10 (s, 3H).
LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 335.0 (M+H).sup.+.
Intermediate 198D:
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl acetate
##STR00939##
[2921] Intermediate I-9 (0.062 g, 0.206 mmol) and Intermediate 198C
(0.069 g, 0.206 mmol) were dissolved in DMF (1 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (10.09 mg, 0.012 mmol) was
added, and the reaction was degassed by bubbling with argon for 15
minutes. A 3 M aqueous solution of Na.sub.2CO.sub.3 (0.100 ml,
0.300 mmol) was added, and the reaction was degassed for 5 minutes.
The reaction vessel was sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction was filtered and purified on
ISCO using 24 g column with a 0-100% EtOAc in hexanes gradient to
yield Intermediate 198D (0.069 g, 0.161 mmol, 78% yield) as an off
white solid. LC-MS: method H, RT=0.55 min, MS (ESI) m/z: 429.1
(M+H).sup.+.
Intermediate 198E:
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethanol
##STR00940##
[2923] To a suspension of Intermediate 198D (0.021 g, 0.049 mmol)
in THF (1 mL) and MeOH (0.333 mL) was added NaOH (0.147 mL, 0.147
mmol) at room temperature. The mixture was stirred for 1 h. The
mixture was diluted with EtOAc and 1N HCl. The layers were
separated, and the aqueous layer was back extracted with EtOAc. The
combined organic layer was washed with water, washed with brine,
dried with Na.sub.2SO.sub.4, and concentrated under reduced
pressure to yield Intermediate 198E (0.020 g, 0.052 mmol, 106%
yield) as a white solid. Will be used without further purification
in the next step. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.58
(d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.01 (d, J=10.1 Hz, 1H), 7.79-7.77
(m, 1H), 4.71-4.63 (m, 2H), 4.13 (s, 3H), 4.08 (d, J=7.5 Hz, 2H),
2.65 (s, 3H). LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 387.1
(M+H).sup.+.
Intermediate 198F:
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl carbonochloridate
##STR00941##
[2925] To a solution of Intermediate 198E (0.025 g, 0.065 mmol) in
THF (3 mL) at room temperature was added 15% phosgene in toluene
(0.228 mL, 0.323 mmol), and the mixture was stirred at room
temperature for 2 h. Solvent was completely removed and the sample
was under vacuum overnight to yield Intermediate 198F (0.029 g,
0.065 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.30
min, MS (ESI) m/z: 448.6 (M+H).sup.+.
Example 198
[2926] To a solution of Intermediate 198F (15 mg, 0.033 mmol) in
DCM (1 mL) and THF (0.5 mL) was added 5-aminopicolinonitrile (13.93
mg, 0.117 mmol) followed by DIEA (0.058 mL, 0.334 mmol). The
mixture was stirred at room temperature for 1 h. The reaction
mixture was quenched with 0.2 mL of MeOH. The reaction mixture was
concentrated. The reaction mixture was diluted with DMSO, filtered,
and purified by preparative HPLC (Method D, 55% to 85% B in 20
minutes) to yield Example 198 (4.6 mg, 8.22 .mu.mol, 24.60% yield):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.56 (br. s., 1H),
8.72 (d, J=8.8 Hz, 2H), 8.56 (br. s., 1H), 8.50 (d, J=11.3 Hz, 1H),
8.11 (d, J=8.0 Hz, 1H), 7.96-7.94 (m, 1H), 7.88 (br. s., 1H), 4.82
(br. s., 2H), 4.61 (br. s., 2H), 4.10 (br. s., 3H), 2.65 (br. s.,
3H). LC-MS: method H, RT=1.16 min, MS (ESI) m/z: 532.1 (M+H).sup.+.
Analytical HPLC Method B: 95% purity.
Example 199
N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)-
oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00942##
[2928] In a vial charged with a stirring bar, Intermediate I-28
(130 mg, 0.406 mmol) and Intermediate I-5 (235 mg, 0.527 mmol) were
dissolved in 1,4-dioxane (8 mL). Na.sub.2CO.sub.3 (6 mL, 12.00
mmol) was added, followed by PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (16.56 mg, 0.020 mmol). The mixture was stirred at
100.degree. C. for 1 hour. After cooling to room temperature, the
reaction mixture was diluted by adding 30 mL of EtOAc and 20 mL of
water. After separation, the aqueous layer was extracted with 20 mL
of EtOAc. Then organic phases were combined, washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified by flash chromatography (40 g silica gel column, 0-100%
EtOAc/Hexane) to give Example 199 as a yellow solid (203 mg, 90%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.59 (d,
J=2.2 Hz, 1H), 8.03 (br s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.90 (dd,
J=8.8, 5.2 Hz, 2H), 7.48-7.39 (m, 3H), 6.85 (d, J=1.4 Hz, 1H), 4.07
(s, 3H), 4.04 (s, 2H), 3.22 (br s, 2H), 2.70 (s, 3H); LC-MS: method
J, RT=1.27 min, MS (ESI) m/z: 559.1 (M+H).sup.+.
Examples 200 to 225
[2929] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
199 and the examples above.
TABLE-US-00003 LCMS LCMS Ex. [M + H].sup.+ RT (Min)/ No. Structure
m/z Method NMR 200 ##STR00943## 573.2 1.15/J .sup.1H NMR (500 MHz,
chloroform-d) .delta. 9.14 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.14
(d, J = 2.2 Hz, 1H), 7.97- 7.90 (m, 2H), 7.20 (t, J = 8.5 Hz, 2H),
7.16 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 4.98 (t, J =
6.3 Hz, 1H), 4.86 (s, 2H), 4.11 (t, J = 5.2 Hz, 2H), 3.60 (s, 3H),
3.45 (d, J = 5.5 Hz, 2H), 2.83 (s, 3H). 201 ##STR00944## 386.1
1.29/H .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.18 (s, 1H),
8.84 (s, 1H), 8.32 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.77 (br s,
1H), 7.19 (d, J = 8.8 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s,
3H). 202 ##STR00945## 372.10 2.19/L .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.18 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H),
8.05 (d, J = 9.1 Hz, 1H), 7.77 (br s, 1H), 7.19 (d, J = 8.8 Hz,
1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H). 203 ##STR00946##
436.15 2.882/L .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.22 (s,
1H), 8.82 (br s, 1H), 8.20 (br s, 1H), 7.59 (br s, 1H), 7.04 (br s,
1H), 4.86 (s, 2H), 3.87 (d, J = 1.1 Hz, 3H), 3.50 (s, 3H), 2.76 (s,
3H). 204 ##STR00947## 410.2 2.434/L .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.38 (d, J = 1.9 Hz, 1H), 9.26 (s, 1H), 8.68
(d, J = 1.9 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.03 (s, 1H), 4.86
(s, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 3.50 (s, 3H), 2.76 (s, 3H).
205 ##STR00948## 597.15 2.323/L .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.34 (d, J = 1.7 Hz, 1H), 9.23 (s, 1H), 8.65 (d, J = 1.9
Hz, 1H), 8.04 (br s, 1H), 7.94-7.85 (m, 2H), 7.50-7.38 (m, 3H),
6.88 (s, 1H), 4.85 (s, 2H), 4.06 (t, J = 5.1 Hz, 2H), 4.02 (s, 3H),
3.49 (s, 3H), 3.23 (t, J = 5.0 Hz, 2H), 2.74 (s, 3H). 206
##STR00949## 370.2 1.23/J .sup.1H NMR (400 MHz, chloroform-d)
.delta. 9.12 (s, 1H), 8.85 (dd, J = 9.9, 2.9 Hz, 1H), 7.78 (dd, J =
8.6, 2.9 Hz, 1H), 6.96 (d, J = 1.3 Hz, 1H), 4.86 (s, 2H), 3.91 (s,
3H), 3.60 (s, 3H), 2.83 (s, 3H). 207 ##STR00950## 557.2 1.12/J
.sup.1H NMR (400 MHz, chloroform-d) .delta. 9.12 (s, 1H), 8.85 (dd,
J = 9.7, 2.9 Hz, 1H), 7.99-7.88 (m, 2H), 7.79 (dd, J = 8.4, 2.9 Hz,
1H), 7.24-7.15 (m, 3H), 6.86 (s, 1H), 4.99 (t, J = 5.8 Hz, 1H),
4.86 (s, 2H), 4.11 (t, J = 5.0 Hz, 2H), 3.60 (s, 3H), 3.45 (q, J =
5.5 Hz, 2H), 2.85-2.79 (m, 3H). 208 ##STR00951## 420.05 2.74/L
.sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 9.22 (s, 1H), 9.13
(d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 6.92
(s, 1H), 4.86 (s, 2H), 3.88 (s, 3H), 3.59 (s, 3H), 2.78 (s, 3H).
209 ##STR00952## 629.05 (M + Na).sup.+ 2.625/L .sup.1H NMR (500
MHz, METHANOL-d.sub.4) .delta. 9.23 (s, 1H), 9.13 (d, J = 1.5 Hz,
1H), 8.40 (s, 1H), 7.94-7.87 (m, 2H), 7.26-7.09 (m, 3H), 6.82 (s,
1H), 4.87 (s, 2H), 4.06 (t, J = 5.4 Hz, 2H), 3.59 (s, 3H), 3.35 (t,
J = 5.4 Hz, 2H), 2.77 (s, 3H). 210 ##STR00953## 406.1 1.23/H
.sup.1H NMR (400 MHz, chloroform-d) .delta. 9.14 (s, 1H), 9.08 (d,
J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz,
1H), 7.21 (d, J = 2.4 Hz, 1H), 4.86 (s, 2H), 3.93 (s, 3H), 3.60 (s,
3H). 211 ##STR00954## 363.0 2.633/L .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.97 (br s, 1H), 8.94 (s, 1H), 8.54 (br s,
1H), 7.58 (br s, 1H), 7.05 (br s, 1H), 4.14 (br s, 3H), 3.87 (br s,
3H), 2.78 (br s, 3H). 212 ##STR00955## 372.0 1.06/J .sup.1H NMR
(400 MHz, chloroform-d) .delta. 9.17 (s, 1H), 9.14 (dd, J = 7.5,
1.3 Hz, 1H), 8.20 (dd, J = 8.1, 1.3 Hz, 1H), 7.95 (t, J = 7.9 Hz,
1H), 7.35 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.88 (s,
2H), 3.93 (s, 3H), 3.60 (s, 3H). 213 ##STR00956## 539.20 2.542/L
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.16 (br s, 1H),
9.01-8.94 (m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.06 (br s, 2H), 7.90
(br s, 2H), 7.49-7.38 (m, 3H), 6.86 (br s, 1H), 4.83 (br s, 2H),
4.05 (br s, 2H), 3.47 (br s, 3H), 3.22 (br s, 2H), 2.73 (br s, 3H).
214 ##STR00957## 393.6 1.23/J .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.86 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 7.96 (d, J = 2.4
Hz, 1H), 7.24 (dd, J = 6.7, 1.9 Hz, 1H), 4.15 (s, 3H), 4.02 (s,
3H); .sup.19F NMR (376 MHz, chloroform-d) .delta. -146.29 (d, J =
18.3 Hz, 1F), -160.18 (dd, J = 18.3, 6.9 Hz, 1F). 215 ##STR00958##
410.0 1.45/J .sup.1H NMR (400 MHz, Dioxane) .delta. 8.85 (d, J =
2.4 Hz, 1H), 8.63 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.54 (d, J =
7.5 Hz, 1H), 4.11 (s, 3H), 3.97 (s, 3H); .sup.19F NMR (376 MHz,
dioxane) .delta. -136.60 (s, 1F). 216 ##STR00959## 404.05 2.289/L
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.47 (s, 1H), 8.03 (d,
J = 7.4 Hz, 1H), 7.90 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 2.54 (s,
3H), 2.29 (s, 3H). 217 ##STR00960## 385.10 2.341/K .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.99 (s, 1H), 8.59 (s,
1H), 6.86 (d, J = 7.7 Hz, 1H), 3.99 (s, 3H), 3.25 (br s, 3H). 218
##STR00961## 406.05 2.049/L .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.74 (br s, 2H), 8.01-7.89 (m, 2H), 5.66 (br s, 1H), 4.83
(br s, 2H), 4.09 (br s, 3H), 3.97 (br s, 3H). 219 ##STR00962##
382.15 2.228/L .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (br
s, 2H), 7.91 (br s, 1H), 7.55 (br s, 1H), 5.63 (d, J = 3.9 Hz, 1H),
4.85 (br s, 2H), 4.11 (br s, 3H), 3.91 (br s, 3H), 2.76 (br s, 3H),
2.26 (br s, 3H). 220 ##STR00963## 390.15 1.957/L .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.70 (br s, 2H), 7.90 (br s, 1H), 7.76
(br s, 1H), 5.66 (br s, 1H), 4.83 (br s, 2H), 4.10 (br s, 3H), 3.98
(br s, 3H). 221 ##STR00964## 367.10 2.234/L .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.98 (s, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.55
(d, J = 1.9 Hz, 1H), 8.05-7.98 (m, 2H), 4.13 (s, 3H), 3.97 (s, 3H).
222 ##STR00965## 372.10 1.851/L .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.77 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.01-7.88 (m, 3H),
5.62 (t, J = 5.8 Hz, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.09 (s, 3H),
3.96 (s, 3H). 223 ##STR00966## 369.15 2.010/L .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.68 (s, 1H), 7.91 (s, 1H),
6.87 (s, 1H), 5.62 (t, J = 5.8 Hz, 1H), 4.82 (d, J = 5.5 Hz, 2H),
4.09 (s, 3H), 3.95 (s, 3H), 2.72 (s, 3H). 224 ##STR00967## 424.15
2.106/L .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.87 (s, 1H),
8.61 (s, 1H), 6.21 (s, 1H), 4.87 (d, J = 5.8 Hz, 2H), 4.12 (s, 3H),
3.98 (s, 3H).
Example 225
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-
-(methoxymethyl)quinoxaline-6-carboxamide
##STR00968##
[2930] Intermediate 225A:
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)--
3-(methoxymethyl)quinoxaline-6-carboxylic acid
##STR00969##
[2932] Example 205 (223 mg, 0.374 mmol) was dissolved in THF (10
mL) and water (10 mL). The mixture was treated with LiOH.H2O (31.4
mg, 0.748 mmol) at 40.degree. C. for 1 hour. After cooling to room
temperature, the reaction mixture was diluted by adding 30 mL of
EtOAc and 10 ml of water, followed by 2 mL of 1N HCl (aq.). After
shaking and separation, the organic phase was washed with 10 mL of
brine and dried over Na.sub.2SO.sub.4. Concentration gave the
desired product as a white solid (145 mg, 63.9%). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.40 (s, 1H), 9.21 (s, 1H), 8.63 (s,
1H), 8.04 (t, J=5.4 Hz, 1H), 7.90 (dd, 5.4 Hz, 2H), 7.51-7.35 (m,
3H), 6.86 (s, 1H), 4.85 (s, 2H), 4.05 (t, J=5.0 Hz, 2H), 3.48 (br
s, 3H), 3.22 (d, J=5.0 Hz, 2H), 2.74 (s, 3H); LC-MS: method L,
RT=1.939 min, MS (ESI) m/z: 583.15 (M+H).sup.+.
Example 225
[2933] Intermediate 225A (30 mg, 0.051 mmol) was dissolved in DMF
(1 mL). NH.sub.4Cl (8.26 mg, 0.154 mmol) was added, followed by
HATU (23.49 mg, 0.062 mmol) and DIEA (0.027 mL, 0.154 mmol). The
mixture was stirred at room temperature for 3 h. LCMS showed
starting material remained. Another 3 equivalents of DIEA and
NH.sub.4Cl and 1 equivalents of HATU were added. The reaction
mixture was stirred at room temperature for an additional 2 h. The
crude material was purified via preparative LC with condition D and
dried via centrifugal evaporation to yield the desired product (5.5
mg, 0.0095 mmol, 18.4%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.38 (d, J=1.4 Hz, 1H), 9.22 (s, 1H), 8.74 (d, J=1.7 Hz,
1H), 8.50 (br s, 1H), 8.02 (br s, 1H), 7.90 (dd, J=8.5, 5.2 Hz,
2H), 7.82 (br s, 1H), 7.47 (s, 1H), 7.43 (t, J=8.8 Hz, 2H), 6.88
(s, 1H), 4.86 (s, 2H), 4.06 (t, J=5.2 Hz, 2H), 3.49 (s, 3H),
3.27-3.16 (m, 2H), 2.76 (s, 3H); LC-MS: method L, RT=1.80 min, MS
(ESI) m/z: 582.15 (M+H).sup.+.
Examples 226 to 228
[2934] The following additional examples were prepared, isolated
and characterized using the methods described above for Example
225.
Example 226
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-
-(methoxymethyl)-N,N-dimethylquinoxaline-6-carboxamide
##STR00970##
[2936] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (d, J=1.4
Hz, 1H), 9.22 (s, 1H), 8.74 (d, J=1.7 Hz, 1H), 8.50 (br s, 1H),
8.02 (br s, 1H), 7.90 (dd, 5.2 Hz, 2H), 7.82 (br s, 1H), 7.47 (s,
1H), 7.43 (t, J=8.8 Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06 (t,
J=5.2 Hz, 2H), 3.49 (s, 3H), 3.27-3.16 (m, 2H), 2.76 (s, 3H);
LC-MS: method L, RT=1.80 min, MS (ESI) m/z: 582.15 (M+H).sup.+.
Example 227
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(piperidine-1-carbonyl)quinoxalin-5-
-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00971##
[2938] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.19 (s, 1H),
8.88 (d, J=1.4 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.03 (br s, 1H),
7.90 (dd, 5.2 Hz, 2H), 7.47 (s, 1H), 7.43 (t, J=8.8 Hz, 2H), 6.87
(s, 1H), 4.84 (s, 2H), 4.10-4.02 (m, 2H), 3.71 (br s, 2H), 3.48 (s,
3H), 3.42 (br s, 2H), 3.22 (br s, 2H), 2.72 (br s, 3H), 1.66 (br s,
4H), 1.54 (br s, 2H); LC-MS: method L, RT=2.27 min, MS (ESI) m/z:
650.25 (M+H).sup.+.
Example 228
8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-N-
-(2-methoxyethyl)-3-(methoxymethyl)quinoxaline-6-carboxamide
##STR00972##
[2940] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (d, J=1.7
Hz, 1H), 9.22 (s, 1H), 9.08 (br s, 1H), 8.71 (d, J=1.7 Hz, 1H),
8.03 (br s, 1H), 7.93-7.87 (m, 2H), 7.48 (s, 1H), 7.42 (t, J=8.8
Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06 (t, J=5.0 Hz, 2H), 3.55
(br s, 5H), 3.49 (s, 3H), 3.31 (s, 2H), 3.26-3.19 (m, 2H), 2.76 (s,
3H); LC-MS: method L, RT=1.92 min, MS (ESI) m/z: 640.20
(M+H).sup.+.
Example 229
4-fluoro-N-(2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiaz-
ol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00973##
[2942] To a vial charged with a stirring bar was added Example 199
(20 mg, 0.036 mmol), potassium vinyl trifluoroborate (9.58 mg,
0.072 mmol), Cs.sub.2CO.sub.3 (35.0 mg, 0.107 mmol), (S)-BINAP
(4.46 mg, 7.16 .mu.mol) and PdOAc.sub.2 (0.803 mg, 3.58 .mu.mol).
DMF (1 mL) was added. After degassing with bubbling N.sub.2 for 10
minutes, the vial was sealed and was heated at 120.degree. C. for 1
hour. After cooling to room temperature, the reaction mixture was
diluted by adding 10 mL of EtOAc and 10 mL of water. After
separation, the organic phase was passed through anhydrous
Na.sub.2SO.sub.4 and concentrated on a rotary evaporator. The crude
material was purified via preparative LC/MS (method C) and dried
via centrifugal evaporation to yield the Example 229 (1.9 mg,
0.0034 mmol, 9.6%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.82 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 8.05 (d, J=1.7 Hz, 1H), 8.03
(br s, 1H), 7.97-7.83 (m, 2H), 7.49-7.38 (m, 3H), 7.08 (dd, J=17.6,
11.0 Hz, 1H), 6.86 (d, J=1.4 Hz, 1H), 6.19 (d, J=17.9 Hz, 1H), 5.57
(d, J=11.0 Hz, 1H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (br
s, 2H), 2.74 (s, 3H);); LC-MS: method K, RT=2.59 min, MS (ESI) m/z:
559.1 (M+H).sup.+.
Example 230
N-(2-((2-(7-ethynyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl-
)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00974##
[2943] Intermediate 230A:
4-fluoro-N-(2-((2-(2-methoxy-7-((trimethylsilyl)ethynyl)quinoxalin-5-yl)--
4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00975##
[2945] In a microwave vial charged with a stirring bar, a solution
of Example 199 (20 mg, 0.036 mmol),
PdCl.sub.2(CH.sub.3CN).sub.2(1.856 mg, 7.16 mol),
2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (6.82 mg,
0.014 mmol) and Cs.sub.2CO.sub.3 (29.1 mg, 0.089 mmol) in
acetonitrile (1 mL)) was stirred for 0.5 h at room temperature
under N.sub.2 atmosphere. To the mixture was added
ethynyltrimethylsilane (35.1 mg, 0.358 mmol), and the resultant
mixture was stirred for 1 hour at 90.degree. C. in the microwave.
The reaction mixture was concentrated under reduced pressure, and
the resulting residue was purified by flash chromatography (24 g
silica gel column, 0-50% EtOAc/Hexane gradient) to give
Intermediate 230A as a yellow solid (13.6 mg, 61.2%). LC-MS: method
B, RT=3.0 min, MS (ESI) m/z: 621.1 (M+H).sup.+.
Example 230
[2946] Intermediate 230A (10 mg, 0.016 mmol) was dissolved in MeOH
(0.5 mL)/DCM (0.5 mL) and was treated with K.sub.2CO.sub.3 (1.113
mg, 8.05 .mu.mol) for 1 hour. The solid was filtered and solvent
was removed on a rotary evaporator. The crude material was purified
via preparative LC/MS (method C) and dried via centrifugal
evaporation to yield the title compound (1.4 mg, 0.0025 mmol, 16%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.80 (s, 1H), 8.70 (d,
J=1.7 Hz, 1H), 8.02 (d, J=1.7 Hz, 2H), 7.90 (dd, 5.4 Hz, 2H),
7.47-7.38 (m, 3H), 6.86 (s, 1H), 4.58 (s, 1H), 4.09 (s, 3H), 4.05
(t, J=5.2 Hz, 2H), 3.22 (d, J=5.2 Hz, 2H), 2.72 (s, 3H); LC-MS:
method L, RT=2.58 min, MS (ESI) m/z: 549.15 (M+H).sup.+.
Example 231
N-(2-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)o-
xy)ethyl)-4-fluorobenzenesulfonamide
##STR00976##
[2948] Example 199 (40 mg, 0.072 mmol), Pd.sub.2(dba).sub.3 (19.66
mg, 0.021 mmol), DPPF (23.80 mg, 0.043 mmol), dicyanozinc (8.40 mg,
0.072 mmol) and zinc (7.02 mg, 0.107 mmol) were mixed in NMP (1 mL)
in a microwave vial that was flushed with N.sub.2 for 10 minutes.
The resulting mixture was heated at 120.degree. C. with vigorous
stirring until LCMS showed the disappearance of starting material
(3 h). The mixture was cooled to room temperature, diluted with
ethyl acetate (50 ml), and then washed with water and brine. After
drying over Na.sub.2SO.sub.4, the ethyl acetate solution was
concentrated by rotary evaporation. The crude material was purified
via preparative LC/MS-HPLC, method D and dried via centrifugal
evaporation to give Example 231 (7.4 mg, 0.013 mmol, 18.8%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.92 (s, 1H), 8.87 (d,
J=1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H), 7.90 (dd, J=8.5, 5.5 Hz,
3H), 7.45-7.39 (m, 3H), 6.87 (s, 1H), 4.11 (s, 3H), 4.05 (t, J=5.1
Hz, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.72 (s, 3H); LC-MS: method L,
RT=2.205 min, MS (ESI) m/z: 550.10 (M+H).sup.+.
Examples 232 and 233
[2949] Examples 232 and 233 were prepared, isolated and
characterized using the methods described in Example 231 above.
Example 232
N-(2-((2-(7-cyano-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00977##
[2951] Example 232 was made from Example 200. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.24 (s, 1H), 9.02 (d, J=1.7 Hz, 1H), 8.77
(d, J=1.7 Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 3H), 7.44 (d, J=9.1 Hz,
2H), 6.86 (d, J=1.1 Hz, 1H), 4.84 (s, 2H), 4.05 (t, J=5.2 Hz, 2H),
3.49 (s, 3H), 3.23 (t, J=5.1 Hz, 2H), 2.72 (s, 3H); LC-MS: method
L, RT=2.074 min, MS (ESI) m/z: 564.15 (M+H).sup.+.
Example 233
8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6--
carbonitrile
##STR00978##
[2953] Example 233 was made from Example 201. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 9.28 (s, 1H), 9.25 (d, J=2.0 Hz, 1H), 8.48
(d, J=1.8 Hz, 1H), 7.28-7.27 (m, 1H), 6.99 (dd, J=2.6, 0.9 Hz, 1H),
4.90 (s, 2H), 3.93 (s, 3H), 3.63 (s, 3H), 2.04 (s, 3H); LC-MS:
method J, RT=1.08 min, MS (ESI) m/z: 377.1 (M+H).sup.+.
Example 234
4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-vinylquinoxalin-5-yl)-4-methylbenzo-
[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00979##
[2955] To a vial charged with a stirring bar was added Example 200
(40 mg, 0.070 mmol), potassium vinyl trifluoroborate (18.70 mg,
0.140 mmol), Cs.sub.2CO.sub.3 (68.2 mg, 0.209 mmol), (S)-BINAP
(17.39 mg, 0.028 mmol) and PdOAc.sub.2 (3.13 mg, 0.014 mmol). DMF
(1 mL) was added. After degassing with bubbling N.sub.2 for 10
minutes, the vial was sealed and was heated at 120.degree. C. for 1
hour. After cooling to room temperature, the reaction mixture was
diluted by adding 10 mL of EtOAc and 10 mL of water. After
separation, the organic phase was passed through Na.sub.2SO.sub.4
and concentrated on a rotary evaporator. The crude material was
purified via preparative LC/MS with condition D and dried via
centrifugal evaporation to yield Example 234 (10.6 mg, 0.018 mmol,
25.5%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H),
9.04 (d, J=1.7 Hz, 1H), 8.26 (d, J=1.4 Hz, 1H), 8.04 (br s, 1H),
7.90 (dd, 5.2 Hz, 2H), 7.48-7.39 (m, 3H), 7.13 (dd, J=17.6, 11.0
Hz, 1H), 6.86 (s, 1H), 6.23 (d, J=17.3 Hz, 1H), 5.62 (d, J=11.0 Hz,
1H), 4.81 (s, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.47 (s, 3H), 3.22 (t,
J=5.2 Hz, 2H), 2.75 (s, 3H); LC-MS: method L, RT=2.203 min, MS
(ESI) m/z: 565.15 (M+H).sup.+.
Example 235
4-fluoro-N-(2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylben-
zo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00980##
[2956] Intermediate 235A:
4-fluoro-N-(2-((2-(7-formyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thi-
azol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00981##
[2958] Sodium periodate (0.424 g, 1.983 mmol) was added to a
solution of Example 229 (0.364 g, 0.661 mmol) and osmium(VIII)
oxide (0.084 mL, 0.013 mmol) in THF (10 mL) and water (3 mL). After
6 h, 20 mL of water and 30 mL of EtOAc was added. Phases were
separated, and the aqueous phase was extracted with ethyl acetate
(20 mL) and then the combined organic phases were washed with
sodium thiosulfate solution and brine, dried over sodium sulfate,
filtered and concentrated to give Intermediate 235A (0.319 g, 0.576
mmol, 87.2% yield) as a yellow solid. LC-MS: method J, RT=1.30 min,
MS (ESI) m/z: 553.1 (M+H).sup.+.
Example 235
[2959] Intermediate 235A (16 mg, 0.029 mmol) was dissolved in
1,4-dioxane (1 mL)/MeOH (1 mL) and was treated with NaBH.sub.4
(2.191 mg, 0.058 mmol) at room temperature for 30 minutes. Several
drops of saturated NH.sub.4Cl (aq.) were added to quench the
reaction. The reaction mixture was diluted by adding 15 mL of EtOAc
and 10 mL of water. After separation, the organic phase was washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and solvent was
removed to give crude product. The crude material was purified via
preparative LC/MS with the condition C and dried via centrifugal
evaporation to yield Example 235 (6.3 mg, 0.011 mmol, 39%). .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.73 (s, 1H),
8.03 (t, J=5.8 Hz, 1H), 7.94-7.87 (m, 3H), 7.46-7.39 (m, 3H), 6.86
(s, 1H), 5.61 (t, J=5.8 Hz, 1H), 4.83 (d, J=5.5 Hz, 2H), 4.09 (s,
3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (q, J=5.4 Hz, 2H), 2.73 (s, 3H);
LC-MS: method L, RT=2.046 min, MS (ESI) m/z: 555.15
(M+H).sup.+.
Example 236
N-(2-((2-(7-(1,2-dihydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d-
]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00982##
[2961] Example 229 (7 mg, 0.013 mmol) was suspended in acetone (1
mL)/water (0.3 mL). 4-Methylmorpholine N-oxide (1.787 mg, 0.015
mmol) was added, followed by OsO.sub.4 (1.616 .mu.l, 0.254
.mu.mol). The mixture was stirred at room temperature overnight. On
the next day, solvent was removed on a rotary evaporator and the
residue was dissolved in 5 mL of EtOAc and was washed with 5 mL of
water, dried over Na.sub.2SO.sub.4, filtered and concentrated to
give the crude product. The crude material was purified via
preparative LC/MS with the condition D and dried via centrifugal
evaporation to afford Example 236 (3.9 mg, 0.0064 mmol, 50%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.78 (d, J=1.9 Hz, 1H),
8.76 (s, 1H), 8.03 (br s, 1H), 7.93 (d, J=1.7 Hz, 1H), 7.92-7.87
(m, 2H), 7.46-7.39 (m, 3H), 6.86 (d, J=1.7 Hz, 1H), 5.68 (d, J=3.3
Hz, 1H), 4.87 (br s, 2H), 4.09 (s, 3H), 4.05 (t, J=5.2 Hz, 2H),
3.69-3.56 (m, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.73 (s, 3H); LC-MS:
method L, RT=1.833 min, MS (ESI) m/z: 585.20 (M+H).sup.+.
Example 237
4-fluoro-N-(2-((2-(7-(2-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbe-
nzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00983##
[2963] To a solution of Example 229 (20 mg, 0.036 mmol) in THF (1
mL) under N.sub.2 at 0.degree. C. was added BH.sub.3.THF (0.036 mL,
0.036 mmol) slowly. The reaction mixture was allowed to warm to
room temperature and stir at room temperature for 3 h. The reaction
mixture was cooled in an ice bath, and NaOH (2.91 mg, 0.073 mmol)
in EtOH/H.sub.2O (2:1, 0.6 mL) was added, followed by
H.sub.2O.sub.2 (0.011 mL, 0.109 mmol) dropwise. The mixture was
warmed to room temperature and stirred at room temperature for 18
h. On the next day, a small amount of saturated NH.sub.4Cl (aq.)
was added to quench the reaction. The reaction mixture was diluted
by adding 15 mL EtOAc and 10 mL of water. After separation, the
aqueous layer was passed through anhydrous Na.sub.2SO.sub.4 and
solvent was removed on a rotary evaporator. The crude product was
purified by prep-HPLC with method B and dried on a lyophilizer to
give Example 237 (1.32 mg, 0.002 mmol, 5.9%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.04
(br s, 1H), 7.95-7.86 (m, 3H), 7.48-7.40 (m, 3H), 6.87 (d, J=1.5
Hz, 1H), 4.77 (t, J=5.3 Hz, 1H), 4.10 (s, 3H), 4.06 (t, J=5.3 Hz,
2H), 3.85-3.78 (m, 2H), 3.23 (br s, 2H), 3.07 (t, J=6.6 Hz, 2H),
2.74 (s, 3H); LC-MS: method J, RT=0.83 min, MS (ESI) m/z: 569.1
(M+H).sup.+.
Example 238
N-(2-((2-(7-(aminomethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazo-
l-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00984##
[2964] Intermediate 238A:
N-(2-((2-(7-(((2,4-dimethoxybenzyl)amino)methyl)-2-methoxyquinoxalin-5-yl-
)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00985##
[2966] Intermediate 235A (110 mg, 0.199 mmol) was dissolved in THF
(2 mL) and mixed with (2,4-dimethoxy phenyl) methanamine (133 mg,
0.796 mmol). Acetic acid (0.114 mL, 1.991 mmol) was added and the
reaction mixture was stirred at room temperature for 30 minutes.
Sodium Triacetoxyborohydride (93 mg, 0.438 mmol) was added. The
mixture was stirred at room temperature for 6 h. The reaction
mixture was diluted by adding 30 mL of EtOAc and was washed with
saturated NaHCO.sub.3(aq.) and brine, and concentrated on a rotary
evaporator to give crude product that was purified by flash
chromatography (24 g, 30-100% EtOAc/Hexane in 20 minutes) to give
the title compound (79 mg, 0.092 mmol, 46.2% yield) as a yellow
solid. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.78 (s, 1H),
8.59 (s, 1H), 7.99 (s, 1H), 7.93 (dd, J=8.1, 5.1 Hz, 2H), 7.23-7.17
(m, 3H), 7.15 (s, 1H), 6.82 (s, 1H), 6.49-6.44 (m, 2H), 4.96 (br s,
1H), 4.14 (s, 3H), 4.12-4.05 (m, 5H), 3.87-3.83 (m, 5H), 3.82 (s,
3H), 3.44 (br s, 2H), 2.83 (s, 3H); LC-MS: method H, RT=1.13 min,
MS (ESI) m/z: 704.2 (M+H).sup.+.
Example 238
[2967] Intermediate 238A (76 mg, 0.108 mmol) was dissolved in DCM
(1 mL) and was treated with TFA (1 ml, 12.98 mmol) at room
temperature for 18 h. No product was shown on LCMS. Then mixture
was transferred to a microwave vial and was irradiated at
100.degree. C. for 2 h. Then solvent was removed on a rotary
evaporator, residue was dissolved in small amount of DCM/MeOH and
evaporated. The crude product was purified on prep-HPLC condition D
and dried via centrifugal evaporation to afford Example 238 (24 mg,
0.043 mmol, 40%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.73
(d, J=9.9 Hz, 1H), 7.99 (s, 1H), 7.96-7.86 (m, 2H), 7.48-7.38 (m,
3H), 6.86 (br s, 1H), 4.09 (br s, 3H), 4.06 (d, J=4.4 Hz, 2H),
3.36-3.29 (m, 2H), 3.23 (d, J=4.4 Hz, 2H), 2.74 (s, 2H), 2.52 (br
s, 3H); LC-MS: method L, RT=1.617 min, MS (ESI) m/z: 554.20
(M+H).sup.+.
Example 239
4-fluoro-N-(2-((2-(7-(1-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbe-
nzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00986##
[2969] Intermediate 235A (15 mg, 0.027 mmol) was dissolved in THF
(2 mL) and was treated with CH.sub.3MgBr in ether (0.018 mL, 0.054
mmol) at -78.degree. C. After addition, the mixture was warmed to
room temperature slowly, and a small amount of NH.sub.4Cl (sat.,
aq.) was added to quench the reaction. 10 mL of EtOAc and 5 mL of
water was added to dilute the reaction mixture. After separation,
the organic phase was passed through Na.sub.2SO.sub.4 and solvent
was removed on a rotary evaporator. The crude material was purified
via preparative LC/MS and dried via centrifugal evaporation to
yield Example 239 (1.6 mg, 0.0027 mmol, 10%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.78 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.03
(br s, 1H), 7.94-7.87 (m, 3H), 7.46-7.41 (m, 3H), 6.86 (d, J=1.7
Hz, 1H), 5.58 (d, J=4.1 Hz, 1H), 5.09-5.02 (m, 1H), 4.09 (s, 3H),
4.05 (t, J=5.4 Hz, 2H), 3.22 (t, J=5.4 Hz, 2H), 2.73 (s, 3H), 1.49
(d, J=6.6 Hz, 3H); LC-MS: method K, RT=2.119 min, MS (ESI) m/z:
569.2 (M+H).sup.+.
Example 240
4-fluoro-N-(2-((2-(7-(hydroxy(phenyl)methyl)-2-methoxyquinoxalin-5-yl)-4-m-
ethylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00987##
[2971] Example 240 was made by following the procedure of Example
239. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.83 (d, J=1.9 Hz,
1H), 8.58 (s, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.94-7.89 (m, 2H), 7.51
(d, J=7.4 Hz, 2H), 7.41-7.35 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.19
(t, J=8.5 Hz, 2H), 7.12 (d, J=2.2 Hz, 1H), 6.81 (d, J=1.7 Hz, 1H),
6.14 (d, J=3.3 Hz, 1H), 4.97 (s, 1H), 4.12 (s, 3H), 4.08 (t, J=5.1
Hz, 2H), 3.46-3.40 (m, 2H), 2.79 (s, 3H), 2.51 (d, J=3.6 Hz, 1H);
LC-MS: method L, RT=2.380 min, MS (ESI) m/z: 631.2 (M+H).sup.+.
Example 241
4-fluoro-N-(2-((2-(2-methoxy-7-(prop-1-en-2-yl)quinoxalin-5-yl)-4-methylbe-
nzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00988##
[2973] Example 199 (42.5 mg, 0.076 mmol) was dissolved in
1,4-dioxane (1.5 mL) and mixed with
4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25.6
mg, 0.152 mmol). Na.sub.2CO.sub.3 (1 mL, 2.000 mmol) was added,
followed by PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (6.21 mg, 7.60
.mu.mol). The mixture was stirred in a microwave at 120.degree. C.
for 1 hour. After it cooled to room temperature, the reaction
mixture was diluted by adding 15 mL of EtOAc and 10 mL of water.
After separation, the organic phase was washed with brine and dried
over Na.sub.2SO.sub.4. Removing solvent on a rotary evaporator gave
crude product that was purified by flash chromatography (4 g silica
column, 0-50% EtOAc/Hexane gradient) to give Example 241 (22 mg,
0.035 mmol, 46.6% yield) as a yellow solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.98 (d, J=2.0 Hz, 1H), 8.56 (s, 1H),
8.00-7.90 (m, 3H), 7.24-7.16 (m, 2H), 7.13 (d, J=2.2 Hz, 1H), 6.82
(d, J=1.5 Hz, 1H), 5.75 (s, 1H), 5.36 (s, 1H), 5.03 (t, J=6.1 Hz,
1H), 4.15 (s, 3H), 4.09 (t, J=5.0 Hz, 2H), 3.44 (q, J=5.5 Hz, 2H),
2.82 (s, 3H), 2.35 (s, 3H); LC-MS: method H, RT=1.17 min, MS (ESI)
m/z: 565.1 (M+H).sup.+.
Example 242
4-fluoro-N-(2-((2-(7-(2-hydroxypropan-2-yl)-2-methoxyquinoxalin-5-yl)-4-me-
thylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00989##
[2974] Intermediate 242A:
N-(2-((2-(7-acetyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl-
)oxy)ethyl)-4-fluorobenzenesulfonamide
##STR00990##
[2976] Sodium periodate (22.73 mg, 0.106 mmol) was added into a
solution of Example 241 (20 mg, 0.035 mmol), Osmium tetroxide (5.56
.mu.l, 0.708 .mu.mol) in THF (1 ml) and water (0.3 mL), and stirred
for 6 h. 10 mL of water and 20 mL of EtOAc was added. After
separation, the aqueous layer was extracted with ethyl acetate (10
mL) and then the combined organic phases were washed with sodium
thiosulfate solution and brine, dried over sodium sulfate, filtered
and concentrated to give Intermediate 242A (20.07 mg, 0.035 mmol,
100% yield) as product. LC-MS: method H, RT=1.14 min, MS (ESI) m/z:
566.8 (M+H).sup.+.
Example 242
[2977] Intermediate 242A (20 mg, 0.035 mmol) was dissolved in THF
(2 mL) under N.sub.2 and was cooled to -78.degree. C. CH.sub.3MgBr
(0.047 mL, 0.141 mmol) was added into the reaction mixture slowly.
The mixture was warmed to room temperature slowly, and a small
amount of NH.sub.4Cl (saturated aq.) was added to quench the
reaction. The reaction mixture was diluted by adding 10 mL of EtOAc
and 10 mL of water. After separation, the organic phase was
concentrated, purified via preparative LC/MS with condition D, and
dried via centrifugal evaporation to yield Example 242 (2.4 mg,
0.0038 mmol, 11%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.96
(d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.06 (br s, 1H), 8.00 (d, J=1.9
Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 2H), 7.45-7.40 (m, 3H), 6.85 (d,
J=1.7 Hz, 1H), 5.51 (s, 1H), 4.09 (s, 3H), 4.04 (t, J=5.4 Hz, 2H),
3.21 (t, J=5.1 Hz, 2H), 2.73 (s, 3H), 1.60 (s, 6H); LC-MS: method
L, RT=2.183 min, MS (ESI) m/z: 583.2 (M+H).sup.+.
Example 243
(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-
-yl) methanol
##STR00991##
[2978] Intermediate 243A:
5-fluoro-6-methoxy-2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]t-
hiazole
##STR00992##
[2980] Intermediate 243A was made by following the procedure in
Example 234. LC-MS: method J, RT=1.05 min, MS (ESI) m/z: 382.1
(M+H).sup.+.
Intermediate 243B:
8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxaline--
6-carbaldehyde
##STR00993##
[2982] Intermediate 243B was made by following the procedure in
Intermediate 235A. LC-MS: method J, RT=0.86 min, MS (ESI) m/z:
384.1 (M+H).sup.+.
Example 243
[2983] Example 243 was made by following the procedure in Example
235. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.81 (s, 1H), 8.60
(s, 1H), 7.97 (s, 1H), 7.30 (d, J=7.7 Hz, 1H), 5.02 (d, J=3.0 Hz,
2H), 4.14 (s, 3H), 3.99 (s, 3H), 2.78 (s, 3H), 2.01 (br s, 1H);
LC-MS: method L, RT=2.059 min, MS (ESI) m/z: 386.15
(M+H).sup.+.
Examples 244 to 246
[2984] Examples 244 to 246 were made by following the general
procedure described in Example 239.
Example 244
1-(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-
-6-yl) ethanol
##STR00994##
[2986] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.80 (s, 1H),
8.76 (s, 1H), 7.93 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 5.61 (br s,
1H), 5.06 (br s, 1H), 4.09 (s, 3H), 3.93 (s, 3H), 2.69 (br s, 3H),
1.49 (d, J=5.8 Hz, 3H); LC-MS: method L, RT=2.234 min, MS (ESI)
m/z: 400.15 (M+H).sup.+.
Example 245
(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-
-yl) (phenyl)methanol
##STR00995##
[2988] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.81 (s, 1H),
8.73 (s, 1H), 7.94 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.4
Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.28-7.22 (m, 1H), 6.35 (br s,
1H), 6.06 (br s, 1H), 4.07 (s, 3H), 3.92 (s, 3H), 2.66 (s, 3H);
LC-MS: method L, RT=2.428 min, MS (ESI) m/z: 462.20
(M+H).sup.+.
Example 246
Cyclopropyl(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyq-
uinoxalin-6-yl)methanol
##STR00996##
[2990] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.88 (s, 1H),
8.77 (s, 1H), 7.97 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 5.62 (br s,
1H), 4.31 (br s, 1H), 4.09 (s, 3H), 3.94 (s, 3H), 2.69 (br s, 3H),
1.28-1.11 (m, 1H), 0.59-0.43 (m, 4H); LC-MS: method L, RT=2.324
min, MS (ESI) m/z: 426.15 (M+H).sup.+.
Example 247
4-fluoro-N-(2-((2-(7-fluoro-2-methylquinoxalin-5-yl)-4-methylbenzo[d]thiaz-
ol-6-yl)oxy)ethyl)benzenesulfonamide
##STR00997##
[2992] Example 247 was a side product isolated from the synthesis
of Example 207. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.86
(s, 1H), 8.80 (dd, J=9.8, 3.0 Hz, 1H), 7.99-7.90 (m, 2H), 7.73 (dd,
J=8.5, 3.0 Hz, 1H), 7.21 (t, J=8.6 Hz, 2H), 7.16 (d, J=2.4 Hz, 1H),
6.85 (s, 1H), 5.03-4.96 (m, 1H), 4.11 (t, J=5.0 Hz, 2H), 3.45 (q,
J=5.6 Hz, 2H), 2.84 (s, 3H), 2.82 (s, 3H); LC-MS: method J, RT=1.15
min, MS (ESI) m/z: 527.1 (M+H).sup.+.
Example 248
(8-(5-fluoro-6-isopropoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)me-
thanol
##STR00998##
[2994] Example 248 was prepared from Intermediate I-35 by following
the procedure described in Example 199. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.69 (s, 1H), 8.67 (s, 1H), 7.92 (d, J=3.7
Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 4.72
(dt, J=12.1, 6.0 Hz, 1H), 4.06 (s, 3H), 1.35 (d, J=6.1 Hz, 6H);
LC-MS: method L, RT=2.16 min, MS (ESI) m/z: 399.95 (M+H).sup.+.
Example 249
N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)-
oxy) ethyl)pyridine-3-sulfonamide
##STR00999##
[2995] Intermediate 249A: tert-butyl
(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)o-
xy)ethyl)carbamate
##STR01000##
[2997] Intermediate 249A was made from Intermediate I-28 and
Intermediate I-5D by following the procedure described in Example
199. LC-MS: method J, RT=1.28 min, MS (ESI) m/z: 501.1
(M+H).sup.+.
Intermediate 249B:
2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethanamine, TFA Salt
##STR01001##
[2999] Intermediate 249A (237 mg, 0.473 mmol) was dissolved in DCM
(2 mL) and was treated with TFA (1 mL, 12.98 mmol) at room
temperature for 1 hour. After 1 hour, the solvent was removed on a
rotary evaporator and the residue coevaporated with DCM (3.times.).
The residue was dried in vacuo and the crude product was used in
the next step without further purification. LC-MS: method H,
RT=1.04 min, MS (ESI) m/z: 400.7 (M+H).sup.+.
Example 249
[3000] Intermediate 249B (20 mg, 0.050 mmol) was suspended in DCM
(4 mL). Pyridine-3-sulfonyl chloride hydrochloride (16.02 mg, 0.075
mmol) was added, followed by DIEA (0.035 mL, 0.200 mmol) and the
mixture was stirred at room temperature for 30 minutes. Solvent was
removed and the crude material was purified via preparative LC/MS
with condition C to yield Example 249 (3.5 mg, 0.0064, 13%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.00 (d, J=1.9 Hz, 1H),
8.81 (dd, J=4.8, 1.2 Hz, 1H), 8.77 (s, 1H), 8.61 (d, J=2.2 Hz, 1H),
8.26 (t, J=5.8 Hz, 1H), 8.22 (dt, J=8.3, 1.8 Hz, 1H), 8.01 (d,
J=2.5 Hz, 1H), 7.63 (dd, J=7.8, 4.8 Hz, 1H), 7.41 (d, J=2.5 Hz,
1H), 6.82 (d, J=1.4 Hz, 1H), 4.08 (s, 3H), 4.06 (t, J=5.2 Hz, 2H),
3.29 (m, 2H), 2.70 (s, 3H); LC-MS: method L, RT=2.554 min, MS (ESI)
m/z: 542.15 (M+H).sup.+.
Example 250
Ethyl
2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6--
yl)oxy) acetate
##STR01002##
[3002] Example 250 was prepared from Intermediate I-28 and
Intermediate I-39 by following the procedure described in Example
199. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.81 (d, J=2.4 Hz,
1H), 8.60 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H),
7.01 (dd, J=2.4, 0.9 Hz, 1H), 4.71 (s, 2H), 4.31 (q, J=7.3 Hz, 2H),
4.14 (s, 3H), 2.84 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); LC-MS: method
L, RT=2.834 min, MS (ESI) m/z: 444.10 (M+H).sup.+.
Example 251
2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)acetic acid
##STR01003##
[3004] Example 251 was another product isolated during purification
of 250. .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.81 (d, J=2.2
Hz, 1H), 8.60 (s, 1H), 7.94 (d, J=1.9 Hz, 1H), 7.27 (s, 1H), 7.02
(s, 1H), 4.77 (s, 2H), 4.14 (s, 3H), 2.85 (s, 3H); LC-MS: method L,
RT=2.398 min, MS (ESI) m/z: 416.05 (M+H).sup.+.
Example 252
2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-
-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate
##STR01004##
[3005] Intermediate 252A:
2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethanol
##STR01005##
[3007] Example 250 (230 mg, 0.518 mmol) was dissolved in
1,4-dioxane (5 mL) and was cooled to 0.degree. C. under N.sub.2.
The mixture was treated with LiBH.sub.4 (16.93 mg, 0.777 mmol) at
room temperature for 18 h. On the next morning, a small amount of
saturated NH.sub.4Cl (aq.) was added to quench the reaction. The
reaction mixture was diluted by adding 50 mL of EtOAc and 20 mL of
water. After shaking and separation, 30 mL of EtOAc was used to
extract the aqueous phase. The combined organic phases were dried
over Na.sub.2SO.sub.4, filtered, and concentrated to give
Intermediate 252A, which was used without purification. LC-MS:
method H, RT=0.93 min, MS (ESI) m/z: 402.1 (M+H).sup.+.
Intermediate 252B:
2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)ethanol
##STR01006##
[3009] Intermediate 252B was prepared from Intermediate 252A by
following procedure described in Example 229. LC-MS: method J,
RT=0.81 min, MS (ESI) m/z: 394.1 (M+H).sup.+.
Intermediate 252C:
2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)ethyl carbonochloridate
##STR01007##
[3011] Phosgene in toluene (0.922 mL, 1.398 mmol) was added
dropwise to Intermediate 252B (110 mg, 0.280 mmol) dissolved in
anhydrous THF (10 mL). The mixture was stirred at room temperature
for 4 hours. Solvent was removed by rotary evaporator and the
residue was used in the next step without purification. LC-MS:
method J, RT=1.10 min, MS (ESI) m/z: 456.1 (M+H).sup.+.
Intermediate 252D:
2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy-
)ethyl (6-methoxypyridin-3-yl)carbamate
##STR01008##
[3013] Intermediate 252C (30 mg, 0.066 mmol) was mixed with DIEA
(0.046 mL, 0.263 mmol) in DCM (1 mL) and 6-methoxypyridin-3-amine
(24.51 mg, 0.197 mmol) was added. The mixture was stirred at room
temperature for 18 hours. On the next day, the reaction mixture was
purified by flash chromatography (12 g silica column, 0-100%
EtOAc/Hexane gradient), and the product was purified again by
preparative HPLC with method B and dried on a lyophilizer to give
Intermediate 252D (5.6 mg, 10.30 .mu.mol, 15.66% yield) as a yellow
solid. LC-MS: method H, RT=1.21 min, MS (ESI) m/z: 544.1
(M+H).sup.+.
Intermediate 252E:
2-((2-(7-formyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)ox-
y)ethyl (6-methoxypyridin-3-yl)carbamate
##STR01009##
[3015] Intermediate 252E was prepared from Intermediate 252D by
following the procedure described in Intermediate 235A. LC-MS:
method H, RT=1.11 min, MS (ESI) m/z: 545.8 (M+H).sup.+.
Example 252
[3016] Example 252 was prepared from Intermediate 252E by following
the procedure described in Example 235. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.77 (br s, 1H), 8.75 (s, 1H), 8.72 (d, J=1.7
Hz, 1H), 8.24 (br s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.78 (d, J=7.4
Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.78 (d,
J=8.8 Hz, 1H), 5.61 (t, J=5.8 Hz, 1H), 4.83 (d, J=5.8 Hz, 2H),
4.54-4.41 (m, 2H), 4.40-4.27 (m, 2H), 4.09 (s, 3H), 3.80 (s, 3H),
2.75 (s, 3H); LC-MS: method L, RT=1.955 min, MS (ESI) m/z: 548.2
(M+H).sup.+.
Example 253
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR01010##
[3017] Intermediate 253A: 2-bromo-6-methoxybenzo[d]thiazole
##STR01011##
[3019] To a black solution of Copper (II) bromide (149 mg, 0.666
mmol) in Acetonitrile (1 mL) was added t-Butyl nitrite (0.095 mL,
0.721 mmol) at room temperature followed by
6-methoxybenzo[d]thiazol-2-amine (100 mg, 0.555 mmol). Immediate
bubbling and a mild exotherm was observed upon benzothiazole
addition. After 3 hours, the reaction mixture was diluted with
EtOAc and washed with 1.0 M HCl, saturated NaHCO.sub.3, and then
Brine. The organic phase was dried over MgSO.sub.4, filtered and
concentrated to a reddish-brown solid. The crude material was
purified by ISCO flash chromatography (0-15% EtOAc/Hex over 20 min,
12 g silica gel cartridge, Product at 5%). The desired fractions
were combined and concentrated to yield Intermediate 253A (84 mg,
0.344 mmol, 62.0% yield) as an off-white solid. LC-MS: Method H,
RT=1.12 min, MS (ESI) m/z: 244.0, 246.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.89 (d, J=9.0 Hz, 1H), 7.28 (1H
under CDCl3), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H)
Example 253
[3020] Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 253A
(15.78 mg, 0.065 mmol) were solvated in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.82 mg, 3.45 .mu.mol)
was added and the solution was degassed by sparging with argon for
10 min. Sodium carbonate (9.14 mg, 0.086 mmol) was then added,
followed by water (0.100 mL), and the solution was further degassed
for an additional 5 min. The vial was sealed and heated to
100.degree. C. in the microwave for 30 min. The crude solution was
filtered and purified by preparative HPLC (Method D, 40-80% over 20
minutes) to yield Example 253 (6.7 mg, 0.019 mmol, 43.8% yield).
LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 353.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.89 (d, J=9.0 Hz, 1H),
7.28 (1H Under CDCl.sub.3), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s,
3H).
Example 254
4-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]th-
iazole
##STR01012##
[3021] Intermediate 254A:
4-fluoro-6-methoxybenzo[d]thiazol-2-amine
##STR01013##
[3023] To a solution of 2-fluoro-4-methoxyaniline (150 mg, 1.063
mmol) in Acetonitrile (5.314 mL) was added ammonium thiocyanate
(121 mg, 1.594 mmol). The mixture was stirred at room temperature
for 5 min until fully solvated. Benzyltrimethylammonium tribromide
(414 mg, 1.063 mmol) was then added at room temperature causing the
solution to take on a bright yellow color with solids
precipitating. The mixture was allowed to stir at room temperature
overnight, at which point LCMS indicated complete conversion. The
mixture was diluted with EtOAc and washed with saturated sodium
bicarbonate. The organic layer was collected, washed with brine,
dried over magnesium sulfate, filtered and concentrated. The crude
material was purified by ISCO (0-10% DCM/MeOH over 20 min using a
24 g silica gel cartridge) to give Intermediate 254A (101 mg, 0.510
mmol, 47.9% yield). LC-MS: Method H, RT=0.77 min, MS (ESI) m/z:
199.1 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.01 (d, J=2.0 Hz, 1H), 6.67 (dd, J=12.4, 2.3 Hz, 1H), 3.78 (s,
3H), 3.33-3.28 (m, 2H).
Intermediate 254B: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine
##STR01014##
[3025] To a dark green solution of Copper (II) bromide (125 mg,
0.560 mmol) and Intermediate 254A (101 mg, 0.510 mmol) solvated in
acetonitrile (1 mL) and THF (2 mL) was added t-butyl nitrite (0.088
mL, 0.662 mmol). After stirring for 4 h at room temperature, the
mixture was dilute with EtOAc and washed with 1.0 M HCl followed by
Brine. The organic phase was concentrated and purified by ISCO
flash chromatography (0-10% EtOAc/Hex over 20 min, 24 g silica gel
cartridge-product at 5%) to afford Intermediate 254B (63 mg, 0.240
mmol, 47.2% yield) as a white solid. LC-MS: Method H, RT=1.17 min,
MS (ESI) m/z: 262.0, 264.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.05 (dd, J=2.2, 0.9 Hz, 1H), 6.83 (dd,
J=11.6, 2.3 Hz, 1H), 3.87 (s, 3H).
Example 254
[3026] Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 254B
(14.68 mg, 0.056 mmol) were solvated in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.82 mg, 3.45 .mu.mol)
was added and the solution was degassed by bubbling argon for 10
min. Sodium Carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was then added, and the solution was further degassed for an
additional 5 min. The microwave vial was sealed and heated to
100.degree. C. in the microwave for 30 min. The crude reaction
mixture was diluted with Et.sub.2O and washed with water followed
by brine. The organic phase was concentrated and purified by ISCO
(24 g, 0-50% EtOAc/Hex, 18 min--recovered SM at 10%, Product at
20%). Example 254 (2.2 mg, 5.78 .mu.mol, 13.40% yield) was isolated
as a bright yellow solid. LC-MS: Method H, RT=1.37 min, MS (ESI)
m/z: 370.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.09 (s, 1H), 8.94 (s, 1H), 7.97 (s, 1H), 7.29-7.21 (m, 2H under
CDCl.sub.3), 6.88 (dd, J=11.8, 2.3 Hz, 1H), 4.86 (s, 2H), 3.93 (s,
3H), 3.59 (s, 3H), 2.71 (s, 3H).
Example 255
6-ethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR01015##
[3027] Intermediate 255A: 2-bromo-6-ethoxybenzo[d]thiazole
##STR01016##
[3029] To a solution of Copper (II) bromide (138 mg, 0.618 mmol) in
acetonitrile (1 mL) was added t-butyl nitrite (0.088 mL, 0.669
mmol) at room temperature followed by
6-ethoxybenzo[d]thiazol-2-amine (100 mg, 0.515 mmol). The reaction
mixture was heated to 50.degree. C. for 45 min. The mixture was
cooled to room temperature, diluted with EtOAc and washed with 1.0
M HCl followed by brine. The organic phase was dried over
MgSO.sub.4, filtered and concentrated. The crude material was
purified by ISCO (24 g, 0-15% EtOAc/Hex). Example 255A (62 mg,
0.240 mmol, 46.7% yield) was isolated as a light brown solid.
LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 258.2, 260.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.86 (d,
J=9.0 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.06 (dd, J=8.9, 2.3 Hz,
1H), 4.09 (q, J=7.0 Hz, 2H), 1.46 (t, J=6.9 Hz, 3H).
Example 255
[3030] Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 255A
(16.69 mg, 0.065 mmol) were solvated in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.82 mg, 3.45 .mu.mol)
was added and the solution was degassed by bubbling argon for 10
min. Sodium Carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was then added, and the solution was further degassed for an
additional 5 min. The vial was sealed and heated to 100.degree. C.
in the microwave for 30 min in the microwave. The crude solution
was filtered and purified by preparative HPLC (Method D, 50-90%
over 10 minutes) to yield Example 255 (5.4 mg, 0.015 mmol, 34.3%
yield). LC-MS: Method H, RT=1.38 min, MS (ESI) m/z: 366.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.89 (d,
J=9.0 Hz, 1H), 7.28 (1H Under CDCl.sub.3), 7.09 (dd, J=9.0, 2.6 Hz,
1H), 3.90 (s, 3H).
Example 256
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR01017##
[3031] Intermediate 256A: 2-bromo-6-ethoxybenzo[d]thiazole
##STR01018##
[3033] To a solution of copper (II) bromide (134 mg, 0.600 mmol) in
Acetonitrile (1 mL) was added benzo[d]thiazol-2-amine (100 mg,
0.666 mmol) at room temperature. t-Butyl nitrite (0.106 mL, 0.800
mmol) was then added. Bubbling immediately observed. After 30 min,
diluted with EtOAc and washed with 1.0 M HCl followed by brine. The
organic phase was concentrated and purified by ISCO flash
chromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel
cartridge--product at 2.5%) to afford Intermediate 256A (80 mg,
0.374 mmol, 56.1% yield) as a pink oil. LC-MS: Method H, RT=1.16
min, MS (ESI) m/z: 214.0, 216.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.00 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.9 Hz,
1H), 7.53-7.37 (m, 2H).
Example 256
[3034] Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 256A
(10.0 mg, 0.047 mmol) were solvated in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.05 mg, 3.74 .mu.mol)
was added and the solution was degassed by bubbling argon for 10
min. Sodium Carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was then added, and the solution was further degassed for an
additional 5 min. The vial was sealed and heated to 100.degree. C.
in the microwave for 30 min. The crude solution was filtered and
purified by preparative HPLC (Method D, 45-90% over 10 minutes) to
yield 256 (3.2 mg, 0.008 mmol, 34.3% yield). LC-MS: Method H,
RT=1.37 min, MS (ESI) m/z: 322.0 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.11 (s, 1H), 8.87 (s, 1H), 8.21 (d, J=8.0
Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.58 (t, J=7.7 Hz,
1H), 7.52-7.46 (m, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.70 (s,
3H).
Example 257
4,6-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR01019##
[3035] Intermediate 257A: 2-bromo-4,6-difluorobenzo[d]thiazole
##STR01020##
[3037] To a black solution of copper (II) bromide (144 mg, 0.645
mmol) in Acetonitrile (1 mL) was added t-Butyl nitrite (0.092 mL,
0.698 mmol) followed by 4,6-difluorobenzo[d]thiazol-2-amine (100
mg, 0.537 mmol). The reaction mixture was heated to 50.degree. C.
After 40 min, the reaction mixture was cooled to room temperature,
diluted with EtOAc and washed with 1.0 M HCl followed by brine. The
crude material was concentrated and purified by flash
chromatography (0-15% EtOAc/Hex over 18 min, 12 g silica gel
cartridge). The desired fractions were combined and concentrated to
yield Intermediate 257A (126 mg, 0.504 mmol, 94% yield) as a white
solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: None
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.35 (d,
J=7.5 Hz, 1H), 7.03 (td, J=9.6, 2.2 Hz, 1H). .sup.19F NMR
(CHLOROFORM-d) .delta. -85.7, -91.7
Example 257
[3038] Intermediate I-2 (15.1 mg, 0.048 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.61 mg, 3.20 .mu.mol)
and Intermediate 257A (10 mg, 0.040 mmol) were solvated in DMF (1
mL). Sodium carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was added, and the solution was degassed with argon for 10 min. The
vial was then sealed and heated to 100.degree. C. in the microwave
for 30 min. The crude solution was filtered and purified by
preparative HPLC (Method D, 45-85% over 10 minutes) to yield
Example 257 (8.3 mg, 0.021 mmol, 52.3% yield). LC-MS: Method H,
RT=1.41 min, MS (ESI) m/z: 358.0 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.84 (s, 1H), 8.09 (s, 1H),
8.03-7.97 (m, 1H), 7.51 (t, J=9.4 Hz, 1H), 4.82 (s, 2H), 3.47 (s,
3H), 2.70 (s, 3H).
Example 258
4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
e
##STR01021##
[3039] Intermediate 258A: 2-bromo-4,6-dimethoxybenzo[d]thiazole
##STR01022##
[3041] To a solution of copper (II) bromide (127 mg, 0.571 mmol) in
acetonitrile (1 mL) was added 4,6-dimethoxybenzo[d]thiazol-2-amine
(100 mg, 0.476 mmol) at room temperature. t-Butyl nitrite (0.082
mL, 0.618 mmol) was then added dropwise at room temperature causing
immediate bubbling. After 1 hr, the reaction mixture was diluted
with EtOAc and washed with 1.0 M HCl. The organic phase was dried
over MgSO.sub.4, filtered and concentrated. The crude material was
purified by ISCO flash chromatography (0-30% EtOAc/Hex over 35 min,
12 g silica gel cartridge). Intermediate 258A (56 mg, 0.204 mmol,
43% yield) as a white solid. LC-MS: Method H, RT=1.13 min, MS (ESI)
m/z: 274.0, 276.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 6.81 (d, J=2.0 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.99 (s,
3H), 3.86 (s, 3H).
Example 258
[3042] Intermediate I-2 (13.8 mg, 0.044 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.38 mg, 2.92 .mu.mol)
and Intermediate 258A (10 mg, 0.036 mmol) were solvated in DMF (1
mL). Sodium carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was added, and the solution was degassed with argon for 10 min. The
vial was then sealed and heated to 100.degree. C. in the microwave
for 30 min. The crude solution was filtered and purified by
preparative HPLC (Method D, 45-85% over 10 minutes) to yield
Example 258 (6.4 mg, 0.015 mmol, 41.9% yield). LC-MS: Method H,
RT=1.29 min, MS (ESI) m/z: 382.0 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.77 (s, 1H), 8.02 (s, 1H),
7.29 (s, 1H), 6.68 (s, 1H), 4.81 (s, 2H), 4.00 (s, 3H), 3.87 (s,
3H), 3.47 (s, 3H), 2.69 (s, 3H).
Example 259
4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR01023##
[3043] Intermediate 259A: 2-bromo-4-methoxybenzo[d]thiazole
##STR01024##
[3045] Copper (II) bromide (112 mg, 0.499 mmol) and
4-methoxybenzo[d]thiazol-2-amine (100 mg, 0.555 mmol) were solvated
in Acetonitrile (1 mL) t-Butyl nitrite (0.081 mL, 0.610 mmol) was
added at room temperature. After 30 min, the reaction mixture was
dilute with EtOAc and washed with 1.0 M HCl followed by brine. The
crude material was concentrated and purified by ISCO flash
chromatography (0-10% EtOAc/Hex over 20 min, 24 g silica gel
cartridge) to afford Intermediate 259A (68 mg, 0.279 mmol, 50.2%
yield). LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 242.0. 244.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.39-7.36
(m, 2H), 6.92 (dd, J=6.2, 2.9 Hz, 1H), 4.05 (s, 3H).
Example 259
[3046] Intermediate I-2 (15.4 mg, 0.049 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.68 mg, 3.28 .mu.mol)
and Intermediate 259A (10 mg, 0.041 mmol) were solvated in DMF (1
mL). Sodium Carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was added, and the solution was degassed with argon for 10 min. The
vial was then sealed and heated to 100.degree. C. in the microwave
for 30 min. The crude solution was filtered and purified by
preparative HPLC (Method D, 45-85% over 10 minutes) to yield
Example 259 (4.1 mg, 0.012 mmol, 28.5% yield). LC-MS: Method H,
RT=1.30 min, MS (ESI) m/z: 352.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.84 (s, 1H), 8.06 (s, 1H),
7.73 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz,
1H), 4.82 (s, 2H), 4.03 (s, 3H), 3.47 (s, 3H), 2.71 (s, 3H).
Example 260
4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
##STR01025##
[3047] Intermediate 260A: 2-bromo-4-chlorobenzo[d]thiazole
##STR01026##
[3049] Copper (II) bromide (134 mg, 0.600 mmol) and
4-chlorobenzo[d]thiazol-2-amine (100 mg, 0.542 mmol) were solvated
in acetonitrile (1 mL) and THF (1 mL). t-Butyl nitrite (0.086 mL,
0.650 mmol) was then added at room temperature. After 30 min, the
reaction mixture was dilute with EtOAc and washed with 1.0 M HCl
followed by brine. The crude material was concentrated and purified
by ISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g
silica gel cartridge, product at 2.5%.) to afford Intermediate 260A
(88 mg, 0.279 mmol, 65.4% yield). LC-MS: Method H, RT=1.20 min, MS
(ESI) m/z: 248.0. 250.0, 252.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.72 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.9 Hz,
1H), 7.41-7.33 (m, 1H).
Example 260
[3050] Intermediate I-2 (15.1 mg, 0.048 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.63 mg, 3.22 .mu.mol)
and Intermediate 260A (10 mg, 0.040 mmol) were solvated in DMF (1
mL). Sodium Carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was added, and the solution was degassed with argon for 10 min. The
vial was then sealed and heated to 100.degree. C. in the microwave
for 30 min. The crude solution was filtered and purified by
preparative HPLC (Method D, 45-85% over 10 minutes) to yield
Example 260 (4.6 mg, 0.012 mmol, 30.5% yield). LC-MS: Method H,
RT=1.44 min, MS (ESI) m/z: 356.0, 358.0 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.88 (s, 1H), 8.19
(d, J=7.7 Hz, 1H), 8.11 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.48 (t,
J=7.7 Hz, 1H), 4.83 (s, 2H), 3.47 (s, 3H), 2.72 (s, 3H).
Example 261
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
##STR01027##
[3051] Intermediate 261A: 2-bromo-4-methylbenzo[d]thiazole
##STR01028##
[3053] Copper (II) bromide (122 mg, 0.546 mmol) and
2-bromo-4-methylbenzo[d]thiazole (100 mg, 0.609 mmol) were solvated
in acetonitrile (1 mL) and THF (1 mL). t-Butyl nitrite (0.096 mL,
0.728 mmol) was then added at room temperature. After 30 min, the
reaction mixture was dilute with EtOAc and washed with 1.0 M HCl
followed by brine. The crude material was concentrated and purified
by ISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g
silica gel cartridge, product at 2.5%.) to afford Intermediate 261A
(88 mg, 0.386 mmol, 63.6% yield). LC-MS: Method H, RT=1.25 min, MS
(ESI) m/z: 227.9, 229.9 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.64 (dt, J=7.7, 0.8 Hz, 1H), 7.34-7.27 (m,
2H), 2.72 (s, 3H).
Example 261
[3054] Intermediate I-2 (16.7 mg, 0.053 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.53 mg, 3.10 .mu.mol)
and Intermediate 261A (10 mg, 0.044 mmol) were solvated in DMF (1
mL). Sodium Carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was added, and the solution was degassed with argon for 10 min. The
vial was then sealed and heated to 100.degree. C. in the microwave
for 30 min. The crude solution was filtered and purified by
preparative HPLC (Method D, 55-85% over 10 minutes) to yield
Example 261 (4.5 mg, 0.013 mmol, 29.1% yield). LC-MS: Method H,
RT=1.52 min, MS (ESI) m/z: 336.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H),
8.02-7.97 (m, 1H), 7.38 (d, J=3.9 Hz, 2H), 4.82 (s, 2H), 3.47 (s,
3H), 2.81 (s, 3H), 2.71 (s, 3H).
Example 262
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-6-(trifluoromethoxy-
)benzo[d]thiazole
##STR01029##
[3055] Intermediate 262A:
4-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-amine
##STR01030##
[3057] To a solution of 2-methyl-4-(trifluoromethoxy)aniline (150
mg, 0.785 mmol) in acetonitrile (3.924 mL) was added ammonium
thiocyanate (90 mg, 1.177 mmol) followed by benzyltrimethylammonium
tribromide (306 mg, 0.785 mmol) causing the reaction mixture to
become a bright yellow, heterogeneous suspension. The reaction
mixture was allowed to stir at room temperature overnight. After 13
h, the reaction mixture was diluted with EtOAc and washed with
saturated NaHCO.sub.3 followed by brine. The bright yellow organic
phase was dried over MgSO.sub.4, filtered and concentrated. The
resulting crude mixture was purified by ISCO (24 g Column, 0-70%
EtOAc/Hex, 18 min. Product at 37%) to give Intermediate 262A (112
mg, 0.451 mmol, 57.5% yield) as a white powder. LC-MS: Method H,
RT=1.03 min, MS (ESI) m/z: 249.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.32 (s, 1H), 7.02 (s, 1H), 5.24 (br. s.,
2H), 2.57 (s, 3H). .sup.19F NMR (376 MHz, CHLOROFORM-d) .delta.
-58.12 (s, 1F).
Intermediate 262B:
2-bromo-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole
##STR01031##
[3059] Copper (II) bromide (100 mg, 0.479 mmol) and Intermediate
262A (108 mg, 0.435 mmol) were solvated in acetonitrile (2 mL).
t-Butyl nitrite (0.075 mL, 0.566 mmol) was then added at room
temperature. After 30 min, the reaction mixture was dilute with
EtOAc and washed with 1.0 M HCl followed by brine. The crude
material was concentrated and purified by ISCO flash chromatography
(0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge, product at
2.5%.) to afford Intermediate 262B (124 mg, 0.386 mmol, 91% yield).
LC-MS: Method H, RT=1.42 min, MS (ESI) m/z: 312.0, 314.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.51 (s,
1H), 7.17 (s, 1H), 2.73 (s, 3H). .sup.19F NMR (376 MHz,
CHLOROFORM-d) .delta. -57.93 (s, 1F).
Example 262
[3060] Intermediate I-2 (15.7 mg, 0.050 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.72 mg, 3.33 .mu.mol)
and Intermediate 262B (13 mg, 0.042 mmol) were solvated in DMF (1
mL). Sodium carbonate (2.0 M in H.sub.2O) (100 .mu.L, 0.200 mmol)
was added, and the solution was degassed with argon for 10 min. The
vial was then sealed and heated to 100.degree. C. in the microwave
for 30 min. The crude solution was filtered and purified by
preparative HPLC (Method D, 55-100% over 20 minutes) to yield
Example 262 (5.9 mg, 0.014 mmol, 33.4% yield). LC-MS: Method H,
RT=1.56 min, MS (ESI) m/z: 420.0 (M+H).sup.+. .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. 9.10 (s, 1H), 8.91 (d, J=1.5 Hz, 1H),
7.98 (s, 1H), 7.71 (s, 1H), 7.21 (s, 1H), 4.86 (s, 2H), 3.61 (s,
3H), 2.88 (s, 3H), 2.74 (s, 3H).
Preparation of 2-Aminobenzothiazoles
[3061] The following 2-aminobenzothiazoles were made according to
the following general procedure, which is analogous to the examples
described above
[3062] The appropriately substituted aniline (1.0 equiv) was
solvated in acetonitrile (0.2 M). To this mixture was added
ammonium thiocyanate (1.3 equiv) followed by
benzyltrimethylammonium tribromide (1.0 equiv). After being allowed
to stir at room temperature for the designated amount of time, the
reaction mixture was diluted with CH.sub.2Cl.sub.2 and washed with
saturated NaHCO.sub.3 followed by brine. The organic phase was
dried over MgSO.sub.4, filtered and concentrated before being
purified by silica gel chromatography to provide the desired
material.
TABLE-US-00004 LCMS Retention LCMS Time [M + H].sup.+ (Min)
Intermediate Structure Time Yield m/z Method H NMR 263A
##STR01032## 3 d 80% 231.1 0.95 .sup.1H NMR (400 MHz, CHLOROFORM-
d) .delta. 7.26 (s, 1H), 6.95 (s, 1H), 6.90 (t, J = 74.8 Hz, 1H),
5.39 (br. s., 2H), 2.40 (s, 3H). .sup.19F NMR (376 MHz, CHLOROFORM-
d) .delta. -81.04 (s, 1F). 265A ##STR01033## 7 d 24% 233.3, 235.1
1.04 .sup.1H NMR (400 MHz, CD.sub.3OD-d) .delta. 7.11 (d, J = 7.5
Hz, 1H), 3.87 (s, 3H). 266A ##STR01034## 16 h 72% 203.0 205.0 0.94
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.37 (dd, J = 8.0,
2.5 Hz, 1H), 7.13 (dd, J = 9.1, 2.5 Hz, 1H). 269A ##STR01035## 16 h
77% 217.1 0.89 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.24
(dd, J = 9.6, 6.9 Hz, 1H), 4.06 (d, J = 1.1 Hz, 3H). 270A
##STR01036## 16 h 64% 199.1 0.74 .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 6.96 (dd, J = 8.1, 2.4 Hz, 1H), 6.70 (dd,
J = 11.2, 2.4 Hz, 1H), 3.91 (s, 3H). 271A ##STR01037## 16 h 73%
229.1 0.79 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.08 (d,
J = 7.3 Hz, 1H), 4.01 (d, J = 1.1 Hz, 3H), 3.85 (s, 3H). 276A
##STR01038## 16 h 67% 195.2 0.66 .sup.1H NMR (400 MHz, CHLOROFORM-
d) .delta. 7.33 (d, J = 0.7 Hz, 1H), 7.04 (s, 1H), 4.97 (br. s.,
2H), 3.84 (s, 3H), 2.27 (s, 3H). 277A ##STR01039## 4 d 49% 199.1
0.56 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.34 (d, J =
8.4 Hz, 1H), 7.10 (d, J = 11.9 Hz, 1H), 3.86 (s, 3H).
Preparation of 2-Bromobenzothiazoles
[3063] The following 2-bromobenzothiazoles were made according to
the following general procedure, which is analogous to the examples
described above
[3064] The appropriately substituted 2-aminobenzothiazole (1.0
equiv) was suspended in acetonitrile (0.2 M). To this mixture was
added copper (II) bromide (1.0 equiv) followed by t-butyl nitrite
(1.3 equiv). After being allowed to stir at room temperature for 30
min, the reaction mixture was diluted with EtOAc and washed with
1.0 M HCl followed by brine. The organic phase was dried over
MgSO.sub.4, filtered and concentrated before being purified by
silica gel chromatography to provide the desired material.
TABLE-US-00005 LCMS Retention LCMS Time [M + H].sup.+ (Min)
Intermediate Structure Yield m/z Method H NMR 263B ##STR01040## 64%
294.1, 296.1 1.24 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.45
(s, 1H), 7.10 (s, 1H), 7.04 (t, J = 74.4 Hz, 1H), 2.48 (s, 3H).
264A ##STR01041## 45% 272.1, 274.1 1.22 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.56 (d, J = 1.3 Hz, 1H), 8.16 (dd, J = 8.6,
1.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 3.98 (s, 3H). 265B
##STR01042## 28% 295.9, 297.9, 298.9 1.32 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.22 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H). 266B
##STR01043## 62% 265.9, 267.9, 270.0 1.22 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.49-7.42 (m, 1H), 7.37-7.30 (m, 1H). 268A
##STR01044## 44% 278.0, 280.0, 282.0 1.22 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.00 (s, 1H), 7.30 (s, 1H), 3.98 (s, 4H).
269B ##STR01045## 60% 278.1, 280.1 1.21 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.27 (dd, J = 6.4, 2.6 Hz, 1H), 4.33 (d, J =
2.0 Hz, 3H). 270B ##STR01046## 49% 262.1, 264.1 1.11 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.09 (dd, J = 7.7, 2.2 Hz, 1H),
6.70 (dd, J = 10.9, 2.3 Hz, 1H), 4.03 (s, 3H). 271B ##STR01047##
53% 292.1, 294.1 1.14 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.00 (d, J = 7.0 Hz, 1H), 4.28 (d, J = 2.0 Hz, 3H), 3.95 (s, 3H).
272A ##STR01048## 88% 232.0, 234.0 1.17 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.95 (dd, J = 9.0, 4.8 Hz, 1H), 7.51 (dd, J =
7.9, 2.4 Hz, 1H), 7.23 (appar. td, J = 8.9, 2.6 Hz, 1H). 273A
##STR01049## 91% 232.0, 234.0 1.17 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.59 (d, J = 8.1 Hz, 1H), 7.40 (appar. td, J
= 8.1, 4.6 Hz, 1H), 7.20 (dd, J = 9.6, 8.7 Hz, 1H). 274A
##STR01050## 73% 248.0, 250.1, 252.1 1.25 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.91 (d, J = 8.6 Hz, 1H), 7.82-7.79 (m, 1H),
7.45 (dd, J = 8.7, 2.1 Hz, 1H). 275A ##STR01051## 73% 281.9, 283.9
1.32 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.71 (d, J = 1.8
Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H). 276B ##STR01052## 74% 258.1,
260.1 1.05 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.71 (d, J =
0.7 Hz, 1H), 7.16 (s, 1H), 3.89 (s, 3H), 2.32 (d, J = 0.7 Hz, 3H).
277B ##STR01053## 45% 262.0, 264.0 0.96 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.69 (d, J = 11.0 Hz, 1H), 7.31 (d, J = 7.7
Hz, 1H), 3.96 (s, 3H).
Preparation of Quinoxaline-Benzothiazole Examples
[3065] The following Quinoxaline-Benzothiazole adducts were made
according to the following general procedure, which is analogous to
the examples described above
[3066] The appropriately substituted 2-bromobenzothiazole (1.0
equiv), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.08 equiv), and
the appropriate boronic acid or ester (1.0 equiv) were solvated in
DMF (0.05 M). A 2.0 M solution of aqueous sodium carbonate (4.0
equiv) was then added, and the mixture was degassed by bubbling
argon through the solution for 10 min. The vial was then sealed and
heated to 100.degree. C. in the microwave for 30 min. The crude
solution was filtered and purified by preparative HPLC to yield the
desired example.
TABLE-US-00006 LCMS LCMS RT HPLC [M + (Min) Prep H].sup.+ Method
Method Ex Structure B(OR).sub.2 Br--Bzt m/z H D NMR 263
##STR01054## I-2 263B 402.2 1.43 50-90% 20 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.11 (s, 1H), 8.85 (d, J = 1.7 Hz, 1H),
8.08 (s, 1H), 7.87 (s, 1H), 7.68 (t, J = 74.3 Hz, 1H), 7.21 (s,
1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.71 (s, 3H) [another (s, 3H) was
buried under DMSO at 2.5 ppm]. 264 ##STR01055## I-2 264A 380.2 1.35
55-100% 11 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.14 (s,
1H), 8.92 (d, J = 1.7 Hz, 1H), 8.87 (d, J = 1.7 Hz, 1H), 8.23 (d, J
= 8.8 Hz, 1H), 8.15-8.10 (m, 2H), 4.83 (s, 2H), 3.93 (s, 3H), 3.48
(s, 3H), 2.71 (s, 3H). 265 ##STR01056## I-2 265B 404.1 406.1 1.43
70-100% 10 min .sup.1H NMR (400 MHz, CHLOROFORM- d) .delta. 9.10
(s, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.30-7.27 (m, 1H-
under CDCl.sub.3), 4.86 (s, 2H), 4.02 (s, 3H), 3.59 (s, 3H), 2.73
(s, 3H). 266 ##STR01057## I-2 266B 374.1, 376.1 1.45 55-100% 20 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (s, 1H), 8.84 (s,
1H), 8.14 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 7.72 (d, J = 8.8 Hz,
1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.72 (s, 3H). 267 ##STR01058## I-2
I-41 388.2 1.34 50-90% 20 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.10 (br. s., 1H), 8.81 (br. s., 1H), 8.06 (br. s., 1H),
7.86 (d, J = 5.8 Hz, 1H), 4.83 (br. s., 2H), 4.00 (br. s., 3H),
3.49 (br. s., 3H), 2.70 (br. s., 3H). 268 ##STR01059## I-2 268A
385.5, 387.5 1.32 50-90% 20 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (br. s., 1H), 8.79 (br. s., 1H), 8.20 (br. s., 1H),
8.06 (br. s., 1H), 7.99 (br. s., 1H), 4.83 (br. s., 2H), 3.99 (br.
s., 3H), 3.49 (br. s., 3H), 2.69 (br. s., 3H). 269 ##STR01060## I-2
269B 388.1 1.40 55-90% 25 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (br. s., 1H), 8.86 (br. s., 1H), 8.11 (br. s., 1H),
8.03 (br. s., 1H), 4.83 (br. s., 2H), 4.44 (br. s., 3H), 3.48 (br.
s., 3H), 2.72 (br. s., 3H). 270 ##STR01061## I-2 270B 370.2 1.30
45-85% 20 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.08 (s,
1H), 8.79 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.05 (d,
J = 9.6 Hz, 1H), 4.81 (s, 2H), 4.04 (s, 3H), 3.46 (s, 3H), 2.69 (s,
3H). 271 ##STR01062## I-2 271B 400.2 1.30 45-85% 10 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.80 (d, J = 1.7 Hz,
1H), 8.04 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 4.81 (s, 2H), 4.34 (s,
3H), 3.94 (s, 3H), 3.47 (s, 3H), 2.69 (s, 3H). 272 ##STR01063## I-2
272A 340.1 1.38 35-75% 20 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (s, 1H), 8.85 (s, 1H), 8.17 (dd, J = 8.9, 4.8 Hz, 1H),
8.13 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.46 (td, J = 8.9, 2.1 Hz,
1H), 4.83 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H). 273 ##STR01064## I-2
273A 340.1 1.37 40-80% 20 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.13 (s., 1H), 8.90 (s., 1H), 8.12 (s., 1H), 8.06 (d, J =
7.2 Hz, 1H), 7.52 (s., 1H), 7.47-7.39 (m, J = 9.6 Hz, 1H), 4.84
(s., 2H), 3.49 (s., 3H), 2.72 (s., 3H). 274 ##STR01065## I-2 274A
356.3, 358.2 1.47 60-100% 10 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.13 (s, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.39
(d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.62
(dd, J = 8.5, 2.2 Hz, 1H), 4.84 (s, 2H), 3.48 (s, 3H), 2.71 (s,
3H). 275 ##STR01066## I-2 275A 390.1, 392.0, 394.1 1.57 60-100% 20
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.14 (s, 1H), 8.88
(s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 4.84 (s, 2H),
2.73 (s, 2H) [another (s, 3H) was buried under H.sub.3O at 3.5
ppm]. 276 ##STR01067## I-2 276B 438.2 1.16 45-85% 20 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.79 (s, 1H),
8.02 (br. s., 1H), 7.91 (s, 1H), 7.71 (s, 1H), 4.82 (s, 2H), 3.93
(s, 3H), 3.49 (s, 3H), 2.69 (s, 3H), 2.34 (s, 3H). 277 ##STR01068##
I-2 277B 370.2 1.13 45-95% 15 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.11 (br. s., 1H), 8.81 (br. s., 1H), 8.06
(br. s., 1H), 7.99 (d, J = 9.6 Hz, 2H), 4.83 (br. s., 2H), 3.98
(br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H). 278
##STR01069## I-9 I-41 374.1 1.49 55-95% 15 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.74 (br. s., 1H), 8.59 (br. s., 1H),
7.92-7.76 (m, 2H), 4.09 (br. s., 3H), 3.99 (br. s., 3H), 2.65 (br.
s., 3H). 279 ##STR01070## I-9 276B 438.2 1.16 45-80% 10 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.59 (d, J = 1.9
Hz, 1H), 7.90 (s, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.70 (s, 1H), 4.10
(s, 3H), 3.93 (s, 3H), 2.65 (s, 3H), 2.33 (s, 3H). 280 ##STR01071##
I-9 277B 356.2 1.22 60-100% 20 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 7.99
(d, J = 6.6 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.85 (s, 1H), 4.10
(s, 3H), 3.97 (s, 3H), 2.65 (s, 3H). 281 ##STR01072## I-2 I-40
352.3 1.24 40-80% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.76 (br. s., 1H), 9.08 (s, 1H), 8.79 (d, J = 1.7 Hz, 1H),
8.02 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H),
4.82 (s, 2H), 3.48 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H). 282
##STR01073## I-9 I-43 390.0, 392.0 1.52 70-100% 15 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.78 (br. s., 1H), 8.63 (br. s.,
1H), 7.97 (br. s., 1H), 7.89 (br. s., 1H), 4.10 (br. s., 3H), 3.99
(br. s., 3H), 2.67 (br. s., 3H). 283 ##STR01074## I-2 I-43 404.1,
406.1 1.16 45-80% 20 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.13 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 7.7
Hz, 1H), 4.84 (s, 2H), 4.01 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H).
284 ##STR01075## I-2 I-47 380.2 1.48 70-100% 20 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.84 (d, J = 1.9 Hz,
1H), 8.03 (d, J = 0.8 Hz, 1H), 7.58 (s, 1H), 4.83 (s, 2H), 3.91 (s,
3H), 3.49 (s, 3H), 2.77 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H). 285
##STR01076## I-9 I-52 428.1 1.20 60-100% 10 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 7.97 (s, 1H), 7.86 (s,
1H), 7.75 (d, J = 7.7 Hz, 1H), 4.10 (s, 3H), 3.75 (s, 3H), 2.90 (s,
3H), 2.75 (s, 3H). 286 ##STR01077## I-2 I-52 442.2 1.04 45-85% 15
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.83
(d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 5.00
(s, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 3.48 (s, 3H), 2.72 (d, J = 1.4
Hz, 3H), 2.70 (s, 3H). 287 ##STR01078## I-9 I-57 448.1, 450.1 1.18
60-100% 15 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s,
1H), 8.83 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 8.3 Hz,
1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.48 (s, 3H), 2.72 (d, J = 1.4 Hz,
3H), 2.70 (s, 3H). 288 ##STR01079## I-9 I-53 400.2 1.08 45-80% 10
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.61
(s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.96 (t, J = 5.4
Hz, 1H), 4.17 (t, J = 4.8 Hz, 2H), 4.09 (s, 3H), 3.82 (q, J = 4.8
Hz, 2H), 2.70 (s, 3H), 2.65 (s, 3H). 289 ##STR01080## I-2 I-53
414.2 0.89 30-70% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.09 (s, 1H), 8.82 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.0
Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.82 (s, 2H), 4.17 (t, J = 5.0
Hz, 2H), 3.82 (q, J = 5.1 Hz, 2H), 3.49 (s, 3H), 2.70 (s, 6H). 290
##STR01081## I-2 I-46 370.1 0.93 45-85% 10 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.07 (s, 1H), 8.81 (d, J = 1.1 Hz, 1H),
8.02 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H),
2.70 (s, 3H), 2.69 (d, J = 1.1 Hz, 3H). 291 ##STR01082## I-2 I-44
390.1, 392.0 1.27 30-70% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.07 (s, 1H), 8.79 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.63
(d, J = 7.7 Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H). 292
##STR01083## I-2 I-57 462.1, 464.1 1.04 30-65% 10 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.84 (s,
1H), 8.10 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 5.07 (s, 2H), 4.84 (s,
2H), 3.77 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H). 293 ##STR01084## I-2
I-59 434.1, 436.1 0.89 35-70% 10 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.79 (s, 1H), 8.05 (s,
1H), 8.00 (d, J = 7.7 Hz, 1H), 5.00 (t, J = 5.4 Hz, 1H), 4.82 (s,
2H), 4.22 (t, J = 4.8 Hz, 2H), 3.83 (q, J = 5.0 Hz, 2H), 3.49 (s,
3H), 2.70 (s, 3H). 294 ##STR01085## I-9 I-45 370.2 1.30 55-95% 10
min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76
(s, 1H), 8.64 (s, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 4.10
(s, 3H), 3.95 (s, 3H), 2.71 (s, 3H), 2.66 (s, 3H). 295 ##STR01086##
I-2 I-45 384.1 1.17 50-85% 10 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H),
7.82 (d, J = 8.3 Hz, 1H), 4.83 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H),
2.72 (s, 6H). 296 ##STR01087## I-2 I-49 438.1 1.14 60-100% 15 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.84 (s,
1H), 8.03 (s, 1H), 7.54 (s, 1H), 4.94 (s, 2H), 4.82 (s, 2H), 3.76
(s, 3H), 3.49 (s, 3H), 2.78 (s, 3H), 2.71 (s, 3H), 2.33 (s, 3H).
297 ##STR01088## I-2 I-51 410..2 1.30 45-90% 12 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.83 (s,
1H), 8.01 (s, 1H), 7.56 (s, 1H), 4.90 (t, J = 5.4 Hz, 1H), 4.82 (s,
2H), 4.11 (br. s., 2H), 3.82 (d, J = 4.7 Hz, 2H), 3.48 (s, 3H),
2.76 (s, 3H), 2.70 (s, 3H), 2.29 (s, 3H). 298 ##STR01089## I-2 I-56
400.1, 402.1 1.41 70-100% 10 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.83 (s, 1H), 8.07 (s, 1H),
7.80 (s, 1H), 4.84 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H), 2.72 (s,
3H), 2.41 (s, 3H). 299 ##STR01090## I-9 I-56 386.1, 388.1 1.50
70-100% 15 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (s,
1H), 8.61 (d, J = 1.7 Hz, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 4.10 (s,
3H), 3.95 (s, 3H), 2.67 (s, 3H), 2.40 (s, 3H). 300 ##STR01091## I-2
I-54 395.8 1.06 55-100% 15 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (s, 1H), 8.85 (br. s., 1H), 8.03 (br. s., 1H), 7.69
(s, 1H), 5.20 (br. s., 2H), 5.10-5.04 (m, 1H), 4.82 (s, 2H), 3.92
(s, 3H), 3.48 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H). 301 ##STR01092##
I-9 I-54 381.8 1.16 50-100% 20 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.73 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 7.81
(s, 1H), 7.65 (s, 1H), 5.18 (d, J = 5.2 Hz, 2H), 5.09-5.02 (m, 1H),
4.08 (s, 3H), 3.91 (s, 3H), 2.65 (s, 3H), 2.36 (s, 3H). 302
##STR01093## I-9 I-62 538.1 1.21 60-100% 13 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.15 (br. s., 1H), 8.75 (s, 1H), 8.62
(s, 1H), 8.30 (br. s., 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.97 (s, 1H),
7.84 (s, 1H), 7.19- 7.12 (m, 1H), 4.55 (br. s., 2H), 4.43 (br. s.,
2H), 4.10 (s, 3H), 2.70 (s, 3H), 2.66 (s, 3H). 303 ##STR01094## I-2
I-62 552.1 1.04 45-100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.15 (br. s., 1H), 9.11 (s, 1H), 8.84 (s, 1H), 8.30 (br.
s., 1H), 8.05 (br. s., 1H), 7.97 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H),
7.16 (dd, J = 8.8, 3.0 Hz, 1H), 4.83 (s, 2H), 4.55 (d, J = 4.4 Hz,
2H), 4.45 (d, J = 3.6 Hz, 2H), 3.49 (s, 3H), 2.90 (s, 3H), 2.75 (s,
3H). 304 ##STR01095## I-9 I-63 558.1, 560.1 1.18 70-100% 12 min
.sup.1H NMR (400 MHz, THF) .delta. 8.83 (d, J = 1.5 Hz, 1H), 8.61
(s, 1H), 8.24 (s, 1H), 8.18-8.08 (m, 1H), 7.84 (s, 1H), 7.77 (d, J
= 7.3 Hz, 1H), 6.95 (dd, J = 8.8, 3.5 Hz, 1H), 4.64-4.58 (m, 2H),
4.52-4.46 (m, 2H), 4.15 (s, 3H), 2.70 (s, 3H). 305 ##STR01096## I-2
I-63 572.1, 574.1 1.03 50-100% 10 min .sup.1H NMR (500 MHz,
CHLOROFORM- d) .delta. 9.11 (s, 1H), 9.00 (s, 1H), 8.18 (br. s.,
1H), 8.05 (s, 3H), 6.96 (dd, J = 8.8, 3.0 Hz, 1H), 4.88 (s, 2H),
4.69-4.64 (m, 2H), 4.48-4.41 (m, 2H), 3.62 (s, 3H), 2.76 (s,
3H).
Example 306
2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
##STR01097##
[3067] Intermediate 306A:
2-bromo-6-ethoxy-4-methylbenzo[d]thiazole
##STR01098##
[3069] To a solution of Intermediate I-40 (18 mg, 0.074 mmol)
solvated in DMF (1 mL) was added potassium carbonate (51.0 mg,
0.369 mmol) followed by iodoethane (0.018 mL, 0.221 mmol). The
reaction mixture was allowed to stir at room temperature overnight.
After 15 hours, the reaction mixture was diluted with hexanes and
extracted with water. The organic phase was concentrated in vacuo
to provide Intermediate 306A (18 mg, 0.066 mmol, 90% yield) which
was used without further purification. LC-MS: Method H, RT=1.31
min, MS (ESI) m/z: 272.1, 274.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.07 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4, 0.7
Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.45 (t, J=7.0 Hz,
3H).
Example 306
[3070] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 306A with Intermediate I-2 afforded
Example 306 in 43% yield following purification by preparative HPLC
(Method D, 60-100% over 10 min). LC-MS: Method H, RT=1.49 min, MS
(ESI) m/z: 380.3 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.09 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.53
(d, J=2.2 Hz, 1H), 7.00 (s, 1H), 4.81 (s, 2H), 4.12 (q, J=6.9 Hz,
2H), 3.47 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 1.38 (t, J=7.0 Hz,
3H).
Example 307
6-(benzyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[-
d]thiazole
##STR01099##
[3071] Intermediate 307A:
6-(benzyloxy)-2-bromo-4-methylbenzo[d]thiazole
##STR01100##
[3073] To a solution of Intermediate I-40 (18 mg, 0.074 mmol)
solvated in DMF (1 mL) was added potassium carbonate (51.0 mg,
0.369 mmol) followed by benzyl bromide (0.013 mL, 0.111 mmol). The
reaction mixture was allowed to stir at room temperature overnight.
After 15 hours, the reaction mixture was diluted with hexanes and
extracted with water. The organic phase was concentrated in vacuo
to provide Intermediate 307A (23 mg, 0.066 mmol, 91% yield) which
was used without further purification. LC-MS: Method H, RT=1.37
min, MS (ESI) m/z: 334.1, 336.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.44-7.20 (m, 5H), 7.06 (d, J=2.2 Hz, 1H),
6.89 (s, 1H), 5.02 (s, 2H), 2.59 (s, 3H).
Example 307
[3074] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 307A with Intermediate I-2 afforded
Example 307 in 48% yield following purification by preparative HPLC
(Method D, 55-100% over 10 min). LC-MS: Method H, RT=1.48 min, MS
(ESI) m/z: 442.3 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.08 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.63 (d, J=2.2
Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.38-7.32
(m, 1H), 7.09 (s, 1H), 5.20 (s, 2H), 4.81 (s, 2H), 3.46 (s, 3H),
2.75 (s, 3H), 2.69 (s, 3H).
Example 308
(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)methano-
l
##STR01101##
[3075] Intermediate 308A: ethyl
2-bromobenzo[d]thiazole-6-carboxylate
##STR01102##
[3077] This example was prepared according to the general procedure
for 2-aminobenzothiazoles described in the table above. Thus,
reaction of ethyl 2-aminobenzo[d]thiazole-6-carboxylate afforded
Intermediate 308A in 98% yield. LC-MS: Method A, RT=2.06 min, MS
(ESI) m/z: 286.0, 288.0 (M+H).sup.+. .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. 8.56 (d, J=1.4 Hz, 1H), 8.18 (dd, J=8.5, 1.7
Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.45 (t,
J=7.2 Hz, 3H).
Intermediate 308B: (2-bromobenzo[d]thiazol-6-yl)methanol
##STR01103##
[3079] Intermediate 308A (0.85 g, 2.97 mmol) was dissolved in THF
(20 mL) and cooled to 0.degree. C. 1.0 M Super-Hydride in THF (6.54
mL, 6.54 mmol) was added dropwise to this cooled solution. After
stirring at 0.degree. C. for 1 h, the reaction was quenched with
saturated ammonium chloride and then diluted with EtOAc. The
organic layer was washed with brine, dried over sodium sulfate,
filtered and concentrated. The crude product was purified by silica
gel chromatography (24 g, 5-60% EtOAc/Hexanes, 18 min) to give
Intermediate 308B (0.5 g, 2.048 mmol, 69.0% yield) as a white
solid. LC-MS: Method A, RT=1.54 min, MS (ESI) m/z: 244.0 and 246.0
(M+H).sup.+. .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.93 (d,
J=8.5 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.39 (dd, 1.5 Hz, 1H), 5.08
(s, 2H).
Example 308
[3080] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 308B with Intermediate I-2 afforded
Example 308 in 19% yield following purification by preparative HPLC
(Method D, 20-60% over 10 min). LC-MS: Method H, RT=1.15 min, MS
(ESI) m/z: 352.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.13 (s, 1H), 8.88 (d, J=1.7 Hz, 1H), 8.13 (s, 1H), 8.10
(d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.54 (dd, J=8.5, 1.4 Hz, 1H), 5.38
(t, J=5.8 Hz, 1H), 4.83 (s, 2H), 4.69 (d, J=5.8 Hz, 2H), 3.49 (s,
3H), 2.71 (s, 3H).
Example 309
6-(methoxymethyl)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thi-
azole
##STR01104##
[3081] Intermediate 309A:
2-bromo-6-(methoxymethyl)benzo[d]thiazole
##STR01105##
[3083] Intermediate 308B (52 mg, 0.213 mmol) was solvated in THF
(2.1 mL) and cooled to 0.degree. C. Sodium Hydride (42.6 mg, 1.065
mmol) was added, causing effervescence. After 5 minutes, methyl
iodide (0.067 mL, 1.065 mmol) was added. The mixture was then
allowed to warm to room temperature and stirred for 10 minutes
until all of the bubbling subsided. The reaction was quenched with
saturated NH.sub.4Cl and diluted with EtOAc. The organic phase was
extracted, washed with brine, dried over MgSO.sub.4 and
concentrated. The crude material was purified by ISCO (12 g, 0-20%
EtOAc/Hexanes, 18 min. Product at 8%) to afford Intermediate 309A
(10 mg, 0.039 mmol, 18% yield). LC-MS: Method H, RT=1.19 min, MS
(ESI) m/z: 258.1, 260.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.96 (d, J=8.4 Hz, 1H), 7.81 (d, J=0.7 Hz,
1H), 7.43 (dd, J=8.4, 1.5 Hz, 1H), 4.58 (s, 2H), 3.44 (s, 3H).
Example 309
[3084] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 309A with Intermediate I-2 afforded
Example 309 in 27% yield following purification by preparative HPLC
(Method D, 45-85% over 10 min). LC-MS: Method H, RT=1.33 min, MS
(ESI) m/z: 366.3 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.13 (s, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.15 (s, 1H), 8.12
(d, J=8.3 Hz, 1H), 8.09 (s, 1H), 7.54 (d, J=8.3 Hz, 1H), 4.84 (s,
2H), 4.61 (s, 2H), 3.49 (s, 3H), 3.37 (s, 3H), 2.71 (s, 3H).
Example 310
6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-o-
l
##STR01106##
[3085] Intermediate 310A:
3-((tert-butyldimethylsilyl)oxy)-4-methoxyaniline
##STR01107##
[3087] 5-amino-2-methoxyphenol (500 mg, 3.59 mmol) was solvated in
DMF (3.00 mL) and DCM (15.000 mL). To this solution was added
TBDMS-Cl (596 mg, 3.95 mmol) followed by imidazole (269 mg, 3.95
mmol) at room temperature. After 2 h, the reaction was quenched
with saturated NaHCO.sub.3 and extracted 2.times. with DCM. The
organic phase was concentrated and purified by ISCO (80 g, 0-100%
EtOAc/Hexanes, 33 min. Product at 35%) to give Intermediate 310A
(576 mg, 1.591 mmol, 44.3% yield). LC-MS: Method H, RT=0.99 min, MS
(ESI) m/z: 254.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 6.69 (d, J=8.4 Hz, 1H), 6.31-6.24 (m, 2H), 3.73 (s, 3H),
3.38 (br. s., 2H), 1.00 (s, 9H), 0.16 (s, 6H).
Intermediate 310B:
5-((tert-butyldimethylsilyl)oxy)-6-methoxybenzo[d]thiazol-2-amine
##STR01108##
[3089] This example was prepared according to the general procedure
for the synthesis of 2-aminobenzothiazoles described in the table
above. Thus, Intermediate 310A was reacted to afford Intermediate
310B as a viscous brown oil (36% Yield). LC-MS: Method H, RT=1.16
min, MS (ESI) m/z: 311.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.11 (s, 1H), 7.07 (s, 1H), 4.93 (br. s.,
2H), 3.83 (s, 3H), 1.02 (s, 9H), 0.18 (s, 6H).
Intermediate 310C:
2-bromo-5-((tert-butyldimethylsilyl)oxy)-6-methoxybenzo[d]thiazole
##STR01109##
[3091] This intermediate was prepared according to the general
procedure for the synthesis of 2-bromobenzothiazoles described in
the table above. Thus, Intermediate 310B was reacted to afford
Intermediate 310C as a purple oil (53% yield). LC-MS: Method H,
RT=1.50 min, MS (ESI) m/z: 374.0, 376.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.08 (s, 1H), 6.99 (s, 1H), 3.69
(s, 3H), 0.84 (s, 9H), 0.00 (s, 6H).
Intermediate 310D: 2-bromo-6-methoxybenzo[d]thiazol-5-ol
##STR01110##
[3093] To a solution of Intermediate 310C (76 mg, 0.203 mmol) in
THF (2030 .mu.l) was added TBAF (1.0 M in THF) (264 .mu.l, 0.264
mmol) at room temperature. After 10 min, the reaction mixture was
diluted with EtOAc and washed with brine. The organic phase was
concentrated and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 18
min. Product at 28%) to give Intermediate 310D (28 mg, 0.108 mmol,
53.0% yield) as a white solid. LC-MS: Method H, RT=1.05 min, MS
(ESI) m/z: 260.0, 262.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.53 (s, 1H), 7.21 (s, 1H), 5.80 (s, 1H),
3.99 (s, 3H).
Example 310
[3094] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 310D with Intermediate I-2 afforded
Example 310 in 36% yield following purification by preparative HPLC
(Method D, 15-55% over 20 min). LC-MS: Method H, RT=1.17 min, MS
(ESI) m/z: 368.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.46 (br. s., 1H), 9.09 (s, 1H), 8.79 (s, 1H), 8.01 (s,
1H), 7.69 (s, 1H), 7.47 (s, 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.48
(s, 3H), 2.68 (s, 3H).
Example 311
5,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-
e
##STR01111##
[3095] Intermediate 311A: 2-bromo-5,6-dimethoxybenzo[d]thiazole
##STR01112##
[3097] To a solution of Intermediate 310D (14 mg, 0.054 mmol)
solvated in DMF (1 mL) was added potassium carbonate (37.2 mg,
0.269 mmol) followed by iodomethane (10.10 .mu.l, 0.161 mmol). The
reaction mixture was allowed to stir at room temperature overnight.
After 14 h, the reaction mixture was diluted with hexanes and
washed with water followed by brine. The organic phase was dried
over MgSO.sub.4, filtered and concentrated to provide Intermediate
311A (11 mg, 0.040 mmol, 75% yield) as a white solid, which was
taken on without further purification. LC-MS: Method H, RT=1.13
min, MS (ESI) m/z: 274.0, 276.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.46 (s, 1H), 7.22 (s, 1H), 3.97 (s, 3H),
3.96 (s, 3H.)
Example 311
[3098] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 311A with Intermediate I-2 afforded
Example 311 in 30% yield following purification by preparative HPLC
(Method D, 30-70% over 10 min). LC-MS: Method H, RT=1.27 min, MS
(ESI) m/z: 382.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H),
7.67 (s, 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.48 (s,
3H), 2.69 (s, 3H).
Example 312
(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5--
yl) methanol
##STR01113##
[3099] Intermediate 312A: 2-methoxy-5-nitrobenzonitrile
##STR01114##
[3101] To a vessel charged with 2-bromo-1-methoxy-4-nitrobenzene (1
g, 4.31 mmol), zinc cyanide (0.506 g, 4.31 mmol), zinc (0.028 g,
0.431 mmol) and palladium tetrakis (0.174 g, 0.151 mmol) was added
DMF (14.37 ml), and the mixture was sparged with argon for 20 min.
The vial was sealed and heated to 90.degree. C. overnight. After 22
h, the black solution was diluted with water and EtOAc. The organic
phase was extracted, washed with brine, concentrated and purified
by ISCO (80 g, 0-100% EtOAc/Hexanes, 28 min. Product at 50%) to
provide Intermediate 312A (520 mg, 2.92 mmol, 67.7% yield) as an
off-white solid. LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: None
Observed (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.49 (d, J=2.6 Hz, 1H), 8.48-8.43 (m, 1H), 7.10 (d, J=9.2 Hz, 1H),
4.08 (s, 3H).
Intermediate 312B: 2-methoxy-5-nitrobenzaldehyde
##STR01115##
[3103] A solution of Intermediate 312A (520 mg, 2.92 mmol) in
Et.sub.2O (23.400 mL) was cooled to 0.degree. C. under an
atmosphere of N.sub.2. A solution of DIBAl-H (1.0 M in Toluene)
(4.38 mL, 4.38 mmol) was then added dropwise causing bubbling to
occur. After 5 min of stirring, the reaction mixture was allowed to
thaw to room temperature. After an additional 3 h, the orange
solution was poured into a mixture of ice and 10 mL of glacial
acetic acid. This mixture was stirred while the ice melted, diluted
with EtOAc and DI water and then extracted. The organic phase was
concentrated and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 28
min. Product at 55%) to afford Intermediate 312B (410 mg, 1.811
mmol, 62.0% yield) as a light orange solid. LC-MS: Method H,
RT=0.77 min, MS (ESI) m/z: 182.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 10.46 (s, 1H), 8.71 (d, J=2.9 Hz, 1H), 8.45
(dd, J=9.2, 2.9 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 4.08 (s, 3H).
Intermediate 312C: (2-methoxy-5-nitrophenyl)methanol
##STR01116##
[3105] A solution of Intermediate 312B (410 mg, 2.263 mmol) in
Toluene (11.500 mL) and THF (11.50 mL) was cooled to -78.degree. C.
under an atmosphere of N.sub.2. DIBAL-H (1.0 M in Toluene) (3.40
mL, 3.40 mmol) was then added to the cooled solution dropwise.
After the initial bubbling had subsided, the reaction mixture was
allowed to thaw to room temperature. After 1 h, the reaction
mixture was cooled to 0.degree. C. and quenched with 1.0 M HCl. The
resulting suspension was stirred vigorously for 45 min to fully
cleave the aluminate complex. The mixture was then diluted with
EtOAc and extracted. The organic phase was washed with brine, dried
over MgSO.sub.4, filtered and concentrated. The resulting crude
product was purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 33 min.
Product at 50%) to give Intermediate 312C (370 mg, 1.717 mmol, 76%
yield) as a light yellow solid. LC-MS: Method H, RT=0.68 min, MS
(ESI) m/z: 184.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 8.29 (d, J=2.9 Hz, 1H), 8.21 (dd, J=9.0, 2.6 Hz, 1H), 6.94
(d, J=9.0 Hz, 1H), 4.75 (d, J=6.4 Hz, 2H), 3.97 (s, 3H), 2.07 (t,
J=6.4 Hz, 1H).
Intermediate 312D:
tert-butyl((2-methoxy-5-nitrobenzyl)oxy)dimethylsilane
##STR01117##
[3107] To a solution of Intermediate 312C (370 mg, 1.717 mmol) and
triethylamine (0.479 mL, 3.43 mmol) in DCM (17.200 mL) was added
TBS-Cl (336 mg, 2.232 mmol) followed by DMAP (42.0 mg, 0.343 mmol).
After 2 h, the reaction mixture was concentrated and the crude
material was purified by ISCO (80 g, 0-20% EtOAc/Hexanes, 28 min.
Product at 15%.) to give Intermediate 312D (490 mg, 1.647 mmol, 96%
yield) as a yellow oil. LC-MS: Method H, RT=1.24 min, MS (ESI) m/z:
None Observed (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 8.45-8.35 (m, 1H), 8.17 (dd, 2.6 Hz, 1H), 6.88 (d, J=8.8
Hz, 1H), 4.75 (s, 2H), 3.94 (s, 3H), 0.99 (s, 9H), 0.15 (s,
6H).
Intermediate 312E:
3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxyaniline
##STR01118##
[3109] Degussa grade Pd/C (175 mg, 0.165 mmol) was added to a 250
mL round bottom flask containing Intermediate 312D (490 mg, 1.647
mmol). The mixture was carefully wet with a few mL of MeOH before
adding the total volume of solvent (14.0 mL). The head space of the
flask was evacuated until the solvent began to slightly bubble and
then back-filled with N.sub.2. A hydrogen balloon was attached to
the flask, and the solution was sparged with H.sub.2 for about 5
minutes through a vent needle. The vent was removed and the
reaction mixture was stirred vigorously under the H.sub.2
atmosphere for 1 h before being filtered over celite to remove the
Pd/C. The celite was rinsed with EtOAc, and the filtrate was
concentrated to afford Intermediate 312E (430 mg, 1.608 mmol, 98%
yield) as a brown oil. LC-MS: Method H, RT=0.81 min, MS (ESI) m/z:
268.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.88
(d, J=2.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.55 (dd, J=8.4, 2.9 Hz,
1H), 4.72 (s, 2H), 3.75 (s, 3H), 3.43 (br. s., 2H), 0.97 (s,
9H).
Intermediate 312F:
5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxybenzo[d]thiazol-2-amine
Intermediate 312G:
(2-amino-6-methoxybenzo[d]thiazol-5-yl)methanol
##STR01119##
[3111] To a solution of Intermediate 312E (430 mg, 1.608 mmol) in
acetonitrile (13.700 mL) was added ammonium thiocyanate (159 mg,
2.090 mmol). The mixture was stirred at room temperature for 10 min
followed by the addition of benzyltrimethylammonium tribromide (627
mg, 1.608 mmol). After 3 days the reaction mixture was diluted with
saturated NaHCO.sub.3 and extract with EtOAc 3.times.. The organic
phase was dried over MgSO.sub.4, filtered, concentrated and
purified by ISCO (40 g, 0-100% EtOAc/Hexanes, 19 min. Product at
50%) to give Intermediate 312F (219 mg, 0.675 mmol, 42.0% yield) as
a brown oil. LC-MS: Method H, RT=0.89 min, MS (ESI) m/z: 325.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.69 (s,
1H), 7.06 (s, 1H), 4.97 (br. s., 2H), 4.80 (d, J=0.9 Hz, 2H), 3.84
(s, 3H), 0.98 (s, 9H), 0.13 (s, 6H). The silica gel column was
further flushed (0-20% DCM/MeOH, 19 min. Product at 12%) to afford
Intermediate 312G (166 mg, 0.790 mmol, 49.1% yield) as a tan solid.
LC-MS: Method H, RT=0.47 min, MS (ESI) m/z: 211.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.41 (s, 1H), 7.21
(s, 1H), 4.64 (s, 2H), 3.83 (s, 3H).
Intermediate 312H:
(2-bromo-6-methoxybenzo[d]thiazol-5-yl)methanol
##STR01120##
[3113] To a suspension of Intermediate 312G (160 mg, 0.761 mmol) in
acetonitrile (7610 .mu.l) was added copper (II) bromide (170 mg,
0.761 mmol) followed by t-Butyl nitrite (131 .mu.l, 0.989 mmol).
After 1 h of stirring, the reaction mixture was diluted with EtOAc,
and poured into a 1.0 M HCl solution. The organic phase was dried
over MgSO.sub.4, filtered, concentrated and purified by ISCO (40 g,
0-70% EtOAc/Hexanes, 19 min. Product at 35%) to afford Intermediate
312H (119 mg, 0.434 mmol, 57.0% yield) as an off-white solid.
LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 274.1, 276.1
(M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.93
(s, 1H), 7.50 (s, 1H), 4.71 (d, J=0.7 Hz, 2H), 3.91 (s, 3H).
Example 312
[3114] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 312H with Intermediate I-2 afforded
Example 312 in 47% yield following purification by preparative HPLC
(Method D, 30-70% over 20 min). LC-MS: Method H, RT=0.96 min, MS
(ESI) m/z: 382.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.11 (br. s., 1H), 8.82 (br. s., 1H), 8.08 (br. s., 1H),
8.04 (br. s., 1H), 7.74 (br. s., 1H), 4.83 (br. s., 2H), 4.65 (br.
s., 2H), 3.92 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s.,
3H).
Example 313
6-chloro-5-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)
benzo[d]thiazole
##STR01121##
[3115] Intermediate 313A:
1-chloro-2-fluoro-3-methoxy-4-nitrobenzene
##STR01122##
[3117] To a 0.degree. C. solution of
1-chloro-2-fluoro-3-methoxybenzene (1.606 g, 10 mmol) in acetic
acid (5.00 ml) was added fuming nitric acid (0.933 ml, 20.00 mmol)
followed by the dropwise addition of sulfuric acid (2.132 ml, 40.0
mmol). After 30 min, the reaction mixture was poured into water and
diluted with ethyl acetate. The organic phase was separated and
washed 2.times. with saturated NaHCO.sub.3 followed by a final
brine wash. The organic solution was then dried over MgSO.sub.4,
filtered, concentrated and purify by ISCO (120 g, 10-50%
EtOAc/Hexanes, 25 min. Desired regioisomer eluted first) affording
Intermediate 313A (900 mg, 4.38 mmol, 44% yield) as a yellow solid.
LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: None Observed
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.60 (dd,
J=9.0, 2.2 Hz, 1H), 7.24 (dd, J=9.0, 6.6 Hz, 1H), 4.11 (d, J=1.8
Hz, 3H). Regiochemistry confirmed through NMR analysis of both
regioisomeric products.
Intermediate 313B: 4-chloro-3-fluoro-2-methoxyaniline
##STR01123##
[3119] A solution of Intermediate 313A (700 mg, 3.41 mmol) in MeOH
(17.000 mL, 0.2 M) was added NH.sub.4Cl (3643 mg, 68.1 mmol) and
zinc dust (2226 mg, 34.1 mmol) was heated to reflux for 1 h. The
resulting mixture was allowed to cool to room temperature and the
solvent was removed in vacuo. The resulting residue was diluted
with EtOAc and saturated sodium bicarbonate (0.2 M of each) and
stirred vigorously for an additional 1 hr. The mixture was filtered
over celite, the organic layer was separated, washed with brine,
dried over MgSO.sub.4, filtered and concentrated to give
Intermediate 313B (466 mg, 2.66 mmol, 78% yield) as a dark brown
solid. This material was taken on without further purification.
LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 176.1, 178.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.87 (dd,
7.5 Hz, 1H), 6.43 (dd, J=8.7, 1.9 Hz, 1H), 3.92 (d, J=1.5 Hz, 3H),
3.49 (s, 2H).
Intermediate 313C:
6-chloro-5-fluoro-4-methoxybenzo[d]thiazol-2-amine
##STR01124##
[3121] This example was prepared according to the general procedure
for 2-aminobenzothiazoles described in the table above. Thus,
reaction of Intermediate 313B afforded Intermediate 313C in 21%
yield. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 233.1, 235.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.30 (d,
J=6.2 Hz, 1H), 5.38 (br. s., 2H), 4.15 (d, J=1.8 Hz, 3H).
Intermediate 313D:
6-chloro-5-fluoro-4-methoxybenzo[d]thiazol-2-amine
##STR01125##
[3123] Intermediate 313D was prepared according to the general
procedure for 2-bromobenzothiazoles described in the table above.
Thus, reaction of Intermediate 313C afforded Intermediate 313D in
58% yield. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 296.0,
298.0, 299.9 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.50 (d, J=5.7 Hz, 1H), 4.30 (d, J=1.8 Hz, 3H).
Example 313
[3124] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 313D with Intermediate I-2 afforded
Example 313 in 8% yield following purification by preparative HPLC
(Method D, 60-100% over 20 min). LC-MS: Method H, RT=1.49 min, MS
(ESI) m/z: 404.1, 406.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.13 (s, 1H), 8.89 (s, 1H), 8.20 (d, J=6.1
Hz, 1H), 8.13 (br. s., 1H), 4.84 (s, 2H), 4.41 (s, 3H), 3.48 (s,
3H), 2.73 (s, 3H).
Example 314
4-cyclopropyl-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-
-yl)benzo[d]thiazole
##STR01126##
[3126] Example 283 (19 mg, 0.047 mmol) was solvated in a solution
of cyclopropylzinc(II) bromide (0.5 M in THF, 1411 .mu.l, 0.706
mmol) and transferred to a microwave vial containing
Pd(dppf).sub.2Cl.sub.2--CH.sub.2Cl.sub.2 adduct (3.84 mg, 4.70
.mu.mol). The solution was sparged with argon for 5 min, sealed and
then heated to 100.degree. C. in the microwave. The crude reaction
mixture was then concentrated, retaken in DMF, filtered and
purified by preparatory HPLC (Method D, 60-100% over 20 min) to
afford Example 314 (1.1 mg, 2.69 .mu.mol, 6% yield). LC-MS: Method
H, RT=1.47 min, MS (ESI) m/z: 410.1, (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.73 (d, J=1.7 Hz, 1H),
8.05 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 4.86-4.78 (m, 2H), 3.94 (s,
3H), 3.49 (s, 3H), 2.70 (s, 3H), 2.66-2.58 (m, 1H), 1.18-1.13 (m,
2H), 0.87 (t, J=6.9 Hz, 2H).
Example 315
6-ethoxy-4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
e
##STR01127##
[3127] Intermediate 315A:
2-bromo-6-ethoxy-4,5-difluorobenzo[d]thiazole
##STR01128##
[3129] To a vial charged with Intermediate I-42 (13 mg, 0.049 mmol)
and Cs.sub.2CO.sub.3 (80 mg, 0.244 mmol) was added DMF (1 mL). The
resulting mixture was vigorously stirred for 5 min before the
addition of iodoethane (0.012 mL, 0.147 mmol). After 16 h of
stirring at room temperature, the reaction mixture was diluted with
hexanes and extracted with water. The organic phase was dried over
MgSO.sub.4, filtered, concentrated and purified by ISCO (12 g,
0-20% EtOAc/Hexanes, 16 min. Product at 8%) to afford Intermediate
315A (9 mg, 0.031 mmol, 62.6% yield) as a white solid. LC-MS:
Method H, RT=1.27 min, MS (ESI) m/z: 294.0, 296.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.08 (dd, J=6.6, 2.0
Hz, 1H), 4.16 (q, J=6.9 Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).
Example 315
[3130] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 315A with Intermediate I-2 afforded
Example 315 in 22% yield following purification by preparative HPLC
(Method D, 60-100% over 20 min). LC-MS: Method H, RT=1.48 min, MS
(ESI) m/z: 388.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.76 (s, 1H), 8.62 (s, 1H), 7.87 (s, 1H), 7.83 (d, J=6.9
Hz, 1H), 4.26 (q, J=6.9 Hz, 2H), 4.10 (s, 3H), 2.66 (s, 3H), 1.45
(t, J=7.0 Hz, 3H).
Example 316
N-(2-((4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-
-yl)oxy)ethyl)-3-fluorobenzenesulfonamide
##STR01129##
[3131] Intermediate 316A: tert-butyl
(2-((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethyl)carbamate
##STR01130##
[3133] A solution of Intermediate I-42 (100 mg, 0.376 mmol) and
triphenylphosphine (197 mg, 0.752 mmol) in THF (2 mL) was heated to
reflux. To this refluxing mixture was added a pre-mixed solution of
DIAD (0.219 mL, 1.128 mmol) and tert-butyl
(2-hydroxyethyl)carbamate (182 mg, 1.128 mmol) in THF (2 mL) over
the course of 2 h via syringe pump. The crude reaction mixture was
concentrated and purified by ISCO (40 g, 0-30% DCM/EtOAc, 22 min,
Product at 8%) to afford Intermediate 316A (53 mg, 0.130 mmol,
34.5% yield) as a yellow amorphous solid. LC-MS: Method H, RT=1.25
min, MS (ESI) m/z: 409.0, 411.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.11 (dd, J=6.5, 1.9 Hz, 1H), 5.03 (br. s.,
1H), 4.14 (t, J=5.2 Hz, 2H), 3.60 (q, J=5.4 Hz, 2H), 1.45 (s,
9H).
Intermediate 316B:
2((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethanamine HCl
##STR01131##
[3135] To a flask charged with Intermediate 316A (53 mg, 0.130
mmol) was added 4.0 N HCl in dioxane (2.43 mL, 9.71 mmol) causing a
white slurry to immediately form. After 1 h, the solution was
concentrated in vacuo to afford Intermediate 316B as an HCl salt.
LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 265.1, 267.1
(M+H--CH.sub.2CH.sub.2NH.sub.2).sup.+. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.59 (dd, J=6.9, 2.1 Hz, 1H), 4.42-4.36
(m, 2H), 3.46 (t, J=4.8 Hz, 2H).
Intermediate 316C:
N-(2-((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzen-
esulfonamide
##STR01132##
[3137] To a solution of Intermediate 316B (44 mg, 0.127 mmol) in
THF (1.5 mL) was added DIEA (0.067 mL, 0.382 mmol) and
3-fluorobenzene-1-sulfonyl chloride (37.2 mg, 0.191 mmol). The
white slurry was stirred for 1 hr before being quenched with water
and extracted with EtOAc. The organic phase was further washed with
brine, concentrated, and purified by ISCO (12 g, 0-50%
EtOAc/Hexanes, 20 min. Product at 38%) to afford Intermediate 316C
(53 mg, 0.113 mmol, 89% yield) as a pale yellow, amorphous solid.
LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 467.0, 469.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.72-7.67
(m, 1H), 7.63-7.56 (m, 1H), 7.51 (td, 5.3 Hz, 1H), 7.31-7.24 (m,
1H), 7.03 (dd, J=6.6, 2.0 Hz, 1H), 5.16 (t, J=6.2 Hz, 1H), 4.16 (t,
J=5.1 Hz, 2H), 3.53-3.46 (m, 2H).
Example 316
[3138] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 316C with Intermediate I-9 afforded
Example 316 in 43% yield following purification by preparative HPLC
(Method D, 50-100% over 20 min). LC-MS: Method H, RT=1.36 min, MS
(ESI) m/z: 561.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.67 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.23 (br. s., 1H),
7.79 (s, 1H), 7.72-7.67 (m, 2H), 7.67-7.61 (m, 2H), 7.48 (td,
J=8.5, 1.9 Hz, 1H), 4.18 (t, J=5.1 Hz, 2H), 4.08 (s, 3H), 3.36-3.30
(m, 2H-buried under DMSO), 2.62 (s, 3H).
Example 317
N-(2-((4,5-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]t-
hiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide
##STR01133##
[3140] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 316C with Intermediate I-2 afforded
Example 317 in 6% yield following purification by preparative HPLC
(Method D, 45-90% over 20 min). LC-MS: Method H, RT=1.30 min, MS
(ESI) m/z: 575.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.25-9.04 (m, 1H), 8.83 (br. s., 1H), 8.25 (br. s., 1H),
8.08 (br. s., 1H), 7.79 (d, J=6.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H),
7.63 (d, J=7.7 Hz, 1H), 7.46 (br. s., 1H), 4.82 (br. s., 2H), 4.20
(d, J=4.4 Hz, 2H), 3.49 (d, J=5.0 Hz, 3H), 3.36-3.30 (m, 2H-buried
under DMSO) 2.70 (br. s., 3H).
Example 318
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)ethanol
##STR01134##
[3141] Intermediate 318A:
2-((4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenz-
o[d]thiazol-6-yl)oxy)ethanol
##STR01135##
[3143] A 20 mL microwave vial was charged with Intermediate I-1
(623 mg, 1.853 mmol), Intermediate I-59 (605 mg, 1.853 mmol) and
[1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (76 mg, 0.093 mmol). These
solids were suspended in a combination of Toluene (11.600 mL), EtOH
(3.87 mL) and a 2.0 M solution of Na.sub.2CO.sub.3 (1.389 mL, 2.78
mmol). The resulting mixture was sparged with argon for 10 min,
sealed and then heated in a microwave at 130.degree. C. for 30 min.
The crude reaction mixture was diluted with 100 mL EtOAc and
filtered over celite. The organic solution was concentrated onto
celite and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 36 min.
Product dragged from 50%-100%) to afford Intermediate 318A (630 mg,
1.382 mmol, 74.6% yield) as a bright yellow solid. LC-MS: Method H,
RT=1.13 min, MS (ESI) m/z: 456.0, 458.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.00 (s, 1H), 8.76 (d, J=1.8 Hz,
1H), 8.03 (d, J=7.7 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.90 (t,
J=71.1 Hz, 1H), 4.99 (t, J=5.5 Hz, 1H), 4.22 (t, J=4.8 Hz, 2H),
3.82 (q, J=5.2 Hz, 2H), 2.70 (s, 3H).
Example 318
[3144] To a solution of Intermediate 318A (630 mg, 1.382 mmol) in
THF (27.600 mL) was added a 0.5 M solution of NaOMe in MeOH (27.6
mL, 13.82 mmol). After 1 h of stirring, the reaction mixture was
quenched with 1.0 N HCl (27.6 mL) and diluted with EtOAc. The
organic phase was washed with brine, and concentrated in vacuo to
afford Example 318 (650 mg, 1.393 mmol, 91% yield). The majority of
this crude material was taken on without further purification, but
a small portion was further purified by preparative HPLC for
characterization (Method D, 45-80% over 13 min, 100% for 5 min).
LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 420.1, 422.1
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.76 (s,
1H), 8.61 (d, J=1.8 Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.87 (s, 1H),
4.99 (t, J=5.4 Hz, 1H), 4.22 (t, J=5.0 Hz, 2H), 4.10 (s, 3H), 3.82
(q, J=5.2 Hz, 2H), 2.67 (s, 3H).
Example 319
1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thia-
zol-6-yl)oxy)-2-methylpropan-2-ol
##STR01136##
[3145] Intermediate 319A:
1-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol
##STR01137##
[3147] A solution of Intermediate I-49 (16 mg, 0.048 mmol) in THF
(1 mL) was cooled to -78.degree. C. To this cold solution was added
MeMgBr (3.0 M in Et.sub.2O) (0.162 mL, 0.485 mmol) dropwise. The
resulting mixture was allowed to warm to 0.degree. C. Once at
0.degree. C. the reaction was quenched with 1 mL of 1 M HCl. This
mixture was then concentrated and purified by ISCO (12 g, 0-50%
EtOAc/Hexanes, 16 min. Product at 25%,) to afford Intermediate 319A
(5 mg, 0.015 mmol, 31.2% yield) as a colorless oil. LC-MS: Method
H, RT=1.29 min, MS (ESI) m/z: 330.1, 332.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.06 (s, 1H), 3.83 (s, 2H), 2.65
(s, 3H), 2.30 (s, 3H), 2.14 (s, 1H), 1.40 (s, 6H).
Example 319
[3148] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 319A with Intermediate I-2 afforded
Example 319 in 67% yield following purification by preparative HPLC
(Method D, 70-100% over 10 min). LC-MS: Method H, RT=1.16 min, MS
(ESI) m/z: 438.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.10 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.53 (s, 1H),
4.82 (s, 2H), 4.71 (s, 1H), 3.83 (s, 2H), 3.49 (s, 3H), 2.77 (s,
3H), 2.70 (s, 3H), 2.31 (s, 3H), 1.30 (s, 6H).
Example 320
2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thia-
zol-6-yl)oxy)ethyl methyl carbonate
##STR01138##
[3149] Intermediate 320A:
2-((2-chloro-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethyl methyl
carbonate
##STR01139##
[3151] To a solution of Intermediate I-51 (30 mg, 0.099 mmol) in
THF (1 mL) was added Hunig's Base (0.087 mL, 0.496 mmol) followed
by a solution of phosgene (15% by wt in toluene) (0.210 mL, 0.298
mmol). After 15 min of stirring, 1 mL of MeOH was added and the
reaction mixture was concentrated. The crude residue was purified
by ISCO (12 g, 0-30% EtOAc/Hexanes, 16 min. Product at 15%) to
afford Intermediate 320A (12 mg, 0.038 mmol, 38.3% yield) as a
white solid. LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 316.1,
318.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.02
(d, J=8.4 Hz, 1H), 4.59-4.53 (m, 2H), 4.25-4.18 (m, 2H), 3.82 (s,
3H), 2.63 (d, J=5.1 Hz, 3H), 2.26 (s, 3H).
Example 320
[3152] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 320A with Intermediate I-2 afforded
Example 320 in 50% yield following purification by preparative HPLC
(Method D, 60-100% over 15 min). LC-MS: Method H, RT=1.17 min, MS
(ESI) m/z: 468.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.09 (s, 1H), 8.82 (s, 1H), 8.01 (s, 1H), 7.59 (s, 1H),
4.82 (s, 2H), 4.54 (br. s., 2H), 4.32 (br. s., 2H), 3.76 (s, 3H),
3.49 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.25 (s, 3H).
Example 321
2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thia-
zol-6-yl)oxy)propan-1-ol (racemate)
##STR01140##
[3153] Intermediate 321A:
2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol
##STR01141##
[3155] This example was prepared in a manner analogous to
Intermediate I-51. Thus, Intermediate I-50 (rac) was reacted to
afford Intermediate 321A (rac) (91% yield) as an off-white,
amorphous solid. LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 314.0,
316.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.14
(s, 1H), 4.57-4.46 (m, 1H), 3.80 (d, J=5.3 Hz, 2H), 2.64 (s, 3H),
2.26 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 1.26 (br. s, 1H).
Example 321
[3156] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 321A (rac) with Intermediate I-2 afforded
Example 321 (rac) in 66% yield following purification by
preparative HPLC (Method D, 40-75% over 10 min, 100% for 5 min).
LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 423.9 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.83 (s,
1H), 8.01 (s, 1H), 7.62 (s, 1H), 4.88 (t, J=5.5 Hz, 1H), 4.82 (s,
2H), 4.60-4.48 (m, 1H), 3.66 (dt, J=11.1, 5.3 Hz, 1H), 3.60-3.52
(m, 1H), 3.49 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.27 (s, 3H),
1.30 (d, J=5.8 Hz, 3H).
Example 322
1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thia-
zol-6-yl)oxy)propan-2-ol (racemate)
##STR01142##
[3157] Intermediate 322A:
2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetaldehyde
##STR01143##
[3159] A solution of Intermediate I-51 (20 mg, 0.066 mmol) in DCM
(1 mL) was cooled to 0.degree. C. To this cooled mixture was added
Dess-Martin Periodinane (84 mg, 0.199 mmol). After 1 h, the
solution was allowed to thaw to room temperature and stirred
vigorously for an additional 5 h. The reaction mixture was then
concentrated and the residue was purified by ISCO (12 g, 0-50%
EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate 322A
(11 mg, 0.037 mmol, 55.4% yield) as a white solid. LC-MS: Method H,
RT=1.09 min, MS (ESI) m/z: 317.7, 319.7 (M+H+H.sub.2O).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.90 (t, J=1.1 Hz, 1H),
6.93 (s, 1H), 4.62 (d, J=1.1 Hz, 2H), 2.69-2.63 (m, 3H), 2.35 (s,
3H).
Intermediate 322B:
1-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol
(racemate)
##STR01144##
[3161] A solution of Intermediate 322A (11 mg, 0.037 mmol) in THF
(2 mL) was cooled to -78.degree. C. MeMgBr (3.0 M in Et.sub.2O)
(0.122 mL, 0.366 mmol) was then added dropwise to this cold
solution. After 1 h of vigorous stirring, the reaction mixture was
quenched with saturated NH.sub.4Cl and then allowed to thaw to room
temperature. Once at room temperature, the mixture was diluted with
EtOAc, the organic phase was extracted, dried over MgSO.sub.4,
filtered, concentrated, and purified by ISCO (12 g, 0-50%
EtOAc/Hexanes, 16 min. Product at 28%) to afford Intermediate 322B
(rac) (6 mg, 0.013 mmol, 36.2% yield). LC-MS: Method H, RT=1.57
min, MS (ESI) m/z: 315.9, 317.9 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.06 (s, 1H), 4.62 (d, J=1.1 Hz, 1H), 4.27
(ddd, J=10.1, 6.8, 3.2 Hz, 1H), 4.01-3.94 (m, 1H), 3.85 (dd, J=9.1,
7.4 Hz, 1H), 2.64 (s, 3H), 2.28 (s, 3H), 1.33 (d, J=6.6 Hz, 3H)
Example 322
[3162] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 322B with Intermediate I-2 afforded
Example 322 (rac) in 46% yield following purification by
preparative HPLC (Method D, 45-90% over 10 min, 100% for 5 min).
LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 424.2 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.83 (s,
1H), 8.02 (s, 1H), 7.55 (s, 1H), 4.92 (d, J=3.9 Hz, 1H), 4.82 (s,
2H), 4.11-4.03 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.85 (m, 1H), 3.49
(s, 3H), 2.77 (s, 3H), 2.71 (s, 3H), 2.29 (s, 3H), 1.25 (d, J=6.1
Hz, 3H).
Example 323
3-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thia-
zol-6-yl)oxy)butan-2-ol (diastereomeric mixture)
##STR01145##
[3163] Intermediate 323A:
2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propanal
(racemate)
##STR01146##
[3165] This example was prepared in a manner analogous to
Intermediate 322A. Thus, Intermediate 321A (rac) was reacted to
afford Intermediate 323A (rac) (71% yield). LC-MS: Method H,
RT=1.37 min, MS (ESI) m/z: 214.0, 216.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.72 (d, J=2.0 Hz, 1H), 6.93 (s,
1H), 4.64 (qd, 2.0 Hz, 1H), 2.66 (s, 3H), 2.33 (s, 3H), 1.55 (d,
J=6.8 Hz, 3H).
Intermediate 323B:
3-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol
(diastereomeric mixture)
##STR01147##
[3167] This example was prepared in a manner analogous to
Intermediate 322B. Thus, Intermediate 323A (rac) was reacted to
afford Intermediate 323B (diastereomeric mixture) (57% yield).
LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 330.0, 332.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.10 (s,
1H), 4.36 (qd, J=6.3, 3.4 Hz, 1H), 4.06 (br. s., 1H), 2.64 (s, 3H),
2.27 (s, 3H), 1.95 (br. s., 1H), 1.30 (d, J=6.4 Hz, 3H), 1.30-1.25
(m, 3H) [Major Diastereomer]. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.13 (s, 1H), 4.20 (quin, J=6.3 Hz, 1H), 3.97-3.88 (m, 1H),
2.64 (s, 3H), 2.42 (br. s., 1H), 2.27 (s, 3H), 1.30 (d, J=6.4 Hz,
3H), 1.30-1.24 (m, 3H) [Minor Diastereomer].
Example 323
[3168] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 323B (diastereomeric mixture) with
Intermediate I-2 afforded Example 323 (diastereomeric mixture) in
62% yield following purification by preparative HPLC (Method D,
50-100% over 40 min). LC-MS: Method H, RT=1.13 min, MS (ESI) m/z:
438.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10
(s, 1H), 8.84 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.23-6.95 (m,
1H), 4.82 (s, 2H), 4.36 (d, J=5.8 Hz, 1H), 3.81 (d, J=4.4 Hz, 1H),
3.49 (s, H), 2.76 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H), 1.30 (d,
J=5.8 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H) [Major Diastereomer]. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.84 (s, 1H),
8.02 (s, 1H), 7.60 (br. s., 1H), 7.24-6.96 (m, 1H), 4.82 (s, 2H),
4.45 (br. s., 1H), 3.88 (d, J=3.6 Hz, 1H), 3.49 (s, 3H), 2.76 (s,
3H), 2.71 (s, 3H), 2.27 (s, 3H), 1.26 (d, J=5.5 Hz, 3H), 1.17 (d,
J=6.1 Hz, 3H) [Minor Diastereomer].
Example 324
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)-1-morpholinoethanone
##STR01148##
[3169] Intermediate 324A:
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)acetic acid
##STR01149##
[3171] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate I-58 with Intermediate I-9 afforded
Intermediate 324A in 52% yield. LC-MS: Method H, RT=0.79 min, MS
(ESI) m/z: 434.0, 436.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.60 (s, 1H), 7.86 (s, 1H),
7.64 (d, J=7.3 Hz, 1H), 4.38 (br. s., 2H), 4.09 (s, 3H), 2.66 (s,
3H).
Example 324
[3172] To a suspension of Intermediate 324A (10 mg, 0.023 mmol) in
DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.024 mL,
0.138 mmol) followed by
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(50% solution in DMF) (0.041 mL, 0.069 mmol). The reaction mixture
was stirred at room temperature for 2 min until all of starting
material had solvated, then morpholine (5.96 .mu.l, 0.069 mmol) was
added. After 15 min, the reaction mixture was filtered and purified
by preparative HPLC (Method D, 45-85% over 20 min, 100% for 5 min)
to afford Example 324 (3.0 mg, 5.96 .mu.mol, 26% yield). LC-MS:
Method H, RT=1.14 min, MS (ESI) m/z: 503.1, 505.1 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.62 (s,
1H), 7.91 (d, J=7.7 Hz, 1H), 7.88 (s, 1H), 5.13 (s, 2H), 4.10 (s,
3H), 3.69 (br. s., 2H), 3.62 (br. s., 2H), 3.49 (br. s., 4H), 2.67
(s, 3H).
Example 325
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-
-yl) methanol (bis-deuterated)
##STR01150##
[3173] Intermediate 325A:
(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)methanol
(bis-deuterated)
##STR01151##
[3175] A solution of Intermediate I-54D (50 mg, 0.158 mmol) in
toluene (791 .mu.l) and THF (791 .mu.l) was cooled to -78.degree.
C. under an atmosphere of N.sub.2. To this mixture was added
DIBAL-D (0.7 M in toluene) (904 .mu.l, 0.633 mmol). After 30 min of
stirring, the solution was allowed to thaw to room temperature
before being quenched with 3 mL 1 M HCl. The resulting mixture was
stirred vigorously for 30 min before being dilute with EtOAc. The
organic phase was then extracted, washed with brine, dried over
MgSO.sub.4, filtered, concentrated and purified by ISCO (12 g,
0-100% EtOAc/Hexanes, 16 min. Product at 38%) to afford
Intermediate 325A (5 mg, 0.017 mmol, 10.90% yield) as a white
solid. LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 289.7, 291.7
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.14 (s,
1H), 3.88 (s, 3H), 3.35 (s, 1H), 2.33 (s, 3H)
Example 325
[3176] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 325A with Intermediate I-2 afforded
Example 325 in 61% yield following purification by preparative HPLC
(Method D, 30-65% over 15 min, 100% for 5 min). LC-MS: Method H,
RT=1.06 min, MS (ESI) m/z: 397.8 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.10 (s, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.03
(s, 1H), 7.69 (s, 1H), 5.02 (s, 1H), 4.82 (s, 2H), 3.92 (s, 3H),
3.48 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H).
Example 326
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d-
]thiazol-4-yl)ethanol
##STR01152##
[3177] Intermediate 326A:
1-(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)ethanol
##STR01153##
[3179] A solution of Intermediate I-55 (40 mg, 0.140 mmol) in THF
(1398 .mu.l) was cooled to -78.degree. C. MeMgBr (3.0 M in
Et.sub.2O) (466 .mu.l, 1.398 mmol) was added dropwise to this cold
mixture. After 30 min, the reaction was quenched with saturated
NH.sub.4Cl and the resulting mixture was allowed to thaw to room
temperature. Once at room temperature, the mixture was diluted with
EtOAc and washed with saturated NH.sub.4Cl followed by brine. The
organic phase was dried over MgSO.sub.4, filtered, concentrated and
purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min. Product at
20%) to afford Intermediate 326A (12 mg, 0.040 mmol, 28.4% yield).
LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 302.0, 304.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.10 (s,
1H), 5.33-5.29 (m, 1H), 3.87 (s, 3H), 2.26 (s, 3H), 1.62-1.58 (m,
3H).
Example 326
[3180] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 326A with Intermediate I-2 afforded
Example 326 in 54% yield following purification by preparative HPLC
(Method D, 45-80% over 20 min, 100% for 5 min). LC-MS: Method H,
RT=1.11 min, MS (ESI) m/z: 410.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. 9.09 (s, 1H), 8.71 (s, 1H), 7.95 (s, 1H),
7.29 (s, 1H), 6.72 (d, J=10.7 Hz, 1H), 5.49-5.39 (m, 1H), 4.85 (s,
2H), 3.94 (s, 3H), 3.74 (s, 1H), 3.58 (s, 3H), 2.71 (s, 3H), 2.32
(s, 3H), 1.72 (d, J=6.6 Hz, 3H).
Example 327
2-((4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d-
]thiazol-6-yl)oxy)ethanol
##STR01154##
[3181] Intermediate 327A:
2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-ol
##STR01155##
[3183] This example was prepared in a manner analogous to
Intermediate I-44. Thus, Intermediate I-56 was reacted to afford
Intermediate 327A (36% yield) as a light pink solid. LC-MS: Method
H, RT=0.94 min, MS (ESI) m/z: 277.7, 279.7, 281.6 (M+H).sup.+.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.19 (s, 1H), 2.37
(s, 3H).
Intermediate 327B: methyl
2((2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-yl)oxy) acetate
##STR01156##
[3185] This example was prepared in a manner analogous to
Intermediate I-49. Thus, Intermediate 327A was reacted to afford
Intermediate 327B (79% yield) as an off-white solid. LC-MS: Method
H, RT=1.02 min, MS (ESI) m/z: 350.0, 352.0, 353.9 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.01 (s, 1H), 4.71 (s,
2H), 3.82 (s, 3H), 2.48 (s, 3H).
Intermediate 327C:
2-((2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol
##STR01157##
[3187] This intermediate was prepared in a manner analogous to
Intermediate I-51. Thus, Intermediate 327B was reacted to afford
Intermediate 327C (82% yield) as an off-white, amorphous solid.
LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 321.9, 324.0, 325.9
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.13 (s,
1H), 4.17-4.12 (m, 2H), 4.05 (q, J=4.9 Hz, 2H), 2.43 (s, 3H), 1.99
(t, J=6.1 Hz, 1H)
Example 327
[3188] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 327C with Intermediate I-2 afforded
Example 327 in 49% yield following purification by preparative HPLC
(Method D, 45-90% over 20 min, 100% for 5 min). LC-MS: Method H,
RT=1.10 min, MS (ESI) m/z: 430.1, 432.1 (M+H).sup.+. .sup.1H NMR
(500 MHz, CHLOROFORM-d) .delta. 9.07 (s, 1H), 8.95 (s, 1H), 7.95
(s, 1H), 7.31 (s, 1H), 4.84 (s, 2H), 4.21 (t, J=4.3 Hz, 2H), 4.08
(d, J=3.9 Hz, 2H), 3.58 (s, 3H), 2.71 (s, 3H), 2.49 (s, 3H),
2.08-1.98 (m, 1H).
Example 328
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d-
]thiazol-4-yl)-2,2-dimethylpropan-1-ol (racemate)
##STR01158##
[3189] Intermediate 328A:
1-(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-o-
l (racemate)
##STR01159##
[3191] A solution of Intermediate I-55 (20 mg, 0.070 mmol) in THF
(1 mL) was cooled to -78.degree. C. tert-butylmagnesium chloride
(0.091 mL, 0.091 mmol) was added. After 30 min, the reaction
mixture was warmed to -10.degree. C. and then quenched with
saturated NH.sub.4Cl The resulting mixture was then diluted with
EtOAc, and the organic phase was extracted, dried over MgSO.sub.4,
filtered, concentrated and purified by ISCO (12 g, 0-100%
EtOAc/Hexanes, 16 min. Product at 16%) to afford Intermediate 328A
(rac) (8.5 mg, 0.025 mmol, 35.3% yield). LC-MS: Method H, RT=1.16
min, MS (ESI) m/z: 344.0, 346.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.12 (s, 1H), 4.96 (d, J=11.4 Hz, 1H), 3.88
(s, 3H), 2.28 (s, 3H), 0.96 (s, 9H).
Example 328
[3192] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 328A (rac) with Intermediate I-2 afforded
Example 328 (rac) in 18% yield following purification by
preparative HPLC (Method D, 65-100% over 15 min). LC-MS: Method H,
RT=1.23 min, MS (ESI) m/z: 452.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.64 (s, 1H), 8.07 (s, 1H),
7.73 (s, 1H), 6.34 (d, J=10.7 Hz, 1H), 5.00 (d, J=10.7 Hz, 1H),
4.83 (br. s., 2H), 3.94 (s, 3H), 3.49 (s, 3H), 2.72 (br. s., 3H),
2.30 (s, 3H), 1.00 (br. s., 9H).
Example 329
5-fluoro-6-isopropoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d-
]thiazole
##STR01160##
[3193] Intermediate 329A:
2-bromo-5-fluoro-6-isopropoxybenzo[d]thiazole
##STR01161##
[3195] To a solution of Intermediate I-60 (34 mg, 0.137 mmol) in
DMF (685 .mu.l) was added 2-iodopropane (68.5 .mu.l, 0.685 mmol)
followed by K.sub.2CO.sub.3 (47.4 mg, 0.343 mmol). After 3 h of
vigorous stirring, the reaction mixture was diluted with EtOAc,
filtered over celite, concentrated and purified by ISCO (12 g,
0-10% EtOAc/Hexanes, 16 min. Product at 3%) to afford Intermediate
329A (38 mg, 0.131 mmol, 96% yield) as a white solid. LC-MS: Method
H, RT=1.07 min, MS (ESI) m/z: 290.1, 292.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.68 (d, J=11.0 Hz, 1H), 7.33 (d,
J=7.5 Hz, 1H), 4.57 (spt, J=6.1 Hz, 1H), 1.41 (d, J=5.9 Hz,
6H).
Example 329
[3196] This example was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 329A with Intermediate I-2 afforded
Example 329 in 32% yield following purification by preparative HPLC
(Method D, 55-100% over 20 min). LC-MS: Method H, RT=1.20 min, MS
(ESI) m/z: 398.3 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.10 (s, 1H), 8.80 (s, 1H), 8.05 (s, 1H), 8.01 (d, J=8.0
Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 4.83 (s, 2H), 4.81-4.73 (m, 1H),
3.49 (s, 3H), 2.69 (s, 3H), 1.39 (d, J=6.1 Hz, 6H).
Example 330
N-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)ethyl)benzenesulfonamide
##STR01162##
[3197] Intermediate 330A:
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethyl methanesulfonate
##STR01163##
[3199] To a solution of Example 318 (18 mg, 0.043 mmol) in DCM (1
mL) was added triethylamine (0.012 mL, 0.086 mmol) followed by
methanesulfonic anhydride (9.71 mg, 0.056 mmol). After 30 min, the
reaction mixture was further diluted with DCM and washed with
saturated NaHCO.sub.3 followed by brine. The organic phase was
dried over MgSO.sub.4, filtered and concentrated in vacuo to afford
Intermediate 330A (18 mg, 0.036 mmol, 84% yield) as an amorphous
yellow solid. This material was taken forward without further
purification. LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 498.1,
500.1 (M+H).sup.+. .sup.1H NMR (400 MHz, THF) .delta. 8.68 (d,
J=1.5 Hz, 1H), 8.46 (s, 1H), 7.69 (dd, J=2.0, 0.9 Hz, 1H), 7.62 (d,
J=7.5 Hz, 1H), 4.55-4.47 (m, 2H), 4.39-4.33 (m, 2H), 4.00 (s, 3H),
3.01 (s, 3H), 2.55 (s, 3H).
Example 330
[3200] To a solution of Intermediate 330A (8 mg, 0.016 mmol) in DMF
(1 mL) was added benzenesulfonamide (7.58 mg, 0.048 mmol) followed
by K.sub.2CO.sub.3 (11.10 mg, 0.080 mmol). The reaction vial was
sealed and heated to 100.degree. C. in the microwave for 30 min.
The crude reaction mixture was filtered and purified by preparative
HPLC (Method D, 60-100% over 20 min) to afford Example 330 (1.6 mg,
2.78 .mu.mol, 17% yield). LC-MS: Method H, RT=1.22 min, MS (ESI)
m/z: 559.1, 561.2 (M+H).sup.+. .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. 8.73 (br. s., 1H), 8.54 (br. s., 1H), 7.91 (br. s., 2H),
7.77 (br. s., 1H), 7.60-7.47 (m, 3H), 7.25 (br. s., 1H), 5.12 (br.
s., 1H), 4.19-4.09 (m, 5H), 3.49 (br. s., 2H), 2.67 (br. s.,
3H).
Example 331
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)ethyl pyridin-3-ylcarbamate
##STR01164##
[3202] To a suspension of Example 318 (75 mg, 0.179 mmol) in THF
(3.6 mL) was added a solution of phosgene (15% by wt. in toluene)
(1.2 mL, 1.790 mmol). After 30 min, the resulting chloroformate
intermediate was concentrated down to a yellow residue. This
residue was retaken in THF (3.6 mL) and pyridin-3-amine (50.4 mg,
0.537 mmol) was added followed by Hunig's Base (313 .mu.l, 1.79
mmol). After an additional 5 min, the reaction mixture was
concentrated, retaken in DMF, filtered and purified by preparative
HPLC (Method D, 50-100% over 10 min) to afford Example 331 (17.9
mg, 0.032 mmol, 18.19% yield) as a yellow solid. LC-MS: Method H,
RT=0.98 min, MS (ESI) m/z: 540.2, 542.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.99 (br. s., 1H), 8.68 (s, 1H),
8.53 (d, J=1.8 Hz, 1H), 8.19 (br. s., 1H), 7.98 (d, J=7.7 Hz, 1H),
7.84 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.29 (br. s., 1H), 4.48 (d,
J=4.2 Hz, 2H), 4.41 (d, J=4.4 Hz, 2H), 4.02 (s, 3H), 2.59 (s, 3H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -135.91.
Preparation of Carbamate Examples
[3203] The following carbamates were prepared according to the
following general procedure, which is analogous to Example 331
described above
[3204] To a solution of the appropriately substituted
Quinoxaline-Benzothiazole Alcohol (1.0 equiv) in THF (0.05 M) was
added a solution of phosgene (15% by wt. in toluene, 10 equiv). The
combined solution was stirred at room temperature for the
designated amount of time before the intermediate chloroformate was
concentrated in vacuo. This intermediate was retaken in THF (0.05
M) and the appropriately substituted aminopyridine, aniline or
amine (3.0 equiv) was added. After a minute of vigorous stirring,
an excess of diisopropylethylamine (10 equiv) or pyridine (10
equiv) was added. After an additional 5 min of stirring, the
resulting mixture was concentrated, retaken in DMF, filtered and
purified by preparative HPLC to yield the desired example.
TABLE-US-00007 LCMS LCMS RT HPLC [M + (Min) Prep H].sup.+ Method
Method Ex Structure R--OH Time m/z H D NMR 332 ##STR01165## 318 1 h
570.1, 572.1 1.20 65-100% 20 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.76 (br. s., 1H), 8.61 (br. s., 1H), 8.24
(br. s., 1H), 7.97 (br. s., 2H), 7.88 (br. s., 1H), 6.79 (br. s.,
1H), 6.59 (br. s., 1H), 4.62- 4.43 (m, 2H), 4.33 (br. s., 2H), 4.10
(br. s., 3H), 3.80 (br. s., 3H), 2.75 (br. s., 3H). 333
##STR01166## 318 1 h 596.2, 598.2 0.87 55-100% 23 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.50 (br. s., 1H), 9.87 (br. s.,
1H), 8.75 (br. s., 1H), 8.60 (br. s., 1H), 8.05 (br. s., 1H), 7.87
(br. s., 1H), 7.51 (br. s., 1H), 7.17 (br. s., 1H), 7.01 (d, J =
7.7 Hz, 1H), 4.54 (br. s., 2H), 4.48 (br. s., 2H), 4.10 (br. s.,
3H), 2.67 (br. s., 3H). 334 ##STR01167## 318 1 h 545.1, 547.1 1.21
55-100% 23 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.70 (s,
1H), 8.56 (br. s., 1H), 8.14 (br. s., 1H), 7.97 (d, J = 7.2 Hz,
2H), 7.82 (br. s., 1H), 4.56-4.36 (m, 2H), 4.08 (br. s., 2H), 3.83
(br. s, 3H), 2.65 (br. s., 3H). 335 ##STR01168## 318 1 h 540.2,
542.2 1.19 55-95% 20 min, 100% 5 min .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.32 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H),
8.39 (d, J = 6.6 Hz, 2H), 8.07 (d, J = 7.3 Hz, 1H), 7.89 (s, 1H),
7.46 (d, J = 6.6 Hz, 2H), 4.58 (br. s., 2H), 4.48 (br. s., 2H),
4.15-4.05 (m, 4H), 2.66 (s, 3H). 336 ##STR01169## 318 1 h 554.2,
556.2 1.14 40-80% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.23 (br. s., 1H), 8.72 (s, 1H), 8.57 (s,
1H), 8.25 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.84 (br.
s., 1H), 7.31 (br. s., 1H), 7.28 (d, J = 4.9 Hz, 1H), 4.56 (br. s.,
2H), 4.47 (br. s., 2H), 4.17-4.10 (m, 2H), 4.08 (s, 3H), 2.65 (s,
3H), 2.38 (s, 3H). 337 ##STR01170## 318 1 h 558.2, 600.2 1.17
50-90% 15 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.38 (br. s., 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.49 (s,
1H), 8.23 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.91-7.81 (m, 2H),
4.58 (br. s., 2H), 4.49 (br. s., 2H), 4.10 (s, 3H), 2.66 (s, 3H).
338 ##STR01171## 318 1 h 622.1, 624.1 1.16 50-90% 15 min, 100% 5
min 339 ##STR01172## I-66 1 h 506.2 0.93 40-90% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.07 (br. s., 1H),
8.76 (s, 1H), 8.66 (br. s., 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.23 (d,
J = 4.1 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 11.6 Hz,
1H), 7.91 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.34 (dd, J = 8.4, 4.5
Hz, 1H), 4.58-4.53 (m, 2H), 4.48-4.40 (m, 2H), 4.09 (s, 3H), 2.64
(s, 3H). 340 ##STR01173## I-66 1 h 524.2 1.16 50-85% 20 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.13 (br. s., 1H),
8.73 (s, 1H), 8.56 (s, 1H), 8.29 (br. s., 1H), 8.04 (br. s., 1H),
8.02- 7.96 (m, 2H), 7.82 (s, 1H), 7.15 (dd, J = 8.9, 3.2 Hz, 1H),
4.54 (d, J = 4.1 Hz, 2H), 4.45 (d, J = 4.1 Hz, 2H), 4.08 (s, 3H),
2.63 (s, 3H). 341 ##STR01174## I-66 1 h 536.2 1.15 50-85% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (s,
1H), 8.59 (d, J = 1.7 Hz, 1H), 8.24 (br. s., 1H), 8.06-7.96 (m,
3H), 7.85 (s, 1H), 7.78 (br. s., 1H), 6.79 (d, J = 8.8 Hz, 1H),
4.51 (d, J = 4.7 Hz, 2H), 4.44 (d, J = 4.4 Hz, 2H), 4.09 (s, 3H),
3.80 (s, 3H), 2.64 (s, 3H). 342 ##STR01175## I-66 1 h 506.2 0.95
40-80% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.31 (s, 1H), 8.75 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.39
(d, J = 6.1 Hz, 2H), 8.02 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 11.6
Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.48- 7.44 (m, 2H), 4.59-4.53
(m, 2H), 4.46 (d, J = 4.1 Hz, 2H), 4.09 (s, 3H), 2.64 (s, 3H). 343
##STR01176## I-66 1 h 562.2 1.10 45-80% 20 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.87 (br. s., 1H), 8.74 (s,
1H), 8.58 (d, J = 1.7 Hz, 1H), 8.04-7.95 (m, 2H), 7.87- 7.81 (m,
1H), 7.50 (br. s., 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.5
Hz, 1H), 4.56-4.49 (m, 2H), 4.47-4.39 (m, 2H), 4.09 (s, 3H), 2.63
(s, 3H). 344 ##STR01177## I-71 16 h 520.2 0.97 35-75% 20 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.20 (br. s.,
1H), 8.76-8.70 (m, 2H), 8.57 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 4.4
Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.97
(d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.49 (dd, J = 8.5,
5.0 Hz, 1H), 4.91 (td, J = 6.1, 3.2 Hz, 1H), 4.46-4.41 (m, 1H),
4.40- 4.34 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.3
Hz, 3H). 345 ##STR01178## I-70 16 h 520.2 0.97 50-90% 20 min, 100%
6 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.20 (br. s.,
1H), 8.76-8.70 (m, 2H), 8.57 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 4.4
Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.97
(d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.49 (dd, J = 8.5,
5.0 Hz, 1H), 4.91 (td, J = 6.1, 3.2 Hz, 1H), 4.46-4.41 (m, 1H),
4.40- 4.34 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.3
Hz, 3H). 346 ##STR01179## I-68 24 h 520.2 0.98 45-100% 20 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.98 (br. s.,
1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H),
8.24-8.18 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 11.8 Hz,
1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.32 (dd,
J = 8.3, 4.7 Hz, 1H), 5.27 (td, J = 6.3, 3.2 Hz, 1H), 4.40-4.33 (m,
1H), 4.31- 4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J =
6.3 Hz, 3H). 347 ##STR01180## I-67 24 h 520.2 0.98 45-100% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.98 (br.
s., 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H),
8.24-8.18 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 11.8 Hz,
1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.32 (dd,
J = 8.3, 4.7 Hz, 1H), 5.27 (td, J = 6.3, 3.2 Hz, 1H), 4.40-4.33 (m,
1H), 4.31-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J =
6.3 Hz, 3H). 348 ##STR01181## I-67 24 h 538.2 1.18 50-100% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.73 (s,
1H), 8.56 (d, J = 1.7 Hz, 1H), 8.29 (br. s., 1H), 8.03 (br. s.,
1H), 8.02-7.93 (m, 3H), 7.82 (s, 1H), 7.18-7.10 (m, 1H), 5.26 (td,
J = 6.3, 3.3 Hz, 1H), 4.40-4.32 (m, 1H), 4.31-4.24 (m, 1H), 4.08
(s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H). 349 ##STR01182##
I-67 24 h 520.2 0.94 55-95% 22 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.62 (s, 1H), 8.46 (br. s., 3H),
7.94-7.87 (m, 2H), 7.73 (s, 1H), 7.62 (br. s., 2H), 5.75-5.75 (m,
1H), 5.32 (d, J = 2.7 Hz, 1H), 4.37 (d, J = 8.2 Hz, 1H), 4.32-4.24
(m, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H). 350
##STR01183## I-67 24 h 576.2 1.13 45-90% 20 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.47 (s, 1H), 8.73 (s, 1H),
8.56 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.97 (d, J =
11.6 Hz, 1H), 7.82 (s, 1H), 7.53- 7.46 (m, 1H), 7.17 (d, J = 8.5
Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.24 (td, J = 6.3, 3.4 Hz, 1H),
4.40-4.32 (m, 1H), 4.32-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H),
1.42 (d, J = 6.6 Hz, 3H). 351 ##STR01184## I-67 24 h 545.2 1.21
45-100% 25 min, 100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.77- 8.72 (m, 2H), 8.58 (d, J = 1.9 Hz, 1H), 8.10 (dd, J =
8.5, 2.5 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 11.6 Hz,
1H), 7.94 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 1.8, 1.0 Hz, 1H), 5.29
(td, J = 6.3, 3.2 Hz, 1H), 4.43-4.35 (m, 1H), 4.33- 4.26 (m, 1H),
4.09 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.3 Hz, 3H). 352
##STR01185## I-67 24 h 514.2 1.06 35-75% 20 min, 75% 10 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.66 (s, 1H), 8.50 (s, 1H),
7.94-7.87 (m, 2H), 7.76 (s, 1H), 7.33 (br. s., 1H), 7.15 (br. s.,
1H), 6.80 (br. s., 1H), 5.06 (br. s., 1H), 4.19 (br. s., 2H), 4.05
(s, 3H), 3.17 (d, J = 5.8 Hz, 2H), 2.59 (s, 3H), 2.24 (t, J = 6.9
Hz, 2H), 1.30 (d, J = 6.1 Hz, 3H). 353 ##STR01186## I-67 24 h 521.2
1.00 40-80% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.53 (s, 1H), 9.21 (d, J = 2.2 Hz, 1H), 8.98 (d, J = 6.1
Hz, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.99
(d, J = 11.6 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 5.8, 2.8 Hz, 1H),
5.31 (td, J = 6.3, 3.0 Hz, 1H), 4.43-4.37 (m, 1H), 4.30 (dd, J =
11.0, 6.1 Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.45 (d, J = 6.3 Hz,
3H). 354 ##STR01187## I-67 24 h 559.2 1.07 20-100% 10 min, 100% 5
min 355 ##STR01188## I-67 24 h 558.2 1.21 20-100% 10 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.46 (br. s., 1H),
8.65 (s, 1H), 8.49 (s, 1H), 7.95-7.89 (m, 2H), 7.75 (s, 1H), 7.68
(br. s., 1H), 7.28 (d, J = 3.0 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H),
6.34 (br. s., 1H), 5.24 (d, J = 3.4 Hz, 1H), 4.40-4.20 (m, 2H),
4.05 (s, 3H), 2.59 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H). 356
##STR01189## I-67 24 h 572.2 1.25 20-100% 10 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.49 (br. s., 1H), 8.65
(s, 1H), 8.50 (s, 1H), 7.98-7.88 (m, 2H), 7.76 (s, 1H), 7.68 (br.
s., 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.22
(br. s., 1H), 6.33 (br. s., 1H), 5.24 (d, J = 3.0 Hz, 1H),
4.38-4.19 (m, 2H), 4.05 (s, 3H), 3.74 (s, 2H), 2.59 (s, 3H), 1.42
(d, J = 6.4 Hz, 3H). 357 ##STR01190## I-67 24 h 535.2 1.14 40-80%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.03 (br. s., 1H), 8.73 (br. s., 2H), 8.59 (s, 1H), 8.43 (br. s.,
1H), 7.86 (d, J = 10.4 Hz, 2H), 7.71 (s, 1H), 5.25 (br. s., 1H),
4.33 (d, J = 8.4 Hz, 1H), 4.24 (dd, J = 10.6, 6.2 Hz, 1H), 4.03 (s,
3H), 3.68 (br. s., 3H), 2.56 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 358
##STR01191## 318 1 h 463.1, 465.1 1.15 45-90% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H), 8.59 (s,
1H), 7.97 (d, J = 7.9 Hz, 1H), 7.86 (br. s., 1H), 6.57 (br. s.,
2H), 4.36 (d, J = 7.3 Hz, 4H), 4.09 (s, 3H), 2.66 (s, 3H). 359
##STR01192## 318 1 h 579.2, 581.2 1.09 50-100% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80 (br. s., 1H), 8.73
(s, 1H), 8.59 (s, 1H), 8.29 (br. s., 1H), 8.12 (br. s., 1H), 8.02
(d, J = 7.0 Hz, 1H), 7.86 (s, 1H), 7.49 (br. s., 1H), 6.46 (br. s.,
1H), 4.60 (br. s., 2H), 4.52 (br. s., 2H), 4.14 (s, 3H), 2.70 (s,
3H). 360 ##STR01193## 318 1 h 578.2, 580.2 1.22 50-100% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.57 (br.
s., 1H), 8.63 (s, 1H), 8.50 (br. s., 1H), 7.92 (d, J = 7.0 Hz, 1H),
7.78 (br. s., 1H), 7.73 (br. s., 1H), 7.40-7.31 (m, 2H), 7.21 (br.
s., 1H), 6.41 (br. s., 1H), 4.57 (br. s., 2H), 4.48 (br. s., 2H),
4.11 (s, 3H), 2.66 (br. s., 3H). 361 ##STR01194## 318 1 h 598.2,
600.2 1.18 65-95% 25 min, 95% 10 min .sup.1H NMR (500 MHz,
CHLOROFORM- d) .delta. 8.67 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H),
8.08-8.03 (m, 1H), 7.71 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.95
(br. s., 1H), 4.59 (br. s., 2H), 4.34 (br. s., 2H), 4.06 (s, 3H),
3.92 (s, 3H), 2.60 (s, 3H). 362 ##STR01195## 318 1 h 555.2, 557.2
1.16 50-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, CHLOROFORM-
d) .delta. 8.74-8.61 (m, 3H), 8.47 (s, 1H), 7.71 (s, 1H), 7.34 (d,
J = 7.2 Hz, 1H), 6.66 (br. s., 1H), 4.61-4.52 (m, 2H), 4.35-4.31
(m, 2H), 4.06 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H). 363 ##STR01196##
318 1 h 577.2, 579.2 1.19 50-100% 20 min, 100% 5 min .sup.1H NMR
(500 MHz, CHLOROFORM- d) .delta. 8.76 (br. s., 1H), 8.57 (br. s.,
1H), 7.80 (br. s., 1H), 7.63 (br. s., 1H), 7.44 (br. s., 1H), 4.67
(br. s., 2H), 4.43 (br. s., 2H), 4.16 (br. s., 6H), 2.69 (br. s.,
3H). 364 ##STR01197## 318 1 h 529.2, 531.2 1.16 50-80% 25 min, 100%
7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.61 (s, 1H),
8.65 (s, 1H), 8.52 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H),
7.60 (br. s., 2H), 4.55 (br. s., 2H), 4.46 (br. s., 2H), 4.11 (s,
3H), 2.67 (s, 3H). 365 ##STR01198## 318 1 h 543.2, 545.2 1.21
50-90% 25 min, 100% 10 min .sup.1H NMR (500 MHz, CD.sub.2Cl.sub.2)
.delta. 8.65 (br. s., 1H), 8.46 (br. s., 1H), 7.70 (br. s., 1H),
7.51 (br. s., 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.27 (br. s., 1H),
6.49 (br. s., 1H), 4.50 (br. s., 2H), 4.30 (br. s., 2H), 4.05 (br.
s., 3H), 3.76 (br. s., 3H), 2.59 (br. s., 3H). 366 ##STR01199## 318
1 h 545.1, 547.1 1.12 60-90% 22 min, 100% 7 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.62 (s, 1H), 8.49 (br. s., 1H), 7.92
(s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.77 (br. s., 1H), 4.49 (br. s.,
2H), 4.38 (br. s., 2H), 4.04 (s, 3H), 2.88 (s, 3H), 2.72 (s, 3H).
367 ##STR01200## 318 1 h 607.2, 609.2 1.19 60-100% 20 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.67 (br. s., 1H),
8.60 (s, 1H), 8.47 (br. s., 1H), 8.15 (br. s., 1H), 7.90 (br. s.,
2H), 7.75 (br. s., 1H), 6.15 (br. s., 1H), 4.51 (br. s., 2H), 4.43
(br. s., 2H), 4.04 (s, 3H), 3.51 (s, 3H), 2.60 (s, 3H), 2.38 (br.
s., 3H). 368 ##STR01201## 318 1 h 554.2, 556.2 1.02 50-95% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.69 (s,
1H), 8.55 (s, 1H), 8.46 (br. s., 1H), 8.43 (br. s., 1H), 7.93 (br.
s., 2H), 7.82 (s, 1H), 7.64 (br. s., 1H), 7.33 (br. s., 1H), 4.38
(d, J = 9.8 Hz, 4H), 4.22 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 2.63
(s, 3H). 369 ##STR01202## 318 1 h 554.2, 556.2 1.01 50-100% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72 (br.
s., 1H), 8.60-8.51 (m, 3H), 8.11- 7.88 (m, 2H), 7.85 (br. s., 1H),
7.32 (d, J = 4.6 Hz, 2H), 4.47 (d, J = 15.9 Hz, 4H), 4.30 (d, J =
6.1 Hz, 2H), 4.13 (s, 3H), 2.69 (s, 3H). 370 ##STR01203## I-69 24 h
575.4, 577.4 1.19 60-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.71 (br. s., 1H), 8.56 (br. s., 1H), 7.99
(d, J = 7.02 Hz, 1H), 7.83 (br. s., 1H), 5.33 (br. s., 1H), 4.41
(d, J = 10.68 Hz, 1H), 4.30 (br. s., 1H), 4.09 (br. s., 3H), 1.43
(d, J = 5.49 Hz, 3H). 371 ##STR01204## I-69 24 h 579.4, 581.4 1.22
70-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.73 (br. s., 1H), 8.63 (br. s., 1H), 8.48 (br. s., 1H),
8.08 (d, J = 8.55 Hz, 1H), 7.86-8.00 (m, 3H), 7.76 (br. s., 1H),
5.30 (br. s., 1H), 4.22-4.46 (m, 2H), 4.06 (br.
s., 3H), 2.62 (br. s., 3H), 1.44 (d, J = 4.88 Hz, 3H). 372
##STR01205## I-69 24 h 554.1, 556.1 1.24 60-100% 13 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.97 (br. s., 1H), 8.65
(br. s., 2H), 8.50 (br. s., 1H), 8.21 (br. s., 1H), 7.86-8.00 (m,
2H), 7.78 (br. s., 1H), 7.33 (br. s., 1H), 5.28 (br. s., 1H),
4.24-4.45 (m, 2H), 4.07 (s, 3H), 2.62 (s, 3H), 1.43 (d, J = 5.80
Hz, 3H). 373 ##STR01206## I-69 24 h 611.1, 613.1 1.20 65-100% 13
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.63-
9.76 (m, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 7.98-8.05 (m, 1H), 7.85
(s, 1H), 7.71- 7.79 (m, 1H), 7.36-7.49 (m, 1H), 7.05- 7.17 (m, 1H),
6.89-6.97 (m, 1H), 4.99- 5.34 (m, 1H), 4.23-4.43 (m, 2H), 4.08 (s,
3H), 3.08-3.19 (m, 1H), 2.64 (s, 3H), 1.40 (d, J = 6.10 Hz, 3H).
374 ##STR01207## I-69 24 h 622.2, 624.2 1.36 60-100% 20 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.39 (br. s., 1H),
8.76 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 8.55 Hz,
1H), 7.98 (d, J = 7.63 Hz, 1H), 7.74-7.87 (m, 2H), 5.29 (br. s.,
1H), 4.22-4.47 (m, 2H), 4.07 (s, 3H), 2.62 (s, 3H), 1.43 (d, J =
6.41 Hz, 3H). 375 ##STR01208## I-69 24 h 593.2, 595.2 1.15 55-85%
16 min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.43 (br. s., 1H), 9.42-9.72 (m, 1H), 8.59 (s, 1H), 8.46 (s, 1H),
8.19 (br. s., 1H), 8.02 (br. s., 1H), 7.84-7.94 (m, 1H), 7.74 (s,
1H), 7.39 (br. s., 1H), 6.37 (br. s., 1H), 5.24 (d, J = 3.36 Hz,
1H), 4.19-4.40 (m, 2H), 4.04 (s, 3H), 2.59 (s, 3H), 1.40 (d, J =
6.41 Hz, 3H). 376 ##STR01209## I-69 24 h 568.2, 570.2 1.06 40-100%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.46
(br. s., 1H), 8.66 (br. s., 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.30
(d, J = 4.58 Hz, 1H), 7.84 (d, J = 7.63 Hz, 1H), 7.68 (s, 1H), 7.48
(d, J = 5.19 Hz, 1H), 5.22 (dd, J = 3.05, 6.10 Hz, 1H), 4.14-4.41
(m, 2H), 3.99 (s, 3H), 2.54 (s, 3H), 2.13-2.33 (m, 3H), 1.37 (d, J
= 6.41 Hz, 3H). 377 ##STR01210## I-69 24 h 568.2, 570.2 1.07
60-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.80 (br. s., 1H), 8.11-8.68 (m, 3H), 7.59- 7.89 (m, 3H),
7.15 (d, J = 8.24 Hz, 1H), 5.23 (br. s., 1H), 4.20-4.48 (m, 2H),
4.02 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 1.40 (d, J = 6.41 Hz,
3H). 378 ##STR01211## 318 1 h 600.2, 602.2 1.28 50-85% 20 min, 100%
7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.48- 9.57 (m,
1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.90-8.00 (m, 1H), 7.80 (s, 1H),
6.95- 7.11 (m, 1H), 6.52-6.68 (m, 1H), 4.25- 4.47 (m, 4H), 4.03 (s,
3H), 3.64 (br. s., 2H), 3.34-3.45 (m, 6H), 2.59 (s, 3H).
Example 379
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy-
)-3-isobutoxypropan-2-yl pyridin-3-ylcarbamate
##STR01212##
[3205] Intermediate 379A:
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)-3-isobutoxypropan-2-ol
##STR01213##
[3207] To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) in
THF (1 mL) was added tetrabutylammonium bromide (28.3 mg, 0.088
mmol) followed by a 0.33 M solution of KOH (0.20 mL, 0.066 mmol).
2-(isobutoxymethyl)oxirane (0.1 mL) was then added, and the
resulting mixture was heated to 65.degree. C. in a sealed tube.
After 16 h, the reaction was quenched with saturated NH.sub.4Cl and
diluted with EtOAc. The organic phase was washed with brine, dried
over MgSO.sub.4, filtered, concentrated and purified by ISCO (4 g,
0-60% EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate
379A (14 mg, 0.024 mmol, 54.1% yield) as a yellow solid. LC-MS:
Method H, RT=1.23 min, MS (ESI) m/z: 472.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.60 (d, J=1.8 Hz, 1H), 8.54 (s,
1H), 7.81 (d, J=11.4 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.50 (d,
J=7.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.22-4.15 (m, 2H), 4.13 (s, 3H),
3.70-3.61 (m, 2H), 3.32-3.25 (m, 2H), 2.65 (s, 3H), 2.62 (d, J=4.8
Hz, 1H), 1.97-1.80 (m, 1H), 0.92 (d, J=6.8 Hz, 6H).
Example 379
[3208] This example was prepared according to the general procedure
for carbamates described in the table above. Thus, reaction of
Intermediate 379A with 3-aminopyridine afforded Example 379 in 77%
yield following purification by preparative HPLC (Method D, 45-100%
over 15 min). LC-MS: Method H, RT=1.03 min, MS (ESI) m/z: 592.3
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.37 (br.
s., 1H), 8.79 (br. s., 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.36 (d,
J=4.3 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.97
(d, J=11.6 Hz, 1H), 7.82 (s, 1H), 7.61-7.53 (m, 1H), 5.42-5.32 (m,
1H), 4.53-4.45 (m, 1H), 4.45-4.37 (m, 1H), 4.09 (s, 3H), 3.80 (d,
J=5.2 Hz, 2H), 3.37-3.29 (m, 1H), 3.28-3.22 (m, 1H), 2.63 (s, 3H),
1.84 (dt, J=13.2, 6.7 Hz, 1H), 0.93-0.81 (m, 6H).
Example 380
1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate
##STR01214##
[3209] Intermediate 380A:
1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)propan-2-ol
##STR01215##
[3211] To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) in
THF (1 mL) was added tetrabutylammonium bromide (28.3 mg, 0.088
mmol) followed by a 0.33 M solution of KOH (0.20 mL, 0.066 mmol).
2-((benzyloxy)methyl)oxirane (72.2 mg, 0.439 mmol) was then added,
and the resulting mixture was heated to 65.degree. C. in a sealed
tube. After 16 h, the reaction was quenched with saturated
NH.sub.4Cl and diluted with EtOAc. The organic phase was washed
with brine, dried over MgSO.sub.4, filtered, concentrated and
purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16 min. Product at 35%)
to afford Intermediate 380A (16 mg, 0.032 mmol, 72.0% yield) as a
yellow solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 506.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.60 (d,
J=2.0 Hz, 1H), 8.53 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.74 (dd,
J=1.8, 0.9 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.38-7.27 (m, 5H), 4.61
(s, 2H), 4.33-4.24 (m, 1H), 4.23-4.17 (m, 2H), 4.12 (s, 3H),
3.77-3.68 (m, 2H), 2.66-2.62 (m, 4H).
Example 380
[3212] Example 380 was prepared according to the general procedure
for carbamates described in the table above. Thus, reaction of
Intermediate 380A with 3-aminopyridine afforded Example 380 in 34%
yield following purification by preparative HPLC (Method D, 45-100%
over 18 min). LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 626.3
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.28 (br.
s., 1H), 8.74 (br. s., 2H), 8.58 (br. s., 1H), 8.31 (br. s., 1H),
8.07-7.95 (m, 3H), 7.85 (br. s., 1H), 7.50 (br. s., 1H), 7.39-7.27
(m, 5H), 5.41 (br. s., 1H), 4.60 (d, J=7.3 Hz, 2H), 4.47 (d, J=17.4
Hz, 2H), 4.09 (br. s., 3H), 3.86 (br. s., 2H), 2.64 (br. s.,
3H).
Example 381
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate (racemate)
##STR01216##
[3213] Intermediate 381A: methyl
2((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) propanoate
(racemate)
##STR01217##
[3215] Intermediate 381A was prepared in a manner analogous to
Intermediate I-50. Thus, Intermediate I-44 was reacted to afford
Intermediate 381A (rac) (46% yield) as a white solid. LC-MS: Method
H, RT=1.12 min, MS (ESI) m/z: 368.0, 370.0, 372.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.23 (d, J=6.8 Hz, 1H),
4.81 (q, J=6.8 Hz, 1H), 3.78 (s, 3H), 1.71 (d, J=6.8 Hz, 3H).
Intermediate 381B:
2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-1-ol
(racemate)
##STR01218##
[3217] Intermediate 381B was prepared in a manner analogous to
Intermediate I-51. Thus, Intermediate 381A (rac) was reacted to
afford Intermediate 381B (rac) (75% yield) as an off-white,
amorphous solid. LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 339.9,
341.9, 343.9 (M+H).sup.+. .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.71 (d, J=7.3 Hz, 1H), 4.64-4.52 (m, 1H), 3.79-3.67 (m,
2H), 1.34 (d, J=6.2 Hz, 3H)
Intermediate 381C:
2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propyl
(6-methoxypyridin-3-yl)carbamate (racemate)
##STR01219##
[3219] Intermediate 381C was prepared according to the general
procedure for carbamates described in the table above. Thus,
reaction of Intermediate 381B (rac) with 3-amino-6-methoxypyridine
afforded Intermediate 381C (rac) in 90% yield. LC-MS: Method H,
RT=1.11 min, MS (ESI) m/z: 489.9, 491.9, 493.9 (M+H).sup.+. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 8.05 (br. s., 1H), 7.73 (br.
s., 1H), 7.35 (d, J=7.3 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.53 (br.
s., 1H), 4.76-4.59 (m, 1H), 4.36 (d, J=5.3 Hz, 2H), 3.91 (s, 3H),
1.43 (d, J=6.4 Hz, 3H).
Example 381
[3220] Example 381 was prepared according to the general procedure
for quinoxaline-benzothiazoles described in the table above. Thus,
reaction of Intermediate 381C (rac) with Intermediate I-9 afforded
Example 381 (rac) in 23% yield following purification by
preparative HPLC (Method D, 55-95% over 30 min). LC-MS: Method H,
RT=1.31 min, MS (ESI) m/z: 584.1, 586.1 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.71 (br. s., 1H), 8.73 (s, 1H),
8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H),
7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td,
J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H),
2.66 (s, 3H), 1.43 (d, J=6.3 Hz, 3H)
Example 382
(S)-2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thi-
azol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate
##STR01220##
[3222] This example was prepared by subjecting Example 381 (rac) to
chiral, super-critical fluid chromatography conditions (Berger
Multigram II SFC, Chiralpak OJ, 21.times.250 mm, 5 micron, 45%
EtOH/-0.1% DEA/55% CO.sub.2, 40 mL/min flow rate) to give Example
382 as the second eluting enantiomer. The absolute stereochemistry
of this example was assigned by analogy to other biologically
active enantiomers in the same series. LC-MS: Method H, RT=1.31
min, MS (ESI) m/z: 584.1, 586.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.71 (br. s., 1H), 8.73 (s, 1H), 8.58 (d,
J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H), 7.85 (s,
1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td, J=6.2,
3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 2.66
(s, 3H), 1.43 (d, J=6.3 Hz, 3H).
Example 383
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)ethyl (2-chlorothiazol-4-yl)carbamate
##STR01221##
[3224] To a suspension of Example 318 (12 mg, 0.029 mmol) and
2-chlorothiazole-4-carboxylic acid (9.35 mg, 0.057 mmol) in Toluene
(1 mL) was added triethylamine (7.97 .mu.l, 0.057 mmol) followed by
diphenylphosphoryl azide (15.73 mg, 0.057 mmol). The reaction
vessel was then sealed and heated to 110.degree. C. for 3 hours.
The resulting mixture was cooled to room temperature, concentrated
and purified by preparative HPLC (Method D, 60-100% over 20 min,
hold at 100% for 10 min) to afford Example 383 in 20% yield. LC-MS:
Method H, RT=1.35 min, MS (ESI) m/z: 580.1 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.71 (br. s., 1H), 8.73 (s, 1H),
8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H),
7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td,
J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H),
2.66 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).
Example 384
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)ethyl thiazol-5-ylcarbamate
##STR01222##
[3226] Example 384 was prepared in a manner analogous to Example
383. Thus, Example 318 was reacted with thiazole-5-carboxylic acid
to afford Example 384 (3% yield) following purification by
preparative HPLC (Method D, 40-80% over 20 min, hold at 100% for 5
min). LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 546.1, 548.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.66-8.85
(m, 1H), 8.53-8.62 (m, 1H), 8.38-8.51 (m, 1H), 7.71-7.85 (m, 1H),
7.53-7.64 (m, 1H), 7.36-7.45 (m, 1H), 7.28-7.33 (m, 1H), 4.67 (br.
s., 2H), 4.41 (br. s., 2H), 4.14 (br. s., 3H), 2.68 (br. s.,
3H).
Example 385
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thi-
azol-6-yl)oxy)propan-2-yl
(6-(hydroxymethyl)pyridin-3-yl)carbamate
##STR01223##
[3227] Intermediate 385A: (5-aminopyridin-2-yl)methanol
##STR01224##
[3229] To a suspension of methyl 5-aminopicolinate (70 mg, 0.460
mmol) in THF (3 mL) was added a solution of LAH (1 M in THF) (0.920
mL, 0.920 mmol) at 0.degree. C. The mixture was allowed to warm to
room temperature and stirred overnight. After 16 h, the reaction
was quenched with water (0.1 mL) at 0.degree. C. A solution of
sodium hydroxide (2 N, 0.1 mL) was subsequently added followed by
an additional quantity of water (0.3 mL). Magnesium sulfate was
added and the mixture was stirred for 1 hour before being filtered
over a pad of celite and washed with THF. The filtrate was
concentrated in vacuo to afford Intermediate 385A (35 mg, 0.282
mmol, 61.3% yield) as a yellow solid. This material was taken on
without further purification. LC-MS: Method H, RT=0.44 min, MS
(ESI) m/z: 125.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.80-7.88 (m, 1H), 7.05-7.16 (m, 1H), 6.83-6.96 (m, 1H),
4.88-5.04 (m, 1H), 4.27-4.41 (m, 2H).
Intermediate 385B:
6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine
##STR01225##
[3231] To a stirred solution of crude Intermediate 385A (225 mg,
1.812 mmol) in DMF (5 mL) was added TBDMS-Cl (410 mg, 2.72 mmol)
followed by imidazole (222 mg, 3.26 mmol). The reaction mixture was
stirred for 1 h at room temperature before being concentrated and
purified by ISCO (24 g, 0-100% EtOAc/Hexanes, 15 min. Product at
65%) to afford Intermediate 385B (132 mg, 0.554 mmol, 30.5% yield),
as a yellow solid. LC-MS: Method H, RT=0.81 min, MS (ESI) m/z:
239.4 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.79
(d, J=2.64 Hz, 1H), 7.00 (s, 1H), 6.77-6.91 (m, 1H), 5.13 (s, 2H),
4.50 (s, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Intermediate 385C:
(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)propan-2-yl
(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)carbamate
##STR01226##
[3233] This intermediate was prepared according to the general
procedure for carbamates described in the table above. Thus,
reaction of Intermediate I-69 with Intermediate 385B afforded
Intermediate 385C, which was telescoped into the subsequent
silyl-deprotection reaction. LC-MS: Method H, RT=1.26 min, MS (ESI)
m/z: 698.5, 700.5 (M+H).sup.+.
Example 385
[3234] Intermediate 385C was concentrated and redissolved in 10 mL
mixture of MeOH (9.5 mL) and 12 M HCl (0.5 mL). The resulting
solution was stirred for 10 minutes before being concentrated down
and purified by preparative HPLC (Method D, 50-100% over 10 min,
hold at 100% for 10 min) to afford Example 385 in 9% overall yield
as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z:
584.3, 586.3 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.69-9.99 (m, 1H), 8.77 (s, 1H), 8.60-8.65 (m, 1H),
8.53-8.57 (m, 1H), 8.02-8.10 (m, 1H), 7.82-7.93 (m, 2H), 7.33-7.42
(m, 1H), 5.21-5.37 (m, 2H), 4.46-4.52 (m, 2H), 4.38-4.45 (m, 1H),
4.24-4.35 (m, 1H), 2.67 (s, 4H), 1.43 (d, J=6.38 Hz, 3H).
Example 386
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01227##
[3236] Example 386 was prepared according to the general procedure
for carbamates described in the table above. Thus, reaction of
Intermediate I-72 with 2-methylpyrimidin-5-amine and pyridine
afforded Example 386 in 46% yield following purification by Prep
HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS:
Method H, RT=1.20 min, MS (ESI) m/z: 549.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.74 (s, 2H), 8.63 (d, J=1.5 Hz,
1H), 8.57 (s, 1H), 7.85 (d, J=11.4 Hz, 1H), 7.79 (s, 1H), 7.58-7.52
(m, 1H), 6.51 (br. s., 1H), 5.18 (dd, J=6.5, 3.0 Hz, 1H), 4.69-4.59
(m, 1H), 4.16 (s, 3H), 2.70 (s, 3H), 2.68 (s, 3H), 1.50 (d, J=6.6
Hz, 3H), 1.46 (d, J=6.4 Hz, 3H).
Example 387
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
##STR01228##
[3238] Example 387 was prepared according to the general procedure
for carbamates described in the table above. Thus, reaction of
Intermediate I-72 with
6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine afforded
the TBS-protected intermediate of the desired product. The crude
reaction mixture was concentrated and retaken in a 20:1 mixture of
MeOH/concentrated HCl to affect the desired silyl deprotection and
afford Example 387 in 46% yield following purification by Prep HPLC
(Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method
H, RT=0.98 min, MS (ESI) m/z: 578.2 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.79 (br. s., 1H), 8.73 (s, 1H), 8.58
(d, J=1.8 Hz, 1H), 8.53 (br. s., 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96
(d, J=11.7 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=7.0 Hz, 1H), 7.20 (d,
J=8.4 Hz, 1H), 5.10 (qd, J=6.5, 2.9 Hz, 1H), 4.82-4.73 (m, 1H),
4.08 (s, 3H), 3.67 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.63
(s, 3H), 1.39 (m, 6H)
Example 388
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate
##STR01229##
[3240] Example 388 was prepared according to the general procedure
for carbamates described in the table above. Thus, reaction of
Intermediate I-72 with
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-4-amine afforded
the TBS-protected intermediate of the desired product. Excess TBAF
(10 equiv, 1 M in THF) was added to the crude reaction mixture to
afford Example 388 in 26% yield following purification by Prep HPLC
(Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method
H, RT=1.06 min, MS (ESI) m/z: 594.2 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.99 (s, 1H), 8.67 (s, 1H), 8.51 (d,
J=1.8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H),
7.86 (d, J=5.9 Hz, 1H), 7.77 (s, 1H), 6.96 (dd, J=5.7, 1.8 Hz, 1H),
6.83 (d, J=1.3 Hz, 1H), 5.10-5.00 (m, 1H), 4.76-4.67 (m, 2H), 4.12
(t, J=5.1 Hz, 2H), 4.01 (s, 3H), 3.58 (q, J=5.4 Hz, 2H), 2.56 (s,
3H), 1.32 (m, 6H).
Example 389
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01230##
[3242] To a solution of Intermediate I-73 (30 mg, 0.051 mmol) in
THF (1.5 mL) was added ethanol (0.5 mL, 8.56 mmol) followed by
sodium hydride (20.53 mg, 0.513 mmol, 60% suspension in mineral
oil). The reaction mixture was stirred for 10 min at room
temperature before being quenched with saturated NH.sub.4Cl
(.about.0.15 mL). The resulting mixture was diluted with EtOAc,
filtered over celite, concentrated, retaken in DMF, filtered and
purified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for
8 min) to afford Example 389 (17.7 mg, 0.030 mmol, 58% yield) as a
yellow solid. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 563.2
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.96 (br.
s., 1H), 8.71 (br. s., 2H), 8.63 (s, 1H), 8.50 (s, 1H), 8.00 (d,
J=8.2 Hz, 1H), 7.91 (d, J=11.3 Hz, 1H), 7.75 (s, 1H), 5.10 (dd,
J=6.7, 2.4 Hz, 1H), 4.78 (d, J=4.0 Hz, 1H), 4.49 (q, J=7.0 Hz, 2H),
2.59 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.42 (t, J=7.2 Hz,
3H), 1.38 (m, 6H).
Example 390
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylamino)quinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01231##
[3244] To a vial charged with Intermediate I-73(10 mg, 0.017 mmol)
was added methanamine (33% solution in EtOH) (1 mL, 8.00 mmol). The
mixture was stirred at room temperature for 16 h before being
concentrated and purified by Prep HPLC (Method D, 50-100% over 10
min, hold 100% for 8 min) to afford Example 390 (17.7 mg, 0.030
mmol, 58% yield) as a yellow solid. LC-MS: Method H, RT=0.92 min,
MS (ESI) m/z: 548.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.97 (br. s., 1H), 8.72 (br. s., 2H), 8.42
(s, 1H), 8.27 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.92 (d, J=11.3 Hz,
1H), 7.56 (s, 1H), 5.10 (d, J=4.9 Hz, 1H), 4.79 (d, J=4.0 Hz, 1H),
2.96 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.38 (m, 6H).
Example 391
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate
##STR01232##
[3246] To a vial charged with Intermediate I-74 (20 mg, 0.034 mmol)
was added ammonia (7M solution in MeOH) (1 mL, 14.00 mmol). The
mixture was sealed and heated to 65.degree. C. for 24 h before
being concentrated and purified by Prep HPLC (Method D, 50-100%
over 10 min, hold 100% for 8 min) to afford Example 391 (8 mg,
0.013 mmol, 38% yield) as a yellow solid. LC-MS: Method H, RT=1.21
min, MS (ESI) m/z: 577.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.18 (br. s., 1H), 8.71-8.61 (m, 2H), 8.52
(s, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.98-7.89 (m, 3H), 7.79 (s, 1H),
7.45 (br. s., 1H), 5.12 (d, J=5.8 Hz, 1H), 4.80 (d, J=6.1 Hz, 1H),
4.05 (s, 3H), 2.60 (s, 3H), 1.39 (m, 6H).
Example 392
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl
(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)carbamate
##STR01233##
[3248] To a solution of Intermediate I-74 (10 mg, 0.017 mmol) in
THF (1 mL) was added ethanolamine (0.1 mL). The reaction mixture
was allowed to stir at room temperature for 16 h before being
concentrated and purified by Prep HPLC (Method D, 50-100% over 10
min, hold 100% for 8 min) to afford Example 392 (8.7 mg, 0.014
mmol, 81% yield) as a yellow solid. LC-MS: Method H, RT=1.15 min,
MS (ESI) m/z: 621.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.15 (br. s., 1H), 8.63 (d, J=5.8 Hz, 2H),
8.53-8.43 (m, 2H), 7.97 (d, J=8.5 Hz, 2H), 7.94-7.86 (m, 2H), 7.76
(s, 1H), 5.11 (d, J=5.8 Hz, 1H), 4.89-4.84 (m, 1H), 4.81 (br. s.,
1H), 4.04 (s, 3H), 3.48 (d, J=5.5 Hz, 2H), 3.32 (d, J=5.5 Hz, 2H),
2.58 (s, 3H), 1.38 (m, 6H).
Example 393
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01234##
[3250] To a solution of Intermediate I-75 (13 mg, 0.022 mmol) in
THF (1 mL) was added methanamine (33% solution in EtOH) (0.2 mL,
1.60 mmol). The reaction mixture was allowed to stir at room
temperature for 16 h before being concentrated and purified by Prep
HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to afford
Example 393 (5 mg, 0.008 mmol, 37% yield) as a yellow solid. LC-MS:
Method H, RT=0.99 min, MS (ESI) m/z: 576.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.48 (s, 1H), 9.07 (d, J=4.9 Hz,
1H), 8.83 (s, 1H), 8.73 (br. s., 2H), 8.11-8.01 (m, 2H), 7.94 (d,
J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.3 Hz, 1H),
2.98-2.90 (m, 3H), 2.70 (s, 3H), 2.52 (br. s., 3H), 1.40 (m,
6H).
Preparation of Carbamate Examples
[3251] The Carbamates in the table below were prepared according to
the following general procedure, which is analogous to Intermediate
I-82 described above
[3252] To a solution of the appropriately substituted
quinoxaline-benzothiazole alcohol (1.0 equiv) in THF (0.05 M) was
added a solution of phosgene (15% by wt. in toluene, 10 equiv).
This solution was stirred at room temperature overnight, and the
intermediate chloroformate was concentrated in vacuo. This crude
chloroformate was then retaken in THF (0.05 M) and added dropwise
to a pre-mixed solution of pyridine (10 equiv) and the
appropriately substituted amino-heterocycle or amine (3.0 equiv) in
either THF (0.05 M) or DCM (0.05) (whichever gave the best reagent
solubility). After 10 min of stirring, the combined mixture was
concentrated and purified by preparative HPLC to yield the desired
example.
TABLE-US-00008 LCMS LCMS RT HPLC [M + (Min) Prep Ex. H].sup.+
Method Method No. Structure R--OH m/z H D NMR 394 ##STR01235## I-67
568.3 1.13 30- 65% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H),
7.99-7.94 (m, 2H), 7.83 (s, 1H), 7.14 (t, J = 5.5 Hz, 1H),
5.13-5.04 (m, 1H), 4.27- 4.16 (m, 2H), 4.09 (s, 3H), 3.31-3.16 (m,
6H), 2.63 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.88-1.78 (m, 2H),
1.73 (quin, J = 6.7 Hz, 2H), 1.32 (d, J = 6.6 Hz, 3H) 395
##STR01236## 318 565.2, 567.3 1.22 60- 100% 20 min, 100% 8 min --
396 ##STR01237## 318 545.2, 556.2 1.02 50- 100% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.53 (br.
s., 1H), 8.46 (br. s., 1H), 7.92 (br. s., 1H), 7.88 (d, J = 6.4 Hz,
1H), 7.81 (br. s., 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.38-7.30 (m,
1H), 7.29-7.21 (m, 1H), 4.39 (d, J = 1.6 Hz, 4H), 4.28 (d, J = 5.8
Hz, 2H), 4.05 (s, 3H), 2.62 (s, 3H) 397 ##STR01238## 318 557.2,
559.3 1.21 45- 90% 30 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.59 (s, 1H), 8.45 (br. s., 1H), 7.85-7.81
(m, 1H), 7.72 (br. s., 1H), 7.51 (br. s., 1H), 7.40 (s, 1H), 6.82
(s, 1H), 4.31 (d, J = 8.2 Hz, 4H), 4.00 (m, 5H), 3.47 (br. s., 3H),
2.56 (s, 3H) 398 ##STR01239## 318 557.2, 559.2 1.21 45- 100% 20
min, 100% 5 min .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.67 (s,
1H), 8.47 (s, 1H), 7.70 (s, 1H), 7.33 (d, J = 6.9 Hz, 1H), 7.20
(br. s., 1H), 6.10 (s, 1H), 5.19 (br. s., 1H), 4.46 (br. s., 2H),
4.32 (d, J = 5.5 Hz, 2H), 4.27 (br. s., 2H), 4.06 (s, 3H), 3.78 (s,
3H), 2.60 (s, 3H) 399 ##STR01240## 318 557.2, 559.2 1.18 45- 80% 20
min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.61
(s, 1H), 8.47 (s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.74 (s, 1H), 7.58
(br. s., 1H), 7.47 (s, 1H), 7.24 (s, 1H), 4.31 (d, J = 8.2 Hz, 4H),
4.01 (s, 3H), 3.97 (d, J = 5.8 Hz, 2H), 3.71 (s, 3H), 2.57 (s, 3H)
400 ##STR01241## I-69 580.2, 582.2 1.30 50- 100% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.04 (s, 2H), 8.73 (s,
1H), 8.58 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 5.36
(br. s., 1H), 4.53-4.45 (m, 1H), 4.38 (dd, J = 10.8, 6.0 Hz, 1H),
4.13 (s, 3H), 2.69 (s, 3H), 1.51 (d, J = 6.4 Hz, 3H) 401
##STR01242## I-69 590.2, 592.2 1.34 50- 100% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.80 (s, 2H), 8.74 (s,
1H), 8.59 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.86 (s,
1H), 5.27 (td, J = 6.3, 3.0 Hz, 1H), 4.44-4.39 (m, 1H), 4.32 (dd, J
= 10.9, 5.9 Hz, 1H), 4.09 (s, 3H), 2.65 (s, 3H), 1.43 (d, J = 6.6
Hz, 3H) 402 ##STR01243## I-69 586.1, 588.1 1.35 50- 100% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.69 (s,
1H), 8.54 (s, 1H), 8.13 (br. s., 1H), 7.98 (d, J = 7.3 Hz, 1H),
7.91 (br. s., 1H), 7.81 (s, 1H), 5.31 (br. s., 1H), 4.47-4.39 (m,
1H), 4.34 (dd, J = 10.4, 6.1 Hz, 1H), 4.12 (s, 3H), 2.67 (s, 3H),
2.25 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H) 403 ##STR01244## I-69 632.0,
634.0, 636.0 1.30 60- 90% 20 min, 100% 5 min .sup.1H NMR (400 MHz,
THF) .delta. 9.25 (br. s., 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.60 (s,
1H), 8.41 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 8.7, 2.8 Hz, 1H), 7.83
(dd, J = 1.8, 0.9 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.44 (d, J =
8.8 Hz, 1H), 5.42-5.26 (m, 1H), 4.44-4.27 (m, 2H), 4.15 (s, 3H),
2.70 (s, 3H), 1.55-1.49 (m, 3H) 404 ##STR01245## I-81 568.2, 570.2
1.10 40- 80% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.07 (br. s., 1H), 8.67 (br. s., 1H), 8.62 (s, 1H), 8.48
(s, 1H), 8.24 (br. s., 1H), 7.98 (d, J = 6.7 Hz, 2H), 7.75 (s, 1H),
7.45 (br. s., 1H), 5.08 (d, J = 6.7 Hz, 1H), 4.76 (br. s., 1H),
4.01 (s, 3H), 2.57 (s, 3H), 1.36 (d, J = 6.1 Hz, 3H), 1.33 (d, J =
6.4 Hz, 3H) 405 ##STR01246## I-72 548.1 1.05 15- 100% 15 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.81 (br. s.,
1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.49 (br. s., 1H), 8.02 (d, J =
8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.77 (br. s.,
1H), 7.19 (d, J = 7.9 Hz, 1H), 5.09 (d, J = 4.6 Hz, 1H), 4.77 (br.
s., 1H), 4.07 (s, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 1.38 (m, 6H) 406
##STR01247## I-72 590.1 1.22 25- 100% 20 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.47 (s, 1H), 9.67 (br. s.,
1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.94 (d,
J = 11.3 Hz, 1H), 7.81 (s, 1H), 7.45 (br. s., 1H), 7.12 (br. s.,
1H), 6.96 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.77 (br.
s., 1H), 4.06 (s, 3H), 2.61 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.36
(d, J = 6.7 Hz, 3H) 407 ##STR01248## I-72 565.1 1.26 50- 100% 15
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.88
(br. s., 1H), 8.77 (s, 1H), 8.68 (br. s., 2H), 8.62 (s, 1H), 8.09
(d, J = 7.9 Hz, 1H), 8.01 (d, J = 11.6 Hz, 1H), 7.88 (s, 1H), 5.15
(d, J = 6.4 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H), 4.14 (s, 3H), 3.90
(s, 3H), 2.68 (s, 3H), 1.48- 1.40 (m, 6H) 408 ##STR01249## I-67
551.1 1.22 50- 100% 12 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.91 (br. s., 1H), 8.69 (s, 1H), 8.63 (br.
s., 2H), 8.52 (s, 1H), 7.99- 7.90 (m, 2H), 7.78 (s, 1H), 5.23 (br.
s., 1H), 4.38- 4.31 (m, 1H), 4.29-4.21 (m, 1H), 4.06 (s, 3H), 3.85
(s, 3H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H) 409 ##STR01250##
I-67 521.1 1.22 45- 78% 25 min, 100% 7 min .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.20 (br. s., 1H), 8.89 (s, 2H), 8.84 (s,
1H), 8.73 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.4 Hz,
1H), 7.97 (d, J = 11.7 Hz, 1H), 7.82 (dd, J = 2.0, 0.9 Hz, 1H),
5.35-5.22 (m, 1H), 4.43-4.35 (m, 1H), 4.33-4.25 (m, 1H), 4.08 (s,
3H), 2.63 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H) 410 ##STR01251## I-72
535.1 1.25 45- 90% 20 min, 100% 5 min .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.13 (br. s., 1H), 8.87 (s, 2H), 8.82 (s,
1H), 8.73 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.1 Hz,
1H), 7.97 (d, J = 11.7 Hz, 1H), 7.84 (dd, J = 2.0, 0.9 Hz, 1H),
5.14 (qd, J = 6.4, 2.8 Hz, 1H), 4.87-4.77 (m, 1H), 4.09 (s, 3H),
2.64 (s, 3H), 1.44-1.38 (m, 6H) 411 ##STR01252## I-67 519.2 1.27
45- 90% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.73 (br. s., 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99-7.91
(m, 2H), 7.80 (s, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.5
Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 5.25 (br. s., 1H), 4.38- 4.31
(m, 1H), 4.30-4.22 (m, 1H), 4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J
= 6.1 Hz, 3H) 412 ##STR01253## I-72 564.1 1.12 70- 100% 20 min,
100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.09 (s,
1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H),
7.97-7.91 (m, 2H), 7.78 (s, 1H), 7.01 (d, J = 5.4 Hz, 1H), 6.91 (s,
1H), 5.12 (dd, J = 6.4, 2.4 Hz, 1H), 4.79 (d, J = 3.7 Hz, 1H), 4.06
(s, 3H), 3.77 (s, 3H), 2.60 (s, 3H), 1.39 (m, 6H) 413 ##STR01254##
I-72 535.1 1.06 40- 95% 21 min, 100% 6 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.54 (br. s., 1H), 9.19 (br. s., 1H), 9.00
(br. s., 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H),
7.94 (d, J = 11.6 Hz, 1H), 7.81 (br. s., 2H), 5.16 (br. s., 1H),
4.81 (br. s., 1H), 4.07 (s, 3H), 2.62 (s, 3H), 1.41 (d, J = 5.8 Hz,
6H) 414 ##STR01255## I-72 577.2 1.27 45- 100% 10 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.90 (br. s., 1H), 8.72
(br. s., 2H), 8.66 (s, 1H), 8.51 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H),
7.91 (d, J = 11.3 Hz, 1H), 7.78 (s, 1H), 5.09 (d, J = 4.3 Hz, 1H),
4.80 (d, J = 3.7 Hz, 1H), 4.05 (s, 3H), 2.71 (t, J = 7.3 Hz, 2H),
2.59 (s, 3H), 1.66 (sxt, J = 7.3 Hz, 2H), 1.38 (t, J = 5.8 Hz, 6H),
0.83 (t, J = 7.3 Hz, 3H) 415 ##STR01256## I-72 603.1 1.31 60- 100%
22 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.51 (br. s., 1H), 9.01 (s, 2H), 8.64 (s, 1H), 8.49 (s, 1H), 7.99
(d, J = 8.1 Hz, 1H), 7.91 (d, J = 11.4 Hz, 1H), 7.77 (s, 1H), 5.14
(dd, J = 6.6, 2.2 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.05 (s, 3H),
2.59 (s, 3H), 1.40 (d, J = 5.7 Hz, 6H) 416 ##STR01257## I-72 549.2
1.11 55- 95% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.64 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.2
Hz, 1H), 7.94 (d, J = 10.4 Hz, 2H), 7.83 (s, 1H), 7.52 (d, J = 9.2
Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.76 (d, J = 5.8 Hz, 1H), 4.08
(s, 3H), 2.63 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.41 (d, J
= 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H) 417 ##STR01258## I-72 549.2
1.27 60- 100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.38 (s, 1H), 8.96 (s, 1H), 8.72 (br. s.,
1H), 8.57 (br. s., 1H), 8.25 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H),
7.97 (d, J = 11.3 Hz, 1H), 7.84 (br. s., 1H), 5.19 (dd, J = 6.4,
2.7 Hz, 1H), 4.82 (d, J = 3.4 Hz, 1H), 4.12 (s, 3H), 2.66 (s, 3H),
2.46 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H)
418 ##STR01259## I-72 549.1 1.15 50- 100% 19 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.35 (s, 1H), 9.04
(br. s., 1H), 8.72 (s, 1H), 8.56 (d, J = 1.5 Hz, 1H), 8.04 (d, J =
8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.83 (s, 1H), 7.60 (s, 1H),
5.20-5.09 (m, 1H), 4.82 (dd, J = 6.4, 2.7 Hz, 1H), 4.08 (s, 3H),
2.63 (s, 3H), 2.51 (br. s., 3H-Buried under d-DMSO signal), 1.41
(d, J = 6.4 Hz, 6H) 419 ##STR01260## I-72 548.2 1.26 25- 100% 15
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.19
(br. s., 1H), 8.73 (s, 1H), 8.61 (br. s., 1H), 8.57 (s, 1H), 8.23
(s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99-7.91 (m, 2H), 7.84 (s, 1H),
5.13 (d, J = 6.4 Hz, 1H), 4.82 (d, J = 5.8 Hz, 1H), 4.09 (s, 3H),
2.63 (s, 3H), 2.32 (s, 3H), 1.41 (d, J = 4.6 Hz, 6H) 420
##STR01261## I-72 564.2 1.28 30- 100% 15 min, 100% 5 min (Meth C)
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.06 (br. s., 1H),
8.72 (s, 1H), 8.57 (s, 1H), 8.31 (br. s., 1H), 8.08- 8.00 (m, 2H),
7.96 (d, J = 11.3 Hz, 1H), 7.83 (s, 1H), 7.64 (br. s., 1H), 5.12
(d, J = 6.4 Hz, 1H), 4.81 (d, J = 6.1 Hz, 1H), 4.08 (s, 3H), 3.81
(s, 2H), 2.63 (s, 3H), 1.40 (t, J = 5.3 Hz, 6H) 421 ##STR01262##
I-72 559.3 1.49 50- 100% 10 min, 100% 10 min (Meth C) .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.27 (br. s., 1H), 8.83 (br. s.,
1H), 8.71 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.25 (br. s., 1H),
8.04 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.82 (s, 1H),
5.13 (d, J = 6.4 Hz, 1H), 4.83 (d, J = 6.1 Hz, 1H), 4.08 (s, 3H),
2.63 (s, 3H), 1.41 (d, J = 6.1 Hz, 6H) 422 ##STR01263## I-72 578.2
1.45 60- 100% 10 min, 100% 10 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.50 (br. s., 1H), 8.72 (s, 1H), 8.57 (s,
1H), 8.02 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 11.3 Hz, 1H), 7.82 (s,
1H), 7.59 (br. s., 1H), 5.06 (d, J = 5.2 Hz, 1H), 4.79 (d, J = 5.8
Hz, 1H), 4.08 (s, 3H), 3.80 (s, 3H), 2.63 (s, 3H), 2.08 (s, 3H),
1.38 (t, J = 7.6 Hz, 6H) 423 ##STR01264## I-72 534.0 1.00 60- 100%
20 min, 100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.93 (br. s., 1H), 8.72 (s, 1H), 8.66 (br. s., 1H), 8.56 (s, 1H),
8.22 (d, J = 4.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J =
11.6 Hz, 1H), 7.91 (br. s., 1H), 7.83 (s, 1H), 7.35 (dd, J = 8.1,
4.7 Hz, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 3.7 Hz, 1H),
4.09 (s, 3H), 2.63 (s, 3H), 1.41 (t, J = 6.3 Hz, 6H) 424
##STR01265## I-66 520.9 1.10 45- 90% 20 min, 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.16 (br. s., 1H), 8.77 (d, J =
4.3 Hz, 3H), 8.59 (s, 1H), 8.06-7.97 (m, 2H), 7.86 (s, 1H), 4.57
(br. s., 2H), 4.46 (br. s., 2H), 4.10 (s, 3H), 2.65 (s, 3H), 2.56
(s, 3H) 425 ##STR01266## I-81 582.9, 584.9 1.26 60- 100% 20 min,
100% 7 min (Meth C) .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.95 (br. s., 1H), 8.78-8.67 (m, 3H), 8.57 (s, 1H), 8.06 (d, J =
7.6 Hz, 1H), 7.84 (s, 1H), 5.13 (dd, J = 6.6, 2.3 Hz, 1H), 4.85 (d,
J = 6.4 Hz, 1H), 4.09 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H), 1.42 (d,
J = 6.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H)
Example 426
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl
(6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate
##STR01267##
[3254] To a vial charged with Intermediate I-74 (10 mg, 0.017 mmol)
was added DCM (1 mL). To this solution was added magnesium chloride
(16.09 mg, 0.169 mmol) followed by morpholine (0.1 mL, 1.148 mmol).
The resulting mixture was sealed, stirred vigorously and heated to
65.degree. C. overnight before being diluted with EtOAc, filtered
over Celite, concentrated, and purified by Prep HPLC (Method C,
25-100% over 15 min, hold 100% for 5 min) to afford Example 426
(9.6 mg, 0.015 mmol, 86% yield). LC-MS: Method H, RT=1.20 min, MS
(ESI) m/z: 647.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.12 (br. s., 1H), 8.64 (s, 1H), 8.59 (br. s., 1H), 8.49
(s, 1H), 7.98 (d, J=7.9 Hz, 2H), 7.91 (d, J=11.6 Hz, 1H), 7.76 (s,
1H), 7.57 (d, J=8.5 Hz, 1H), 5.12 (d, J=4.6 Hz, 1H), 4.80 (d, J=5.8
Hz, 1H), 4.05 (s, 3H), 3.62 (d, J=15.9 Hz, 2H), 3.49 (d, J=17.1 Hz,
2H), 2.59 (s, 3H), 2.52 (br. s., 4H), 1.39 (m, 6H).
Preparation of Amide Examples
[3255] The amides in the accompanying table were prepared according
to the following three general procedures, which are analogous to
the ones used to synthesize Examples 391-392 and 426 described
above.
[3256] Primary Amides
[3257] To a vial charged with the appropriately substituted
hetero-aryl ester (1.0 equiv) was added ammonia (7M solution in
MeOH) (0.02 M). The resulting mixture was sealed and heated to
65.degree. C. overnight before being concentrated and purified by
Prep HPLC (Method D unless otherwise indicated) to afford the
desired example.
[3258] Secondary Amides
[3259] To a solution of the appropriately substituted hetero-aryl
ester (1.0 equiv) in THF (0.02 M) was added the desired amine (100
equiv). The resulting mixture was sealed and heated to 65.degree.
C. overnight before being concentrated and purified by Prep HPLC
(Method D unless otherwise indicated) to afford the desired
example.
[3260] Tertiary Amides
[3261] To a solution of the appropriately substituted hetero-aryl
ester (1.0 equiv) in DCM (0.02 M) was added MgCl.sub.2 (10 equiv)
followed by the desired amine (100 equiv). The resulting mixture
was sealed, stirred vigorously and heated to 65.degree. C.
overnight before being diluted with EtOAc, filtered over Celite,
concentrated and purified by Prep HPLC (Method D unless otherwise
indicated) to afford the desired example.
TABLE-US-00009 LCMS LCMS RT HPLC [M + (Min) Prep Ex. H].sup.+
Method Method No. Structure Ester m/z H D NMR 427 ##STR01268## I-87
597.1, 599.2 1.16 45-95% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.44 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H),
8.42 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H),
7.83 (s, 1H), 7.63 (br. s., 1H), 7.57 (br. s., 1H), 5.30 (br. s.,
1H), 4.46-4.37 (m, 1H), 4.31 (d, J = 5.8 Hz, 1H), 4.07 (s, 3H),
2.64 (s, 3H), 1.44 (d, J = 6.1 Hz, 3H) 428 ##STR01269## I-87 611.1,
613.1 1.17 45-95% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.42 (s, 1H), 8.71-8.63 (m, 2H), 8.54 (s,
1H), 8.42 (d, J = 5.5 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J = 7.6 Hz,
1H), 7.81 (s, 1H), 7.62 (d, J = 4.9 Hz, 1H), 5.29 (br. s., 1H),
4.40 (d, J = 8.5 Hz, 1H), 4.30 (dd, J = 10.5, 6.3 Hz, 1H), 4.07 (s,
3H), 2.78 (d, J = 4.9 Hz, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.4 Hz,
3H) 429 ##STR01270## I-84 564.1 1.10 60-100% 13 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.94 (s, 2H), 8.65 (s,
1H), 8.48 (s, 1H), 8.05 (br. s., 1H), 7.94 (d, J = 8.2 Hz, 1H),
7.91 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 7.63 (br. s., 1H),
5.32-5.17 (m, 1H), 4.39-4.30 (m, 1H), 4.29-4.21 (m, 1H), 4.02 (s,
3H), 2.56 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H) 430 ##STR01271## I-84
578.1 1.12 50-100% 10 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 2H), 8.77-8.69 (m, 2H), 8.55 (s,
1H), 8.00 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.82 (s,
1H), 5.29 (br. s., 1H), 4.40 (d, J = 8.2 Hz, 1H), 4.29 (dd, J =
10.7, 6.1 Hz, 1H), 4.07 (s, 3H), 2.78 (d, J = 4.6 Hz, 3H), 2.62 (s,
3H), 1.44 (d, J = 6.4 Hz, 3H) 431 ##STR01272## I-84 592.2 1.15
60-100% 13 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.39 (br. s., 1H), 8.92 (s, 2H), 8.71 (s, 1H), 8.54 (s,
1H), 7.99 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.80 (s,
1H), 5.29 (d, J = 2.7 Hz, 1H), 4.42-4.35 (m, 1H), 4.32-4.25 (m,
1H), 4.06 (s, 3H), 2.98 (s, 3H), 2.77 (s, 3H), 2.61 (s, 3H), 1.44
(d, J = 6.4 Hz, 3H) 432 ##STR01273## I-82 577.2 1.17 15-100% 20
min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.26
(br. s., 1H), 8.68 (s, 2H), 8.59 (d, J = 4.6 Hz, 1H), 8.52 (s, 1H),
8.02 (d, J = 8.9 Hz, 1H), 7.99-7.90 (m, 3H), 7.79 (s, 1H), 5.27 (d,
J = 3.1 Hz, 1H), 4.37 (d, J = 7.9 Hz, 1H), 4.31-4.23 (m, 1H), 4.06
(s, 3H), 2.77 (d, J = 4.6 Hz, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4
Hz, 3H) 433 ##STR01274## I-82 563.1 1.15 25-65% 20 min, 100% 9 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.24 (br. s., 1H),
8.64 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.03-7.97 (m, 1H),
7.95-7.85 (m, 4H), 7.72 (s, 1H), 7.43 (br. s., 1H), 5.27-5.19 (m,
1H), 4.36-4.29 (m, 1H), 4.26-4.19 (m, 1H), 4.01 (s, 3H), 2.55 (s,
3H), 1.39 (d, J = 6.4 Hz, 3H) 434 ##STR01275## I-82 591.1 1.16
10-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.19 (br. s., 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.51 (s,
1H), 8.02-7.89 (m, 3H), 7.77 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H),
5.27 (d, J = 3.1 Hz, 1H), 4.36 (d, J = 7.9 Hz, 1H), 4.31-4.23 (m,
1H), 4.05 (s, 3H), 2.97 (s, 3H), 2.96 (s, 3H), 2.59 (s, 3H), 1.42
(d, J = 6.7 Hz, 3H) 435 ##STR01276## I-82 633.1 1.17 10-100% 20
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.22
(br. s., 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.01 (d, J
= 8.2 Hz, 1H), 7.98-7.90 (m, 2H), 7.77 (s, 1H), 7.59 (d, J = 8.5
Hz, 1H), 5.27 (d, J = 2.7 Hz, 1H), 4.36 (d, J = 7.9 Hz, 1H), 4.27
(dd, J = 10.7, 6.1 Hz, 1H), 4.05 (s, 3H), 3.62 (m, 4H), 3.52 (m,
4H), 2.59 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H) 436 ##STR01277## I-74
591.1 1.18 25-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.13 (br. s., 1H), 8.67 (s, 1H), 8.64 (br.
s., 1H), 8.55 (d, J = 4.6 Hz, 1H), 8.52 (s, 1H), 8.04-7.96 (m, 2H),
7.95-7.88 (m, 2H), 7.79 (s, 1H), 5.11 (dd, J = 6.4, 2.4 Hz, 1H),
4.82 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H),
2.60 (s, 3H), 1.39 (m, 6H) 437 ##STR01278## I-86 648.2 1.18 20-100%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.25 (br. s., 1H), 8.85 (s, 2H), 8.63 (s, 1H), 8.47 (s, 1H), 7.97
(d, J = 7.9 Hz, 1H), 7.88 (d, J = 11.6 Hz, 1H), 7.74 (s, 1H), 5.08
(dd, J = 6.6, 2.6 Hz, 1H), 4.75 (m, 1H), 4.00 (s, 3H), 3.57 (m,
4H), 3.40 (br. s., 2H), 3.17-3.08 (br. s., 2H), 2.55 (s, 3H), 1.34
(m, 6H) 438 ##STR01279## I-74 605.2 1.19 40-80% 20 min, 100% 10 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.07 (br. s., 1H),
8.65 (s, 1H), 8.58 (br. s., 1H), 8.50 (s, 1H), 7.98 (d, J = 8.2 Hz,
1H), 7.95 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.77 (s,
1H), 7.50 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 4.3 Hz, 1H), 4.79 (d, J
= 4.6 Hz, 1H), 4.04 (s, 3H), 2.95 (s, 3H), 2.91 (s, 3H), 2.58 (s,
3H), 1.38 (m, 6H) 439 ##STR01280## I-74 635.2 1.18 25-100% 15 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.19 (br.
s., 1H), 8.71-8.64 (m, 2H), 8.53 (s, 1H), 8.41 (t, J = 6.0 Hz, 1H),
8.02 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 11.0 Hz, 2H), 7.80 (s, 1H),
5.12 (dd, J = 6.6, 2.3 Hz, 1H), 4.87-4.77 (m, 2H), 4.06 (s, 3H),
3.75 (dt, J = 11.7, 5.6 Hz, 1H), 3.34 (br. s., 1H), 3.19-3.09 (m,
1H), 2.61 (s, 3H), 1.40 (m, 6H), 1.04 (d, J = 6.4 Hz, 3H) 440
##STR01281## I-86 592.1 1.15 30-80% 18 min, 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.93 (s, 2H), 8.71 (d, J = 4.9 Hz,
1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d,
J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.13 (d, J = 4.3 Hz, 1H), 4.84 (d,
J = 4.0 Hz, 1H), 4.06 (s, 3H), 2.76 (d, J = 4.9 Hz, 3H), 2.60 (s,
3H), 1.40 (d, J = 6.4 Hz, 6H) 441 ##STR01282## I-74 635.2 1.19
45-90% 22 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.18 (br. s., 1H), 8.66 (s, 2H), 8.52 (s, 1H), 8.41 (t, J
= 5.8 Hz, 1H), 8.00 (m, 2H), 7.94 (s, 1H), 7.92 (d, J = 4.6 Hz,
1H), 7.78 (s, 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.86 (d, J = 4.6 Hz,
1H), 4.81 (d, J = 6.1 Hz, 1H), 4.05 (s, 3H), 3.75 (dt, J = 11.3,
5.6 Hz, 1H), 3.29 (dt, J = 12.4, 6.1 Hz, 1H), 3.16-3.07 (m, 1H),
2.59 (s, 3H), 1.39 (t, J = 5.3 Hz, 6H), 1.04 (d, J = 6.1 Hz, 3H)
442 ##STR01283## I-83 607.1 1.08 45-90% 20 min, 100% 8 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (s, 1H), 8.69 (t, J = 5.8
Hz, 1H), 8.60 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.22 (s, 1H), 8.05
(d, J = 8.2 Hz, 1H), 8.02 (d, J = 11.6 Hz, 1H), 7.86 (s, 1H), 7.72
(dd, J = 5.5, 1.8 Hz, 1H), 5.36 (d, J = 3.1 Hz, 1H), 4.44 (d, J =
7.9 Hz, 1H), 4.38-4.31 (m, 1H), 4.13 (s, 3H), 3.57 (q, J = 5.6 Hz,
2H), 2.67 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H) 443 ##STR01284## I-83
577.1 1.12 50-100% 20 min, 100% 8 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.52 (s, 1H), 8.77 (d, J = 4.9 Hz, 1H), 8.74
(s, 1H), 8.58 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.20 (s, 1H), 8.02
(d, J = 8.5 Hz, 1H), 8.00 (d, J = 11.6 Hz, 1H), 7.84 (s, 1H), 7.70
(dd, J = 5.3, 2.0 Hz, 1H), 5.36 (d, J = 2.7 Hz, 1H), 4.48-4.41 (m,
1H), 4.38-4.31 (m, 1H), 4.12 (s, 3H), 2.86 (d, J = 4.9 Hz, 3H),
2.66 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H) 444 ##STR01285## I-83 563.1
1.11 25-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.47 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.42 (d, J = 5.2
Hz, 1H), 8.15 (s, 1H), 8.05 (br. s., 1H), 7.98 (d, J = 7.9 Hz, 1H),
7.94 (d, J = 11.6 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J = 5.5 Hz, 1H),
7.60 (br. s., 1H), 5.29 (br. s., 1H), 4.40-4.34 (m, 1H), 4.31-4.24
(m, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H) 445
##STR01286## I-82 607.0 1.22 30-70% 20 min, 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.29 (br. s., 1H), 8.70 (br. s.,
1H), 8.65 (s, 1H), 8.57- 8.51 (m, 1H), 8.50 (s, 1H), 8.05 (d, J =
8.2 Hz, 1H), 8.00-7.89 (m, 3H), 7.77 (s, 1H), 5.29 (br. s., 1H),
4.89 (t, J = 4.9 Hz, 1H), 4.42-4.34 (m, 1H), 4.32-4.24 (m, 1H),
4.06 (s, 3H), 3.53-3.48 (m, 2H), 3.36 (d, J = 5.8 Hz, 2H), 2.60 (s,
3H), 1.44 (d, J = 6.1 Hz, 3H) 446 ##STR01287## I-74 663.1 1.28
50-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.15 (br. s., 1H), 8.70-8.59 (m, 3H), 8.50 (s, 1H),
8.04-7.97 (m, J = 8.2 Hz, 2H), 7.94-7.88 (m, 2H), 7.77 (s, 1H),
5.13 (d, J = 6.1 Hz, 1H), 4.83 (d, J = 5.8 Hz, 1H), 4.06 (s, 3H),
3.35 (m, 2H), 2.60 (s, 3H), 1.61 (t, J = 7.2 Hz, 2H), 1.41 (t, J =
6.3 Hz, 6H), 1.14 (s, 6H) 447 ##STR01288## I-83 591.0 1.14 45-90%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.41 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.38 (d, J = 5.5 Hz,
1H), 7.96-7.89 (m, 2H), 7.76 (s, 1H), 7.59 (s, 1H), 7.51 (d, J =
5.5 Hz, 1H), 5.29 (br. s., 1H), 4.37 (d, J = 9.8 Hz, 1H), 4.27 (dd,
J = 10.5, 6.0 Hz, 1H), 4.06 (s, 3H), 2.98 (s, 3H), 2.89 (s, 3H),
2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H) 448 ##STR01289## I-82 635.1
1.24 45-90% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.30 (br. s., 1H), 8.70 (br. s., 1H), 8.64 (s, 1H), 8.48
(s, 1H), 8.37-8.29 (m, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.99 (d, J =
8.5 Hz, 1H), 7.95-7.89 (m, 2H), 7.75 (s, 1H), 5.29 (br. s., 1H),
4.80 (s, 1H), 4.41-4.34 (m, 1H), 4.31-4.24 (m, 1H), 4.05 (s, 3H),
3.26 (d, J = 5.8 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H),
1.10 (s, 6H) 449 ##STR01290## I-82 621.2 1.18 45-90% 25 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.22 (br. s., 1H),
8.70-8.61 (m, 2H), 8.50 (s, 1H), 8.49-8.45 (m, 1H), 8.01 (br. s.,
1H), 7.96- 7.89 (m, 3H), 7.80 (s, 1H), 5.34-5.22 (m, J = 8.1 Hz,
1H), 4.37 (d, J = 8.8 Hz, 1H), 4.30-4.22 (m, 1H), 4.05 (s, 3H),
3.80 (m, 1H), 3.28 (d, J = 5.4 Hz, 1H), 3.20- 3.07 (m, 1H), 2.60
(s, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H) 450
##STR01291## I-82 621.2 1.18 45-90% 25 min, 100% 8 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.73 (s, 1H), 8.60
(s, 1H), 8.44 (br. s., 1H), 8.11-7.96 (m, 4H), 7.86 (s, 1H), 5.31
(br. s., 1H), 4.84 (d, J = 4.9 Hz, 1H), 4.41 (d, J = 8.5 Hz, 1H),
4.34-4.28 (m, 1H), 4.10 (s, 3H), 3.79 (br. s., 1H), 3.39-3.28 (m,
1H), 3.21-3.12 (m, 1H), 2.65 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H),
1.07 (d, J = 6.1 Hz, 3H) 451 ##STR01292## I-85 621.3 1.08 60-95% 20
min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.39
(s, 1H), 8.68 (s, 1H), 8.62 (t, J = 5.7 Hz, 1H), 8.53 (s, 1H), 8.42
(d, J = 5.7 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94
(d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J = 3.7 Hz, 1H), 5.15
(dd, J = 6.4, 2.4 Hz, 1H), 4.86-4.78 (m, 2H), 4.07 (s, 3H), 3.51
(q, J = 5.8 Hz, 2H), 3.40-3.31 (m, 2H), 2.61 (s, 3H), 1.41 (d, J =
4.7 Hz, 6H) 452 ##STR01293## I-85 653.3 1.11 60-100% 20 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.39 (s, 1H), 8.69
(s, 1H), 8.60-8.51 (m, 2H), 8.43 (d, J = 5.7 Hz, 1H), 8.16 (s, 1H),
8.04 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.4 Hz, 1H), 7.80 (s, 1H),
7.63 (d, J = 4.0 Hz, 1H), 5.15 (dd, J = 6.4, 2.4 Hz, 1H), 4.81 (dd,
J = 6.4, 2.4 Hz, 1H), 4.07 (s, 3H), 3.82-3.71 (m, 1H), 3.43-3.27
(m, 1H), 3.22-3.10 (m, 1H), 2.61 (s, 3H), 1.41 (m, 6H), 1.06 (d, J
= 6.1 Hz, 3H) 453 ##STR01294## I-85 577.2 1.10 60-100% 18 min, 100%
7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.38 (s, 1H),
8.70 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.16 (s, 1H),
8.08-8.01 (m, 2H), 7.95 (d, J = 11.4 Hz, 1H), 7.80 (s, 1H),
7.66-7.56 (m, 2H), 5.15 (d, J = 4.4 Hz, 1H), 4.81 (d, J = 4.0 Hz,
1H), 4.07 (s, 3H), 2.62 (s, 3H), 1.41 (m, 6H) 454 ##STR01295## I-86
578.2 1.12 45-90% 20 min, 100% 7 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.39 (br. s., 1H), 8.97 (s, 2H), 8.71 (s,
1H), 8.55 (s, 1H), 8.09 (br. s., 1H), 8.05 (d, J = 8.1 Hz, 1H),
7.96 (d, J = 11.4 Hz, 1H), 7.81 (s, 1H), 7.67 (br. s., 1H),
5.21-5.11 (m, 1H), 4.83 (d, J = 4.0 Hz, 1H), 4.08 (s, 3H), 2.62 (s,
3H), 1.42 (m, 6H) 455 ##STR01296## I-86 622.3 1.09 45-90% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.38 (br.
s., 1H), 8.96 (s, 2H), 8.70 (s, 1H), 8.64 (t, J = 5.9 Hz, 1H), 8.55
(s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.4 Hz, 1H), 7.81
(s, 1H), 5.15 (d, J = 6.7 Hz, 1H), 4.88-4.83 (m, 1H), 4.81 (t, J =
5.6 Hz, 1H), 4.07 (s, 3H), 3.51 (q, J = 6.1 Hz, 2H), 3.34 (m, 2H),
2.62 (s, 3H), 1.42 (m, 6H) 456 ##STR01297## I-86 636.3 1.11 45-90%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.39 (br. s., 1H), 8.97 (br. s., 2H), 8.69 (s, 1H), 8.59- 8.50 (m,
2H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.80 (s,
1H), 5.15 (d, J = 6.4 Hz, 1H), 4.85 (d, J = 4.7 Hz, 2H), 4.07 (s,
3H), 3.83-3.71 (m, 1H), 3.28 (dt, J = 12.4, 6.1 Hz, 1H), 3.16 (dt,
J = 12.9, 6.2 Hz, 1H), 2.62 (s, 3H), 1.42 (m, 6H), 1.06 (d, J = 6.1
Hz, 3H) 457 ##STR01298## I-86 650.3 1.13 45-90% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.40 (br. s., 1H),
8.98 (s, 2H), 8.69 (s, 1H), 8.54 (s, 1H), 8.39 (t, J = 6.1 Hz, 1H),
8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.81 (s, 1H),
5.15 (d, J = 4.4 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.71 (s, 1H),
4.07 (s, 3H), 3.25 (d, J = 6.4 Hz, 2H), 2.62 (s, 3H), 1.42 (m, 6H),
1.10 (s, 6H) 458 ##STR01299## I-86 664.2 1.14 45-90% 20 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.35 (br. s., 1H),
8.94 (s, 2H), 8.79 (t, J = 5.6 Hz, 1H), 8.68 (s, 1H), 8.53 (s, 1H),
8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H), 7.79 (s, 1H),
5.20-5.09 (m, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.47 (s, 1H), 4.07 (s,
3H), 3.38- 3.30 (m, 2H), 2.61 (s, 3H), 1.62 (t, J = 7.4 Hz, 2H),
1.41 (m, 6H), 1.14 (s, 6H) 459 ##STR01300## I-85 664.2 1.14 45-90%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.35 (br. s., 1H), 8.94 (s, 2H), 8.79 (t, J = 5.6 Hz, 1H), 8.68
(s, 1H), 8.53 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 11.8
Hz, 1H), 7.79 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 4.0 Hz, 1H),
4.47 (s, 1H), 4.07 (s, 3H), 3.38-3.30 (m, 2H), 2.61 (s, 3H), 1.62
(t, J = 7.4 Hz, 2H), 1.41 (m, 6H), 1.14 (s, 6H) 460 ##STR01301##
I-74 649.3 1.19 55-95% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.21 (br. s., 1H), 8.68 (s, 2H), 8.53 (s,
1H), 8.30 (t, J = 6.1 Hz, 1H), 8.09-8.00 (m, 2H), 7.99-7.90 (m,
2H), 7.80 (s, 1H), 5.14 (dd, J = 6.4, 2.4 Hz, 1H), 4.83 (d, J = 3.7
Hz, 1H), 4.07 (s, 3H), 3.24 (d, J = 6.4 Hz, 2H), 2.61 (s, 3H),
1.45-1.37 (m, 6H), 1.09 (s, 6H)
461 ##STR01302## I-85 635.2 1.11 60-100% 18 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.39 (s, 1H), 8.68 (s, 1H),
8.60-8.50 (m, 2H), 8.42 (d, J = 5.7 Hz, 1H), 8.15 (s, 1H), 8.03 (d,
J = 8.1 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 7.63 (d,
J = 3.7 Hz, 1H), 5.15 (dd, J = 6.6, 2.5 Hz, 1H), 4.88 (d, J = 4.7
Hz, 1H), 4.81 (dd, J = 6.2, 2.5 Hz, 1H), 4.06 (s, 3H), 3.77 (dt, J
= 11.4, 5.6 Hz, 1H), 3.36- 3.27 (m, 1H), 3.20-3.10 (m, 1H), 2.61
(s, 3H), 1.47-1.35 (m, 6H), 1.05 (d, J = 6.1 Hz, 3H) 462
##STR01303## I-86 636.3 1.11 45-90% 20 min, 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.38 (br. s., 1H), 8.96 (br. s.,
2H), 8.67 (s, 1H), 8.56 (t, J = 5.7 Hz, 1H), 8.52 (s, 1H), 8.03 (d,
J = 8.1 Hz, 1H), 7.94 (d, J = 11.4 Hz, 1H), 7.79 (s, 1H), 5.15 (dd,
J = 6.6, 2.2 Hz, 1H), 4.90-4.79 (m, 2H), 4.07 (s, 3H), 3.78 (dt, J
= 11.3, 5.8 Hz, 1H), 3.29 (dt, J = 12.2, 6.2 Hz, 1H), 3.20-3.10 (m,
1H), 2.61 (s, 3H), 1.41 (m, 6H), 1.06 (d, J = 6.1 Hz, 3H) 463
##STR01304## I-86 662.3 1.15 50-100% 22 min, 100% 7 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.41 (br. s., 1H), 8.97 (s, 2H),
8.70 (s, 1H), 8.55 (s, 1H), 8.36 (t, J = 5.9 Hz, 1H), 8.04 (d, J =
8.1 Hz, 1H), 7.95 (d, J = 11.8 Hz, 1H), 7.81 (s, 1H), 5.40 (s, 1H),
5.20-5.09 (m, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.08 (s, 3H), 2.62 (s,
3H), 2.01-1.87 (m, 4H), 1.70-1.57 (m, 1H), 1.56-1.43 (m, 1H), 1.42
(m, 6H) 464 ##STR01305## I-82 649.2 1.21 45-90% 19 min, 100% 10 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.81 (s, 1H), 8.75 (br.
s., 2H), 8.65 (br. s., 1H), 8.18- 7.99 (m, 4H), 7.91 (br. s., 1H),
5.37 (br. s., 1H), 4.46 (br. s., 1H), 4.38 (br. s., 1H), 4.16 (s,
43), 3.46 (m, 2H), 2.71 (s, 3H), 1.70 (m, 2H), 1.51 (d, J = 6.4 Hz,
3H), 1.22 (s, 6H) 465 ##STR01306## I-85 649.3 1.14 40-80% 20 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.37 (s,
1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.44 (d, J = 5.2 Hz, 2H), 8.17 (s,
1H), 8.03 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.81 (s,
1H), 7.66-7.60 (m, 1H), 5.15 (dd, J = 6.7, 2.4 Hz, 1H), 4.81 (dd, J
= 6.1, 2.4 Hz, 1H), 4.74 (s, 1H), 4.08 (s, 3H), 3.26 (d, J = 6.1
Hz, 2H), 2.62 (s, 3H), 1.41 (m, 6H), 1.10 (s, 6H) 466 ##STR01307##
I-85 591.1 1.15 45-90% 25 min, 100% 7 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.34 (s, 1H), 8.73-8.62 (m, 2H), 8.54 (s,
1H), 8.41 (d, J = 4.9 Hz, 1H), 8.13 (br. s., 1H), 8.02 (d, J = 8.2
Hz, 1H), 7.93 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 7.62 (br. s.,
1H), 5.15 (dd, J = 6.4, 2.7 Hz, 1H), 4.81 (dd, J = 6.3, 2.6 Hz,
1H), 4.07 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H), 2.62 (s, 3H), 1.41 (m,
6H) 467 ##STR01308## I-85 605.1 1.08 40-75% 25 min, 100% 7 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.30 (s, 1H), 8.68 (s,
1H), 8.53 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 8.2 Hz,
1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 7.58 (s, 1H),
7.51-7.43 (m, 1H), 5.14 (dd, J = 6.6, 2.6 Hz, 1H), 4.81 (dd, J =
6.3, 2.6 Hz, 1H), 4.07 (s, 3H), 2.98 (s, 3H), 2.89 (s, 3H), 2.61
(s, 3H), 1.41 (m, 6H) 468 ##STR01309## I-86 606.2 1.19 45-90% 22
min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.27
(br. s., 1H), 8.91 (s, 2H), 8.69 (s, 1H), 8.53 (s, 1H), 8.03 (d, J
= 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.15 (dd, J
= 6.6, 2.6 Hz, 1H), 4.87-4.76 (m, 1H), 4.07 (s, 3H), 2.99 (s, 3H),
2.76 (s, 3H), 2.62 (s, 3H), 1.45-1.37 (m, 6H) 469 ##STR01310## I-82
607.9 1.06 45-80% 25 min, 80% 4 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 2H), 8.67 (t, J = 5.8 Hz, 1H), 8.64
(s, 1H), 8.48 (s, 1H), 7.95-7.87 (m, 2H), 7.75 (s, 1H), 5.35-5.23
(m, 1H), 4.94-4.88 (m, 1H), 4.38 (d, J = 8.2 Hz, 1H), 4.28 (dd, J =
10.7, 6.1 Hz, 1H), 4.05 (s, 3H), 3.55-3.49 (m, 2H), 3.36 (q, J =
6.0 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
Preparation of Hindered Amide Examples
[3262] The sterically hindered amides in the accompanying table
were prepared according to the following two-step procedure.
[3263] Saponification
[3264] To a solution of the appropriately substituted hetero-aryl
ester (1.0 equiv) in THF (0.05 M) was added a 1 M solution of LiOH
(5 equiv). The resulting mixture was stirred vigorously at for 3 h
before being quenched with a 1 M solution of HCl (10 equiv). The
solution was concentrated to a crude residue in vacuo and taken on
to the subsequent HATU coupling without purification.
[3265] HATU Coupling
[3266] The crude saponified residue above (1.0 equiv) was retaken
in DMF (0.1 M) and stirred at room temperature. To this solution
was added diisopropylethylamine (10 equiv) and the appropriate
amine substrate (1.5 equiv) followed by HATU (1.5 equiv). The
resulting mixture was stirred for 10 min before being quenched with
methanol (100 equiv), concentrated, and purified by Prep HPLC
(Method D, unless otherwise indicated) to afford the desired
example.
TABLE-US-00010 LCMS RT HPLC LCMS (Min) Prep Ex. [M + H].sup.+
Method Method No. Structure Ester m/z H D NMR 470 ##STR01311## I-82
663.1 1.13 45-90% 20 min, 100% 6 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.29 (br. s., 1H), 8.87 (t, J = 6.3 Hz, 1H),
8.72 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H),
8.02-7.91 (m, 3H), 7.79 (s, 1H), 5.30 (d, J = 3.1 Hz, 1H), 5.05 (t,
J = 5.5 Hz, 1H), 4.39 (d, J = 6.1 Hz, 3H), 4.33-4.23 (m, 3H), 4.07
(s, 3H), 3.64-3.54 (m, 4H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
471 ##STR01312## I-82 621.2 1.10 30-100% 20 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.22 (br. s., 1H), 8.73 (s,
1H), 8.71-8.64 (m, 1H), 8.57 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H),
8.03-7.96 (m, 2H), 7.85 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.35
(br. s., 1H), 4.43 (d, J = 8.5 Hz, 1H), 4.38-4.30 (m, 1H), 4.13 (s,
3H), 3.56 (br. s., 3H), 3.47 (br. s., 1H), 3.06 (br. s., 3H), 2.67
(s, 3H), 1.49 (d, J = 6.1 Hz, 3H) 472 ##STR01313## I-82 649.2 1.22
35-100% 20 min, 100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.32 (br. s., 1H), 8.79 (s, 1H), 8.76 (br. s., 1H), 8.68
(br. s., 1H), 8.63 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.08-8.01 (m,
3H), 7.90 (s, 1H), 5.37 (br. s., 1H), 4.47 (d, J = 8.5 Hz, 1H),
4.38 (br. s., 1H), 4.16 (s, 3H), 3.28- 3.21 (m, 5H), 2.70 (s, 3H),
1.51 (d, J = 6.1 Hz, 3H), 0.89 (s, 6H) 473 ##STR01314## I-82 661.3
1.19 50-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.25 (br. s., 1H), 8.72 (s, 1H), 8.66 (d, J = 12.2 Hz,
2H), 8.56 (s, 1H), 8.06 (d, J = 10.4 Hz, 1H), 8.01-7.93 (m, 3H),
7.84 (s, 1H), 5.29 (br. s., 1H), 4.43-4.37 (m, 1H), 4.33- 4.25 (m,
1H), 4.09 (s, 3H), 3.40 (br. s., 4H), 2.63 (s, 3H), 1.86-1.65 (m,
6H), 1.43 (d, J = 6.4 Hz, 3H) 474 ##STR01315## I-82 649.2 1.15
45-100% 11 min, 100% 6 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.16 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H), 8.64- 8.57 (m,
1H), 8.49 (s, 1H), 7.99 (br. s., 1H), 7.95-7.88 (m, 2H), 7.77 (s,
1H), 7.56-7.46 (m, 1H), 5.28 (br. s., 1H), 4.36 (d, J = 10.1 Hz,
1H), 4.31-4.24 (m, 1H), 4.06 (s, 3H), 3.58 (s, 2H), 3.10-3.00 (m,
3H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.15 (s, 3H), 0.91 (s,
3H) 475 ##STR01316## I-82 633.2 1.10 45-100% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.19 (d, J = 6.1 Hz,
1H), 8.64 (s, 2H), 8.49 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H),
7.96-7.85 (m, 2H), 7.79-7.67 (m, 2H), 5.28 (br. s., 1H), 4.41-4.33
(m, 1H), 4.33-4.23 (m, 2H), 4.06 (s, 3H), 3.81-3.59 (m, 2H),
3.54-3.37 (m, 2H), 2.59 (s, 3H), 1.96- 1.85 (m, 1H), 1.80 (br. s.,
1H), 1.43 (d, J = 6.4 Hz, 3H) 476 ##STR01317## I-82 647.2 1.10
35-75% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.18 (br. s., 1H), 8.68-8.59 (m, 2H), 8.50 (s, 1H), 8.00
(br. s., 1H), 7.96-7.88 (m, 2H), 7.77 (s, 1H), 7.71 (d, J = 8.2 Hz,
1H), 5.28 (br. s., 1H), 4.41-4.34 (m, 1H), 4.28 (dd, J = 10.7, 6.1
Hz, 1H), 4.06 (s, 3H), 3.79-3.66 (m, 1H), 3.49-3.35 (m, 3H),
3.34-3.28 (m, 1H), 3.27-3.20 (m, 1H), 2.60 (s, 3H), 2.34-2.24 (m,
1H), 1.96- 1.85 (m, 1H), 1.67-1.55 (m, 1H), 1.43 (d, J = 6.4 Hz,
3H) 477 ##STR01318## I-82 663.3 1.10 40-85% 16 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.20 (br. s., 1H),
8.67 (s, 1H), 8.63 (br. s., 1H), 8.51 (s, 1H), 8.02 (d, J = 8.5 Hz,
1H), 7.97-7.89 (m, 2H), 7.78 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H),
5.28 (br. s., 1H), 4.46- 4.33 (m, 2H), 4.28 (dd, J = 10.5, 6.0 Hz,
1H), 4.06 (s, 3H), 3.97-3.84 (m, 1H), 3.77 (br. s., 1H), 3.51-3.33
(m, 3H), 3.31-3.11 (m, 1H), 3.02-2.88 (m, 1H), 2.67 (d, J = 10.1
Hz, 1H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H) 478 ##STR01319##
I-82 633.2 1.10 35-95% 20 min 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.18 (br. s., 1H), 8.67-8.59 (m, 2H), 8.49
(s, 1H), 8.01 (br. s., 1H), 7.95-7.87 (m, 2H), 7.76 (s, 1H), 7.72
(dd, J = 12.5, 8.5 Hz, 1H), 5.28 (d, J = 3.1 Hz, 1H), 4.37 (d, J =
9.5 Hz, 1H), 4.27 (dd, J = 10.5, 6.0 Hz, 2H), 4.05 (s, 3H),
3.78-3.69 (m, 1H), 3.59 (s, 2H), 3.52 (d, J = 11.6 Hz, 1H), 3.42
(d, J = 13.1 Hz, 1H), 2.59 (s, 3H), 1.90 (dd, J = 8.9, 4.0 Hz, 1H),
1.80 (br. s., 1H), 1.43 (d, J = 6.4 Hz, 3H) 479 ##STR01320## I-82
647.2 1.10 45-90% 19 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.18 (br. s., 1H), 8.65 (s, 1H), 8.62 (br.
s., 1H), 8.50 (s, 1H), 8.01 (t, J = 7.3 Hz, 1H), 7.95- 7.88 (m,
2H), 7.77 (s, 1H), 7.73-7.68 (m, 1H), 6.62 (d, J = 8.5 Hz, 1H),
5.28 (br. s., 1H), 4.37 (d, J = 8.2 Hz, 1H), 4.28 (dd, J = 10.8,
6.3 Hz, 1H), 4.06 (s, 3H), 3.78- 3.66 (m, 1H), 3.48-3.35 (m, 3H),
3.34- 3.27 (m, 1H), 3.24 (dd, J = 12.4, 7.2 Hz, 1H), 2.60 (s, 3H),
2.35-2.23 (m, 1H), 1.96- 1.84 (m, 1H), 1.67-1.54 (m, 1H), 1.43 (d,
J = 6.7 Hz, 3H) 480 ##STR01321## I-82 663.3 1.10 40-85% 15 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.20 (br.
s., 1H), 8.67 (s, 1H), 8.63 (br. s., 1H), 8.51 (s, 1H), 8.02 (d, J
= 8.5 Hz, 1H), 7.97-7.87 (m, 2H), 7.78 (s, 1H), 7.59 (d, J = 5.2
Hz, 1H), 5.29 (br. s., 1H), 4.48- 4.23 (m, 3H), 4.06 (s, 3H),
3.96-3.84 (m, 1H), 3.82-3.72 (m, 1H), 3.51-3.06 (m, 4H), 3.00-2.89
(m, 1H), 2.67 (d, J = 9.8 Hz, 1H), 2.60 (s, 3H), 1.43 (d, J = 6.4
Hz, 3H) 481 ##STR01322## I-74 661.2 1.20 45-90% 25 min, 100% 6 min
-- 482 ##STR01323## I-74 661.2 1.17 45-90% 25 min, 100% 6 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.09 (br. s., 1H),
8.70-8.65 (m, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.53 (s, 1H),
8.07-7.90 (m, 3H), 7.79 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 5.13
(br. s., 1H), 4.83 (br. s., 1H), 4.78-4.65 (m, 1H), 4.12-4.02 (m,
3H), 3.73 (dd, J = 19.1, 11.7 Hz, 1H), 3.66- 3.51 (m, 1H),
3.46-3.35 (m, 3H), 3.35- 3.17 (m, 1H), 2.66-2.59 (m, 3H), 2.35-
2.21 (m, 1H), 1.89 (br. s., 1H), 1.60 (d, J = 7.9 Hz, 1H), 1.41 (t,
J = 5.0 Hz, 6H) 483 ##STR01324## I-74 661.2 1.20 45-90% 25 min,
100% 6 min -- 484 ##STR01325## I-82 647.3 1.22 45-90% 15 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.19 (br. s.,
1H), 8.69 (s, 1H), 8.64 (br. s., 1H), 8.53 (s, 1H), 8.07- 7.91 (m,
3H), 7.79 (s, 1H), 7.58-7.46 (m, 1H), 5.29 (br. s., 1H), 4.38 (d, J
= 8.9 Hz, 1H), 4.33-4.26 (m, 1H), 4.23 (d, J = 11.3 Hz, 1H), 4.07
(s, 3H), 3.87 (d, J = 13.1 Hz, 1H), 3.67-3.38 (m, 2H), 3.16 (br.
s., 1H), 3.06-2.94 (m, 1H), 2.83-2.71 (m, 1H), 2.61 (s, 3H),
1.94-1.81 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H), 1.44 (d, J
= 6.1 Hz, 4H), 1.38 (d, J = 9.5 Hz, 1H) 485 ##STR01326## I-82 647.3
1.22 45-90% 15 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.19 (br. s., 1H), 8.69 (s, 1H), 8.63 (br. s., 1H), 8.53
(s, 1H), 8.07- 7.90 (m, 3H), 7.79 (s, 1H), 7.59-7.46 (m, 1H), 5.29
(br. s., 1H), 4.38 (d, J = 8.9 Hz, 1H), 4.33-4.17 (m, 1H),
4.12-4.01 (m, 3H), 3.88 (br. s., 1H), 3.68-3.53 (m, 1H), 3.16 (br.
s., 1H), 3.01 (d, J = 7.6 Hz, 1H), 2.77 (t, J = 10.5 Hz, 1H), 2.61
(s, 3H), 1.96-1.80 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H),
1.51-1.30 (m, 5H) 486 ##STR01327## I-74 677.2 1.21 40-90% 19 min,
100% 5 min -- 487 ##STR01328## I-74 677.2 1.20 45-90% 20 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.11 (br. s.,
1H), 8.72 (s, 1H), 8.61 (br. s., 1H), 8.57 (d, J = 1.2 Hz, 1H),
8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.96 (d, J =
11.6 Hz, 1H), 7.83 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.14 (dd, J =
6.4, 2.4 Hz, 1H), 4.81 (dd, J = 6.3, 2.6 Hz, 1H), 4.32 (br. s.,
1H), 4.16-3.98 (m, 4H), 3.97-3.85 (m, 1H), 3.82-3.40 (m, 3H), 2.63
(s, 3H), 1.41 (dd, J = 6.3, 4.1 Hz, 6H). 488 ##STR01329## I-82
663.3 1.21 40-100% 15 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.21 (br. s., 1H), 8.73 (s, 1H), 8.62 (br.
s., 1H), 8.56 (s, 1H), 8.05-7.99 (m, 2H), 7.97 (d, J = 11.6 Hz,
1H), 7.82 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.28 (dd, J = 8.9, 6.1
Hz, 1H), 4.88 (br. s., 1H), 4.42-4.36 (m, 1H), 4.35-4.25 (m, 1H),
4.08 (s, 3H), 4.02 (d, J = 11.3 Hz, 1H), 3.97-3.85 (m, 1H), 3.78
(d, J = 11.6 Hz, 1H), 3.70 (d, J = 6.7 Hz, 1H), 3.57 (br. s., 1H),
3.50 (d, J = 13.4 Hz, 1H), 2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
489 ##STR01330## I-82 663.3 1.21 40-100% 15 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.21 (br. s., 1H), 8.74 (s,
1H), 8.62 (br. s., 1H), 8.57 (s, 1H), 8.05- 7.94 (m, 3H), 7.83 (s,
1H), 7.57 (d, J = 8.5 Hz, 1H), 5.29 (dd, J = 9.2, 6.1 Hz, 1H),
5.00-4.78 (m, 1H), 4.43-4.36 (m, 1H), 4.35-4.24 (m, 1H), 4.16-3.99
(m, 4H), 3.98-3.85 (m, 1H), 3.82-3.66 (m, 1H), 3.66-3.42 (m, 2H),
2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
Example 490
(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[-
d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01331##
[3268] To a solution Intermediate I-72B (150 mg, 0.334 mmol) in THF
(6.5 mL) was added a 15% phosgene solution in toluene (2354 .mu.l,
3.34 mmol). The resulting slurry was allowed to stir overnight
before concentrated down to a crude yellow residue. This
intermediate chloroformate was retaken in THF (6.5 mL) and added
dropwise to a premixed solution of 2-methylpyrimidin-5-amine (39.9
mg, 0.365 mmol) and pyridine (0.134 mL, 1.660 mmol) in THF (6.5
mL). After 10 min of stirring, the reaction mixture was
concentrated and loaded directly onto an ISCO cartridge for
purification (40 g, 0-100% EtOAc/DCM, product at 85%) to afford
Example 490 (182 mg, 0.331 mmol, 94% yield) as a yellow solid. A
small amount of material was purified by Prep HPLC for final
characterization (Method D, 50-100% over 10 min, hold 100% for 5
min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 585.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (d,
J=2.0 Hz, 1H), 8.72 (br. s., 2H), 8.69 (s, 1H), 7.86-7.78 (m, 2H),
7.66 (t, J=71.8 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 6.49 (br. s., 1H),
5.21-5.12 (m, 1H), 4.63 (dd, J=6.4, 3.3 Hz, 1H), 2.69 (s, 3H), 2.68
(s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.44 (d, J=6.4 Hz, 3H). .sup.19F
NMR (376 MHz, CDCl.sub.3) .delta. -89.78 (s, 3F), -132.17 (s,
1F).
Preparation of Substituted Quinoxalines
[3269] The substituted quinoxalines in the accompanying table were
prepared according to the following general procedure, which is
analogous to the procedure used to synthesize Example 389.
[3270] To a solution of THF (0.05 M) and the appropriate alcohol
(100 equiv) was added sodium hydride (60% by wt., 10 equiv). After
the bubbling subsided, a solution of Example 490 (1.0 equiv) in THF
(0.05 M) was added dropwise. After 20 min of vigorous stirring at
RT, the reaction mixture was quenched with a few drops of saturated
NH.sub.4Cl, diluted with EtOAc, filtered over Celite, concentrated
and purified by Prep HPLC (Method D, unless otherwise indicated) to
afford the desired example.
TABLE-US-00011 LCMS LCMS HPLC Ex. Quinox- [M + H].sup.+ RT (Min)
Prep No. Structure aline m/z Method H Method D NMR 491 ##STR01332##
490 577.2 1.31 75-100% 15 min, 100% 10 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.71 (br. s., 2H), 8.64
(s, 1H), 8.49 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 11.3
Hz, 1H), 7.73 (s, 1H), 5.09 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 4.3
Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 2.58 (s, 3H), 2.50 (s, 3H-Buried
under d-DMSO), 1.82 (sxt, J = 7.0 Hz, 2H), 1.38 (m, 6H), 1.02 (t, J
= 7.3 Hz, 3H) 492 ##STR01333## 490 577.2 1.30 75-100% 15 min, 100%
10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.95 (br. s.,
1H), 8.71 (br. s., 2H), 8.59 (s, 1H), 8.50 (s, 1H), 8.01 (d, J =
8.2 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 5.45 (dt, J =
12.2, 6.1 Hz, 1H), 5.09 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 4.3 Hz,
1H), 2.59 (s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.41 (d, J =
6.1 Hz, 6H), 1.38 (m, 6H) 493 ##STR01334## 490 579.2 1.07 20-60% 20
min, 100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.67
(br. s., 2H), 8.63 (s, 1H), 8.47 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H),
7.88 (d, J = 11.3 Hz, 1H), 7.71 (s, 1H), 5.04 (d, J = 6.1 Hz, 1H),
4.73 (d, J = 4.3 Hz, 1H), 4.43 (d, J = 4.3 Hz, 2H), 3.77 (br. s.,
2H), 2.55 (s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.33 (m,
6H)
Preparation of Alcohol Examples
[3271] The Alcohols in the accompanying table were prepared
according to the following two general procedures.
[3272] Primary Alcohols
[3273] A solution of the appropriately substituted hetero-aryl
ester (1.0 equiv) in THF (0.2 M) was cooled to -78.degree. C. To
this cooled reaction mixture was added DIBAl-H (1 M solution in
toluene, 3.0 equiv) and the reaction mixture was to stirred at
-78.degree. C. for 1 hour. The reaction mixture was then quenched
with saturated Rochelle's salt and allowed to stir for 2 h at room
temperature. The resulting mixture was diluted with water and
extracted with EtOAc. The organic layer was washed with brine,
dried with magnesium sulfate, filtered over a pad of silica gel and
concentrated. [Note: If crude NMR analysis of the isolated residue
showed a substantial amount of the intermediate aldehyde remaining,
then the material was resubjected to the DIBAl-H conditions
described above in order to achieve complete reduction.] The crude
material was purified by Prep HPLC (Method D, unless otherwise
indicated) to afford the desired example.
[3274] Tertiary Alcohols
[3275] A solution of the appropriately substituted hetero-aryl
ester (1.0 equiv) in THF (0.05 M) was cooled to -78.degree. C. To
this cooled reaction mixture was added methyl magnesium bromide
(3.0 M solution in ether, 10 equiv). The reaction mixture was
allowed to warm to room temperature and stirred for 30 minutes at
ambient temperature. The reaction mixture was then quenched with
saturated ammonium chloride, diluted with water and extracted with
EtOAc. The organic layer was washed with brine, dried with
magnesium sulfate, filtered over Celite and concentrated. The
resulting residue was purified by Prep HPLC (Method D, unless
otherwise indicated) to afford the desired example.
TABLE-US-00012 LCMS RT HPLC LCMS (Min) Prep Ex. [M + H].sup.+
Method Method No. Structure Ester m/z H D NMR 494 ##STR01335## I-87
584.1, 586.1 1.05 70-95% 20 min, 100% 7 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.27 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H),
8.33 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 7.3 Hz, 1H), 7.88 (s, 1H),
7.67 (s, 1H), 7.38 (br. s., 1H), 5.35 (br. s., 1H), 4.54 (d, J =
5.2 Hz, 2H), 4.49-4.41 (m, 1H), 4.39-4.32 (m, 1H), 4.14 (s, 3H),
2.70 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H) 495 ##STR01336## I-83 550.2
0.99 40-80% 25 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.93 (br. s., 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.43 (d, J
= 6.1 Hz, 1H), 8.03-7.92 (m, 2H), 7.82 (s, 2H), 7.61 (d, J = 5.2
Hz, 1H), 5.32 (br. s., 1H), 4.66 (s, 2H), 4.40 (d, J = 9.2 Hz, 1H),
4.29 (dd, J = 10.8, 6.3 Hz, 1H), 4.07 (s, 3H), 3.90 (s, 1H), 2.62
(s, 3H), 1.45 (d, J = 6.4 Hz, 3H) 496 ##STR01337## I-84 551.2 1.11
45-90% 25 min, 100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.91 (br. s., 2H), 8.77 (s, 1H), 8.60 (s, 1H), 8.09-7.98
(m, 2H), 7.87 (s, 1H), 5.34 (d, J = 3.1 Hz, 1H), 4.60 (d, J = 4.9
Hz, 2H), 4.49-4.40 (m, 1H), 4.34 (dd, J = 10.8, 6.0 Hz, 1H), 4.13
(s, 3H), 2.68 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H) 497 ##STR01338##
I-84 579.2 1.20 40-75% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.85 (br. s., 2H), 8.66 (s, 1H), 8.50 (s,
1H), 7.95 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 11.6 Hz, 1H), 7.76 (s,
1H), 5.33-5.21 (m, 1H), 4.36 (dd, J = 10.7, 2.7 Hz, 1H), 4.30-4.23
(m, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 1.45 (s, 6H), 1.43 (d, J = 6.7
Hz, 3H) 498 ##STR01339## I-82 578.2 1.03 70-100% 20 min, 100% 10
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.90 (br. s., 1H),
8.68 (s, 1H), 8.55-8.49 (m, 2H), 7.94 (t, J = 11.0 Hz, 2H), 7.85
(d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.25
(d, J = 3.4 Hz, 1H), 4.36-4.31 (m, 1H), 4.29-4.22 (m, 1H), 4.05 (s,
3H), 2.59 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.39 (s, 6H) 499
##STR01340## I-74 564.1 1.03 30-90% 25 min 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.83 (br. s., 1H), 8.68 (s, 1H),
8.53 (br. s., 2H), 8.01 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 11.6 Hz,
1H), 7.84 (br. s., 1H), 7.79 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H),
5.09 (dd, J = 6.6, 2.6 Hz, 1H), 4.77 (d, J = 3.7 Hz, 1H), 4.46 (s,
2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.38 (m, 6H) 500 ##STR01341## I-74
592.1 1.14 45-95% 12 min 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.82 (br. s., 1H), 8.69 (s, 1H), 8.56-8.48
(m, 2H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.83
(br. s., 1H), 7.79 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 5.11 (d, J =
5.5 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H),
1.43-1.37 (m, 12H) 501 ##STR01342## I-86 593.2 1.27 40-90% 15 min,
100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.06 (br.
s., 1H), 8.83 (br. s., 2H), 8.69 (s, 1H), 8.54 (s, 1H), 8.03 (d, J
= 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.13 (d, J
= 4.3 Hz, 1H), 4.82 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 2.61 (s,
3H), 1.44 (s, 6H), 1.41 (m, 6H) 502 ##STR01343## I-86 565.0 1.23
30-70% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.08 (br. s., 1H), 8.83 (br. s., 2H), 8.74 (s, 1H), 8.58
(s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.85
(s, 1H), 5.29 (t, J = 6.1 Hz, 1H), 5.13 (d, J = 5.8 Hz, 1H), 4.82
(br. s., 1H), 4.52 (d, J = 6.1 Hz, 2H), 4.09 (s, 3H), 3.47 (br. s.,
2H), 2.64 (s, 3H), 1.40 (m, 6H)
Preparation of Quinoxaline Examples
[3276] The quinoxalines in the accompanying table were prepared
according to the following general procedure, which is analogous to
the procedure described for Example 263. Thus, the appropriately
substituted 2-bromobenzothiazole (1.0 equiv),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.08 equiv), and
Intermediate I-9 (1.1 equiv) were solvated in a 3:1 mixture of
toluene and ethanol (0.05 M). A 2.0 M solution of aqueous sodium
carbonate (9 equiv) was then added, and the mixture was degassed by
bubbling argon through the solution for 10 min. The vial was then
sealed under an atmosphere of argon and heated to 105.degree. C.
thermally for 1 h. The resulting crude solution was diluted with
EtOAc, filtered over Celite, concentrated, and purified by
preparative HPLC (Method D, unless otherwise indicated) to yield
the desired example.
TABLE-US-00013 LCMS LCMS Ex. [M + H].sup.+ RT (Min) HPLC Prep No.
Structure Br-Bzt m/z Method H Method D NMR 503 ##STR01344## 260A
341.9, 343.9 1.38 75-100% 25 min, 100% 4 min 1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.78 (s, 1H), 8.68 (s, 1H), 8.19 (d, J = 7.6
Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 1H),
4.11 (s, 3H), 2.69 (s, 3H) 504 ##STR01345## 256A 308.0 1.30 60-100%
18 min, 100% 10 min 1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (s,
1H), 8.67 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.2 Hz,
1H), 7.88 (s, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.53-7.47 (m, 1H),
4.10 (s, 3H), 2.66 (s, 3H) 505 ##STR01346## 261A 322.0 1.40 80-100%
25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (s,
1H), 8.67 (s, 1H), 7.99 (d, J = 3.7 Hz, 1H), 7.88 (s, 1H),
7.42-7.34 (m, 2H), 4.10 (s, 3H), 2.81 (s, 3H), 2.67 (s, 3H) 506
##STR01347## 93D 371.9, 373.9 1.37 60-100% 18 min, 100% 15 min 1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.59 (s, 1H),
7.86 (s, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H),
4.10 (s, 3H), 3.90 (s, 3H), 2.66 (s, 3H) 507 ##STR01348## 268A
371.9, 373.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H),
7.96 (s, 1H), 7.86 (br. s., 2H), 4.10 (s, 3H), 3.98 (s, 3H), 2.65
(s, 3H) 509 ##STR01349## I-3 351.9 1.37 60-100% 18 min, 100% 15 min
1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.60 (s, 1H),
7.83 (s, 1H), 7.53 (s, 1H), 7.01 (s, 1H), 4.10 (s, 3H), 3.86 (s,
3H), 2.76 (s, 3H), 2.66 (s, 3H) 510 ##STR01350## 273A 326.0 1.32
65-100% 25 min, 100% 4 min 1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.78 (s, 1H), 8.68 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H),
7.55-7.48 (m, 1H), 7.45-7.38 (m, 1H), 4.11 (s, 3H), 2.67 (s,
3H)
Preparation of Quinoline Examples
[3277] The Quinolines in the accompanying table were prepared
according to the following general procedure, which is analogous to
the procedure described for Example 263. Thus, Intermediate I-88
(1.0 equiv), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.08 equiv),
and the appropriately substituted quinoline (1.1 equiv) were
solvated in a 3:1 mixture of toluene and ethanol (0.05 M). A 2.0 M
solution of aqueous sodium carbonate (9 equiv) was added, and the
mixture was degassed by bubbling argon through the solution for 10
min. The vial was then sealed then sealed under an atmosphere of
argon and thermally heated to 105.degree. C. 1 h. The crude
solution was diluted with EtOAc, filtered over Celite, concentrated
and purified by preparative HPLC (Method D, unless otherwise
indicated) to yield the desired example.
TABLE-US-00014 LCMS RT HPLC LCMS (Min) Prep Ex. [M + H].sup.+
Method Method No. Structure Quin m/z H D NMR 512 ##STR01351## I-121
614.0, 616.1 1.14 40-90% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.76 (br. s., 1H), 8.58 (d, J = 2.4 Hz, 3H),
8.34 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H),
7.74 (d, J = 11.6 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 5.13-5.03 (m,
1H), 4.74 (d, J = 3.7 Hz, 1H), 4.21 (t, J = 4.6 Hz, 2H), 3.88 (s,
2H), 1.43-1.31 (m, 6H) 513 ##STR01352## I-126 628.0, 629.9 1.19
50-100% 25 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.80 (br. s., 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.61 (br. s.,
3H), 8.16 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.3 Hz,
1H), 7.90 (br. s., 1H), 5.10 (d, J = 6.4 Hz, 1H), 4.81 (d, J = 6.1
Hz, 1H), 4.32-4.17 (m, 4H), 3.68 (d, J = 4.6 Hz, 2H), 1.46 (t, J =
6.9 Hz, 3H), 1.43-1.32 (m, 6H) 514 ##STR01353## I-124 594.1 1.03
40-100% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.81 (br. s., 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.60 (br. s.,
3H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.87 (d,
J = 6.1 Hz, 2H), 5.09 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 3.4 Hz,
1H), 4.23 (d, J = 4.6 Hz, 2H), 3.99 (s, 3H), 3.69 (d, J = 4.3 Hz,
2H), 2.61 (s, 3H), 1.39 (d, J = 6.1 Hz, 6H) 515 ##STR01354## I-124
650., 652.0 1.14 50-90% 23 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.81 (br. s., 1H), 9.06 (d, J = 1.8 Hz, 1H),
8.77 (s, 1H), 8.61 (br. s., 2H), 8.35 (d, J = 5.2 Hz, 2H), 8.07 (d,
J = 7.9 Hz, 1H), 7.98 (d, J = 11.6 Hz, 1H), 7.51 (t, J = 74.2 Hz,
1H), 5.11 (d, J = 6.1 Hz, 1H), 4.83 (d, J = 4.3 Hz, 1H), 4.24 (t, J
= 4.9 Hz, 2H), 3.69 (d, J = 4.9 Hz, 2H), 1.45-1.36 (m, 6H)
Example 516
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy-
)-3-methoxypropan-2-yl pyridin-3-ylcarbamate (rac)
##STR01355##
[3278] Intermediate 516A:
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)-3-methoxypropan-2-ol
##STR01356##
[3280] To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) and
tetrabutylammonium bromide (28.3 mg, 0.088 mmol) in THF (1 mL) was
added potassium hydroxide (0.33 M in H.sub.2O) (0.200 mL, 0.066
mmol) followed by racemic 2-(methoxymethyl)oxirane (38.7 mg, 0.439
mmol). The mixture was then sealed and heated to 65.degree. C.
overnight. After 15 h, the reaction was quenched with saturated
NaHCO.sub.3 and diluted with EtOAc. The organic phase was washed
with brine, dried over MgSO.sub.4, filtered over Celite,
concentrated and purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16
min. Product at 40%) to afford Intermediate 516A (11 mg, 0.026
mmol, 58.3% yield) as a yellow solid. LC-MS: Method H, RT=1.09 min,
MS (ESI) m/z: 430.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.59 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 7.80 (d, J=11.2 Hz,
1H), 7.74 (d, J=0.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 4.26 (quin,
J=5.2 Hz, 1H), 4.21-4.16 (m, 2H), 4.12 (s, 3H), 3.69-3.57 (m, 2H),
3.45 (s, 3H), 3.43 (d, J=6.6 Hz, 1H), 2.64 (s, 3H).
Example 516 (Rac)
[3281] To a solution of Intermediate 516A (10 mg, 0.023 mmol) in
THF (1 mL) was added 15% phosgene in toluene (0.164 mL, 0.233 mmol)
at room temperature. The reaction mixture was allowed to stir
overnight. After 16 h, the reaction mixture was concentrated to
afford the desired chloroformate intermediate as a crude yellow
residue. This crude material was retaken in THF (1 mL) and added
dropwise to a pre-mixed solution of pyridin-3-amine (4.38 mg, 0.047
mmol) and pyridine (0.019 mL, 0.232 mmol) After 5 min of stirring,
the reaction mixture was concentrated and purified by prep HPLC
(Method C, 20-60% over 20 min, hold 100% for 5 min) to afford
Example 516 (10.5 mg, 0.023 mmol, 78% yield) as a yellow solid.
LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 550.2 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.41 (br. s., 1H),
8.81 (br. s., 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.37 (d, J=4.4 Hz,
1H), 8.12 (d, J=7.9 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.93 (d,
J=11.5 Hz, 1H), 7.77 (s, 1H), 7.60 (dd, J=8.4, 5.0 Hz, 1H), 5.37
(d, J=4.6 Hz, 1H), 4.50-4.43 (m, 1H), 4.43-4.36 (m, 1H), 4.07 (s,
3H), 3.82-3.72 (m, 2H), 3.37 (s, 3H), 2.61 (s, 3H).
Example 517
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy)butan-2-yl pyridin-3-ylcarbamate
##STR01357##
[3282] Intermediate 517A:
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)butan-2-ol
##STR01358##
[3284] This intermediate was prepared in a manner analogous to
Intermediate 516A. Thus, Intermediate I-64 was reacted with
(R)-2-ethyloxirane to afford Intermediate 517A (77% yield) as a
yellow solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 414.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.59 (d,
J=2.0 Hz, 1H), 8.53 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.74 (s, 1H),
7.45 (d, J=7.9 Hz, 1H), 4.16-4.09 (m, 4H), 4.08-3.95 (m, 2H), 2.64
(s, 3H), 2.44 (d, J=3.7 Hz, 1H), 1.74-1.63 (m, 2H), 1.07 (t, J=7.5
Hz, 3H).
Example 517
[3285] This intermediate was prepared in a manner analogous to
Example 516. Thus, Intermediate 517A was reacted with phosgene
followed by pyridin-3-amine. The crude reaction residue was
purified by Prep HPLC (Method D, 55-100% over 20 min, hold 100% for
5 min) to afford Example 517 (68% yield) as a yellow solid. LC-MS:
Method H, RT=0.97 min, MS (ESI) m/z: 534.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.59 (d, J=2.0 Hz, 1H), 8.53 (s, 1H),
7.81 (d, J=11.4 Hz, 1H), 7.74 (s, 1H), 7.45 (d, J=7.9 Hz, 1H),
4.16-4.09 (m, 4H), 4.08-3.95 (m, 2H), 2.64 (s, 3H), 2.44 (d, J=3.7
Hz, 1H), 1.74-1.63 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).
Example 518
4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)-N-(pyridin-3-yl)butanamide
##STR01359##
[3286] Intermediate 518A: tert-butyl
4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)butanoate
##STR01360##
[3288] To a solution of Intermediate I-65 (100 mg, 0.266 mmol) in
DMF (1330 .mu.l) was added tert-butyl 4-bromobutanoate (89 mg,
0.399 mmol) followed by potassium carbonate (73.6 mg, 0.532 mmol).
The reaction vessel was sealed and the red colored solution was
heated to 65.degree. C. After 2 h, the reaction mixture was cooled
to room temperature and quenched with a few drops of AcOH. The
resulting mixture was diluted with EtOAc, filtered over Celite and
concentrate in vacuo to afford crude Intermediate 518A, which was
telescoped into the next reaction without purification. LC-MS:
Method H, RT=1.43 min, MS (ESI) m/z: [Not observed](M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.66 (s, 1H), 8.44 (s,
1H), 7.69 (br. s., 1H), 7.29 (d, J=7.5 Hz, 1H), 4.19-4.04 (m, 5H),
2.63 (s, 3H), 2.58-2.44 (m, 2H), 2.15 (dq, J=12.8, 6.4 Hz, 2H),
1.45 (s, 9H).
Intermediate 518B:
4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)butanoic acid
##STR01361##
[3290] To a solution of crude Intermediate 518A (138 mg, 0.266
mmol) in DCM (2664 .mu.l) was added TFA (2664 .mu.l). The resulting
solution immediately became dark red in color. After stirring at
room temperature for 30 min, the reaction mixture was concentrated
in vacuo to afford crude Intermediate 518B, which was telescoped
into the next reaction without purification. LC-MS: Method H,
RT=1.25 min, MS (ESI) m/z: 462.1, 464.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.69 (d, J=1.8 Hz, 1H), 8.49 (s, 1H),
7.75-7.70 (m, 1H), 7.33 (d, J=7.3 Hz, 1H), 4.16-4.10 (m, 5H), 2.65
(s, 3H), 2.47 (t, J=7.4 Hz, 2H), 2.04-1.93 (m, 2H).
Example 518
[3291] To a brown suspension crude Intermediate 518B (15 mg, 0.032
mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine
(0.034 mL, 0.195 mmol) followed by
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(50% in DMF) (0.058 mL, 0.097 mmol). The reaction mixture was
stirred at room temperature for 2, then pyridin-3-amine (9.17 mg,
0.097 mmol) was added. After an additional 10 min of stirring, the
reaction mixture was concentrated and purified by prep HPLC (Method
D, 50-100% over 15 min, hold 100% for 7 min) to afford Example 518
(3.3 mg, 0.006 mmol, 18% yield) as a yellow solid over the three
step sequence. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 538.2,
540.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.27 (s, 1H), 8.79 (br. s., 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.27
(d, J=4.3 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H),
7.85 (s, 1H), 7.39 (dd, J=8.2, 4.6 Hz, 1H), 4.26 (t, J=6.1 Hz, 2H),
4.08 (s, 3H), 2.65 (s, 3H), 2.60 (t, J=7.3 Hz, 2H), 2.15 (t, J=6.6
Hz, 2H).
Example 519
1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)ethyl)-3-(pyridin-3-yl)urea
##STR01362##
[3292] Intermediate 519A: tert-butyl
(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yl)oxy)ethyl)carbamate
##STR01363##
[3294] To a dark red solution of Intermediate I-65 (85 mg, 0.226
mmol) and cesium carbonate (221 mg, 0.679 mmol) in DMF (2262 .mu.l)
was added tert-butyl (2-bromoethyl)carbamate (76 mg, 0.339 mmol) as
a cold solid from the freezer [Note: did not allow reagent to
melt]. The reaction mixture was sealed and heated to 65.degree. C.
After 1 h of heating, the reaction was quenched with 0.3 mL AcOH,
diluted with EtOAc, filtered over Celite and concentrated to a dark
yellow solid. The crude material was purified by ISCO (12 g, 0-20%
EtOAc/DCM, 16 min.) to afford Intermediate 519A (81 mg, 0.156 mmol,
69.0% yield) as a yellow solid. LC-MS: Method H, RT=1.31 min, MS
(ESI) m/z: 519.2, 521.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.65 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 7.69 (dd,
J=2.0, 0.9 Hz, 1H), 7.26 (d, J=6.4 Hz, 1H), 5.17 (br. s., 1H),
4.17-4.15 (m, 2H), 4.10 (s, 3H), 3.63 (d, J=5.3 Hz, 2H), 2.63 (s,
3H), 1.48 (s, 9H).
Intermediate 519B:
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)ethanamine, TFA
##STR01364##
[3296] To a suspension of Intermediate 519A (40 mg, 0.077 mmol) in
DCM (2 mL) was added TFA (1.0 mL). The resulting solution
immediately became bright red in color. After stirring at room
temperature for 15 min, the reaction mixture was concentrated in
vacuo to afford crude Intermediate 519B (41.1 mg, 0.077 mmol, 100%
yield). This material was telescoped into subsequent reactions
without further purification. LC-MS: Method H, RT=0.95 min, MS
(ESI) m/z: 419.4, 421.4 (M+H).sup.+.
Example 519
[3297] To a solution of Intermediate 519B (20 mg, 0.038 mmol) in
THF (2 mL) was added diisopropylethylamine (0.13 mL, 0.75 mmol)
followed by 3-isocyanatopyridine (13.52 mg, 0.113 mmol) at room
temperature. After 15 h, the reaction mixture was concentrated and
purified by prep HPLC (Method D, 45-95% over 15 min, hold 100% for
5 min) to afford Example 519 (1.2 mg, 0.002 mmol, 6% yield) as a
yellow solid over the two step sequence. LC-MS: Method H, RT=0.98
min, MS (ESI) m/z: 539.1, 541.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.84 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H),
8.54 (s, 1H), 8.11 (d, J=4.6 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.88
(d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.26 (dd, J=8.4, 4.7 Hz, 1H),
6.64-6.56 (m, 1H), 4.24 (t, J=5.0 Hz, 2H), 4.07 (s, 3H), 3.59 (d,
J=5.5 Hz, 2H), 2.63 (s, 3H).
Example 520
1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thia-
zol-6-yl)oxy)ethyl)-1-methyl-3-(2-methylpyrimidin-5-yl)urea
##STR01365##
[3298] Intermediate 520A: tert-butyl
(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiaz-
ol-6-yl)oxy)ethyl)(methyl)carbamate
##STR01366##
[3300] To a suspension of Intermediate 519A (43 mg, 0.083 mmol) in
THF (1 mL) was added sodium hydride (9.94 mg, 0.249 mmol). The
bright red solution was stirred at room temperature for 5 min
before methyl iodide (2.0 M in MTBE) (0.207 mL, 0.414 mmol) was
added. The reaction was then allowed to stir overnight before being
quenched with AcOH, concentrated, and loaded directly onto an ISCO
cartridge for purification (12 g, 0-50% EtOAc/Hexanes, 16 min.
Product at 25%) to afford Intermediate 520A (24 mg, 0.045 mmol,
54.3% yield) as a yellow solid. LC-MS: Method H, RT=1.37 min, MS
(ESI) m/z: 533.1, 535.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.73 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.77 (d,
J=0.7 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 4.25 (d, J=17.6 Hz, 2H),
4.13 (s, 3H), 3.74-3.66 (m, 2H), 3.05 (s, 3H), 2.66 (s, 3H), 1.48
(s, 9H).
Intermediate 520B:
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)-N-methylethanamine, TFA
##STR01367##
[3302] To a suspension of Intermediate 520A (24 mg, 0.045 mmol) in
DCM (2 mL) was added TFA (1.0 mL). The resulting solution
immediately became bright red in color. After stirring for 20 min
at room temperature, the reaction mixture was concentrated in vacuo
to afford crude Intermediate 520B (24.63 mg, 0.045 mmol, 100%
yield). This material was telescoped into the subsequent reactions
without further purification. LC-MS: Method H, RT=0.92 min, MS
(ESI) m/z: 433.0, 435.0 (M+H).sup.+.
Example 520
[3303] To a mixture of crude Intermediate 520B (12 mg, 0.022 mmol)
and DIPEA (0.057 mL, 0.329 mmol) in THF (1 mL) was added 15%
phosgene in toluene (0.108 mL, 0.154 mmol) at room temperature. The
solution immediately became smoky and deposited white salts. After
10 min, 2-methylpyrimidin-5-amine (7.18 mg, 0.066 mmol) and silver
nitrate (18.64 mg, 0.110 mmol) were added. The reaction mixture was
then sealed and heated to 65.degree. C. for 1 h. The resulting
reaction mixture was cooled to room temperature, diluted with
EtOAc, filtered over Celite, concentrated and purified by prep HPLC
(Method D, 40-75% over 25 min, hold 100% for 7 min) to afford
Example 520 (1.1 mg, 0.002 mmol, 8% yield) as a yellow solid over
the two step sequence. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z:
568.3, 570.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.76 (s, 2H), 8.69 (s, 1H), 8.55 (s, 1H), 7.95 (d, J=7.3
Hz, 1H), 7.81 (s, 1H), 4.34 (br. s., 2H), 4.07 (s, 3H), 3.81 (br.
s., 2H), 3.11 (s, 3H), 2.63 (s, 3H), 2.52 (s, 3H).
Example 521
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy) butan-2-yl
(6-(morpholinomethyl)pyridin-3-yl)carbamate
##STR01368##
[3305] To a solution of Example 426 (9 mg, 0.014 mmol) in THF (1
mL) was added diacetoxyzinc (5.11 mg, 0.028 mmol) followed by
triethoxysilane (0.026 mL, 0.139 mmol). The resulting mixture was
sealed and heated to 65.degree. C. overnight. The resulting
reaction mixture was diluted with EtOAc, washed with brine, dried
over MgSO.sub.4, filtered and purified by prep HPLC (Method D,
45-100% over 20 min, hold 100% for 6 min) to afford Example 521
(1.4 mg, 0.002 mmol, 14% yield) as a yellow solid. LC-MS: Method H,
RT=1.07 min, MS (ESI) m/z: 633.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.94-9.68 (m, 1H), 8.67 (s, 1H), 8.51 (s,
2H), 7.98 (d, J=8.2 Hz, 1H), 7.90 (d, J=11.6 Hz, 1H), 7.78 (s, 2H),
7.29 (br. s., 1H), 5.04 (d, J=5.8 Hz, 1H), 4.73 (br. s., 1H), 4.01
(s, 3H), 3.52 (br. s., 2H) [note: morpholine protons appear to
under-integrate], 2.56 (s, 3H), 1.32 (m, 6H).
Example 522
(2R,3S)-3-((2-(2-(dimethylamino)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01369##
[3307] To a vial containing Intermediate I-73 (10 mg, 0.017 mmol)
was added dimethylamine (2 M in THF) (1 mL, 2.000 mmol) followed by
2-propanol (1 mL). The vial was sealed and heated to 65.degree. C.
After 6 h of heating the reaction mixture was concentrated, and
purified by prep HPLC (Method D, 40-80% over 20 min, hold 100% for
5 min) to afford Example 522 (7.8 mg, 0.014 mmol, 80% yield) as a
yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 562.2
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.98 (br.
s., 1H), 8.76 (s, 1H), 8.74 (br. s., 2H), 8.30 (s, 1H), 8.01 (d,
J=8.2 Hz, 1H), 7.94 (d, J=11.3 Hz, 1H), 7.57 (s, 1H), 5.11 (d,
J=6.1 Hz, 1H), 4.83 (d, J=6.4 Hz, 1H), 3.27 (br. s., 6H), 2.55 (br.
s., 3H), 1.40 (br. s., 6H).
Example 523
5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinic acid,
TFA
##STR01370##
[3309] To a solution of Intermediate I-74 (8.5 mg, 0.015 mmol) in
THF (1 mL) was added lithium hydroxide (1 M) (0.2 mL, 0.200 mmol).
The reaction mixture was sealed and heated to 65.degree. C. After 1
h, the reaction mixture was quenched with 1 M HCl, diluted with
EtOAc, extracted, concentrated, and purified by prep HPLC (Method
C, 30-100% over 20 min, hold 100% for 5 min) to afford Example 523
(4.6 mg, 0.008, 54% yield) as a yellow solid. LC-MS: Method H,
RT=1.17 min, MS (ESI) m/z: 578.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.77 (br. s., 1H), 8.72 (s, 1H), 8.57 (s,
1H), 8.11-8.01 (m, 3H), 7.98 (d, J=11.6 Hz, 1H), 7.84 (s, 1H), 5.20
(d, J=6.4 Hz, 1H), 4.87 (d, J=4.3 Hz, 1H), 4.13 (s, 3H), 2.66 (s,
3H), 1.47 (t, J=6.3 Hz, 6H).
Example 524
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy) butan-2-yl carbamate
##STR01371##
[3311] To a solution Intermediate I-72 (85 mg, 0.206 mmol) in THF
(4112 .mu.l) was added 15% phosgene in toluene (1450 .mu.l, 2.056
mmol). The resulting slurry was allowed to stir overnight before
being concentrated down to a crude yellow residue. This
chloroformate intermediate was retaken in THF (1 mL) and added
dropwise to a separate vial containing a solution of ammonia (0.5 M
in dioxane) (0.420 mL, 0.210 mmol). After 5 min of stirring at RT,
the reaction mixture was concentrated and purified by prep HPLC
(Method D, 45-80% over 30 min, hold 100% for 8 min) to afford
Example 524 (5.7 mg, 0.012 mmol, 59% yield) as a yellow solid.
LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 457.3 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.59 (s,
1H), 8.02 (d, J=7.9 Hz, 1H), 7.98 (d, J=11.3 Hz, 1H), 7.85 (s, 1H),
6.63 (br. s., 2H), 4.95 (dd, J=6.3, 3.2 Hz, 1H), 4.71 (dd, J=6.1,
3.4 Hz, 1H), 4.13 (s, 3H), 2.67 (s, 3H), 1.40 (d, J=6.4 Hz, 3H),
1.34 (d, J=6.4 Hz, 3H).
Example 525
1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy-
)-3-isobutoxypropan-2-yl (2-methylpyrimidin-5-yl)carbamate
(rac)
##STR01372##
[3313] This example was prepared in a manner analogous to Example
379 above. Thus, reaction of Intermediate 379A with
2-methylpyrimidin-5-amine afforded Example 525 (rac) in 76% yield
following purification by preparative HPLC (Method C, 60-95% over
25 min, hold at 100% for 10 min). LC-MS: Method H, RT=1.24 min, MS
(ESI) m/z: 607.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.17 (br. s., 1H), 8.76 (br. s., 2H), 8.72 (s, 1H), 8.56
(s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 7.82 (s,
1H), 5.33 (br. s., 1H), 4.50-4.43 (m, 1H), 4.43-4.36 (m, 1H), 4.09
(s, 3H), 3.78 (d, J=5.2 Hz, 2H), 3.42-3.20 (m, 2H), 2.63 (s, 3H),
1.82 (dt, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.4 Hz, 6H).
Example 526
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
##STR01373##
[3315] To a solution of Intermediate I-80 (300 mg, 0.702 mmol) in
THF (1.4 mL, 0.05 M) was added 15% phosgene in toluene (4949 .mu.l,
7.02 mmol). The resulting slurry was allowed to stir overnight.
After 16 h, the reaction mixture was concentrated down to a yellow
residue. This crude chloroformate intermediate was retaken in THF
(2 mL) and slowly added to a premixed solution of Intermediate
I-109 (33.5 mg, 0.133 mmol) and pyridine (0.083 mL, 1.021 mmol) in
THF (2 mL). After 5 min of stirring at room temperature, the
reaction mixture was concentrated to remove excess pyridine and
then retaken in THF (2 mL). To this mixture was added TBAF (1 M in
THF) (0.306 mL, 0.306 mmol), and the resulting solution was stirred
at room temperature for 6 h. The resulting mixture was concentrated
and purified by prep HPLC (Method D, 50-100% over 20 min, hold 100%
for 5 min) to afford Example 526 (31.4 mg, 0.051 mmol, 50% yield)
as a yellow solid. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z:
592.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.81
(br. s., 1H), 8.73 (s, 1H), 8.60 (s, 1H), 8.58 (br. s., 1H), 8.09
(d, J=8.2 Hz, 1H), 8.00 (d, J=11.6 Hz, 1H), 7.87-7.78 (m, 1H), 7.23
(d, J=8.5 Hz, 1H), 5.16 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.0 Hz, 1H),
4.67 (t, J=5.0 Hz, 1H), 4.58 (q, J=7.0 Hz, 2H), 3.74 (q, J=6.2 Hz,
2H), 2.85 (t, J=6.9 Hz, 2H), 2.67 (s, 3H), 1.50 (t, J=7.0 Hz, 3H),
1.45 (t, J=7.5 Hz, 6H).
Example 527
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
##STR01374##
[3317] The following example was prepared in a manner analogous to
the general hindered amide procedure described in the table above.
Thus, Intermediate I-89 was reacted with
1-amino-2-methylpropan-2-ol (100 equiv) and magnesium chloride (10
equiv) to afford Example 527 in 36% yield following purification by
preparative HPLC (Method D, 45-90% over 20 min, hold at 100% for 8
min). LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 663.2
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.23 (br.
s., 1H), 8.73 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.35 (t, J=6.1
Hz, 1H), 8.12-8.05 (m, 2H), 8.04-7.98 (m, 2H), 7.84 (s, 1H), 5.19
(dd, J=6.6, 2.6 Hz, 1H), 4.92-4.85 (m, 1H), 4.81 (s, 1H), 4.59 (q,
J=7.0 Hz, 2H), 3.33-3.27 (m, 2H), 2.68 (s, 3H), 1.50 (t, J=7.2 Hz,
3H), 1.47 (t, J=5.8 Hz, 6H), 1.15 (s, 6H).
Example 528
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01375##
[3319] Intermediate I-86 (55 mg, 0.093 mmol) was solvated in THF (1
mL) and cooled to -78.degree. C. To this mixture was added DIBAl-D
(0.7 M in toluene) (0.398 mL, 0.278 mmol). After 1 h of stirring at
-78.degree. C., the reaction mixture was quenched with 1 mL of a 1
M HCl solution at -78.degree. C. The resulting mixture was allowed
to thaw to room temperature and stirred for a total of 30 min until
the solution became fluid and bright yellow. The reaction mixture
was then diluted with EtOAc and washed with saturated NH.sub.4Cl
before being dried over MgSO.sub.4 and filtered over a pad of
SiO.sub.2 gel to remove aluminates. The resulting filtrate was
concentrated and resubjected to the reduction conditions above to
push any remaining deutero-aldehyde intermediate to the desired
deutero-alcohol product. Following a repeat of the previous work-up
procedure, the crude product was purified by prep HPLC (Method D,
35-100% over 20 min, hold 100% for 5 min) to afford Example 528
(16.3 mg, 0.028 mmol, 30% yield) as a yellow solid. LC-MS: Method
H, RT=1.11 min, MS (ESI) m/z: 567.1 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.80 (br. s., 2H), 8.68 (s, 1H), 8.53
(s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.80 (s,
1H), 5.16-5.04 (m, 1H), 4.80 (d, J=3.4 Hz, 1H), 4.48 (d, J=5.5 Hz,
1H), 4.06 (s, 3H), 2.60 (s, 3H), 1.38 (t, J=5.8 Hz, 6H).
Example 529
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01376##
[3321] The following example was made in a manner analogous to the
primary alcohol procedure described in the table above. Thus,
Intermediate I-90 was reacted with DIBAl-H to afford Example 529 in
53% yield following purification by preparative HPLC (Method D,
50-100% over 21 min, hold at 100% for 6 min). LC-MS: Method H,
RT=1.20 min, MS (ESI) m/z: 579.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.82 (br. s., 2H), 8.69 (s, 1H), 8.55 (s,
1H), 8.03 (d, J=8.2 Hz, 1H), 7.95 (d, J=11.6 Hz, 1H), 7.81 (s, 1H),
5.13 (d, J=4.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 4.59-4.47 (m, 4H),
2.63 (s, 3H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=5.5 Hz, 6H).
Example 530
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl-
)oxy) propan-2-yl
(6-((2-methyl-2-(phosphonooxy)propyl)carbamoyl)pyridin-3-yl)carbamate,
TFA
##STR01377##
[3322] Intermediate 530A:
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)(Boc)carbamate
##STR01378##
[3324] To a solution of Example 448 (55 mg, 0.087 mmol) in THF (5
mL) was added DMAP (26.5 mg, 0.217 mmol) followed by BOC-Anhydride
(0.024 mL, 0.104 mmol). After 30 min of stirring at room
temperature, the reaction was quenched with methanol, concentrated
and purified by ISCO (12 g, 0-100% EtOAc/Hex, Product at 75%) to
afford Intermediate 530A (52 mg, 0.071 mmol, 82% yield) as a yellow
foaming solid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 735.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.61 (d,
J=1.8 Hz, 1H), 8.54 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.24 (t, J=6.2
Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.83 (d, J=11.4 Hz, 1H), 7.75 (dd,
J=1.8, 0.9 Hz, 1H), 7.65 (dd, J=8.1, 2.4 Hz, 1H), 7.35 (d, J=7.7
Hz, 1H), 5.42-5.31 (m, 1H), 4.16-4.08 (m, 5H), 3.99 (dd, J=10.3,
6.8 Hz, 1H), 3.48-3.40 (m, 1H), 3.37-3.29 (m, 1H), 2.64 (s, 3H),
2.04 (s, 1H), 1.42 (s, 9H), 1.38 (d, J=6.4 Hz, 3H), 1.24 (s, 3H),
1.21 (s, 3H).
Intermediate 530B:
(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-y-
l)oxy)propan-2-yl
(6-((2-((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)-2-methylpropyl)carb-
amoyl)pyridin-3-yl)(Boc)carbamate
##STR01379##
[3326] To a solution of Intermediate 530A (20 mg, 0.027 mmol) and
1H-tetrazole (9.53 mg, 0.136 mmol) in DCM (1 mL) was added
bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (49.8 mg,
0.136 mmol). The reaction mixture was sealed and heated to
50.degree. C. for 30 min. After the desired phosphite intermediate
was formed (monitored by TLC), the resulting solution was cooled to
room temperature and hydrogen peroxide (35% wt. in H.sub.2O) (0.119
mL, 1.361 mmol) was added. After 20 min of additional stirring, the
crude phosphate was diluted with EtOAc, and washed with saturated
Na.sub.2S.sub.2O.sub.3. The organic phase was dried over
MgSO.sub.4, filtered over Celite and concentrated to give
Intermediate 530B (27.6 mg, 0.027 mmol, 100% yield) as a yellow
oil. Quantitative yield was assumed and the crude intermediate was
telescoped into the next reaction without further purification.
LC-MS: Method H, RT=1.55 min, MS (ESI) m/z: 1015.4 (M+H).sup.+.
Example 530
[3327] To a solution of crude Intermediate 530B (28 mg, 0.028 mmol)
in DCM (2 mL) was added TFA (1.0 mL) at room temperature. After 10
min of stirring, the reaction mixture was concentrated and purified
by Prep HPLC (Method C, 50-100% over 10 min, hold 100% for 5 min)
to afford Example 530 (7.4 mg, 0.009 mmol, 31% yield) as a yellow
TFA salt over the three step sequence. LC-MS: Method H, RT=1.09
min, MS (ESI) m/z: 715.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.27 (s, 1H), 8.69 (s, 1H), 8.67-8.59 (m,
2H), 8.52 (d, J=1.5 Hz, 1H), 8.07-8.00 (m, 1H), 7.98-7.88 (m, 3H),
7.78 (d, J=0.9 Hz, 1H), 5.22 (td, J=6.2, 3.2 Hz, 1H), 4.37-4.29 (m,
1H), 4.27-4.17 (m, 1H), 4.02 (s, 3H), 3.49 (d, J=5.1 Hz, 2H), 2.56
(s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (s, 6H). .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. -73.51, -134.32.
Example 531
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate, TFA
##STR01380##
[3329] Intermediate I-89 (70 mg, 0.116 mmol) was solvated in THF
(1.156 mL) and (S)-1-aminopropan-2-ol (0.12 mL, 1.524 mmol) was
added to the solution. The reaction vial was sealed and heated to
65.degree. C. After 18 h of heating, the reaction mixture was
concentrated and purified by prep HPLC (Method C, 50-100% over 19
min, hold 100% for 10 min) to afford Example 531 (55 mg, 0.070
mmol, 61% yield) as a yellow solid. LC-MS: Method H, RT=1.27 min,
MS (ESI) m/z: 649.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.16 (br. s., 1H), 8.67 (s, 1H), 8.63 (s,
1H), 8.52 (s, 1H), 8.42 (t, J=5.8 Hz, 1H), 8.07-7.98 (m, 2H),
7.98-7.89 (m, 2H), 7.76 (s, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.82 (d,
J=5.2 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 3.82-3.72 (m, 1H), 3.48 (br.
s., 1H), 3.37-3.26 (m, 1H), 3.18-3.08 (m, 1H), 2.61 (s, 3H),
1.47-1.42 (m, 3H), 1.41 (t, J=5.8 Hz, 6H), 1.05 (d, J=6.1 Hz,
3H).
Example 532
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(2-((phosphonooxy)methyl)pyrimidin-5-yl)carbamate
##STR01381##
[3330] Intermediate 532A:
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-(((bis(2-(trimethylsilyl)ethoxy)
phosphoryl)oxy)methyl)pyrimidin-5-yl)carbamate
##STR01382##
[3332] To a solution of Example 529 (20 mg, 0.035 mmol) and
1H-tetrazole (24.21 mg, 0.346 mmol) in DCM (3457 .mu.l) was added
bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (126 mg,
0.346 mmol) at room temperature. After 1 h, the reaction mixture
was cooled to 0.degree. C. and hydrogen peroxide (35% wt. in
H.sub.2O) (90.8 .mu.l, 1.037 mmol) was added. The resulting mixture
was allowed to thaw to room temperature and stirred vigorously for
30 min. The reaction mixture was then diluted with EtOAc and washed
with saturated Na.sub.2S.sub.2O.sub.3. The organic phase was dried
over MgSO.sub.4, filtered over Celite and concentrated to give
Intermediate 532A (29.7 mg, 0.035 mmol, 100% yield) as a yellow oil
mixed with excess phosphate reagent. Quantitative yield was
assumed, and the crude intermediate was telescoped into the next
reaction without further purification. LC-MS: Method H, RT=1.52
min, MS (ESI) m/z: 859.5 (M+H).sup.+.
Example 532
[3333] Crude Intermediate 532A (29 mg, 0.034 mmol) was solvated in
DCM (2 mL). TFA (0.500 mL) was added causing the solution to turn
dark yellow and bubble vigorously. After 10 min, the reaction
mixture was concentrated and purified by Prep HPLC (Method C,
50-100% over 10 min, hold 100% for 5 min) to afford Example 532
(12.2 mg, 0.018, 54% yield) as a yellow solid over the three step
sequence. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 659.1
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.08 (br.
s., 1H), 8.78 (s, 2H), 8.62 (s, 1H), 8.48 (s, 1H), 7.98 (d, J=8.1
Hz, 1H), 7.88 (d, J=11.7 Hz, 1H), 7.72 (s, 1H), 5.06 (dd, J=6.4,
2.6 Hz, 1H), 4.83-4.74 (m, 2H), 4.74-4.64 (m, 1H), 4.46 (q, J=7.0
Hz, 2H), 2.55 (s, 3H), 1.37 (t, J=7.0 Hz, 3H), 1.33 (d, J=6.6 Hz,
6H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -133.47 (s, 1F).
.sup.31P NMR (162 MHz, DMSO-d.sub.6) .delta. 24.2 (s, 1P)
Example 533
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-yl (5-hydroxypyridin-3-yl)carbamate
##STR01383##
[3334] Intermediate 533A:
5-((tert-butyldimethylsilyl)oxy)pyridin-3-amine
##STR01384##
[3336] To a vial containing 5-aminopyridin-3-ol (75 mg, 0.681 mmol)
was added DCM (6986 .mu.l) and THF (3493 .mu.l) followed by
Et.sub.3N (285 .mu.l, 2.043 mmol). TBS-Cl (123 mg, 0.817 mmol) was
then added to the solution at room temperature. After 1 h of
stirring, MeOH (551 .mu.l, 13.62 mmol) was added to quench the
remaining TBS-Cl. The reaction mixture was then diluted with EtOAc
and washed with brine. The resulting organic phase was dried over
MgSO.sub.4, filtered over Celite, concentrated and co-evaporated
with toluene to afford Intermediate 533A (150 mg, 0.669 mmol, 98%
yield) as a brown oil. LC-MS: Method H, RT=0.77 min, MS (ESI) m/z:
225.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73
(d, J=2.4 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 6.49 (t, J=2.3 Hz, 1H),
3.65 (br. s., 2H), 0.98 (s, 9H), 0.21 (s, 6H).
Intermediate 533B:
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-((tert-butyldimethyl
silyl)oxy)pyridin-3-yl) carbamate
##STR01385##
[3338] To a solution Intermediate I-72 (95 mg, 0.230 mmol) in THF
(4595 .mu.l) was added 15% phosgene in toluene (1620 .mu.l, 2.298
mmol). The resulting slurry was allowed to stir at room temperature
overnight. After 16 h, the reaction mixture was concentrated to
remove excess phosgene. The resulting crude chloroformate was
retaken in DCM (2290 .mu.l) and slowly added to a pre-mixed
suspension of Intermediate 533A and pyridine (185 .mu.l, 2.290
mmol) in DCM (2290 .mu.l). After 10 min, the reaction mixture was
concentrated and purified by ISCO (24 g, 0-80% DCM/EtOAc, Product
at 33%) to afford Intermediate 533B (110 mg, 0.133 mmol, 57.9%
yield) as a yellow solid. LC-MS: Method H, RT=1.22 min, MS (ESI)
m/z: 664.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.60 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.92
(d, J=2.4 Hz, 1H), 7.82 (d, J=11.2 Hz, 1H), 7.77 (dd, J=1.8, 0.9
Hz, 1H), 7.60 (br. s., 1H), 7.53 (d, J=7.7 Hz, 1H), 6.67 (br. s.,
1H), 5.21-5.12 (m, 1H), 4.60 (qd, J=6.2, 3.3 Hz, 1H), 4.13 (s, 3H),
2.65 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H), 0.23
(s, 6H), 0.00 (s, 9H).
Example 533
[3339] To a solution of Intermediate 533B (25 mg, 0.030 mmol) in
THF (1 mL) was added acetic acid (0.017 mL, 0.301 mmol) followed by
TBAF (1 M in THF) (0.090 mL, 0.090 mmol) (10:35 am). The resulting
mixture was stirred at room temperature for 20 min, before being
concentrated and purified by Prep HPLC (Method D, 45-90% over 22
min, hold at 100% for 5 min) to afford Example 533 (9.3 mg, 0.016
mmol, 54% yield). LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 550.1
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.82 (br.
s., 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.10 (br. s., 1H), 7.99 (d,
J=7.9 Hz, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.77 (s, 2H), 7.45 (br. s.,
1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.77 (dd, J=6.4, 2.7 Hz, 1H),
4.06 (s, 3H), 2.60 (s, 3H), 1.39 (dd, J=10.7, 6.4 Hz, 6H).
Example 534
(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy) butan-2-yl (5-(2-hydroxyethoxy)pyridin-3-yl)carbamate
##STR01386##
[3341] Intermediate 534A: methyl
2-((5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo-
[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyridin-3-yl)oxy)acetate
##STR01387##
[3342] To a solution of Example 533 (25 mg, 0.045 mmol) in DMF (1
mL) was added cesium carbonate (22.23 mg, 0.068 mmol) followed by
methyl bromoacetate (5.03 .mu.l, 0.055 mmol). After 1.5 h of
vigorous stirring and room temperature, the reaction mixture was
diluted with EtOAc and filtered over a short pad of SiO.sub.2 gel.
The resulting organic phase was concentrated to remove residual
DMF, retaken in EtOAc, washed with brine, dried over MgSO.sub.4,
filtered and concentrated to afford Intermediate 534A (22 mg, 0.035
mmol, 78% yield) as a thick yellow oil. LC-MS: Method H, RT=1.07
min, MS (ESI) m/z: 622.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.59 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 8.07 (d,
J=1.8 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.81 (d, J=11.2 Hz, 1H),
7.75 (s, 1H), 7.70 (br. s., 1H), 7.51 (d, J=7.9 Hz, 1H), 6.92 (br.
s., 1H), 5.20-5.09 (m, 1H), 4.67 (s, 2H), 4.64-4.54 (m, 1H), 4.12
(s, 3H), 3.81 (s, 3H), 2.64 (s, 3H), 1.46 (d, J=6.6 Hz, 3H),
1.44-1.41 (m, 3H).
Example 534
[3343] A solution of Intermediate 534A (11 mg, 0.018 mmol) in THF
(1 mL) was cooled to -78.degree. C. To this mixture was added
DIBAL-H (1 M in toluene) (0.088 mL, 0.088 mmol). Following the
reagent addition, the reaction mixture was allowed to thaw to room
temperature. After 30 min of vigorous stirring, the reaction
mixture was quenched with 1 M HCl, concentrated, and purified by
Prep HPLC (Method D, 45-90% over 20 min, hold 100% for 5 min) to
afford Example 534 (1.8 mg, 0.002 mmol, 16% yield) as a yellow
solid. LC-MS: Method H, RT=0.91 min, MS (ESI) m/z: 594.2
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.87 (br.
s., 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.22 (br. s., 1H), 7.98 (d,
J=7.9 Hz, 1H), 7.91 (d, J=11.3 Hz, 2H), 7.78 (s, 1H), 7.51 (br. s.,
1H), 5.10 (d, J=6.4 Hz, 1H), 4.79 (d, J=4.0 Hz, 1H), 4.06 (s, 3H),
3.99 (t, J=4.6 Hz, 2H), 3.72-3.59 (m, 2H), 2.60 (s, 3H), 1.38 (dd,
J=9.6, 6.6 Hz, 6H).
Example 535
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(2-((S)-1-hydroxyethyl)pyrimidin-5-yl)carbamate
##STR01388##
[3345] A solution of Intermediate I-90 (50 mg, 0.085 mmol) in THF
(1693 .mu.l) was cooled to -78.degree. C. To this cooled mixture
was added DIBAl-H (1 M in toluene) (425 .mu.l, 0.425 mmol), which
caused the solution to take on a reddish hue. After 1 h, the
reaction mixture was quenched cold with 1.7 mL of Rochelle's Salt,
allowed to thaw to room temperature, and stirred vigorously
overnight. After 16 h, the reaction mixture was diluted with EtOAc
and extracted. The organic phase was dried over MgSO.sub.4,
filtered over Celite and concentrated. The crude residue was
purified by ISCO (12 g, 0-100% EtOAc/DCM, Pdt at 50%) to afford
Example 535 (44 mg, 0.074 mmol, 88% yield) as a diastereomeric
mixture. This material was further purified by chiral HPLC
(Chiracel OD, Semi-prep-80% Heptane/20% EtOH/MeOH(1:1) isocratic
eluent with a 16 mL/min flow rate. Diastereomer retention time
60-75 min) to afford homochiral Example 535 (16.4 mg, 0.027 mmol,
37% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 593.0
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.95 (br.
s., 1H), 8.75 (s, 2H), 8.64 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 7.98
(d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H), 7.75 (dd, 0.9 Hz, 1H),
5.11-4.98 (m, 2H), 4.77-4.69 (m, 1H), 4.68-4.59 (m, 1H), 4.47 (q,
J=7.0 Hz, 2H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.33 (dd,
J=6.5, 2.5 Hz, 6H), 1.28 (d, J=6.4 Hz, 3H).
Example 536
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy) butan-2-yl
(2-(((R)-1-hydroxyethyl)pyrimidin-5-yl)carbamate
##STR01389##
[3347] Example 536 was synthesized concurrently with Example 535
above. Thus, the above diastereomeric mixture was purified by
chiral HPLC (Chiracel OD, Semi-prep-80% Heptane/20% EtOH/MeOH(1:1)
isocratic eluent with a 16 mL/min flow rate. Diastereomer retention
time 85-100 min) to afford homochiral Example 536 (17.2 mg, 0.028
mmol, 37% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 593.0
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.95 (br.
s., 1H), 8.75 (s, 2H), 8.64 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 7.98
(d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H), 7.75 (s, 1H), 5.10-4.99
(m, 2H), 4.74 (dd, J=6.3, 2.8 Hz, 1H), 4.68-4.60 (m, 1H), 4.47 (q,
J=7.0 Hz, 2H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.33 (dd,
J=6.3, 2.5 Hz, 6H), 1.28 (d, J=6.6 Hz, 3H).
Example 537
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy-
)ethyl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
##STR01390##
[3348] Intermediate 537A:
2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)ox-
y)ethyl (2-(2-((tert-butyldiphenyl
silyl)oxy)ethyl)pyrimidin-5-yl)carbamate
##STR01391##
[3350] To a solution Intermediate I-66 (15 mg, 0.039 mmol) in THF
(1 mL) was added 15% phosgene in toluene (0.274 mL, 0.389 mmol).
The resulting slurry was allowed to stir overnight. After 16 h the
reaction mixture was concentrated to a crude yellow residue. The
resulting chloroformate intermediate was retaken in THF (1 mL) and
added dropwise to a pre-mixed solution of Intermediate I-98 (13.49
mg, 0.036 mmol) and pyridine (0.014 mL, 0.179 mmol) in THF (1 mL).
After 10 min of stirring at room temperature, the reaction mixture
was concentrated in vacuo to remove excess pyridine, and
Intermediate 537A was telescoped into the subsequent deprotection
step without further purification. LC-MS: Method H, RT=1.46 min, MS
(ESI) m/z: 789.0 (M+H).sup.+.
Example 537
[3351] To a crude solution of Intermediate 537A (14 mg, 0.018 mmol)
in THF (0.75 mL) and MeOH (0.75 mL) was added
(R)-(-)-camphorsulfonic acid (12.37 mg, 0.053 mmol). The reaction
vial was sealed and heated to 65.degree. C. After 1.5 h of heating,
the reaction mixture was cooled to room temperature and quenched
with triethylamine (0.025 mL, 0.177 mmol). The resulting mixture
was concentrated, and purified by Prep HPLC (Method D, 40-80% over
22 min, hold at 100% for 5 min) to afford Example 537 (5.2 mg,
0.009 mmol, 52% yield) as a yellow solid over the three step
sequence. LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 550.9
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.16 (br.
s., 1H), 8.79 (s, 2H), 8.72 (s, 1H), 8.55 (s, 1H), 8.03-7.94 (m,
2H), 7.82 (s, 1H), 4.57 (br. s., 2H), 4.45 (br. s., 2H), 4.08 (s,
3H), 3.82 (q, J=6.4 Hz, 2H), 2.97 (t, J=6.7 Hz, 2H), 2.63 (s,
3H).
Example 538
(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
##STR01392##
[3353] Example 538 was prepared in a manner analogous to Example
536 above. Thus, Intermediate I-81 was reacted with phosgene,
followed by Intermediate I-98, followed by CSA to afford Example
538 (66% yield over the three step sequence) after purification by
Prep HPLC (Method D, 55-90% over 25 min, hold at 90% for 4 min).
LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 612.9, 614.9
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.97 (br.
s., 1H), 8.76 (br. s., 2H), 8.70 (s, 1H), 8.56 (s, 1H), 8.06 (d,
J=7.6 Hz, 1H), 7.83 (s, 1H), 5.14 (dd, J=6.6, 2.6 Hz, 1H), 4.85 (d,
J=6.4 Hz, 1H), 4.09 (s, 3H), 3.84-3.74 (m, 2H), 3.34 (br. s., 1H),
2.94 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.40
(d, J=6.4 Hz, 3H).
Example 539
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01393##
[3354] Intermediate 539A: methyl
5-(((((2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thi-
azol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
##STR01394##
[3356] To a solution Intermediate I-91 (30 mg, 0.069 mmol) in THF
(1386 .mu.l) was added 15% phosgene in toluene (489 .mu.l, 0.693
mmol). The resulting slurry was allowed to stir overnight. After 16
h, the mixture was concentrated to remove the excess phosgene. The
resulting chloroformate was retaken in DCM (7.00 mL) and slowly
added to a pre-mixed solution of Intermediate I-107 (39.6 mg, 0.209
mmol) and pyridine (0.084 mL, 1.044 mmol) in DCM (1.4 mL). After 30
min, the reaction mixture was concentrated and purified by ISCO (12
g, 0-100% EtOAC/DCM) to afford Intermediate 539A (24 mg, 0.029
mmol, 42.3% yield). LC-MS: Method H, RT=1.14 min, MS (ESI) m/z:
612.2, 614.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.04 (s, 2H), 8.75 (d, J=3.1 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H),
7.84-7.75 (m, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.38 (d, J=2.9 Hz, 1H),
5.23-5.10 (m, 1H), 4.70-4.60 (m, 1H), 4.02 (s, 3H), 3.99 (s, 3H),
1.48 (d, J=6.4 Hz, 3H), 1.45 (d, J=6.4 Hz, 4H).
Example 539
[3357] Example 539 was prepared in a manner analogous to the
primary alcohols described in the table above. Thus, Intermediate
539A was reacted with DIBAl-H to afford Example 539 (10% yield)
following purification by Prep HPLC (Method D, 45-90% over 22 min,
hold at 100% for 5 min). LC-MS: Method H, RT=1.09 min, MS (ESI)
m/z: 584.2, 586.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.04 (br. s., 1H), 8.88 (br. s., 1H), 8.83 (br. s., 2H),
8.64 (br. s., 1H), 8.21 (br. s., 1H), 8.06 (d, J=7.6 Hz, 1H),
8.01-7.91 (m, 2H), 5.14 (br. s., 1H), 4.82 (br. s., 1H), 4.51 (br.
s., 2H), 4.00 (br. s., 3H), 1.41 (br. s., 6H).
Example 540
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
##STR01395##
[3358] Intermediate 540A:
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(2-(((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-yl)carbamate
##STR01396##
[3360] To a solution of Intermediate I-91 (40 mg, 0.092 mmol) in
THF (1848 .mu.l) was added 15% phosgene in toluene (652 .mu.l,
0.924 mmol). The resulting slurry was allowed to stir overnight.
After 16 h, the mixture was concentrated to remove the excess
phosgene. The resulting chloroformate was retaken in THF (1.0 mL)
and added dropwise to a pre-mixed solution of Intermediate I-104
(19.19 mg, 0.068 mmol) and pyridine (0.036 mL, 0.451 mmol) in THF
(1 mL). After 10 min, the reaction mixture was concentrated to
remove excess pyridine and telescoped into the TBS deprotection
without further purification. LC-MS: Method H, RT=1.48 min, MS
(ESI) m/z: 742.0, 744.0 (M+H).sup.+.
Example 540
[3361] To a crude solution of Intermediate 540A (33 mg, 0.044 mmol)
in THF (0.75 mL) and MeOH (0.750 mL) was added R(-(-)-camphor
sulfonic acid (31.0 mg, 0.133 mmol). The reaction vial was sealed
and heated to 65.degree. C. After 30 min of heating, the mixture
was cooled to room temperature and triethylamine (0.062 mL, 0.445
mmol) was added to quench the reaction. The reaction mixture was
concentrated and purified by Prep HPLC (Method D, 55-100% over 20
min, hold at 100% for 7 min) to afford Example 540 (17.6, 0.027
mmol, 62% yield) as a yellow solid. LC-MS: Method H, RT=1.17 min,
MS (ESI) m/z: 628.0, 629.9 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.80 (br. S., 1H), 8.86 (br. S., 1H), 8.62
(br. S., 3H), 8.19 (s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.97 (d, J=11.3
Hz, 1H), 7.94 (br. S., 1H), 5.10 (d, J=6.4 Hz, 1H), 4.82 (br. S.,
1H), 4.12-4.06 (m, 1H), 4.03-3.97 (m, 4H), 3.92 (d, J=10.7 Hz, 1H),
1.40 (t, J=6.3 Hz, 6H), 1.12 (d, J=6.1 Hz, 3H).
Example 541
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan-2-yl
(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
##STR01397##
[3363] Example 541 was prepared in a manner analogous Example 540
described above. Thus, Intermediate I-91 was reacted with phosgene,
followed by Intermediate I-103, followed by CSA to afford Example
541 (72% yield over the three step sequence) after purification by
Prep HPLC (Method D, 60-100% over 20 min, hold at 100% for 6 min).
LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 628.0, 629.9
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80 (br.
s., 1H), 8.84 (d, J=2.1 Hz, 1H), 8.60 (br. s., 3H), 8.17 (s, 1H),
8.03 (d, J=7.9 Hz, 1H), 7.95 (d, J=11.3 Hz, 1H), 7.92 (d, J=2.4 Hz,
1H), 5.10 (d, J=6.4 Hz, 1H), 4.89 (d, J=4.9 Hz, 1H), 4.82 (d, J=4.0
Hz, 1H), 4.12-4.05 (m, 1H), 4.05-4.00 (m, 1H), 3.99 (s, 3H), 3.93
(dt, J=11.4, 5.6 Hz, 1H), 1.44-1.34 (m, 6H), 1.11 (d, J=6.4 Hz,
3H).
Preparation of Carbamate Examples
[3364] To a solution of the appropriately substituted
quinoxaline-benzothiazole alcohol (1.0 equiv) in THF (0.05 M) was
added a solution of phosgene (15% by wt. in toluene, 10 equiv).
This solution was stirred at room temperature overnight before the
intermediate chloroformate was concentrated in vacuo. This crude
chloroformate was retaken in THF (0.05 M) and added dropwise to a
pre-mixed solution of pyridine (10 equiv) and the appropriately
substituted amino-heterocycle (1.1-3.0 equiv) in either THF (0.05
M) or DCM (0.05), whichever gave the best reagent solubility. After
30 min of stirring, the combined mixture was concentrated, retaken
in DMF, filtered and purified by preparative HPLC to yield the
desired example.
[3365] If the reactant amino-heterocycle contained a silyl
protecting group, the silyl group was removed according to
Procedure J before final purification. If the reactant
amino-heterocycle contained an acetonide protecting group, the
ketal was removed according to Procedure K before final
purification.
TABLE-US-00015 HPLC LCMS LCMS Prep Ex. [M + H].sup.+ RT Method No.
Structure R--OH R--NH.sub.2 m/z (Min) D NMR 542 ##STR01398## I-69
I-109 598.1 Ortho- gonal HPLC method B Injection 2, 2.136 45- 90%
20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.90
(br. s., 1H), 8.40-8.75 (m, 3H), 7.70-7.99 (m, 3H), 7.26 (d, J =
8.24 Hz, 1H), 5.32 (br. s., 1H), 4.27-4.49 (m, 2H), 4.11 (s, 3H),
3.75 (br. s., 2H), 2.81-2.91 (m, 2H), 2.66 (s, 3H), 1.48 (d, J =
6.10 Hz, 3H). 543 ##STR01399## I-67 I-109 564.2 Ortho- gonal HPLC
method B Injection 2, 1.962 40- 80% 5 min, 100% 20 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.96-9.57 (m, 1H), 8.75 (s, 1H),
8.62-8.49 (m, 2H), 8.10- 7.94 (m, 2H), 7.84 (s, 1H), 7.81-7.74 (m,
1H), 7.19 (d, J = 8.5 Hz, 1H), 5.32-5.15 (m, 1H), 4.67-4.53 (m,
1H), 4.41- 4.23 (m, 2H), 4.13-4.05 (m, 3H), 3.69 (t, J = 6.9 Hz,
2H), 2.80 (t, J = 7.0 Hz, 2H), 2.66- 2.59 (m, 3H), 1.42 (d, J = 6.6
Hz, 3H). 544 ##STR01400## I-67 I-112 564.1 Ortho- gonal HPLC method
B Injection 2, 1.961 40- 80% 20 min, 100% 6 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.81 (br. s., 1H), 8.63 (s, 1H), 8.46
(s, 1H), 8.34 (br. s., 1H), 7.95-7.81 (m, 3H), 7.72 (s, 1H), 5.19
(d, J = 3.1 Hz, 1H), 4.40 (br. s., 2H), 4.32-4.11 (m, 2H), 2.54 (s,
3H), 2.44 (br. s., 3H), 2.26 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H). 545
##STR01401## I-67 I-94 564.15 Ortho- gonal HPLC method B Injection
2, 1.960 50- 100% 15 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.11 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H),
8.21 (d, J = 5.5 Hz, 1H), 7.98-7.84 (m, 2H), 7.74 (s, 1H), 7.29 (s,
1H), 7.23 (d, J = 5.2 Hz, 1H), 5.20 (d, J = 3.1 Hz, 1H), 4.33-4.26
(m, 1H), 4.26-4.16 (m, 1H), 4.00 (s, 3H), 3.63 (t, J = 6.9 Hz, 2H),
2.71 (t, J = 6.7 Hz, 2H), 2.55 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).
546 ##STR01402## I-67 I-385B 550.2 Ortho- gonal HPLC method B
Injection 2, 1.995 15- 100% 15 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.96 (br. s., 1H), 8.70 (s, 1H),
8.62-8.45 (m, 2H), 8.06-7.84 (m, 3H), 7.80 (s, 1H), 7.40 (d, J =
8.2 Hz, 1H), 5.25 (d, J = 3.1 Hz, 1H), 4.50-4.46 (m, 2H), 4.39-4.18
(m, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.50-1.20 (m, 3H). 547
##STR01403## I-72 I-94 578.19. Ortho- gonal HPLC method B Injection
2, 2.058 30- 80% 15 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.13 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H),
8.31 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.00 (d, J =
11.3 Hz, 1H), 7.87 (s, 1H), 7.46-7.28 (m, 2H), 5.18 (d, J = 4.6 Hz,
1H), 4.84 (br. s., 1H), 4.13 (s, 3H), 3.75 (t, J = 6.7 Hz, 2H),
3.57-3.43 (m, 1H), 2.89-2.76 (m, 2H), 2.67 (s, 3H), 1.46 (t, J =
6.4 Hz, 6H). 549 ##STR01404## I-72 I-111 608.20 Ortho- gonal HPLC
method B Injection 2, 2.178 30- 80% 22 min, 100% 7 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.08 (s, 1H), 8.72 (s, 1H), 8.56
(s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.99-7.89 (m, 2H), 7.82 (s, 1H),
7.01 (d, J = 5.4 Hz, 1H), 6.85 (s, 1H), 5.19-5.01 (m, 2H),
4.89-4.74 (m, J = 3.7 Hz, 1H), 4.08 (s, 3H), 3.56-3.34 (m, 2H),
2.63 (s, 3H), 1.40 (t, J = 6.1 Hz, 6H), 1.17 (d, J = 6.1 Hz, 3H).
550 ##STR01405## I-72 I-111 608.20 Ortho- gonal HPLC method B
Injection 2, 2.167 30- 80% 22 min, 100% 7 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.10 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H),
8.05-7.89 (m, 3H), 7.80 (s, 1H), 7.02 (d, J = 4.7 Hz, 1H), 6.91 (s,
1H), 5.12 (d, J = 4.0 Hz, 1H), 4.79 (br. s., 1H), 4.04-3.85 (m,
3H), 2.62 (s, 3H), 1.40 (t, J = 5.6 Hz, 6H), 1.09 (d, J = 6.4 Hz,
3H). 552 ##STR01406## I-67 I-110 580.1 Ortho- gonal HPLC method B
Injection 2, 2.003 30- 100% 20 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.17 (s, 1H), 8.70 (s, 1H), 8.59-8.49
(m, J = 1.5 Hz, 1H), 8.03-7.89 (m, 3H), 7.80 (s, 1H), 7.06 (dd, J =
5.6, 1.7 Hz, 1H), 6.93 (s, 1H), 5.35-5.21 (m, 1H), 4.43-4.24 (m,
2H), 4.24-4.16 (m, J = 5.0, 5.0 Hz, 2H), 4.07 (s, 3H), 3.68 (q, J =
5.5 Hz, 2H), 3.43 (br. s., 2H), 2.62 (s, 3H), 1.43 (d, J = 6.4 Hz,
3H). 553 ##STR01407## I-67 I-106 595.15. Ortho- gonal HPLC method B
Injection 2, 2.265 45- 100% 20 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.85 (br. s., 1H), 8.65 (s, 1H), 8.60
(br. s., 2H), 8.50 (s, 1H), 7.97-7.87 (m, 2H), 7.77 (s, 1H),
5.29-5.19 (m, 1H), 5.10-4.97 (m, 1H), 4.42-4.20 (m, 2H), 4.06 (s,
3H), 3.60-3.55 (m, 2H), 2.60 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H). 554
##STR01408## I-72 I-106 609.19 Ortho- gonal HPLC method B Injection
2, 2.348 50- 100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.89-9.70 (m, 1H), 8.68 (s, 1H), 8.59 (br.
s., 2H), 8.53 (s, H), 8.01 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 11.6
Hz, 1H), 7.80 (s, 1H), 5.20-4.53 (m, 3H), 4.07 (s, 3H), 3.60-3.47
(m, 1H), 2.61 (s, 3H), 1.44-1.31 (m, 6H), 1.21 (d, J = 6.1 Hz, 3H).
555 ##STR01409## I-67 I-97 581.1. LCMS Method H, 1.11 50- 100% 10
min, 100% 5 min .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.76
(s, 1H), 8.68-8.54 (m, 3H), 8.12-7.94 (m, 2H), 7.85 (s, 1H),
5.34-5.14 (m, 1H), 4.99- 4.75 (m, 1H), 4.44-4.32 (m, 1H), 4.32-4.17
(m, J = 5.0, 5.0 Hz, 3H), 4.09 (s, 3H), 3.75-3.61 (m, 2H), 2.64 (s,
3H), 1.42 (d, J = 6.6 Hz, 3H). 556 ##STR01410## I-72 I-97 595.2
LCMS Method H, 1.16 50- 100% 10 min, 100% 8 min .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.72 (br. s., 1H), 8.67 (s, 1H), 8.53
(br. s., 2H), 8.51 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H),
7.89 (d, J = 11.7 Hz, 1H), 7.77 (d, J = 0.7 Hz, 1H), 5.02 (qd, J =
6.5, 2.8 Hz, 1H), 4.80-4.68 (m, 2H), 4.16 (t, J = 5.1 Hz, 2H), 4.02
(s, 3H), 3.60 (q, J = 5.4 Hz, 2H), 2.56 (s, 3H), 1.31 (m, 6H). 557
##STR01411## I-67 I-92 592.36 Ortho- gonal HPLC method B Injection
2, 2.052 40- 100% 10 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.86 (br. s., 1H), 8.67 (s, 1H), 8.57-8.45
(m, 2H), 8.05-7.89 (m, 2H), 7.84-7.71 (m, 2H), 7.23 (d, J = 8.2 Hz,
1H), 5.30- 5.16 (m, J = 6.3, 3.2 Hz, 1H), 4.40-4.19 (m, 2H), 4.06
(s, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.06 (s, 6H). 558
##STR01412## I-67 I-105 595.20 Ortho- gonal HPLC method B Injection
2, 2.270 45- 100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.67 (br. s., 2H), 8.58 (s,
1H), 8.05-7.93 (m, 2H), 7.85 (s, 1H), 5.40-5.25 (m, 1H), 5.15-4.91
(m, 1H), 4.46-4.27 (m, 2H), 3.57 (s, 3H), 2.62 (s, 2H), 1.48 (d, J
= 6.4 Hz, 3H), 1.28 (d, J = 6.1 Hz, 3H). 559 ##STR01413## I-72 I-92
606.35 Ortho- gonal HPLC method B Injection 2, 2.138 40- 100% 12
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.83-9.57 (m, 1H), 8.62 (s, 1H), 8.52-8.42 (m, 2H), 7.96 (d, J =
8.2 Hz, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.75 (s, 2H), 7.19 (d, J =
8.5 Hz, 1H), 5.09 (dd, J = 6.4, 2.7 Hz, 1H), 4.77 (dd, J = 6.3, 2.6
Hz, 1H), 4.05 (s, 3H), 1.38 (dd, J = 11.1, 6.3 Hz, 7H), 1.03 (s,
6H). 560 ##STR01414## I-72 I-105 609.20 Ortho- gonal HPLC method B
Injection 2, 2.362 35- 75% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.73 (br. s., 1H), 8.76-8.34 (m, 4H),
8.02-7.85 (m, 3H), 7.75 (s, 1H), 5.16-4.91 (m, 2H), 4.79 (br. s.,
1H), 4.09-3.97 (m, 4H), 3.72-3.65 (m, 3H), 2.58 (s, 3H), 1.43-1.33
(m, 6H), 1.18 (d, J = 6.4 Hz, 3H). 561 ##STR01415## I-72 1-95
606.22 Ortho- gonal HPLC method B Injection 2, 2.253 15- 100% 19
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72
(s, 1H), 8.57 (s, 1H), 8.04-7.86 (m, 3H), 7.83 (s, 1H), 6.44-6.31
(m, 2H), 6.13 (br. s., 1H), 4.95 (dd, J = 6.4, 3.1 Hz, 1H), 4.73
(dd, J = 6.1, 3.1 Hz, 1H), 4.09 (s, 3H), 3.10-3.02 (m, 1H),
2.99-2.92 (m, 1H), 2.63 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H),
1.37-1.29 (m, J = 5.8, 5.8 Hz, 7H). 562 ##STR01416## I-72 I-96
622.21 Ortho- gonal HPLC method B Injection 2, 2.199 50- 100% 20
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.13
(s, 1H), 8.75 (s, 1H), 8.60 (d, J = 1.5 Hz, 1H), 8.16- 7.80 (m,
4H), 7.12-6.86 (m, 2H), 5.30-5.11 (m, J = 6.4, 2.7 Hz, 1H),
4.97-4.81 (m, J = 6.4, 2.7 Hz, 1H), 4.13 (s, 3H), 4.02 (s, 2H),
2.67 (s, 3H), 1.45 (t, J = 6.1 Hz, 6H), 1.20 (s, 6H). 563
##STR01417## I-72 I-108 636.26 Ortho- gonal HPLC method B Injection
2, 2.190 50- 100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.97 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H),
7.94 (d, J = 8.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.73 (s, 1H), 6.92 (d,
J = 4.3 Hz, 1H), 6.80 (s, 1H), 5.09-4.99 (m, J = 6.7, 2.7 Hz, 1H),
4.78- 4.67 (m, J = 6.3, 2.6 Hz, 1H), 4.21 (t, J = 7.2 Hz, 2H), 4.00
(s, 3H), 2.55 (s, 3H), 1.71 (t, J = 7.3 Hz, 2H), 1.32 (t, J = 6.6
Hz, 6H), 1.06 (s, 6H). 564 ##STR01418## I-67 I-98 565.15 Ortho-
gonal HPLC method B Injection 2, 2.111 45- 85% 25 min, 100% 6 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.80-8.62 (m, 3H), 8.50
(s, 1H), 7.99-7.88 (m, 2H), 7.78 (s, 1H), 5.27 (d, J = 2.7 Hz, 1H),
4.40-4.32 (m, J = 8.2 Hz, 1H), 4.31-4.20 ( m, J = 10.8, 6.3 Hz,
1H), 4.06 (s, 3H), 3.81 (q, J = 6.4 Hz, 2H), 2.95 (t, J = 6.7 Hz,
2H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H). 565 ##STR01419## I-72
I-98 579.18 Ortho- gonal HPLC method B Injection 2 Injection 2,
2.298 45- 90% 25 min, 100% 6 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.78-8.67 (m, 3H), 8.55 (s, 1H), 8.04-7.89
(m, 2H), 7.83 (s, 1H), 5.19-5.05 (m, 1H), 4.85- 4.77 (m, 1H), 3.79
(d, J = 5.8 Hz, 2H), 2.93 (t, J = 6.7 Hz, 2H), 1.39 (t, J = 6.9 Hz,
6H). 566 ##STR01420## I-80 I-98 593.24 Ortho- gonal HPLC method B
Injection 2, 2.359 50- 100% 20 min, 100% 10 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.75 (br. s., 2H),
8.63 (s, 1H), 8.51 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.92 (d, J =
11.3 Hz, 1H), 7.76 (s, 1H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.79
(d, J = 4.0 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 4.51 (q, J = 7.0 Hz,
2H), 3.87-3.62 (m, 2H), 2.94 (t, J = 6.7 Hz, 2H), 2.56 (s, 3H),
1.54-1.28 (m, 9H). 567 ##STR01421## I-67 I-108 622.2 Ortho- gonal
HPLC method B Injection 2, 2.087 50- 100% 20 min, 100% 7 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.13 (s, 1H), 8.70 (s,
1H), 8.54 (s, 1H), 8.09-7.91 (m, 3H), 7.81 (s, 1H), 7.01 (d, J =
5.8 Hz, 1H), 6.90 (s, 1H), 5.26 (br. s., 1H), 4.45-4.14 (m, 4H),
4.08 (s, 3H), 2.62 (s, 3H), 1.79 (t, J = 7.2 Hz, 2H), 1.42 (d, J =
6.4 Hz, 3H), 1.14 (s, 6H). 568 ##STR01422## I-80 I-97 609.19 Ortho-
gonal HPLC method B Injection 2, 2.408 30- 100% 15 min, 100% 10 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.57 (s,
3H), 8.06-7.92 (m, 2H), 7.82 (s, 1H), 5.14-5.03 (m, 1H), 4.94-4.89
(m, 1H), 4.85-4.75 (m, 1H), 4.55 (d, J = 7.0 Hz, 2H), 4.23 (br. s.,
2H), 3.74-3.63 (m, J = 4.9 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J = 7.0
Hz, 3H), 1.42-1.31 (m, 6H). 569 ##STR01423## I-67 I-100 623.15
Ortho- gonal HPLC method B Injection 2, 2.345 45- 100% 21 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.88 (br. s.,
1H), 8.71-8.56 (m, 3H), 8.50 (s, 1H), 8.02-7.86 (m, 2H), 7.76 (s,
1H), 5.24 (br. s., 1H), 4.41-4.18 (m, 4H), 3.97 (s, 3H), 2.59 (s,
3H), 1.81 (br. s., 2H), 1.41 (d, J = 6.1 Hz, 3H), 1.14 (br. s.,
6H). 570 ##STR01424## I-72 I-100 637.2 Ortho- gonal HPLC method B
Injection 2, 2.436 50- 100% 6 min, 100% 22 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.77 (br. s., 1H), 8.70-8.42 (m, 4H),
8.09-7.86 (m, 2H), 7.77 (s, 1H), 5.16-5.03 (m, 1H), 4.91-4.72 (m, J
= 6.4 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.05 (s, 3H), 2.59 (s,
3H), 1.79 (t, J = 7.1 Hz, 2H), 1.45-1.31 (m, J = 6.7 Hz, 6H),
1.19-1.01 (m, 6H). 571 ##STR01425## I-72 I-93 594.15 Ortho- gonal
HPLC method B Injection 2, 2.303 35- 100% 15 min, 100% 10 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.57 (br. s., 1H), 8.65
(s, 1H), 8.50 (s, 1H), 8.16 (br. s., 1H), 8.01-7.86 (m, 2H), 7.77
(s, 2H), 6.75 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 6.1 Hz, 1H), 4.77
(d, J = 6.1 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 4.06 (s, 3H), 3.67
(d, J = 4.9 Hz, 1H), 3.59-3.55 (m, 2H), 2.60 (s, 3H), 1.38 (dd, J =
12.1, 6.3 Hz, 6H). 572 ##STR01426## I-67 I-93 580.17 Ortho- gonal
HPLC method B Injection 2, 2.215 35- 100% 10 min, 100% 10 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80-9.39 (m, 1H), 8.66
(s, 1H), 8.51 (s, 1H), 8.19 (br. s., 1H), 7.97-7.87 (m, 2H), 7.78
(br. s., 2H), 6.77 (d, J = 8.5 Hz, 1H), 5.23 (br. s., 1H),
4.36-4.23 (m, 2H), 4.19 (d, J = 4.9 Hz, 2H), 4.06 (s, 3H), 3.68 (d,
J = 4.9 Hz, 1H), 3.59 (br. s., 1H), 2.60 (s, 3H), 1.40 (d, J = 6.4
Hz, 3H). 573 ##STR01427## I-72 I-99 644.18 Ortho- gonal HPLC method
B Injection 2, 2.541 45- 100% 15 min, 100% 10 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.65 (br. s., 1H), 8.67 (s, 1H), 8.52
(s, 1H), 8.20 (br. s., 1H), 8.02-7.88 (m, 2H), 7.79 (br. s., 2H),
6.86 d, J = 8.2 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.78 (d, J = 4.0
Hz, 1H), 4.51 (t, J = 13.4 Hz, 2H), 4.06 (s, 3H), 3.78-3.65 (m,
2H), 2.61 (s, 3H), 1.38 (dd, J = 11.0, 6.4 Hz, 6H). 574
##STR01428## I-67 I-99 630.16 Ortho- gonal HPLC method B Injection
2, 2.460 35- 100% 15 min, 100% 10 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.85-9.51 (m, 1H), 8.61 (s, 1H), 8.46 (s,
1H), 8.20 (br. s., 1H), 7.93-7.68 (m, 4H), 6.86 (d, J = 8.9 Hz,
1H), 5.22 (br. s., 1H), 4.51 (t, J = 13.4 Hz, 2H), 4.37-4.18 (m,
2H), 4.04 (s, 3H), 3.75-3.73 (m, 2H), 2.56 (s, 3H), 1.39 (d, J =
6.4 Hz, 3H). 575 ##STR01429## I-72 I-101 623.2 Ortho- gonal HPLC
method B Injection 2, 2.418 40- 80% 30 min, 100% 6 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.72 (br. s., 1H), 8.61 (s, 1H),
8.53 (br. s., 2H), 8.46 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.86 (d,
J = 11.3 Hz, 1H), 7.73 (s, 1H), 5.02 (d, J = 6.4 Hz, 1H), 4.73 (d,
J = 4.0 Hz, 1H), 4.63 (s, 1H), 4.00 (s, 3H), 3.95-3.89 (m, 2H),
2.54 (s, 3H), 1.38- 1.26 (m, 6H), 1.10 (s, 6H). 576 ##STR01430##
I-67 I-101 609.19 Ortho- gonal HPLC method B Injection 2, 2.340 50-
83% 20 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.68 (s, 1H), 8.62 (br. s., 2H), 8.52 (s, 1H), 8.00-7.90 (m, 2H),
7.79 (s, 1H), 5.35-5.03 (m, 1H), 4.44-4.22 (m, 2H), 4.07 (s, 3H),
2.61 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.18 (s, 6H). 577
##STR01431## I-72 I-102 607.21 Ortho- gonal HPLC method B Injection
2, 2.366 40- 80% 25 min, 100% 6 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.14-9.80 (m, 1H), 8.84-8.76 (m, 2H),
8.75-8.71 (m, 1H), 8.61-8.55 (m, 1H), 8.08-8.03 (m, 1H), 7.99-7.93
(m, 1H), 7.87-7.83 (m,
1H), 5.19-5.03 (m, 1H), 4.91-4.73 (m, 1H), 4.13-4.06 (m, 3H),
2.66-2.59 (m, 3H), 1.45-1.32 (m, 6H), 1.11-1.04 (m, 6H). 578
##STR01432## I-72 I-103 609.19 Ortho- gonal HPLC method B Injection
2, 2.333 35- 100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.85-9.67 (m, 1H), 8.70 (d, J = 2.1 Hz, 1H),
8.62-8.51 (m, 3H), 8.06-7.90 (m, 2H), 7.81 (s, 1H), 5.16-5.04 (m, J
= 6.7 Hz, 1H), 4.90 (br. s., 1H), 4.84-4.73 (m, J = 6.1, 2.4 Hz,
1H), 4.07 (s, 4H), 4.04-3.83 (m, 2H), 3.44-3.34 (m, 3H), 2.62 (s,
3H), 1.38 (t, J = 6.1 Hz, 6H), 1.10 (d, J = 6.4 Hz, 3H). 579
##STR01433## I-91 I-98 598.13 Ortho- gonal HPLC method B Injection
2, 2.232 45- 90% 20 min, 100% 7 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.11-9.73 (m, 1H), 8.88 (br. s., 1H), 8.76
(br. s., 2H), 8.64 (br. s., 1H), 8.20 (br. s., 1H), 8.06 (d, J =
7.3 Hz, 1H), 8.01- 7.90 (m, 2H), 5.20-5.04 (m, 1H), 4.87-4.73 (m,
1H), 4.00 (br. s., 3H), 3.83-3.65 (m, 2H), 2.97-2.84 (m, 2H),
1.47-1.35 (m, 6H). 580 ##STR01434## I-80 I-103 623.21 Ortho- gonal
HPLC method B Injection 2, 2.466 50- 100% 10 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.79 (br. s., 1H),
8.76-8.32 (m, 4H), 8.05-7.88 (m, 2H), 7.78 (s, 1H), 5.18-5.03 (m,
1H), 4.87-4.73 (m, 1H), 4.52 (q, J = 7.0 Hz, 2H), 4.14-3.76 (m,
3H), 2.61 (s, 3H), 1.52-1.33 (m, 10H), 1.11 (d, J = 6.1 Hz, 3H).
581 ##STR01435## I-72 I-104 609.1 Ortho- gonal HPLC method B
Injection 2, 2.35 50- 100% 22 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.79 (br. s., 1H), 8.76-8.45 (m, 4H), 8.03
(d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.82 (s, 1H),
5.17-5.06 (m, J = 4.0 Hz, 1H), 4.86-4.74 (m, J = 3.4 Hz, 1H),
4.17-4.05 (m, 4H), 4.04-3.86 (m, 2H), 2.63 (s, 3H), 1.45-1.35 (m,
6H), 1.12 (d, J = 6.1 Hz, 3H). 582 ##STR01436## I-80 I-104 623.0
Ortho- gonal HPLC method B Injection 2, 2.51 45- 90% 22 min, 100% 5
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80 (br. s., 1H),
8.74-8.43 (m, 4H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz,
1H), 7.79 (s, 1H), 5.17-5.05 (m, J = 6.1 Hz, 1H), 4.88-4.73 (m,
1H), 4.54 (q, J = 6.9 Hz, 2H), 4.18- 3.86 (m, 3H), 2.62 (s, 3H),
1.45 (t, J = 7.0 Hz, 3H), 1.40-1.36 (m, J = 6.7 Hz, 6H), 1.12 (d, J
= 6.1 Hz, 3H). 583 ##STR01437## I-80 I-114 639.2 Ortho- gonal HPLC
method B Injection 2, 2.402 45- 90% 22 min, 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.93-9.60 (m, 1H), 8.68 (s, 1H),
8.62 (br. s., 2H), 8.55 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (d,
J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.10 (dd, J = 6.6, 2.6 Hz, 1H),
4.80 (dd, J = 6.4, 2.7 Hz, 1H), 4.66 (s, 1H), 4.53 (q, J = 7.0 Hz,
2H), 4.26 (dd, J = 11.0, 4.3 Hz, 1H), 4.13 (dd, J = 10.8, 6.6 Hz,
1H), 3.79 (d, J = 4.9 Hz, 1H), 3.43 (t, J = 5.6 Hz, 1H), 3.39-3.28
(m, 1H), 2.62 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.42-1.36 (m, 6H).
584 ##STR01438## 612 I-98 579.2 Ortho- gonal HPLC method B
Injection 2, 2.24 45- 90% 22 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.03 (br. s., 1H), 8.79 (br. s., 2H), 8.73
(s, 1H), 8.57 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6
Hz, 1H), 7.70 (dd, J = 6.9, 2.3 Hz, 2H), 5.19-5.05 (m, 1H),
4.79-4.68 (m, 1H), 4.61 (t, J = 5.5 Hz, 1H), 4.09 (s, 3H), 3.81 (q,
J = 6.2 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H), 2.63 (s, 3H), 1.45-1.45
(m, 1H), 1.39 (dd, J = 11.9, 6.4 Hz, 6H). 585 ##STR01439## I-72
I-113 625.3 Ortho- gonal HPLC method B Injection 2, 2.25 45- 90% 18
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.82
(br. s., 1H), 8.71 (s, 1H), 8.62 (br. s., 2H), 8.56 (s, 1H), 8.03
(d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.11
(dd, J = 6.4, 2.7 Hz, 1H), 4.81 (dd, J = 6.1, 2.7 Hz, 1H),
4.29-4.23 (m, 1H), 4.14 (ddd, J = 10.5, 6.6, 3.7 Hz, 1H), 4.08 (s,
3H), 3.84-3.71 (m, 1H), 3.46-3.40 (m, 1H), 3.52-3.13 (m, 2H), 2.63
(s, 3H), 1.46-1.21 (m, 6H). 586 ##STR01440## I-69 I-98 600.1 Ortho-
gonal HPLC method B Injection 2, 2.24 50- 100% 20 min, 100% 5 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.07 (br. s., 1H),
8.78 (br. s., 2H), 8.67 (s, 1H), 8.52 (s, 1H), 7.96 (d, J = 7.6 Hz,
1H), 7.79 (s, 1H), 5.36-5.17 (m, J = 2.7 Hz, 1H), 4.44-4.36 (m,
1H), 4.33-4.27 (m, J = 10.8, 6.0 Hz, 1H), 4.08 (s, 3H), 3.87-3.74
(m, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.63 (s, 3H), 1.44 (d, J = 6.4
Hz, 3H). 587 ##STR01441## I-72 I-114 625.0 Ortho- gonal HPLC method
B Injection 2, 2.17 45- 90% 18 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.81 (br. s., 1H), 8.71 (s, 1H), 8.62
(br. s., 2H), 8.55 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J =
11.3 Hz, 1H), 7.81 (s, 1H), 5.10 (dd, J = 6.4, 2.4 Hz, 1H), 4.96
(d, J = 5.2 Hz, 1H), 4.85-4.74 (m, 1H), 4.68 (t, J = 5.5 Hz, 1H),
4.26 (dd, J = 11.0, 4.0 Hz, 1H), 4.13 (dd, J = 10.8, 6.6 Hz, 1H),
3.84-3.74 (m, 1H), 3.68-3.54 (m, 1H), 3.46-3.31 (m, 1H), 2.63 (s,
3H), 1.46-1.17 (m, 6H). 588 ##STR01442## I-80 I-113 639.1 Ortho-
gonal HPLC method B Injection 2, 2.337 55- 90% 25 min, 100% 4 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.82 (br. s., 1H), 8.70
(s, 1H), 8.62 (br. s., 2H), 8.57 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H),
7.96 (d, J = 11.6 Hz, 1H), 7.81 (s, 1H), 5.10 (d, J = 6.7 Hz, 1H),
4.95 (d, J = 5.2 Hz, 1H), 4.80 (br. s., 1H), 4.66 (t, J = 5.6 Hz,
1H), 4.54 (q, J = 7.0 Hz, 2H), 4.32-4.23 (m, 1H), 4.19-4.10 (m,
1H), 3.83-3.68 (m, 1H), 3.43 (t, J = 5.6 Hz, 1H), 3.39- 3.31 (m,
1H), 2.63 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.42-1.36 (m, 6H). 589
##STR01443## I-69 -- 569.05 Ortho- gonal HPLC method B Injection 2,
2.218 45- 85% 22 min, 100% 7 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.74 (br. s., 2H), 8.66 (s, 1H), 8.51 (s,
1H), 7.95 (d, J = 7.32 Hz, 1H), 7.78 (s, 1H), 5.25 (br. s., 1H),
4.35-4.46 (m, 1H), 4.22-4.32 (m, 1H), 4.06 (s, 3H), 2.62 (s, 3H),
2.52 (s, 3H), 1.42 (d, J = 6.41 Hz, 3H). 590 ##STR01444## I-69 --
569.05 Ortho- gonal HPLC method B Injection 2, 2.229 40- 100% 20
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.15
(br. s., 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.20 (d, J = 4.27 Hz,
1H), 7.97 (d, J = 7.32 Hz, 1H), 7.81 (s, 1H), 7.71 (d, J = 7.93 Hz,
1H), 6.98-7.25 (m, 1H), 5.24 (br. s., 1H), 4.36 (br. s., 1H), 4.27
(br. s., 1H), 4.06 (s, 3H), 2.63 (s, 3H), 2.37 (s, 3H), 1.39 (d, J
= 6.41 Hz, 3H. 591 ##STR01445## I-69 -- 555.10 Ortho- gonal HPLC
method B Injection 2, 2.452 30- 90% 21 min, 100% 5 min .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.05-10.37 (m, 1H), 8.88 (s, 2H),
8.84 (s, 1H), 8.72 (s, 1H), 8.56 (d, J = 1.38 Hz, 1H), 8.01 (d, J =
7.70 Hz, 1H), 7.83 (s, 1H), 5.29 (dd, J = 3.03, 6.33 Hz, 1H), 4.41
(dd, J = 3.03, 10.73 Hz, 1H), 4.31 (dd, J = 5.91, 10.87 Hz, 1H),
4.07-4.11 (m, 3H), 2.64 (s, 4H), 1.44 (d, J = 6.60 Hz, 4H). 592
##STR01446## I-67 -- 534.2 Ortho- gonal HPLC method B Injection 2,
2.063 40- 80% 22 min, 100% 10 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.84 (br. s., 1H), 8.70 (s, 1H), 8.55-8.42
(m, 2H), 8.01-7.91 (m, 2H), 7.82-7.67 (m, 2H), 7.16 (d, J = 8.2 Hz,
1H), 5.36- 5.02 (m, 1H), 4.41-4.17 (m, 2H), 4.06 (s, 3H), 2.60 (s,
3H), 2.40-2.23 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H). 593 ##STR01447##
I-80 I-117 634.9 Ortho- gonal HPLC method B Injection 2, 2.63 60-
100% 15 min, 100% 10 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.92 (br. s., 1H), 8.70 (br. s., 2H), 8.61 (s, 1H), 8.49
(s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 11.6 Hz, 1H), 7.75
(s, 1H), 5.18-5.02 (m, J = 6.6, 2.6 Hz, 1H), 4.87-4.71 (m, J = 4.0
Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 3.54 (s, 2H), 3.03 (t, J = 7.0
Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.53- 1.12 (m,
9H). 594 ##STR01448## 612 -- 533.9 Ortho- gonal HPLC method B
Injection 2, 2.15 45- 90% 22 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.03 (br. s., 1H), 8.75 (s, 1H), 8.69 (br.
s., 1H), 8.59 (s, 1H), 8.26 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 8.2
Hz, 1H), 7.97 (d, J = 11.6 Hz, 2H), 7.84 (s, 1H), 7.44-7.33 (m,
1H), 5.18- 4.96 (m, 1H), 4.79-4.64 (m, 1H), 4.10 (s, 3H), 2.56 (s,
3H), 1.39 (dd, J = 12.8, 6.4 Hz, 6H). 595 ##STR01449## 612 -- 549.0
Ortho- gonal HPLC method B Injection 2, 2.40 50- 100% 20 min, 100%
5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.02 (br. s.,
1H), 8.90-8.68 (m, 3H), 8.56 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H),
7.95 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.27-4.96 (m, 1H),
4.81-4.55 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 2.56 (s, 3H), 1.39
(dd, J = 11.9, 6.4 Hz, 6H). 596 ##STR01450## I-69 I-385A 584.1
Ortho- gonal HPLC method B Injection 2, 2.13 35- 68% 25 min 100% 7
min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.88 (br. s., 1H),
8.34-8.65 (m, 3H), 7.82-7.98 (m, 2H), 7.73 (s, 1H), 7.37 (d, J =
8.54 Hz, 1H), 5.16-5.33 (m, 1H), 4.47 (br. s., 2H), 4.20-4.38 (m,
2H), 4.04 (s, 3H), 2.59 (s, 3H), 1.41 (d, J = 6.71 Hz, 3H). 597
##STR01451## I-67 I-115 564.2 Ortho- gonal HPLC method B Injection
2, 2.25 25- 100% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.44 (br. s., 1H), 8.72 (s, 1H), 8.56 (s,
1H), 8.37 (br. s., 1H), 7.96 (d, J = 11.0 Hz, 2H), 7.82 (s, 1H),
5.29-5.07 (m, 1H), 4.32 (br. s., 2H), 4.07 (s, 3H), 3.05 (br. s.,
6H), 2.62 (s, 3H), 1.38 (d, J = 5.8 Hz, 3H). 598 ##STR01452## I-72
I-115 578.2 Ortho- gonal HPLC method B Injection 2, 2.308 40- 80%
15 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34
(br. s., 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.33 (br. s., 2H),
8.07-7.87 (m, 2H), 7.78 (s, 1H), 5.03 (d, J = 4.3 Hz, 1H), 4.76
(br. s., 1H), 4.05 (s, 3H), 3.02 (s, 6H), 2.59 (s, 3H), 1.43-1.27
(m, 6H). 599 ##STR01453## I-72 -- 577.20 Ortho- gonal HPLC method B
Injection 2, 2.762 70- 100% 12 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.32 (br. s., 1H), 8.69 (s, 1H), 8.53
(s, 1H), 8.11 (br. s., 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.93 (d, J =
11.6 Hz, 1H), 7.79 (s, 1H), 7.57 (br. s., 1H), 6.58 (d, J = 8.5 Hz,
1H), 5.04 (d, J = 4.3 Hz, 1H), 4.75 (br. s., 1H), 4.06 (s, 3H),
2.93 (s, 6H), 2.60 (s, 3H), 1.36 (dd, J = 13.4, 5.8 Hz, 6H). 600
##STR01454## I-72 -- 619.15 Ortho- gonal HPLC method B Injection 2,
2.41 50- 100% 10 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.78 (br. s., 1H), 8.68 (s, 1H), 8.53 (s,
1H), 8.37 (br. s., 1H), 8.06-7.83 (m, 4H), 7.79 (s, 1H), 5.08 (dd,
J = 6.6, 2.6 Hz, 1H), 4.80 (dd, J = 6.3, 2.6 Hz, 1H), 4.51-4.30 (m,
2H), 4.12- 3.97 (m, 5H), 2.60 (s, 3H), 1.38 (t, J = 6.9 Hz, 6H).
601 ##STR01455## I-72 -- 591.20 Ortho- gonal HPLC method B
Injection 2, 2.104 50- 100% 12 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.35 (s, 1H), 9.75 (br. s., 1H), 8.67
(s, 1H), 8.53 (s, 1H), 8.35 (br. s., 1H), 8.09-7.89 (m, 2H), 7.79
(s, 1H), 5.08 (dd, J = 6.4, 2.4 Hz, 1H), 4.79 (dd, J = 6.1, 2.7 Hz,
1H), 4.06 (s, 3H), 2.60 (s, 3H), 2.03 (s, 3H), 1.38 (t, J = 6.6 Hz,
6H). 602 ##STR01456## I-72 -- 549.20 Ortho- gonal HPLC method B
Injection 2, 2.034 45- 90% 25 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.25 (br. s., 1H), 8.70 (s, 1H), 8.54 (s,
1H), 8.01 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.3 Hz, 2H), 7.80 (s,
1H), 7.43 (br. s., 1H), 6.40 (d, J = 8.5 Hz, 1H), 5.03 (d, J = 4.0
Hz, 1H), 4.73 (br. s., 1H), 4.06 (s, 3H), 2.61 (s, 3H), 1.44-1.30
(m, 6H). 603 ##STR01457## I-72 -- 619.21 Ortho- gonal HPLC method B
Injection 2, 2.267 30- 100% 15 min, 100% 5 min .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.51-9.30 (m, 1H), 8.77-8.72 (m, 1H),
8.63-8.52 (m, 1H), 8.25-8.13 (m, 1H), 8.07-8.01 (m, 1H), 8.00-7.93
(m, 1H), 7.88-7.82 (m, 1H), 7.73-7.58 (m, 1H), 6.90-6.70 (m, 1H),
5.13-4.99 (m, 1H), 4.86-4.59 (m, 1H), 4.09 (s, 3H), 3.75-3.61 (m,
8H), 2.64 (s, 3H), 1.42-1.31 (m, 6H). 604 ##STR01458## I-72 --
706.05 Ortho- gonal HPLC method B Injection 2, 2.525 30- 70% 20
min, 100% 5 min .sup.1H NMR (400MHz, DMSO-d.sub.6) .delta. 11.06
(br. s., 1H), 10.12-9.78 (m, 1H), 8.79 (br. s., 2H), 8.72 (s, 1H),
8.58 (d, J = 1.8 Hz, 1H), 8.19 (dd, J = 7.3, 2.2 Hz, 1H), 8.06 (d,
J = 8.1 Hz, 1H), 8.03-7.92 (m, 2H), 7.87-7.76 (m, 1H), 7.57 (t, J =
9.0 Hz, 1H), 5.14 (dd, J = 6.6, 2.6 Hz, 1H), 4.86 (dd, J = 6.4, 2.6
Hz, 1H), 4.15-4.02 (m, 3H), 2.64 (s, 3H), 1.51-1.37 (m, 6H). 605
##STR01459## I-72 -- 602.55 Ortho- gonal HPLC method B Injection 2,
2.196 40- 80% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.25 (br. s., 1H), 8.68 (s, 1H), 8.53 (s,
1H), 8.11-7.88 (m, 4H), 7.78 (s, 1H), 7.53 (br. s., 1H), 6.35 (br.
s., 1H), 5.03 (d, J = 4.3 Hz, 1H), 4.75 (br. s., 1H), 4.11-4.02 (m,
3H), 3.27 (br. s., 2H), 2.60 (s, 3H), 1.88 (br. s., 4H), 1.36 (dd,
J = 14.5, 5.3 Hz, 8H). 606 ##STR01460## I-72 -- 622.0 Ortho- gonal
HPLC method B Injection 2, 2.219 30- 70% 20 min, 100% 5 min .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (br. s., 1H), 8.67 (s,
1H), 8.52 (s, 1H), 8.27 (br. s., 2H), 8.03-7.88 (m, 2H), 7.78 (s,
1H), 5.03 (d, J = 6.4 Hz, 1H), 4.75 (br. s., 1H), 4.05 (s, 3H),
3.22 (d, J = 5.8 Hz, 2H), 2.60 (s, 3H), 1.47-1.24 (m, 6H), 1.06 (s,
6H). 607 ##STR01461## I-72 I-116 642.16 Ortho- gonal HPLC method B
Injection 2, 2.517 30- 70% 20 min, 100% 5 min .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 8.76-8.61 (m, 2H), 8.56-8.45 (m, 2H),
7.79-7.68 (m, 3H), 5.18-5.05 (m, 1H), 4.12 (s, 3H), 3.36 (d, J =
1.5 Hz, 6H), 2.63 (s, 3H), 1.45 (d, J = 6.4 Hz, 6H). 608
##STR01462## I-72 -- 620.12 Ortho- gonal HPLC method B Injection 2,
2.438 40- 80% 20 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.46 (br. s., 1H), 8.69 (s, 1H), 8.54 (s,
1H), 8.40 (br. s., 2H), 8.07-7.89 (m, 2H), 7.80 (s, 1H), 5.04 (d, J
= 4.9 Hz, 1H), 4.79 (br. s., 1H), 4.06 (s, 4H), 3.68- 3.50 (m, 8H),
2.61 (s, 3H), 1.75-1.75 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H). 609
##STR01463## I-67 -- 605.16 Ortho- gonal HPLC method B Injection 2,
2.362 20- 100% 15 min, 100% 5 min .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.88 (br. s., 1H), 8.67 (s, 1H), 8.51 (s,
1H), 8.41 (br. s., 1H), 8.01-7.86 (m, 4H), 7.78 (s, 1H), 5.25 (br.
s., 1H), 4.55-4.19 (m, 4H), 4.16-3.99 (m, 5H), 3.62- 3.52 (m, 3H),
2.60 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H). 610 ##STR01464## I-67 --
577.17 Ortho- gonal HPLC method B Injection 2, 2.056 20- 100% 20
min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.36
(s, 1H), 8.72 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.38 (br. s., 1H),
8.06-7.91 (m, 3H), 7.87-7.78 (m, 2H), 5.24 (td, J = 6.3, 3.4 Hz,
1H), 4.43-4.22 (m, 2H), 4.08 (s, 3H), 3.90 (s, 3H), 1.42 (d, J =
6.3 Hz, 3H).
611 ##STR01465## I-67 I-119 550.20 2.155 45- 95% 13 min, 100% 6 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.96-9.57 (m, 1H), 8.75
(s, 1H), 8.62-8.49 (m, 2H), 8.10- 7.94 (m, 2H), 7.84 (s, 1H),
7.81-7.74 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.32-5.15 (m, 1H),
4.67-4.53 (m, 1H), 4.41-4.23 (m, 2H), 4.13-4.05 (m, 3H), 3.69 (t, J
= 6.9 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.66-2.59 (m, 3H), 1.42
(d, J = 6.6 Hz, 3H).
Example 612
(2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol--
6-yl)oxy)butan-2-ol
##STR01466##
[3367] This intermediate was prepared from (2R,3S)-butane-2,3-diol
using the same synthetic sequence as described for Intermediate
I-72. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 414.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.70-8.62
(m, 1H), 8.58 (s, 1H), 7.90-7.83 (m, 1H), 7.82-7.77 (m, 1H),
7.60-7.45 (m, 1H), 4.36-4.19 (m, 1H), 4.16 (s, 3H), 4.05-3.87 (m,
1H), 2.68 (s, 3H), 2.65-2.58 (m, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.34
(d, J=6.4 Hz, 3H).
Example 613
(2R,3S)-3-((2-(2-carbamoyl-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazo-
l-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01467##
[3369] Intermediate I-75 was dissolved in a 7 M ammonia solution in
MeOH (2 mL, 92 mmol) and the resulting mixture stirred for 12 h at
65.degree. C. The reaction mixture was then concentrated and
purified by reverse phase HPLC (Method D, 30-70% 20 min, 100% 5
min) to yield Example 613 (8.4 mg, 0.014 mmol, 74% yield). LC-MS:
Method H, RT=0.99 min, MS (ESI) m/z: 562.20 (M+H).sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.52 (s, 1H), 8.87 (s, 1H),
8.73 (br. s., 2H), 8.44 (s, 1H), 8.19-7.73 (m, 4H), 5.12 (dd,
J=6.4, 2.4 Hz, 1H), 4.83 (dd, J=6.3, 2.6 Hz, 1H), 3.48-3.26 (m,
2H), 2.71 (s, 3H), 1.41 (t, J=6.4 Hz, 7H).
Example 614
(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[-
d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01468##
[3371] Example 614 was prepared from methylamine (33% in EtOH)
using the method described for Example 613. LC-MS: Method H,
RT=0.99 min, MS (ESI) m/z: 576.18 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.48 (s, 1H), 9.07 (d, J=4.9 Hz, 1H),
8.83 (s, 1H), 8.73 (br. s., 2H), 8.11-8.01 (m, 2H), 7.94 (d, J=11.6
Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.3 Hz, 1H), 2.98-2.90
(m, 3H), 2.70 (s, 3H), 2.52 (br. s., 3H), 1.40 (t, J=6.9 Hz,
6H).
Example 615
(2R,3S)-3-((2-(2-(dimethylcarbamoyl)-7-methylquinoxalin-5-yl)-5-fluorobenz-
o[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR01469##
[3373] Example 615 was prepared from dimethylamine (2M in THF)
using the method as described for Example 613. LC-MS: Method H,
RT=0.99 min, MS (ESI) m/z: 590.20 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.96 (br. s., 1H), 9.19 (s, 1H), 8.84
(s, 1H), 8.72 (br. s., 2H), 8.09-8.03 (m, 2H), 7.96 (d, J=11.3 Hz,
1H), 5.12 (d, J=6.1 Hz, 1H), 4.82 (d, J=5.5 Hz, 1H), 3.26-3.07 (m,
6H), 2.69 (s, 3H), 1.40 (t, J=6.4 Hz, 6H).
Example 616
(2R,3S)-3-((5-fluoro-2-(2-((2-hydroxyethyl)carbamoyl)-7-methylquinoxalin-5-
-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR01470##
[3375] Example 616 was prepared from 2-aminoethanol using the same
method as described for Example 613. LC-MS: Method H, RT=1.09 min,
MS (ESI) m/z: 606.0 (M+H).sup.+.
Preparation of Alcohol Examples
[3376] The alcohols in the accompanying table were prepared
according to the following three general procedures.
[3377] Primary Alcohols
[3378] The appropriately substituted hetero-aryl ester was
subjected to conditions described in Procedure G. Purification by
Prep HPLC (Method D) afforded the desired example.
[3379] Secondary Alcohols
[3380] The appropriately substituted hetero-aryl aldehyde was
subjected to conditions described in Procedure H. Purification by
Prep HPLC (Method D) afforded the desired example.
[3381] Tertiary Alcohols
[3382] The appropriately substituted hetero-aryl ester was
subjected to conditions described in Procedure H. Purification by
Prep HPLC (Method D) afforded the desired example.
TABLE-US-00016 Orthog- onal HPLC HPLC Ester/ LCMS method B Prep Ex.
Alde- [M + H].sup.+ Injection Method No. Structure hyde m/z 2 D NMR
617 ##STR01471## I-118 564.0 2.037 45-90% 20 min, 100% 7 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.89 (br. s., 1H), 8.72
(s, 1H), 8.56 (s, 1H), 8.51 (br. s., 1H), 8.15 (s, 1H), 8.04 (d, J
= 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.89 (br. s., 1H), 7.82
(s, 1H), 5.33 (t, J = 5.6 Hz, 1H), 5.19-5.03 (m, J = 6.6, 2.6 Hz,
1H), 4.83- 4.73 (m, 1H), 4.49 (d, J = 5.5 Hz, 2H), 4.09 (s, 3H),
2.63 (s, 3H), 1.41 (t, J = 6.3 Hz, 6H) 618 ##STR01472## I-74 592.1
2.126 45-90% 12 min, 100% 5 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.82 (br. s., 1H), 8.69 (s, 1H), 8.56-8.48 (m, 2H), 8.02
(d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.83 (br. s., 1H),
7.79 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H),
4.79 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H), 1.43-1.37 (m,
12H) 619 ##STR01473## I-85 564.1 2.092 55-85% 25 min, 85% 4 min
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.18 (s, 1H), 8.71 (s,
1H), 8.56 (s, 1H), 8.27 (d, J = 5.5 Hz, 1H), 8.04 (d, J = 8.2 Hz,
1H), 7.96 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.34
(d, J = 4.0 Hz, 1H), 5.14 (dd, J = 6.4, 2.7 Hz, 1H), 4.80 (dd, J =
6.4, 2.7 Hz, 1H), 4.49 (d, J = 4.6 Hz, 2H), 4.08 (s, 3H), 2.63 (s,
3H), 1.41 (t, J = 6.0 Hz, 6H) 620 ##STR01474## I-120 579.2 2.384
45-90% 20 min, 100% 7 min .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.04 (br. s., 1H), 8.83 (br. s., 2H), 8.72 (s, 1H), 8.56
(s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.82
(s, 1H), 5.14 (d, J = 5.2 Hz, 1H), 4.82 (d, J = 3.7 Hz, 1H),
4.76-4.66 (m, 1H), 4.09 (s, 3H), 3.40-3.37 (m, 1H), 2.63 (s, 3H),
1.41 (dd, J = 6.0, 4.1 Hz, 6H), 1.36 (d, J = 6.4 Hz, 3H)
Example 621
2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-6-yl)oxy)ethyl isothiazol-5-ylcarbamate
##STR01475##
[3384] Example 318 (12 mg, 0.029 mmol), isothiazole-5-carboxylic
acid (7.38 mg, 0.057 mmol) and triethylamine (7.97 .mu.l, 0.057
mmol) were suspended in toluene (1 mL) in a pressure rated 1 dram
vial. Diphenylphosphoryl azide (15.73 mg, 0.057 mmol) was added to
the mixture which was heated to 110.degree. C. for 3 hours. The
crude reaction mixture was purified by reverse phase HPLC (Method
D, 65-100% 20 min, 100% 5 min) to yield Example 621 (1.3 mg, 2.38
mmol, 8% yield). LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 546.10
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (s,
1H), 8.62 (s, 1H), 8.21 (s, 1H), 8.02-8.12 (m, 1H), 7.88 (s, 1H),
6.81 (s, 1H), 4.61-4.69 (m, 2H), 4.46-4.56 (m, 2H), 4.10 (s, 3H),
3.19 (s, 3H).
Example 622
(R)-5-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-6-yl)oxy)methyl)oxazolidin-2-one
##STR01476##
[3385] Intermediate 622A: (R)-5-(chloromethyl)oxazolidin-2-one
##STR01477##
[3387] (R)-2-(chloromethyl)oxirane (285 mg, 3.08 mmol), potassium
cyanate (500 mg, 6.16 mmol) and magnesium sulfate (742 mg, 6.16
mmol) were dissolved in water (10 mL) and the mixture was heated to
100.degree. C. under a reflux condenser for 18 h. The reaction
mixture was then diluted with water and extracted with EtOAc
(3.times.). The combined organic layer was washed with brine, dried
with sodium sulfate, filtered and concentrated to yield
Intermediate 622A (210 mg, 1.549 mmol, 50.3% yield). The product
was brought forward without further purification. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.81 (br. s., 1H), 4.98-4.75 (m, 1H),
3.84-3.65 (m, 3H), 3.57 (ddd, J=9.0, 5.9, 1.0 Hz, 1H).
Example 622
[3388] Intermediate I-65 (30 mg, 0.080 mmol) was dissolved in DMF
(2 mL) along with potassium carbonate (33.1 mg, 0.239 mmol),
Intermediate 622A (21.64 mg, 0.160 mmol) and potassium iodide
(13.25 mg, 0.080 mmol). The reaction mixture was then stirred at
80.degree. C. for 18 h before being diluted with EtOAc. The organic
layer was washed with 10% aq. LiCl (3.times.), brine, dried with
sodium sulfate, filtered, and concentrated. The crude residue was
purified by reverse phase HPLC (Method D, 30-75% 30 min, 100% 5
min) to yield Example 622 (4 mg, 8.00 .mu.mol, 10.02% yield).
LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 475.05 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.60 (s,
1H), 7.99-8.08 (m, 1H), 7.87 (s, 1H), 7.59-7.69 (m, 1H), 4.93-5.09
(m, 1H), 4.27-4.49 (m, 2H), 4.09 (s, 3H), 3.48-3.72 (m, 1H),
3.36-3.45 (m, 1H), 2.65 (s, 3H).
Example 623
4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazo-
l-6-yl)oxy)methyl)oxazol-2-amine
##STR01478##
[3389] Intermediate 623A:
1-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-one
##STR01479##
[3391] 1-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-ol (500 mg,
1.857 mmol) was dissolved in DCM (10 mL). Dess-Martin Periodinane
(1181 mg, 2.79 mmol) was added to the reaction mixture which
stirred at room temperature for 2 hours. The reaction mixture was
concentrated and the resulting residue was dissolved in a small
amount of methylene chloride before being charged to a 12 g silica
gel cartridge which was eluted with a 15 min gradient from 0-100%
EtOAc in hexane. Fractions containing the desired product were
collected and concentrated to yield Intermediate 623A (300 mg,
1.123 mmol, 60.5% yield) as a clear oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.25 (s, 2H), 3.94-4.05 (m, 2H), 0.75-0.89 (m,
9H), -0.10-0.09 (m, 6H).
Example 623
[3392] Intermediate 623A (20 mg, 0.053 mmol) was dissolved in DMF
(2 mL). Potassium carbonate (22.07 mg, 0.160 mmol) was added to the
mixture followed by I-65 (20 mg, 0.053 mmol). The reaction mixture
was stirred for 1 h at room temperature after which additional
Intermediate 623A (20 mg, 0.053 mmol) was added to the mixture. The
reaction mixture was allowed to stir for 2 hours at room
temperature and then quenched with a few drops of AcOH. The mixture
was diluted with EtOAc and the organic layer was washed with 10%
aq. LiCl (3.times.), brine, dried with sodium sulfate, filtered and
concentrated. The resulting residue was dissolved in THF (5
mL)/water (0.500 mL)/acetic acid (0.500 mL). 1M TBAF in THF (0.064
mL, 0.064 mmol) was added to the mixture which was allowed to stir
for 1 hour at room temperature after which additional 1M TBAF in
THF (0.064 mL, 0.064 mmol) was added. The mixture was then diluted
1.5 M dipotassium phosphate solution and extracted with EtOAc
(3.times.). The combined organic layer was washed with brine, dried
with sodium sulfate, filtered and concentrated. The resulting
residue was dissolved in THF (1 mL) along with cyanamide (21.59 mg,
0.514 mmol), 1N aqueous sodium acetate (0.051 mL, 0.051 mmol),
tetrabutylammonium hydroxide (13.33 mg, 0.051 mmol) and 1M aq. NaOH
(0.051 mL, 0.051 mmol). The reaction mixture was allowed to stir at
room temperature for 3 h then a few drops of AcOH added and the
reaction mixture was concentrated and purified by reverse phase
HPLC (Method D, 40-73% 22 min, 100% 7 min) to yield Example 623
(0.6 mg, 0.001 mmol, 2% yield) over the three step sequence. LC-MS:
Method H, RT=1.05 min, MS (ESI) m/z: 472.10 (M+H).sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.61 (s, 1H),
8.10-8.14 (m, 1H), 7.81-7.90 (m, 1H), 7.56 (s, 1H), 6.66 (s, 2H),
5.02 (s, 2H), 4.10 (s, 3H), 2.66 (s, 3H).
Example 624
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-
-yl)oxy)butan-2-yl
(2-(2-(phosphonooxy)ethyl)pyrimidin-5-yl)carbamate
##STR01480##
[3393] Intermediate 624A:
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl
(2-(2-((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)ethyl)
pyrimidin-5-yl)carbamate
##STR01481##
[3395] To a suspension of Example 566 (313 mg, 0.528 mmol) in DCM
(40 mL) was added bis(2-(trimethylsilyl)ethyl)
diisopropylphosphoramidite (0.7 mL, 1.704 mmol) followed by
1H-tetrazole (137 mg, 1.956 mmol) and the resulting mixture was
stirred for 30 minutes at room temperature. The reaction mixture
was then cooled to 0.degree. C. and hydrogen peroxide (35% wt. in
H.sub.2O) (0.3 mL, 3.43 mmol) was added dropwise over 2 minutes.
After stirring for 30 minutes at rt, the reaction mixture was
diluted with 30 mL of DCM and the organic layer was washed with
saturated aqueous sodium sulfite (2.times.), brine (1.times.),
dried with sodium sulfate, filtered and concentrated. The resulting
residue was dissolved in a small amount of DCM and purified by
silica gel chromatography (gradient of 0-100% EtOAc/DCM). The
fractions containing desired product were concentrated to yield
Intermediate 624A (349 mg, 0.4 mmol, 76% yield). LC-MS: Method H,
MS (ESI) m/z: 873.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.79 (br. s., 2H), 8.53 (d, J=2.0 Hz, 1H), 8.46 (s, 1H),
7.77 (d, J=11.4 Hz, 1H), 7.69 (dd, J=2.0, 0.9 Hz, 1H), 7.49 (d,
J=7.7 Hz, 1H), 7.39-7.30 (m, 1H), 5.21-4.99 (m, 1H), 4.60-4.44 (m,
5H), 4.16-3.98 (m, 4H), 3.28 (t, J=6.8 Hz, 2H), 1.48 (t, J=7.0 Hz,
3H), 1.42 (dd, J=16.3, 6.4 Hz, 6H), 1.10-0.98 (m, J=8.6, 8.6, 0.7
Hz, 4H), 0.03-0.04 (m, 18H).
Example 624
[3396] Intermediate 624A (226 mg, 0.259 mmol) was dissolved in DCM
(10 mL). TFA (0.140 mL, 1.812 mmol) and water (0.033 mL, 1.812
mmol) were added to the solution which was stirred at room
temperature. After 5 minutes of stirring, additional TFA (0.140 mL,
1.812 mmol) was added dropwise and the reaction mixture was allowed
to stir for 50 minutes at room temperature. Concentration of the
reaction mixture followed by trituration from ether yielded a
particulate solid. The mother liquor was removed by filtration, and
the remaining solid was redissolved in dioxane and concentrated to
afford 624 in quantitative yield. LC-MS: Method H, RT=1.10 min, MS
(ESI) m/z: 673.2 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.03 (br. s., 1H), 8.78 (br. s., 2H), 8.68 (s, 1H), 8.54
(d, J=1.8 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.94 (d, J=11.7 Hz, 1H),
7.78 (dd, J=2.0, 0.9 Hz, 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.78
(dd, J=6.4, 2.9 Hz, 1H), 4.51 (q, J=7.0 Hz, 2H), 4.23 (q, J=6.8 Hz,
2H), 3.10 (t, J=6.7 Hz, 2H), 2.60 (s, 3H), 1.46-1.29 (m, 9H).
Example 625
2-(6-chloro-3-(methoxymethyl)quinolin-8-yl)-6-methoxy-4-methylbenzo[d]thia-
zole
##STR01482##
[3397] Intermediate 625A:
8-bromo-6-chloro-3-(methoxymethyl)quinoline
##STR01483##
[3399] Intermediate I-123 (33.5 mg, 0.143 mmol), 3-methoxypropanal
(13.8 mg, 0.157 mmol), and sodium methoxide (0.5 M in MeOH, 314
.mu.l, 0.157 mmol) were dissolved in MeOH (1.43 mL) and heated to
reflux. After 3 hours, the reaction mixture was diluted with
saturated NH.sub.4Cl and EtOAc. The layers were separated and the
organic layer was washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 24 g silica gel column, 19
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 625A (23.5 mg, 0.082 mmol, 57%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.99 (d, J=2.2 Hz, 1H),
8.09-8.07 (m, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H),
4.71 (s, 2H), 3.51 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI)
m/z: 286/288 (M+H).sup.+.
Intermediate 625B: (6-chloro-3-(methoxymethyl)quinolin-8-yl)boronic
acid
##STR01484##
[3401] Intermediate 625A (73.2 mg, 0.255 mmol),
bispinacolatodiboron (97 mg, 0.383 mmol), and potassium acetate
(62.7 mg, 0.639 mmol) were dissolved in 1,4-dioxane (2.56 mL) and
degassed for 5 minutes by bubbling with argon.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (16.7 mg, 0.020 mmol) was
added and the reaction degassed for an additional 10 minutes. The
reaction mixture was heated to 130.degree. C. in the microwave for
45 minutes. The reaction mixture was diluted with EtOAc and water.
The aqueous layer was further extracted twice with EtOAc. The
combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by preparative HPLC (Method A, 30-100% B in
15 minutes) to give Intermediate 625B (31.4 mg, 0.125 mmol, 49%)
was a brown solid: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z:
252.1 (M+H).sup.+.
Example 625
[3402] Intermediate 625B (10 mg, 0.040 mmol), Intermediate I-3
(12.32 mg, 0.048 mmol), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (1.95 mg, 2.39 .mu.mol) were dissolved in 1,4-dioxane (306
.mu.L) and Na.sub.2CO.sub.3 (2 M, 179 .mu.L, 0.358 mmol) and heated
to 100.degree. C. After 1 hour, the reaction mixture was cooled to
ambient temperature, diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by preparative HPLC (Method
D, 60-100% B in 20 minutes) to give Example 625 (7.0 mg, 0.018
mmol, 46%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09 (br.
s., 1H), 8.84 (br. s., 1H), 8.45 (br. s., 1H), 8.33 (br. s., 1H),
7.56 (br. s., 1H), 7.02 (br. s., 1H), 4.74 (s, 2H), 3.87 (s, 3H),
3.44 (s, 3H), 2.76 (s, 3H); LC-MS: Method H, RT=1.44 min, MS (ESI)
m/z: 385.1 (M+H).sup.+; Analytical HPLC Method B, 100% purity.
Example 626
2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole
##STR01485##
[3403] Intermediate 626A:
6-methoxy-4-methyl-2-(tributylstannyl)benzo[d]thiazole
##STR01486##
[3405] Intermediate I-3 (300 mg, 1.162 mmol) was dissolved in
Et.sub.2O (4.65 mL) and cooled to -78.degree. C. BuLi (2.5 M in
hexanes, 511 .mu.L, 1.278 mmol) was then added. After 45 minutes,
tributylchlorostannane (315 .mu.L, 1.16 mmol) was added. After 15
minutes, the reaction mixture was warmed to ambient temperature and
concentrated in vacuo. The crude material was suspended in hexanes
and filtered through dry celite. The residue was concentrated in
vacuo to give Intermediate 626A, which was used directly in the
subsequent step.
Intermediate 626B:
2-(3-(benzyloxy)-6-chloroquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazol-
e
##STR01487##
[3407] Intermediate I-122A (270 mg, 0.774 mmol), Intermediate 626A
(526 mg, 1.12 mmol), and potassium acetate (152 mg, 1.55 mmol) were
dissolved in 1,4-dioxane (7.74 mL) and degassed by bubbling with
argon for 15 minutes. Palladium tetrakistriphenylphosphine (44.7
mg, 0.039 mmol) was added and the reaction vessel was sealed and
heated to 120.degree. C. in the microwave for 2 hours. The reaction
mixture was diluted with EtOAc, washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 40 g
silica gel column, 19 minute gradient from 0 to 100% EtOAc in
hexanes) then repurified by column chromatography (ISCO, 40 g
silica gel column, 19 minute gradient from 0 to 100% DCM in
hexanes) to give Intermediate 626B (201 mg, 0.45 mmol, 58%) as a
yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.90 (d,
J=2.9 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H),
7.56-7.38 (m, 6H), 7.28 (s, 1H), 6.96 (dd, J=2.6, 0.9 Hz, 1H), 5.27
(s, 2H), 3.92 (s, 3H), 2.85 (s, 3H); LC-MS: Method H, RT=1.58 min,
MS (ESI) m/z: 447.1 (M+H).sup.+.
Intermediate 626C:
6-chloro-8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)quinolin-3-ol
##STR01488##
[3409] Intermediate 626B (25 mg, 0.056 mmol) and pentamethylbenzene
(58.0 mg, 0.392 mmol) were dissolved in DCM (2.8 mL) and cooled to
-78.degree. C. Boron trichloride (1 M in heptane, 145 .mu.L, 0.145
mmol) was added and the reaction mixture was allowed to slowly warm
to ambient temperature. After stirring overnight, the reaction was
quenched with 1 N HCl and extracted thrice with EtOAc. The combined
organic layers were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 4 g silica gel column, 15
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 626C (17.1 mg, 0.048 mmol, 86%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.87 (d, J=2.4 Hz, 1H),
8.82 (d, J=2.9 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.48 (d, J=2.9 Hz,
1H), 6.96 (dd, J=2.6, 0.9 Hz, 1H), 3.92 (s, 3H), 2.86 (s, 3H);
LC-MS: Method H, RT=1.39 min, MS (ESI) m/z: 357.1 (M+H).sup.+.
Example 626
[3410] Intermediate 626C (17 mg, 0.048 mmol), K.sub.2CO.sub.3 (13.2
mg, 0.095 mmol), and MeI (11.9 .mu.L, 0.191 mmol) were dissolved in
acetone (1.91 mL). After stirring overnight, the reaction mixture
was concentrated in vacuo and purified by preparative HPLC (Method
D, 55-95% B in 10 minutes) to give Example 626 (5.5 mg, 0.015 mmol,
31%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.89 (br. s.,
1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.95 (br. s., 1H), 7.54 (s, 1H),
7.01 (br. s., 1H), 4.00 (s, 3H), 3.86 (s, 3H), 2.75 (s, 3H); LC-MS:
Method H, RT=1.51 min, MS (ESI) m/z: 371.1 (M+H).sup.+; Analytical
HPLC Method B, 100% purity.
Example 627
2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)pro-
pan-2-ol
##STR01489##
[3411] Intermediate 627A:
2-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)propan-2-ol
##STR01490##
[3413] Intermediate I-20C (50 mg, 0.165 mmol) was dissolved in THF
(331 .mu.L) and cooled to -78.degree. C. Methylmagnesium bromide (3
M in Et.sub.2O, 124 .mu.L, 0.372 mmol) was added and the reaction
mixture was allowed to slowly warm to 0.degree. C. in the freezer.
After stirring overnight, the reaction was quenched with saturated
NH.sub.4Cl and extracted with EtOAc. The organic layer was washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 12 g silica gel column, 17 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 627A (13.6
mg, 0.045 mmol, 27%) as a clear oil: LC-MS: Method H, RT=1.00 min,
MS (ESI) m/z: 302/304 (M+H).sup.+.
Example 627
[3414] Intermediate I-9 (11.6 mg, 0.039 mmol), Intermediate 627A
(14 mg, 0.046 mmol), and potassium phosphate, tribasic (16.4 mg,
0.077 mmol) were dissolved in DMF (386 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (4.46 mg, 3.86 .mu.mol) was added and
degassing continued for 5 minutes. The reaction was then sealed and
heated to 85.degree. C. After stirring overnight, the crude
material was purified by preparative HPLC (Method D, 50-100% B in
14 minutes) to give Example 627 (6.6 mg, 0.016 mmol, 42%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.51 (d, J=1.7
Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.35
(d, J=2.5 Hz, 1H), 5.42 (s, 1H), 4.10 (s, 3H), 3.88 (s, 3H), 2.66
(s, 3H), 1.83 (s, 6H); LC-MS: Method H, RT=1.27 min, MS (ESI) m/z:
396.2 (M+H).sup.+; Analytical HPLC Method B, 97% purity.
Example 628
1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol--
4-yl)-2,2-dimethylpropan-1-ol
##STR01491##
[3415] Intermediate 628A:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
##STR01492##
[3417] Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF
(294 .mu.L) and cooled to -78.degree. C. tert-Butylmagnesium
chloride (1 M in THF, 184 .mu.L, 0.184 mmol) was then added and the
reaction mixture was allowed to slowly warm to 0.degree. C. in the
freezer. After stirring overnight, the reaction was quenched with
saturated NH.sub.4Cl and extracted with EtOAc. The organic layer
was washed with water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 12 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 628A (29 mg, 0.088 mmol, 60%) as a white solid: LC-MS:
Method H, RT=1.10 min, MS (ESI) m/z: 330/332 (M+H).sup.+.
Example 628
[3418] Intermediate I-2 (16.6 mg, 0.053 mmol), Intermediate 628A
(14.5 mg, 0.044 mmol), and potassium phosphate, tribasic (18.6 mg,
0.088 mmol) were dissolved in DMF (439 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (5.07 mg, 4.39 .mu.mol) was added and
degassing continued for 5 minutes. The reaction vessel was then
sealed and heated to 85.degree. C. After heating overnight, the
crude material was purified by preparative HPLC (Method D, 45-85% B
in 20 minutes) to give Example 628 (6.4 mg, 0.015 mmol, 33%):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (s, 1H), 8.77 (d,
J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5
Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d, J=4.7 Hz, 1H), 4.83 (s,
2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H), 0.97 (s, 9H); LC-MS:
Method H, RT=1.24 min, MS (ESI) m/z: 437.8 (M+H).sup.+; Analytical
HPLC Method B, 98% purity.
Example 629
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)
(phenyl)methanol
##STR01493##
[3419] Intermediate 629A:
(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(phenyl)methanol
##STR01494##
[3421] Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF
(294 .mu.L) and cooled to -78.degree. C. Phenylmagnesium bromide (3
M in Et.sub.2O, 61.2 .mu.l, 0.184 mmol) was added and the reaction
mixture was allowed to slowly warm to 0.degree. C. in the freezer.
After stirring overnight, the reaction was quenched with saturated
NH.sub.4Cl and extracted with EtOAc. The organic layer was washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 12 g silica gel column, 17 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 629A (33.6
mg, 0.096 mmol, 65%) as a white solid: LC-MS: Method H, RT=1.01
min, MS (ESI) m/z: 350/352 (M+H).sup.+.
Example 629
[3422] Intermediate I-9 (14.1 mg, 0.047 mmol), Intermediate 629A
(16.5 mg, 0.047 mmol), and potassium phosphate, tribasic (20 mg,
0.094 mmol) were dissolved in DMF (471 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (5.44 mg, 4.71 .mu.mol) was added and
degassing continued for 5 minutes. The reaction vessel was then
sealed and heated to 85.degree. C. After heating overnight, the
crude material was purified by preparative HPLC (Method D, 40-75% B
in 15 minutes) then repurified by preparative HPLC (Method D,
60-100% B in 12 minutes) to give Example 629 (7.4 mg, 0.017 mmol,
35%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H),
8.61 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.62-7.55 (m, 3H), 7.35-7.26
(m, 3H), 7.23-7.15 (m, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.10 (d, J=4.1
Hz, 1H), 4.09 (s, 3H), 3.86 (s, 3H), 2.67 (s, 3H); LC-MS: Method H,
RT=1.24 min, MS (ESI) m/z: 443.8 (M+H).sup.+; Analytical HPLC
Method B, 99% purity.
Example 630
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,-
2-dimethylpropan-1-ol
##STR01495##
[3424] Intermediate I-9 (15.8 mg, 0.053 mmol), Intermediate 628A
(14.5 mg, 0.044 mmol), and potassium phosphate, tribasic (18.6 mg,
0.088 mmol) were dissolved in DMF (439 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (5.07 mg, 4.39 .mu.mol) was added and
degassing continued for 5 minutes. The reaction vessel was then
sealed and heated to 85.degree. C. After heating overnight, the
crude material was purified by preparative HPLC (Method D, 50-85% B
in 15 minutes) then repurified by preparative HPLC (Method D,
60-100% B in 20 minutes) to give Example 630 (3.8 mg, 0.0087 mmol,
20%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H),
8.55 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.15
(d, J=2.5 Hz, 1H), 5.43 (s, 1H), 5.34 (br. s., 1H), 4.09 (s, 3H),
3.88 (s, 3H), 2.66 (s, 3H), 0.96 (s, 9H); LC-MS: Method H, RT=1.32
min, MS (ESI) m/z: 423.8 (M+H).sup.+; Analytical HPLC Method B, 97%
purity.
Example 631
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2--
phenylethanol
##STR01496##
[3425] Intermediate 631A:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2-phenylethanol
##STR01497##
[3427] Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF
(294 .mu.L) and cooled to -78.degree. C. Benzylmagnesium chloride
(2 M in Et.sub.2O, 92 .mu.L, 0.184 mmol) was added and the reaction
mixture was allowed to slowly warm to 0.degree. C. in the freezer.
After stirring overnight, the reaction was quenched with saturated
NH.sub.4Cl and extracted with EtOAc. The organic layer was washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 12 g silica gel column, 17 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 631A (18.9
mg, 0.052 mmol, 35%) as a yellow oil: LC-MS: Method H, RT=1.07 min,
MS (ESI) m/z: 364/366 (M+H).sup.+.
Example 631
[3428] Intermediate I-9 (9.39 mg, 0.031 mmol), Intermediate 631A
(9.5 mg, 0.026 mmol), and potassium phosphate, tribasic (11.1 mg,
0.052 mmol) were dissolved in DMF (261 .mu.L) and degassed by
bubbling with argon for 15 minutes. Palladium
tetrakistriphenylphosphine (3.01 mg, 2.61 .mu.mol) was added and
degassing continued for 5 minutes. The reaction was then sealed and
heated to 85.degree. C. After heating overnight, the crude material
was purified by preparative HPLC (Method D, 45-80% B in 20 minutes)
then repurified by preparative HPLC (Method D, 70-100% B in 15
minutes) to give Example 631 (1.2 mg, 0.0026 mmol, 10%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.61 (d, J=1.4
Hz, 1H), 7.85 (s, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.38-7.33 (m, 2H),
7.33-7.27 (m, 2H), 7.23-7.16 (m, 2H), 5.71 (dt, J=8.3, 4.4 Hz, 1H),
5.49 (d, J=5.2 Hz, 1H), 4.10 (s, 3H), 3.87 (s, 3H), 3.29 (dd,
J=13.5, 3.6 Hz, 1H), 2.97 (dd, J=13.6, 8.4 Hz, 1H), 2.69 (s, 3H);
LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 457.8 (M+H).sup.+;
Analytical HPLC Method B, 100% purity.
Example 632
1-(5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-
-4-yl)-2,2-dimethylpropan-1-ol
##STR01498##
[3429] Intermediate 632A:
1-(2-amino-5-fluoro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-o-
l
##STR01499##
[3431] Intermediate I-43C (100 mg, 0.430 mmol) was dissolved in THF
(4.3 mL).
[3432] Sodium hydride (18.9 mg, 0.473 mmol) was then added. After
30 minutes, the reaction mixture was cooled to -78.degree. C. and
tert-butyllithium (1 M, 430 .mu.L, 0.516 mmol) was added. After 45
minutes, pivalaldehyde (96 .mu.L, 0.86 mmol) was added and the
reaction mixture was allowed to warm to ambient temperature. After
the reaction mixture achieved ambient temperature, it was diluted
with EtOAc and washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 632A, which was used immediately in the subsequent
reaction: LC-MS: Method H, RT=0.74 min, MS (ESI) m/z: 285.2
(M+H).sup.+.
Intermediate 632B:
1-(2-chloro-5-fluoro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1--
ol
##STR01500##
[3434] Copper(II) chloride (81 mg, 0.601 mmol) and t-butyl nitrite
(77 .mu.L, 0.644 mmol) were dissolved in MeCN (1.72 mL) and allowed
to stir 10 minutes. Intermediate 632A (122 mg, 0.429 mmol) was
dissolved in MeCN (2.57 mL) and the copper solution was added and
heated to 60.degree. C. After 1.5 hours, the reaction mixture was
diluted with EtOAc, washed with 1 N HCl, saturated NaHCO.sub.3,
then brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 632B (21 mg, 0.021 mmol,
4.8%) as a brown solid: LC-MS: Method H, RT=1.14 min, MS (ESI) m/z:
304.1 (M+H).sup.+.
Example 632
[3435] Intermediate I-9 (24.9 mg, 0.083 mmol) and Intermediate 632B
(21 mg, 0.069 mmol) were dissolved in DMF (691 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.39 mg, 4.15 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Sodium carbonate (2 M, 41.5 .mu.l, 0.083
mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 100.degree. C. in the microwave
for 30 minutes. The material was heated in the microwave for an
additional 30 minutes at 120.degree. C. The crude material was
purified by preparative HPLC (Method D, 70-100% B in 20 minutes)
then repurified by preparative HPLC (Method D, 60-100% B in 20
minutes) to give Example 632 (0.7 mg, 0.0015 mmol, 2.2%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.50 (d, J=1.7
Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.83-7.80 (m, 1H), 5.57 (br. s.,
1H), 5.25 (br. s., 1H), 4.08 (s, 3H), 3.94 (s, 3H), 2.64 (s, 3H),
1.00 (s, 9H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 442.2
(M+H).sup.+; Analytical HPLC Method B, 97% purity.
Example 633
2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]-
thiazol-4-yl)ethanol
##STR01501##
[3436] Intermediate 633A:
1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2,2-trifluoroethanol
##STR01502##
[3438] Intermediate I-21 (207 mg, 0.909 mmol) was dissolved in THF
(18.2 mL). (Trifluoromethyl)trimethylsilane (161 .mu.L, 1.09 mmol)
then TBAF (1 M in THF, 1.09 mL, 1.09 mmol) were added to the
reaction. After stirring overnight, the reaction mixture was
diluted with EtOAc and washed with water, saturated NaHCO.sub.3,
then brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 633A (70.8 mg, 0.238 mmol,
26%) as a white solid: LC-MS: Method H, RT=0.98 min, MS (ESI) m/z:
298.1 (M+H).sup.+.
Intermediate 633B:
2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-4-yl)ethanol (racemic)
##STR01503##
[3440] Intermediate I-9 (70.6 mg, 0.235 mmol) and Intermediate 633A
(70 mg, 0.235 mmol) were dissolved in DMF (2.35 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (11.5 mg, 0.014 mmol) was
added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 141 .mu.L, 0.282 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The reaction
mixture was diluted with water and extracted thrice with EtOAc. The
combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 24 g silica
gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 633B (racemic) (49.9 mg, 0.115 mmol, 49%) as a
yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (s,
1H), 8.48 (d, J=1.8 Hz, 1H), 7.78 (d, J=0.9 Hz, 1H), 7.43 (d, J=2.4
Hz, 1H), 7.35 (d, J=9.9 Hz, 1H), 7.06 (s, 1H), 5.35 (dd, J=9.8, 7.4
Hz, 1H), 4.13 (s, 3H), 3.93 (s, 3H), 2.66 (s, 3H); LC-MS: Method H,
RT=1.21 min, MS (ESI) m/z: 436.1 (M+H).sup.+.
Example 633
[3441] Intermediate 633B (49.9 mg, 0.115 mmol) was purified by
chiral SFC (Chiralpak OJ-H, 21.times.250 mm, 5 micron, 25% IPA/75%
CO.sub.2, 2 mL/min) to give Example 633 (Peak 2, Enantiomer 2, 20.4
mg, 0.044 mmol, 38%, >99% ee) as a yellow solid: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.55 (s, 1H), 8.48 (d, J=1.5 Hz, 1H),
7.78 (dd, J=1.9, 1.0 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.35 (d,
J=9.9 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 5.40-5.30 (m, 1H), 4.13 (s,
3H), 3.93 (s, 3H), 2.66 (s, 3H); LC-MS: Method H, RT=1.21 min, MS
(ESI) m/z: 436.1 (M+H).sup.+.
Example 634
4-(1-fluoro-2,2-dimethylpropyl)-6-methoxy-2-(2-methoxy-7-methylquinoxalin--
5-yl)benzo[d]thiazole
##STR01504##
[3442] Intermediate 634A:
2-bromo-4-(1-fluoro-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazole
##STR01505##
[3444] Intermediate 628A (20 mg, 0.061 mmol) and Deoxofluor (14
.mu.L, 0.076 mmol) were dissolved in DCM (606 .mu.L). After 1 hour,
the reaction mixture was diluted with EtOAc and washed with
saturated NaHCO.sub.3, water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 634A (24
mg, 0.072 mmol, 100%), which was used immediately in the subsequent
reaction: LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 332/334
(M+H).sup.+.
Example 634
[3445] Intermediate I-9 (10.8 mg, 0.036 mmol) and Intermediate 634A
(10 mg, 0.030 mmol) were dissolved in DMF (301 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.48 mg, 1.81 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (18.1 .mu.L, 0.036 mmol) was added and
the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 80-100% B in 15
minutes) to give Example 634 (3.5 mg, 0.0079 mmol, 26%): .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.50 (s, 1H), 8.48 (s, 1H), 7.67
(s, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.37-6.25
(m, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.60 (s, 3H), 1.03 (s, 9H);
LC-MS: Method H, RT=1.47 min, MS (ESI) m/z: 426.2 (M+H).sup.+;
Analytical HPLC Method B, 96% purity.
Example 635
4-(benzyloxy)-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo-
[d]thiazole
##STR01506##
[3446] Intermediate 635A:
2-(benzyloxy)-4-methoxy-1-nitrobenzene
##STR01507##
[3448] 5-Methoxy-2-nitrophenol (1 g, 5.91 mmol), potassium
carbonate (2.45 g, 17.7 mmol), and benzyl bromide (1.06 ml, 8.87
mmol) were dissolved in DMF (11.8 mL). After stirring overnight,
the reaction mixture was diluted with water and extracted twice
with EtOAc. The combined organic layers were washed with water,
then brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 120 g silica gel column, 29 minute gradient from 0 to 100%
EtOAc in hexanes) to give Intermediate 635A (1.51 g, 5.81 mmol,
98%) as a light yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.01 (d, J=9.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.43-7.37 (m,
2H), 7.36-7.30 (m, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.1,
2.5 Hz, 1H), 5.22 (s, 2H), 3.84 (s, 3H); LC-MS: Method H, The
compound did not ionize.
Intermediate 635B: 2-(benzyloxy)-4-methoxyaniline
##STR01508##
[3450] Intermediate 635A (1.51 g, 5.81 mmol) was dissolved in MeOH
(39.7 mL) and THF (4.96 mL). Ammonium chloride (6.21 g, 116 mmol)
and zinc (3.80 g, 58.1 mmol) were added and the reaction mixture
was heated to 40.degree. C. After 3.5 hours, the reaction mixture
was concentrated in vacuo. The crude material was redissolved in
EtOAc/saturated Na.sub.2CO.sub.3 and allowed to stir vigorously for
15 minutes. The mixture was filtered through a sintered glass
funnel. The organic layer was washed with water then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 80 g silica
gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 635B (511 mg, 2.23 mmol, 38%) as a brown oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.46-7.31 (m, 5H), 6.68
(d, J=8.4 Hz, 1H), 6.53 (d, J=2.6 Hz, 1H), 6.38 (dd, J=8.6, 2.6 Hz,
1H), 5.06 (s, 2H), 3.74 (s, 3H), 3.56 (br. s., 2H); LC-MS: Method
H, RT=0.69 min, MS (ESI) m/z: 230.2 (M+H).sup.+.
Intermediate 635C:
4-(benzyloxy)-6-methoxybenzo[d]thiazol-2-amine
##STR01509##
[3452] Intermediate 635B (0.5 g, 2.18 mmol) was dissolved in MeCN
(10.9 mL). Ammonium thiocyanate (0.249 g, 3.27 mmol) was added,
followed by benzyltrimethylammonium tribromide (0.850 g, 2.18
mmol). After stirring for 2 days, the reaction mixture was diluted
with saturated NaHCO.sub.3 and the solid collected by suction
filtration and washed with water to give Intermediate 635C (574 mg,
2 mmol, 92%) as a purple solid: LC-MS: Method H, RT=0.77 min, MS
(ESI) m/z: 287.2 (M+H).sup.+.
Intermediate 635D:
4-(benzyloxy)-2-chloro-6-methoxybenzo[d]thiazole
##STR01510##
[3454] Copper(II) chloride (0.377 g, 2.80 mmol) and t-butyl nitrite
(0.357 mL, 3.00 mmol) were dissolved in MeCN (8 mL) and allowed to
stir 10 minutes. Intermediate 635C (0.573 g, 2.001 mmol) was
dissolved in MeCN (12 mL) and the copper solution was added and the
reaction mixture was heated to 60.degree. C. After 2 hours, the
reaction mixture was concentrated in vacuo to remove the majority
of the MeCN. The reaction was then diluted with EtOAc, washed twice
with 1 N HCl, water, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 80 g silica gel column, 29
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 635D (147 mg, 0.481 mmol, 24%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48 (d, J=7.3 Hz, 2H),
7.40-7.34 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H),
6.54 (d, J=2.2 Hz, 1H), 5.32 (s, 2H), 3.80 (s, 3H); LC-MS: Method
H, RT=1.17 min, MS (ESI) m/z: 306.1 (M+H).sup.+.
Example 635
[3455] Intermediate I-2 (13.2 mg, 0.042 mmol) and Intermediate 635D
(10 mg, 0.035 mmol) were dissolved in DMF (350 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.72 mg, 2.1 .mu.mol) was
added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 21 .mu.L, 0.042 mmol) was added and
the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 40-80% B in 22 minutes)
to give Example 635 (7.6 mg, 0.015 mmol, 44%): .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 9.00 (s, 1H), 8.85 (br. s., 1H), 7.85 (br.
s., 1H), 7.50 (d, J=6.9 Hz, 2H), 7.39-7.22 (m, 3H), 6.95 (br. s.,
1H), 6.52 (br. s., 1H), 5.38 (s, 2H), 4.77 (s, 2H), 3.79 (s, 3H),
3.50 (d, J=1.4 Hz, 3H), 2.61 (br. s., 3H); LC-MS: Method H, RT=1.29
min, MS (ESI) m/z: 458.2 (M+H).sup.+; Analytical HPLC Method B, 93%
purity.
Example 636
1-(2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,-
2-dimethylpropan-1-ol
##STR01511##
[3457] Intermediate I-28 (10.4 mg, 0.044 mmol) and Intermediate
628A (12 mg, 0.036 mmol) were dissolved in DMF (363 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.78 mg, 2.18 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 21.8 .mu.L, 0.044 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 40-100% B in 15
minutes) then repurified by preparative HPLC (Method D, 45-85% B in
22 minutes) to give Example 636 (1.2 mg, 0.0025 mmol, 6.8%):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.82 (s, 1H), 8.60 (d,
J=2.2 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.16
(d, J=2.2 Hz, 1H), 5.41 (br. s., 1H), 5.32 (br. s., 1H), 4.10 (s,
3H), 3.88 (s, 3H), 0.95 (s, 9H); LC-MS: Method H, RT=1.43 min, MS
(ESI) m/z: 444.2 (M+H).sup.+; Analytical HPLC Method B, 91%
purity.
Example 637
1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,-
2-dimethylpropan-1-ol
##STR01512##
[3458] Intermediate 637A:
1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
##STR01513##
[3460] Intermediate 628A (110 mg, 0.333 mmol) was purified by
chiral preparative HPLC (Chiralpak AD, 90% heptane/10% EtOH:MeOH
(50:50)) to give Intermediate 637A (33.8 mg, 0.102 mmol, 31%) as a
clear oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.16 (d, J=2.6
Hz, 1H), 6.98-6.91 (m, 1H), 4.84 (d, J=8.4 Hz, 1H), 4.02 (d, J=8.4
Hz, 1H), 3.86 (s, 3H), 0.96 (s, 9H); LC-MS: Method H, RT=1.14 min,
MS (ESI) m/z: 330/332 (M+H).sup.+.
Example 637
[3461] Intermediate I-9 (5.45 mg, 0.018 mmol) and Intermediate 637A
(5 mg, 0.015 mmol) were dissolved in DMF (151 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.742 mg, 0.908 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 9.08 .mu.L, 0.018 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 70-100% B in 15
minutes) to give Example 637 (4.6 mg, 0.011 mmol, 70%): .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.78 (s, 1H), 8.59 (s, 1H), 7.87
(s, 1H), 7.65 (s, 1H), 7.20 (s, 1H), 5.48 (d, J=4.6 Hz, 1H), 5.38
(d, J=4.6 Hz, 1H), 4.14 (s, 3H), 3.93 (s, 3H), 2.70 (s, 3H), 1.01
(s, 9H); LC-MS: Method H, RT=1.36 min, MS (ESI) m/z: 424.1
(M+H).sup.+; Analytical HPLC Method B, 97% purity.
Example 638
2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)-
benzo[d]thiazol-6-yl)oxy)ethyl (5-cyanopyridin-3-yl)carbamate
##STR01514##
[3462] Intermediate 638A:
1-(2-amino-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
##STR01515##
[3464] Intermediate I-22 (0.5 g, 1.93 mmol) was dissolved in THF
(19.3 mL). Sodium hydride (0.085 g, 2.12 mmol) was added. After 30
minutes, the reaction mixture was cooled to -78.degree. C. and BuLi
(1.68 ml, 3.86 mmol) was added. After 1 hour, methyl pivalate (0.77
mL, 5.79 mmol) was added and the reaction mixture was allowed to
warm to ambient temperature. After achieving ambient temperature,
the reaction mixture was diluted with EtOAc and washed with water,
then brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 24 g silica gel column, 19 minute gradient from 0 to 20%
MeOH in DCM) to give Intermediate 638A (382 mg, 1.45 mmol, 75%) as
a brown solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.14 (d,
J=2.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 5.09 (br. s., 2H), 3.82 (s,
3H), 1.29 (s, 9H); LC-MS: Method H, RT=0.76 min, MS (ESI) m/z:
265.2 (M+H).sup.+.
Intermediate 638B:
1-(2-amino-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
##STR01516##
[3466] Intermediate 638A (380 mg, 1.44 mmol) was dissolved in AcOH
(5.75 mL) and HBr (976 .mu.L, 8.63 mmol) and heated to reflux.
After heating for 2 days, the reaction mixture was concentrated in
vacuo to give Intermediate 638B, which was used directly in the
subsequent reaction: LC-MS: Method H, RT=0.64 min, MS (ESI) m/z:
251.1 (M+H).sup.+.
Intermediate 638C:
2-((2-amino-4-pivaloylbenzo[d]thiazol-6-yl)oxy)ethyl acetate
##STR01517##
[3468] Intermediate 638B (360 mg, 1.44 mmol), Cs.sub.2CO.sub.3
(2.81 g, 8.63 mmol), and 2-bromoethyl acetate (397 .mu.L, 3.60
mmol) were dissolved in DMF (5.75 mL). After stirring overnight,
the reaction mixture was diluted with water and extracted thrice
with EtOAc. The combined organic layers were washed with brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by preparative HPLC (Method A, 30-100%
B in 12 minutes) to give Intermediate 638C (139 mg, 0.412 mmol,
29%) as a white solid: LC-MS: Method H, RT=0.76 min, MS (ESI) m/z:
337.2 (M+H).sup.+.
Intermediate 638D:
2-((2-chloro-4-pivaloylbenzo[d]thiazol-6-yl)oxy)ethyl acetate
##STR01518##
[3470] Copper(II) chloride (78 mg, 0.577 mmol) and t-butyl nitrite
(73.5 .mu.L, 0.618 mmol) were dissolved in MeCN (1.65 mL) and
allowed to stir 10 minutes. Intermediate 638C (139 mg, 0.412 mmol)
was dissolved in MeCN (2.47 mL) and the copper solution was added
and the reaction mixture was heated to 60.degree. C. After 2.5
hours, the reaction mixture was concentrated in vacuo to remove the
majority of the MeCN. The reaction was then diluted with EtOAc,
washed twice with 1 N HCl, water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 638D (134 mg, 0.377 mmol, 91%) as an orange oil:
LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 356.1 (M+H).sup.+.
Intermediate 638E:
1-(2-chloro-6-(2-hydroxyethoxy)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-
-ol
##STR01519##
[3472] Intermediate 638D (134 mg, 0.377 mmol) was dissolved in
toluene (2.51 mL) and THF (1.26 mL) and cooled to -78.degree. C.
DIBAL-H (1 M in toluene, 1.13 mL, 1.13 mmol) was added and the
reaction was warmed to ambient temperature. After 5 hours, more
DIBAL-H (1130 .mu.l, 1.130 mmol) was added. After 45 minutes, the
reaction was quenched with a saturated solution of Rochelle's salt.
After stirring overnight, the reaction mixture was extracted with
EtOAc. The organic layer was further washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes).
The resulting product was purified by chiral preparative HPLC
(Chiralpak AD, 16% MeOH/EtOH (50/50) in heptane) to give
Intermediate 638E (7.2 mg, 0.023 mmol, 6.1%) as a clear oil: LC-MS:
Method H, RT=0.97 min, MS (ESI) m/z: 316.1 (M+H).sup.+.
Intermediate 638F:
2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)eth-
yl carbonochloridate
##STR01520##
[3474] Intermediate 638E (7.2 mg, 0.023 mmol) and phosgene solution
(15% in toluene, 0.114 mmol) were dissolved in THF (228 .mu.L).
After 1.5 hours, the reaction mixture was concentrated in vacuo to
give Intermediate 638F, which was used directly in the subsequent
reaction.
Intermediate 638G:
2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)eth-
yl (5-cyanopyridin-3-yl)carbamate
##STR01521##
[3476] Intermediate 638F (8.6 mg, 0.023 mmol),
5-aminonicotinonitrile (9.48 mg, 0.080 mmol), and pyridine (18.4
.mu.l, 0.227 mmol) were dissolved in DCM (455 .mu.L). After 45
minutes, the reaction mixture was concentrated in vacuo to give
Intermediate 638G, which was used directly in the subsequent
reaction: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 461.1
(M+H).sup.+.
Example 638
[3477] Intermediate I-9 (8.21 mg, 0.027 mmol) and Intermediate 638G
(10.5 mg, 0.023 mmol) were dissolved in DMF (228 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.12 mg, 1.37 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 13.7 .mu.L, 0.027 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 65-100% B in 20
minutes) to give Example 638 (2.0 mg, 0.0033 mmol, 15%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.79 (br. s., 1H), 8.66 (s,
1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.23 (br. s., 1H), 7.89 (s, 1H),
7.75 (s, 1H), 7.58 (br. s., 1H), 7.09 (br. s., 1H), 5.35 (d, J=4.9
Hz, 1H), 5.24 (d, J=4.6 Hz, 1H), 4.49 (br. s., 2H), 4.30 (d, J=11.3
Hz, 2H), 4.01 (s, 3H), 2.58 (s, 3H), 0.88 (s, 9H); LC-MS: Method H,
RT=1.27 min, MS (ESI) m/z: 599.2 (M+H).sup.+; Analytical HPLC
Method B, 100% purity.
Example 639
8-(4-(1-hydroxy-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazol-2-yl)-3-metho-
xyquinoxaline-6-carbonitrile
##STR01522##
[3479] Intermediate I-38 (4.16 mg, 0.018 mmol) and Intermediate
637A (5 mg, 0.015 mmol) were dissolved in DMF (151 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.742 mg, 0.908 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 9.08 .mu.L, 0.018 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 45-90% B in 20 minutes)
to give Example 639 (2.1 mg, 0.0046 mmol, 30%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.02 (s, 1H), 8.93 (s, 1H), 8.59 (s,
1H), 7.69 (br. s., 1H), 7.23 (br. s., 1H), 5.49 (br. s., 1H), 5.38
(d, J=4.0 Hz, 1H), 4.19 (s, 3H), 3.94 (s, 3H), 1.02 (s, 9H); LC-MS:
Method H, RT=1.25 min, MS (ESI) m/z: 435.2 (M+H).sup.+; Analytical
HPLC Method B, 95% purity.
Example 640
1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-
-dimethylpropan-1-ol
##STR01523##
[3480] Intermediate 640A:
1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
##STR01524##
[3482] Copper(II) chloride (0.363 g, 2.70 mmol) and t-butyl nitrite
(0.344 mL, 2.89 mmol) were dissolved in MeCN (7.72 mL) and allowed
to stir 10 minutes. Intermediate 638A (0.51 g, 1.93 mmol) was
dissolved in MeCN (11.6 mL) and the copper solution was added and
the reaction mixture was heated to 60.degree. C. After 2 hours, the
reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 40 g silica gel column, 17
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 640A (211 mg, 0.743 mmol, 39%) as a brown oil: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.23 (d, J=2.6 Hz, 1H), 6.87 (d,
J=2.4 Hz, 1H), 3.87 (s, 3H), 1.30 (s, 9H); LC-MS: Method H, RT=1.15
min, MS (ESI) m/z: 284.2 (M+H).sup.+.
Intermediate 640B:
1-(2-chloro-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
##STR01525##
[3484] Intermediate 640A (190 mg, 0.670 mmol) and borontribromide
(1 M in THF, 2.01 mL, 2.01 mmol) were dissolved in DCM (6.7 mL).
After 2 hours, the reaction mixture was diluted with DCM, washed
with 1 N HCl, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 640B, which was used
directly in the subsequent step: LC-MS: Method H, RT=1.01 min, MS
(ESI) m/z: 270.1 (M+H).sup.+.
Intermediate 640C:
1-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-hydroxybenzo[d]thiaz-
ol-4-yl)-2,2-dimethylpropan-1-one
##STR01526##
[3486] Intermediate I-1 (221 mg, 0.872 mmol) and Intermediate 640B
(196 mg, 0.727 mmol) were dissolved in DMF (7.27 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (35.6 mg, 0.044 mmol) was
added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2M, 436 .mu.L, 0.872 mmol) was added and
the reaction mixture was degassed for 5 minutes, then sealed and
heated to 100.degree. C. in the microwave for 40 minutes. More
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (35.6 mg, 0.044 mmol) was
added and the reaction mixture was heated for an additional 30
minutes in the microwave at 100.degree. C. The reaction mixture was
diluted with water and extracted thrice with EtOAc. The combined
organic layers were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 40 g silica gel column, 19
minute gradient from 0 to 100% EtOAc in hexanes) to give
Intermediate 640C (182 mg, 0.411 mmol, 57%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.68 (d, J=1.8 Hz, 1H),
8.66 (s, 1H), 7.77 (dd, J=1.8, 0.9 Hz, 1H), 7.85-7.44 (m, 1H), 7.38
(d, J=2.4 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 5.18 (s, 1H), 2.66 (s,
3H), 1.39 (s, 9H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z:
444.2 (M+H).sup.+.
Intermediate 640D:
1-(6-hydroxy-2-(2-methoxy-7-methylquinoxalin-5-yl)
benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
##STR01527##
[3488] Intermediate 640C (180 mg, 0.406 mmol) was azeotroped with
toluene and stored on HIVAC overnight. The starting material was
dissolved in THF (8.12 mL). Sodium methoxide (0.5 M in MeOH, 554
.mu.L, 2.03 mmol) was then added. After 1 hour, the reaction
mixture was diluted with 1 N HCl and extracted thrice with EtOAc.
The combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 640D (167 mg, 0.411 mmol, 100%) as an off-white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (d, J=1.8 Hz, 1H),
8.53 (s, 1H), 7.74 (dd, J=1.8, 0.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H),
6.82 (d, J=2.4 Hz, 1H), 5.08 (s, 1H), 4.12 (s, 3H), 2.62 (s, 3H),
1.39 (s, 9H); LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 408.2
(M+H).sup.+.
Intermediate 640E:
1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,-
2-dimethylpropan-1-one
##STR01528##
[3490] Intermediate 640D (20 mg, 0.049 mmol) was dissolved in THF
(982 .mu.L). Cesium carbonate (16 mg, 0.049 mmol) then ethyl iodide
(5.95 .mu.L, 0.074 mmol) were added. After stirring overnight, the
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 640E, which was used directly in the
subsequent reaction: LC-MS: Method H, RT=1.43 min, MS (ESI) m/z:
436.2 (M+H).sup.+.
Example 640
[3491] Intermediate 640E (21 mg, 0.048 mmol) was dissolved in MeOH
(964 .mu.L) and cooled to 0.degree. C. Sodium borohydride (5.47 mg,
0.145 mmol) was then added. After 1.5 hours, the reaction was
warmed to ambient temperature. After 1.5 hours, the reaction
mixture was diluted with EtOAc, washed with water then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by preparative HPLC (Method D, 60-100% B in
30 minutes) to give Example 640 (5.7 mg, 0.013 mmol, 27%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.79 (s, 1H), 8.59 (s, 1H),
7.88 (s, 1H), 7.63 (br. s., 1H), 7.19 (br. s., 1H), 5.47 (br. s.,
1H), 5.38 (br. s., 1H), 4.23-4.16 (m, 2H), 4.15 (s, 3H), 2.71 (s,
3H), 1.46 (t, J=6.7 Hz, 3H), 1.01 (s, 9H); LC-MS: Method H, RT=1.40
min, MS (ESI) m/z: 438.2 (M+H).sup.+; Analytical HPLC Method B,
100% purity.
Example 641
2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)eth-
anol
##STR01529##
[3492] Intermediate 641A: ethyl
2-(5-methoxy-2-nitrophenyl)acetate
##STR01530##
[3494] Ethyl 2-(5-hydroxy-2-nitrophenyl)acetate (100 mg, 0.444
mmol), potassium carbonate (123 mg, 0.888 mmol), and iodomethane
(41.6 .mu.L, 0.666 mmol) were dissolved in acetone (4.44 mL). After
stirring overnight, the reaction mixture was concentrated in vacuo,
diluted with EtOAc, washed with aqueous HCl, water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 641A (102 mg, 0.427 mmol, 96%) as a brown oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (d, J=9.0 Hz, 1H),
6.93 (dd, J=9.1, 2.8 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 4.21 (q,
J=7.1 Hz, 2H), 4.02 (s, 2H), 3.92 (s, 3H), 1.29 (t, J=7.0 Hz, 3H);
LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 240.0 (M+H).sup.+.
Intermediate 641B: 2-(5-methoxy-2-nitrophenyl)ethanol
##STR01531##
[3496] Intermediate 641A (100 mg, 0.418 mmol) was dissolved in
toluene (2.79 mL) and THF (1.39 mL) and cooled to -78.degree. C.
DIBAL-H (1 M in toluene, 920 .mu.L, 0.920 mmol) was added and the
reaction mixture was allowed to warm slowly to ambient temperature.
After 1.5 hours, the reaction was quenched with saturated
Rochelle's salt. After stirring overnight, the reaction mixture was
extracted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 12 g silica
gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 641B (65 mg, 0.33 mmol, 79%) as a yellow oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09 (d, J=9.0 Hz, 1H),
6.91-6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.91 (s, 3H), 3.25 (t,
J=6.3 Hz, 2H); LC-MS: Method H, Did not ionize well.
Intermediate 641C: 2-(2-amino-5-methoxyphenyl)ethanol
##STR01532##
[3498] Intermediate 641B (65 mg, 0.330 mmol) was dissolved in EtOH
(471 .mu.L). Palladium on carbon (7.02 mg, 6.59 .mu.mol) then
ammonium formate (104 mg, 1.65 mmol) were added and the reaction
mixture was heated to reflux. After 1 hour, the reaction mixture
was filtered through celite and concentrated in vacuo to give
Intermediate 641C (54.8 mg, 0.328 mmol, 99%) as a brown oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.29 (s, 1H), 6.69 (s,
2H), 3.94 (t, J=6.1 Hz, 2H), 3.77 (s, 3H), 2.82 (t, J=6.2 Hz, 2H);
LC-MS: Method H, RT=0.51 min, MS (ESI) m/z: 168.0 (M+H).sup.+.
Intermediate 641D:
2-(2-amino-6-methoxybenzo[d]thiazol-4-yl)ethanol
##STR01533##
[3500] Intermediate 641C (55 mg, 0.329 mmol) was dissolved in MeCN
(1.64 mL). Ammonium thiocyanate (37.6 mg, 0.493 mmol) was added,
followed by benzyltrimethylammonium tribromide (128 mg, 0.329
mmol). After stirring for 5 days, the reaction mixture was diluted
with saturated NaHCO.sub.3. The reaction mixture was extracted
thrice with EtOAc. The combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 641D (59.9 mg, 0.267 mmol, 81%) as a
brown solid: LC-MS: Method H, RT=0.59 min, MS (ESI) m/z: 225.0
(M+H).sup.+.
Intermediate 641E:
2-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)ethanol
##STR01534##
[3502] Copper(II) chloride (50.4 mg, 0.375 mmol) and t-butyl
nitrite (47.7 .mu.L, 0.401 mmol) were dissolved in MeCN (1.07 mL)
and allowed to stir 10 minutes. Intermediate 641D (60 mg, 0.268
mmol) was dissolved in MeCN (1.6 mL) and the copper solution was
added and the reaction mixture was heated to 60.degree. C. After
1.5 hours, the reaction mixture was diluted with EtOAc, washed with
1 N HCl, saturated NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 641E (51.6 mg, 0.212 mmol, 79%) as a red oil: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.14 (d, J=2.4 Hz, 1H), 6.96 (d,
J=2.4 Hz, 1H), 4.02 (br. s., 2H), 3.88 (s, 3H), 3.29 (t, J=6.1 Hz,
2H), 2.34 (br. s., 1H); LC-MS: Method H, RT=0.90 min, MS (ESI) m/z:
244.0 (M+H).sup.+.
Example 641
[3503] Intermediate I-9 (14.8 mg, 0.049 mmol) and Intermediate 641E
(10 mg, 0.041 mmol) were dissolved in DMF (410 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.01 mg, 2.46 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 24.6 .mu.L, 0.049 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 40-90% B in 15 minutes)
to give Example 641 (6.4 mg, 0.016 mmol, 40%): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.69 (s, 1H), 8.53 (s, 1H), 7.78 (s,
1H), 7.52 (s, 1H), 7.00 (s, 1H), 4.81 (t, J=5.2 Hz, 1H), 4.06 (s,
3H), 3.88-3.73 (m, 5H), 3.30 (t, J=7.0 Hz, 2H), 2.62 (s, 3H);
LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 382.1 (M+H).sup.+;
Analytical HPLC Method B, 97% purity.
Example 642
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(3-(t-
rifluoromethyl)phenyl)methanol
##STR01535##
[3504] Intermediate 642A:
(2-amino-6-methoxybenzo[d]thiazol-4-yl)(3-(trifluoromethyl)
phenyl)methanol
##STR01536##
[3506] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1.93 mL). Sodium hydride (17 mg, 0.425 mmol) was added. After 30
minutes, the reaction mixture was cooled to -78.degree. C. and BuLi
(2.5 M in hexanes, 101 .mu.L, 0.232 mmol) was added. After 30
minutes, 3-(trifluromethyl)benzaldehyde (50.4 mg, 0.289 mmol) was
added and the reaction mixture was allowed to warm to ambient
temperature. After achieving ambient temperature, the reaction
mixture was diluted with EtOAc, washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 642A, which was used directly in the subsequent
reaction: LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 355.0
(M+H).sup.+.
Intermediate 642B:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(3-(trifluoromethyl)
phenyl)methanol
##STR01537##
[3508] Intermediate 642A (68 mg, 0.192 mmol), lithium chloride
(8.14 mg, 0.192 mmol), copper(II) chloride (25.8 mg, 0.192 mmol),
and tert-butyl nitrite (22.9 .mu.L, 0.192 mmol) were dissolved in
MeCN (1.92 mL). After 2 hours, the reaction mixture was diluted
with EtOAc, washed with 1 N HCl, saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 642B (73.5 mg, 0.197 mmol, 100%) as a red oil:
LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 374.0 (M+H).sup.+.
Example 642
[3509] Intermediate I-9 (15 mg, 0.050 mmol) and Intermediate 642B
(22.4 mg, 0.060 mmol) were dissolved in DMF (250 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.45 mg, 3.00 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 30.0 .mu.L, 0.060 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 45-90% B in 20 minutes)
then repurified by preparative HPLC (Method D, 60-100% B in 15
minutes) to give Example 642 (7.5 mg, 0.015 mmol, 29%): .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.78 (s, 1H), 8.65 (s, 1H), 8.17
(s, 1H), 7.90 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.67 (d, J=2.4 Hz,
1H), 7.64-7.55 (m, 2H), 7.41 (d, J=2.1 Hz, 1H), 6.76 (d, J=4.3 Hz,
1H), 6.44 (d, J=4.3 Hz, 1H), 4.14 (s, 3H), 3.94 (s, 3H), 2.72 (s,
3H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 512.1 (M+H).sup.+;
Analytical HPLC Method B, 100% purity.
Example 643
(2-isopropylphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d-
]thiazol-4-yl)methanol
##STR01538##
[3510] Intermediate 643A:
(2-amino-6-methoxybenzo[d]thiazol-4-yl)(2-isopropylphenyl)methanol
##STR01539##
[3512] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1.93 mL). Sodium hydride (17 mg, 0.425 mmol) was then added. After
30 minutes, the reaction mixture was cooled to -78.degree. C. and
BuLi (2.5 M in hexanes, 101 .mu.L, 0.232 mmol) was added. After 30
minutes, 2-isopropylbenzaldehyde (42.9 mg, 0.289 mmol) was added
and the reaction mixture was allowed to warm to ambient
temperature. After achieving ambient temperature, the reaction
mixture was diluted with EtOAc, washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 643A, which was used directly in the subsequent
reaction: LC-MS: Method H, RT=0.87 min, MS (ESI) m/z: 329.1
(M+H).sup.+.
Intermediate 643B:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(2-isopropylphenyl)methanol
##STR01540##
[3514] Intermediate 643A (63 mg, 0.192 mmol), lithium chloride
(8.13 mg, 0.192 mmol), copper(II) chloride (25.8 mg, 0.192 mmol),
and tert-butyl nitrite (22.9 .mu.L, 0.192 mmol) were dissolved in
MeCN (1.92 mL). After 2 hours, the reaction mixture was diluted
with EtOAc, washed with 1 N HCl, saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 643B, which was used directly in the subsequent
reaction: LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 348
(M+H).sup.+.
Example 643
[3515] Intermediate I-9 (15 mg, 0.050 mmol) and Intermediate 643B
(20.9 mg, 0.060 mmol) were dissolved in DMF (250 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.45 mg, 3.00 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 30.0 .mu.L, 0.060 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 50-100% B in 20
minutes) then repurified by preparative HPLC (Method D, 60-100% B
in 20 minutes) to give Example 643 (1.7 mg, 0.0034 mmol, 6.7%):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.45 (s,
1H), 7.80 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.36-7.26 (m, 3H), 7.20
(t, J=7.6 Hz, 1H), 7.14-7.08 (m, 1H), 6.98 (d, J=4.9 Hz, 1H), 5.92
(d, J=5.2 Hz, 1H), 4.07 (s, 3H), 3.96-3.85 (m, 4H), 2.60 (s, 3H),
1.32 (d, J=7.0 Hz, 3H), 1.21 (d, J=6.7 Hz, 3H); LC-MS: Method H,
RT=1.37 min, MS (ESI) m/z: 486.1 (M+H).sup.+; Analytical HPLC
Method B, 96% purity.
Example 644
Ethyl
1-(hydroxy(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]th-
iazol-4-yl)methyl)cyclobutanecarboxylate
##STR01541##
[3516] Intermediate 644A: Ethyl
1-(2-amino-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate
##STR01542##
[3518] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1.93 mL). Sodium hydride (17 mg, 0.425 mmol) was then added. After
15 minutes, the reaction mixture was cooled to -78.degree. C. and
BuLi (2.5 M in hexanes, 101 .mu.L, 0.232 mmol) was added. After 30
minutes, diethyl cyclobutane-1,1-dicarboxylate (58.0 mg, 0.289
mmol) was added and the reaction mixture was allowed to warm to
ambient temperature. After achieving ambient temperature, the
reaction mixture was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 644A, which was used directly in the
subsequent reaction: LC-MS: Method H, RT=0.77 min, MS (ESI) m/z:
335.0 (M+H).sup.+.
Intermediate 644B: Ethyl
1-(2-chloro-6-methoxybenzo[d]thiazole-4-carbonyl)
cyclobutane-1-carboxylate
##STR01543##
[3520] Intermediate 644A (64.5 mg, 0.193 mmol), lithium chloride
(8.18 mg, 0.193 mmol), copper(II) chloride (25.9 mg, 0.193 mmol),
and tert-butyl nitrite (23 .mu.L, 0.193 mmol) were dissolved in
MeCN (1.93 mL). After 2 hours, the reaction mixture was diluted
with EtOAc, washed with 1 N HCl, saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 12 g
silica gel column, 17 minute gradient from 0 to 100% EtOAc in
hexanes) to give Intermediate 644B (12 mg, 0.034 mmol, 18%) as a
white solid: LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 354.1
(M+H).sup.+.
Intermediate 644C: Ethyl
1-((2-chloro-6-methoxybenzo[d]thiazol-4-yl)(hydroxy)methyl)
cyclobutane-1-carboxylate
##STR01544##
[3522] Intermediate 644B (12 mg, 0.034 mmol) was dissolved in MeOH
(339 .mu.L) at 0.degree. C. Sodium borohydride (2.57 mg, 0.068
mmol). After 45 minutes, the reaction mixture was diluted with
EtOAc, washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 644C,
which was used directly in the subsequent reaction: LC-MS: Method
H, RT=1.07 min, MS (ESI) m/z: 356.0 (M+H).sup.+.
Example 644
[3523] Intermediate I-9 (12.2 mg, 0.040 mmol) and Intermediate 644C
(12 mg, 0.034 mmol) were dissolved in DMF (169 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.65 mg, 2.02 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes.
[3524] Sodium carbonate (20.2 .mu.L, 0.040 mmol) was added and the
reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. The crude material
was purified by preparative HPLC (Method D, 60-100% B in 22
minutes) to give Example 644 (3.1 mg, 0.0062 mmol, 18%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.65 (s, 1H), 8.47 (s, 1H),
7.75 (s, 1H), 7.55 (s, 1H), 7.08 (d, J=1.7 Hz, 1H), 5.83 (d, J=5.4
Hz, 1H), 5.78 (d, J=5.7 Hz, 1H), 4.01 (s, 3H), 3.88-3.78 (m, 3H),
3.76 (dd, J=7.1, 4.4 Hz, 2H), 2.57 (s, 3H), 2.53-2.35 (m, 2H), 2.19
(br. s., 1H), 2.08 (br. s., 1H), 1.67-1.58 (m, 1H), 1.54 (br. s.,
1H), 0.87 (t, J=7.1 Hz, 3H); LC-MS: Method H, RT=1.31 min, MS (ESI)
m/z: 494.1 (M+H).sup.+; Analytical HPLC Method B, 99% purity.
Example 645
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6--
yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01545##
[3526] Intermediate I-121 (12 mg, 0.038 mmol), Intermediate I-130
(18.5 mg, 0.045 mmol) and PdCl.sub.2(dppf) (1.65 mg, 2.25 .mu.mol)
were dissolved in 1,4-dioxane (375 .mu.L) and Na.sub.2CO.sub.3 (2
M, 169 .mu.L, 0.338 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature,
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by preparative HPLC (Method D, 50-100% B in
20 minutes) to give Example 645 (6.6 mg, 0.011 mmol, 30%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.92 (br. s., 1H), 8.82 (br.
s., 1H), 8.71 (br. s., 2H), 8.58 (s, 1H), 8.15 (s, 1H), 8.00 (d,
J=8.2 Hz, 1H), 7.93 (d, J=11.9 Hz, 1H), 7.90 (br. s., 1H), 5.11 (d,
J=6.1 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 3.98 (s, 3H), 2.50 (s, 3H),
1.39 (t, J=6.7 Hz, 6H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z:
568.1 (M+H).sup.+; Analytical HPLC Method B, 96% purity.
Example 646
(1-(hydroxymethyl)cyclobutyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5--
yl) benzo[d]thiazol-4-yl)methanol
##STR01546##
[3527] Intermediate 646A: Methyl
1-(2-amino-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate
##STR01547##
[3529] Intermediate I-22 (1 g, 3.86 mmol) was dissolved in THF
(38.6 mL). Sodium hydride (0.340 g, 8.49 mmol) was then added.
After 15 minutes, the reaction mixture was cooled to -78.degree. C.
and BuLi (2.5 M in hexanes, 2.01 mL, 4.63 mmol) was added. After 45
minutes, dimethyl cyclobutane-1,1-dicarboxylate (0.892 mL, 5.79
mmol) was added and the reaction mixture was allowed to warm to
ambient temperature. After the reaction reached ambient
temperature, it was diluted with EtOAc, washed with water, then
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 646A, which was used directly in the
subsequent step: LC-MS: Method H, RT=0.75 min, MS (ESI) m/z: 321.1
(M+H).sup.+.
Intermediate 646B: Methyl
1-(2-chloro-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate
##STR01548##
[3531] Intermediate 646A (1.24 g, 3.86 mmol), lithium chloride
(0.164 g, 3.86 mmol), copper(II) chloride (0.519 g, 3.86 mmol), and
tert-butyl nitrite (0.460 mL, 3.86 mmol) were dissolved in MeCN
(38.6 mL). After 2 hours, the reaction mixture was diluted with
EtOAc, washed with 1 N HCl, saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 12 g
silica gel column, 17 minute gradient from 0 to 100% EtOAc in
hexanes) to give Intermediate 646B (124 mg, 0.365 mmol, 9.5% over 2
steps) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.76 (d, J=2.6 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 3.68
(s, 3H), 2.80-2.65 (m, 2H), 2.64-2.50 (m, 2H), 2.25-2.11 (m, 1H),
1.94-1.80 (m, 1H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z:
340.1 (M+H).sup.+.
Intermediate 646C:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(hydroxymethyl)
cyclobutyl)methanol
##STR01549##
[3533] Intermediate 646B (124 mg, 0.365 mmol) and NaBH.sub.4 (13.8
mg, 0.365 mmol) were dissolved in MeOH (1.82 mL) at 0.degree. C.
After 4 hours, the reaction mixture was diluted with EtOAc, washed
with water then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 12 g silica gel column, 17 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 646C (23.8
mg, 0.076 mmol, 21%) as a clear oil: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.19 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H),
5.41 (d, J=5.8 Hz, 1H), 3.88 (s, 3H), 3.74-3.67 (m, 1H), 3.46-3.36
(m, 2H), 3.26 (d, J=5.8 Hz, 1H), 2.38-2.22 (m, 2H), 1.89 (dd,
J=9.2, 3.2 Hz, 1H), 1.82-1.72 (m, 2H), 1.53-1.49 (m, 1H); LC-MS:
Method H, RT=0.95 min, MS (ESI) m/z: 314.1 (M+H).sup.+.
Example 646
[3534] Intermediate I-9 (20.1 mg, 0.067 mmol) and Intermediate 646C
(20 mg, 0.064 mmol) were dissolved in DMF (319 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.12 mg, 3.82 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Sodium carbonate (2 M, 38.2 .mu.L, 0.076 mmol) was added
and the reaction degassed for 5 minutes, then sealed and heated to
100.degree. C. in the microwave for 30 minutes. More
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.12 mg, 3.82 .mu.mol)
was added and the reaction mixture was heated in the microwave for
an additional 30 minutes at 100.degree. C. The crude material was
purified by preparative HPLC (Method D, 45-95% B in 20 minutes) to
give Example 646 (12.4 mg, 0.026 mmol, 41%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.47 (br. s., 1H), 7.82 (br.
s., 1H), 7.60 (br. s., 1H), 7.20 (br. s., 1H), 5.64 (br. s., 1H),
5.51 (br. s., 1H), 4.80 (br. s., 1H), 4.08 (s, 3H), 3.47 (br. s.,
1H), 3.26 (d, J=5.5 Hz, 1H), 2.63 (br. s., 3H), 2.35 (br. s., 1H),
2.17 (br. s., 1H), 1.79-1.55 (m, 4H); LC-MS: Method H, RT=1.22 min,
MS (ESI) m/z: 452.1 (M+H).sup.+; Analytical HPLC Method B, 96%
purity.
Example 647
(2R,3S)-3-((2-(6-chloro-3-ethyl
quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimi-
din-5-yl)carbamate
##STR01550##
[3535] Intermediate 647A: 8-bromo-6-chloro-3-ethylquinoline
##STR01551##
[3537] Intermediate I-123 (185 mg, 0.789 mmol), butyraldehyde (71.1
.mu.L, 0.789 mmol), and sodium methoxide (0.5 M in MeOH, 1.74 mL,
0.868 mmol) were dissolved in MeOH (1.58 mL) and heated to reflux.
After heating overnight, the reaction mixture was diluted with
saturated NH.sub.4Cl, partially concentrated in vacuo and diluted
with EtOAc. The layers were separated and the organic layer was
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 24 g silica gel column, 19 minute gradient
from 0 to 50% EtOAc in hexanes) to give Intermediate 647A (192 mg,
0.710 mmol, 90%) as a yellow solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.90 (d, J=2.2 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H),
7.87-7.82 (m, 1H), 7.74 (d, J=2.2 Hz, 1H), 2.88 (q, J=7.5 Hz, 2H),
1.36 (t, J=7.6 Hz, 3H); LC-MS: Method H, RT=1.20 min, MS (ESI) m/z:
270/272 (M+H).sup.+.
Intermediate 647B:
6-chloro-3-ethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinoline
##STR01552##
[3539] Intermediate 647A (192 mg, 0.710 mmol), bispinacolatodiboron
(216 mg, 0.852 mmol), and potassium acetate (174 mg, 1.78 mmol)
were dissolved in 1,4-dioxane (7.1 mL) and degassed for 5 minutes
by bubbling with argon. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct
(46.4 mg, 0.057 mmol) was added and the reaction degassed for an
additional 10 minutes. The reaction mixture was heated to
130.degree. C. in the microwave for 2 hours. The reaction mixture
was diluted with EtOAc and water. The reaction was further
extracted twice with EtOAc. The combined organic layers were washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 647B, which was used directly in the
subsequent reaction: LC-MS: Method H, RT=0.93 min, MS (ESI) m/z:
236.1 (boronic acid mass observed, M+H).sup.+.
Example 647
[3540] Intermediate 647B (15 mg, 0.047 mmol), I-130 (19.4 mg, 0.047
mmol) and PdCl.sub.2(dppf) (2.07 mg, 2.83 .mu.mol) were dissolved
in 1,4-dioxane (472 .mu.L) and Na.sub.2CO.sub.3 (2 M, 213 .mu.L,
0.425 mmol) and heated to 100.degree. C. After 1 hour, the reaction
mixture was cooled to ambient temperature, diluted with EtOAc,
washed with water, then brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 65-100% B in 25 minutes) to give
Example 647 (4.3 mg, 0.0074 mmol, 15%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.93 (br. s., 1H), 9.06 (d, J=2.1 Hz, 1H),
8.77 (d, J=2.1 Hz, 1H), 8.73 (br. s., 2H), 8.34 (s, 1H), 8.28 (d,
J=2.4 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.99 (d, J=11.6 Hz, 1H),
5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.84 (dd, J=6.4, 2.7 Hz, 1H), 2.92
(q, J=7.4 Hz, 2H), 2.55 (s, 3H), 1.40 (dd, J=6.3, 4.4 Hz, 6H), 1.35
(t, J=7.6 Hz, 3H); LC-MS: Method H, RT=1.30 min, MS (ESI) m/z:
566.1 (M+H).sup.+; Analytical HPLC Method B, 98% purity.
Example 648
(2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6--
yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01553##
[3542] Intermediate I-124 (15 mg, 0.050 mmol), Intermediate I-130
(20.6 mg, 0.050 mmol) and PdCl.sub.2(dppf) (2.2 mg, 3.01 .mu.mol)
were dissolved in 1,4-dioxane (501 .mu.L) and Na.sub.2CO.sub.3 (2
M, 226 .mu.L, 0.451 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 45-100% B in 15 minutes) to give
Example 648 (8.4 mg, 0.015 mmol, 30%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.79 (d, J=2.7 Hz, 1H),
8.74 (br. s., 2H), 8.61 (d, J=1.5 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H),
7.94 (d, J=11.6 Hz, 1H), 7.89-7.82 (m, 2H), 5.16-5.05 (m, 1H), 4.80
(dd, J=6.1, 2.7 Hz, 1H), 3.99 (s, 3H), 2.61 (s, 3H), 1.40 (dd,
J=6.4, 2.4 Hz, 6H) (1 methyl group under solvent); LC-MS: Method H,
RT=1.14 min, MS (ESI) m/z: 548.1 (M+H).sup.+; Analytical HPLC
Method B, 99% purity.
Example 649
(2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-y-
l)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01554##
[3544] Intermediate I-126 (15 mg, 0.045 mmol), Intermediate I-130
(18.5 mg, 0.045 mmol) and PdCl.sub.2(dppf) (1.97 mg, 2.70 .mu.mol)
were dissolved in 1,4-dioxane (450 .mu.L) and Na.sub.2CO.sub.3 (2
M, 202 .mu.L, 0.405 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature. The
reaction mixture was concentrated in vacuo. The crude material was
purified by preparative HPLC (Method D, 50-100% B in 20 minutes)
then repurified by preparative HPLC (Method D, 50-100% B in 20
minutes) to give Example 649 (2.5 mg, 0.0041 mmol, 9.2%): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.94 (br. s., 1H), 8.85 (d,
J=2.7 Hz, 1H), 8.73 (br. s., 2H), 8.62 (d, J=2.1 Hz, 1H), 8.18 (d,
J=2.1 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H),
7.93 (d, J=2.7 Hz, 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.82 (dd,
J=6.4, 2.4 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.46 (t,
J=6.9 Hz, 3H), 1.40 (t, J=5.5 Hz, 6H); LC-MS: Method H, RT=1.30
min, MS (ESI) m/z: 582.1 (M+H).sup.+; Analytical HPLC Method B, 96%
purity.
Example 650
(2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01555##
[3546] Intermediate I-127 (22 mg, 0.062 mmol), Intermediate I-130
(25.4 mg, 0.062 mmol) and PdCl.sub.2(dppf) (2.72 mg, 3.71 .mu.mol)
were dissolved in 1,4-dioxane (619 .mu.L) and Na.sub.2CO.sub.3 (2
M, 278 .mu.L, 0.557 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example
650 (3.9 mg, 0.0063 mmol, 10%): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.93 (br. s., 1H), 9.06 (d, J=2.4 Hz, 1H), 8.78 (s, 1H),
8.72 (br. s., 2H), 8.36 (br. s., 2H), 8.07 (d, J=7.9 Hz, 1H), 7.99
(d, J=11.3 Hz, 1H), 7.67-7.34 (m, 1H), 5.11 (dd, J=6.4, 2.1 Hz,
1H), 4.88-4.79 (m, 1H), 2.55 (s, 3H), 1.40 (t, J=5.8 Hz, 6H);
LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 604.1 (M+H).sup.+;
Analytical HPLC Method B, 98% purity.
Example 651
(2R,3S)-3-((2-(6-chloro-3-(2,2-difluoroethoxy)quinolin-8-yl)-5-fluorobenzo-
[d]thiazol-6-yl)oxy)butan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR01556##
[3547] Intermediate 651A:
8-bromo-6-chloro-3-(2,2-difluoroethoxy)quinoline
##STR01557##
[3549] Intermediate I-122 (82 mg, 0.317 mmol), K.sub.2CO.sub.3 (132
mg, 0.952 mmol), and 2-bromo-1,1-difluoroethane (92 mg, 0.634 mmol)
were dissolved in Acetone (3.17 mL) and heated to 50.degree. C. in
a sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 651A (60.4 mg, 0.187 mmol, 59%) as an orange solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.80 (d, J=2.9 Hz, 1H),
7.91 (d, J=2.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.33 (d, J=2.9 Hz,
1H), 6.36-6.02 (m, 1H), 4.34 (td, J=12.8, 4.0 Hz, 2H); LC-MS:
Method H, RT=1.19 min, MS (ESI) m/z: 322/324 (M+H).sup.+.
Intermediate 651B:
6-chloro-3-(2,2-difluoroethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)quinoline
##STR01558##
[3551] Intermediate 651A (60.4 mg, 0.187 mmol),
bispinacolatodiboron (57.1 mg, 0.225 mmol), and potassium acetate
(45.9 mg, 0.468 mmol) were dissolved in 1,4-dioxane (1.87 mL) and
degassed for 5 minutes by bubbling with argon.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (12.2 mg, 0.015 mmol) was
added and the reaction degassed for an additional 10 minutes. The
reaction mixture was heated to 130.degree. C. in the microwave for
2 hours. The reaction mixture was diluted with EtOAc and water. The
reaction was further extracted twice with EtOAc. The combined
organic layers were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 651B,
which was used directly in the subsequent reaction: LC-MS: Method
H, RT=1.14 min, MS (ESI) m/z: 287.9 (M+H).sup.+.
Example 651
[3552] Intermediate 651B (17 mg, 0.046 mmol), Intermediate I-130
(18.9 mg, 0.046 mmol) and PdCl.sub.2(dppf) (2.02 mg, 2.76 .mu.mol)
were dissolved in 1,4-dioxane (460 .mu.L) and Na.sub.2CO.sub.3 (2
M, 207 .mu.L, 0.414 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 50-100% B in 20 minutes) then
repurified by preparative HPLC (Method D, 45-90% in 20 minutes) to
give Example 651 (3.6 mg, 0.0058 mmol, 13%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.94 (br. s., 1H), 8.95 (br. s., 1H), 8.73
(br. s., 2H), 8.67 (s, 1H), 8.18 (s, 1H), 8.11-8.03 (m, 2H), 7.98
(d, J=11.3 Hz, 1H), 6.67-6.42 (m, 1H), 5.11 (d, J=6.4 Hz, 1H), 4.82
(d, J=6.1 Hz, 1H), 4.60 (t, J=13.6 Hz, 2H), 2.55 (s, 3H), 1.40 (t,
J=5.3 Hz, 6H); LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 604.1
(M+H).sup.+; Analytical HPLC Method B, 100% purity.
Example 652
(2R,3S)-3-((2-(6-chloro-3-(methylamino)quinolin-8-yl)-5-fluorobenzo[d]thia-
zol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01559##
[3553] Intermediate 652A: tert-butyl
(8-bromo-6-chloroquinolin-3-yl)(methyl)carbamate
##STR01560##
[3555] Intermediate I-123 (100 mg, 0.426 mmol), tert-butyl
methyl(2-oxoethyl) carbamate (73.9 mg, 0.426 mmol), and sodium
methoxide (0.5 M in MeOH, 938 .mu.L, 0.469 mmol) were dissolved in
MeOH (1.71 mL) and heated to reflux. After heating overnight, the
reaction mixture was diluted with saturated NH.sub.4Cl, partially
concentrated in vacuo and diluted with EtOAc. The layers were
separated and the organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 24 g silica
gel column, 21 minute gradient from 0 to 50% EtOAc in hexanes) to
give Intermediate 652A (64 mg, 0.172 mmol, 40%) as an orange oil:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.02 (d, J=2.5 Hz, 1H),
7.99 (d, J=2.2 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.76 (d, J=2.2 Hz,
1H), 3.42 (s, 3H), 1.51 (s, 9H); LC-MS: Method H, RT=1.39 min, MS
(ESI) m/z: 371/373 (M+H).sup.+.
Intermediate 652B: 8-bromo-6-chloro-N-methylquinolin-3-amine
##STR01561##
[3557] Intermediate 652A (64 mg, 0.172 mmol) was dissolved in DCM
(1.72 mL) and TFA (66.3 .mu.L, 0.861 mmol). After stirring for 4
days, the reaction mixture was diluted with DCM, washed with 1N
NaOH, water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 652B (43.4 mg, 0.160
mmol, 93%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.49 (d, J=2.9 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.58 (d,
J=2.0 Hz, 1H), 6.85 (d, J=2.9 Hz, 1H), 4.27 (br. s., 1H), 2.96 (d,
J=5.1 Hz, 3H); LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 271/273
(M+H).sup.+.
Intermediate 652C:
6-chloro-N-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinolin-3-amine
##STR01562##
[3559] Intermediate 652B (20 mg, 0.074 mmol), bispinacolatodiboron
(37.4 mg, 0.147 mmol), potassium acetate (18.1 mg, 0.184 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (4.81 mg, 5.89 .mu.mol)
were stored on HIVAC for 15 minutes then were dissolved in dry
1,4-dioxane (368 .mu.L) and degassed for 15 minutes by bubbling
with argon. The reaction mixture was heated to 130.degree. C. in
the microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 652C,
which was used directly in the subsequent reaction: LC-MS: Method
H, RT=0.98 min, MS (ESI) m/z: 237.0 (boronic acid mass observed,
M+H).sup.+.
Example 652
[3560] Intermediate 652C (8 mg, 0.025 mmol), Intermediate I-130
(10.3 mg, 0.025 mmol) and PdCl.sub.2(dppf) (1.1 mg, 1.51 .mu.mol)
were dissolved in 1,4-dioxane (251 .mu.L) and Na.sub.2CO.sub.3 (2
M, 113 .mu.L, 0.226 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 40-80% in 20 minutes) to give Example
652 (3.3 mg, 0.0057 mmol, 23%): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.94 (br. s., 1H), 8.73 (br. s., 2H), 8.67 (br. s., 1H),
8.39 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.64-7.48
(m, 1H), 7.14 (br. s., 1H), 5.11 (d, J=6.1 Hz, 1H), 4.81 (d, J=6.1
Hz, 1H), 2.85 (br. s., 3H), 2.55 (s, 3H), 1.40 (d, J=6.1 Hz, 6H);
LC-MS: Method H, compound did not ionize; Analytical HPLC Method B,
98% purity.
Example 653
(2R,3S)-3-((2-(6-(difluoromethyl)-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01563##
[3562] Intermediate I-128 (15 mg, 0.045 mmol), Intermediate I-130
(18.4 mg, 0.045 mmol) and PdCl.sub.2(dppf) (1.96 mg, 2.69 .mu.mol)
were dissolved in 1,4-dioxane (448 .mu.L) and Na.sub.2CO.sub.3 (2
M, 201 .mu.L, 0.403 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 45-90% B in 22 minutes) to give Example
653 (5.1 mg, 0.0087 mmol, 19%): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.91 (br. s., 1H), 8.90 (d, J=2.4 Hz, 1H), 8.82 (s, 1H),
8.70 (br. s., 2H), 8.30 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.99 (d,
J=8.2 Hz, 1H), 7.95 (d, J=11.6 Hz, 1H), 7.33 (t, J=44 Hz, 1H),
5.15-5.06 (m, 1H), 4.81 (d, J=4.0 Hz, 1H), 3.99 (s, 3H), 2.49 (s,
3H), 1.38 (t, J=7.2 Hz, 6H); LC-MS: Method H, RT=1.11 min, MS (ESI)
m/z: 584.1 (M+H).sup.+; Analytical HPLC Method B, 99% purity.
Example 654
(2R,3S)-3-((5-fluoro-2-(6-(fluoromethyl)-3-methoxyquinolin-8-yl)benzo[d]th-
iazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01564##
[3564] Intermediate I-129 (15 mg, 0.047 mmol), Intermediate I-130
(19.4 mg, 0.047 mmol) and PdCl.sub.2(dppf) (2.08 mg, 2.84 .mu.mol)
were dissolved in 1,4-dioxane (473 .mu.L) and Na.sub.2CO.sub.3 (2
M, 213 .mu.L, 0.426 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example
654 (2.5 mg, 0.0043 mmol, 9.1%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.96 (br. s., 1H), 8.89 (d, J=2.7 Hz, 1H),
8.75 (d, J=14.0 Hz, 3H), 8.13 (s, 1H), 8.07-8.00 (m, 2H), 7.96 (d,
J=11.6 Hz, 1H), 5.76 (d, J=20 Hz, 2H), 5.12 (dd, J=6.4, 2.7 Hz,
1H), 4.82 (d, J=3.7 Hz, 1H), 4.01 (s, 3H), 3.45 (s, 3H), 1.46-1.34
(m, 6H); LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 566.1
(M+H).sup.+; Analytical HPLC Method B, 97% purity.
Example 655
(2R,3S)-3-((2-(6-cyano-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-y-
l)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01565##
[3565] Intermediate 655A: methyl
2-amino-3-bromo-5-cyanobenzoate
##STR01566##
[3567] Methyl 2-amino-5-cyanobenzoate (0.25 g, 1.42 mmol) and NBS
(0.253 g, 1.42 mmol) were dissolved in AcOH (2.84 mL) and heated to
120.degree. C. After 2 hours, the reaction mixture was cooled to
ambient temperature and diluted with EtOAc. The reaction was then
quenched with vigorous stirring with saturated NaHCO.sub.3. The
layers were separated and the organic layer further washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 655A (356 mg, 1.4 mmol, 98%) as a white
solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (d, J=1.8 Hz,
1H), 7.82 (d, J=1.8 Hz, 1H), 3.95 (s, 3H); LC-MS: Method H,
compound did not ionize
Intermediate 655B:
4-amino-3-bromo-5-(hydroxymethyl)benzonitrile
##STR01567##
[3569] Intermediate 655A (356 mg, 1.4 mmol) was dissolved in THF
(4.65 mL). Lithium borohydride (60.8 mg, 2.79 mmol) was added and
the reaction mixture was heated to 50.degree. C. After 1 hour, the
reaction mixture was diluted with water. The reaction mixture was
then extracted thrice with EtOAc. The combined organic layers were
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, dry load, 40 g silica gel column, 19 minute
gradient from 0 to 100% EtOAc in hexanes, polar weighted) to give
Intermediate 655B (106 mg, 0.465 mmol, 33%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71 (d, J=1.8 Hz, 1H),
7.32 (d, J=1.8 Hz, 1H), 5.35 (br. s., 2H), 4.73 (s, 2H), 1.79 (br.
s., 1H); LC-MS: Method H, compound did not ionize
Intermediate 655C: 4-amino-3-bromo-5-formylbenzonitrile
##STR01568##
[3571] Intermediate 655B (106 mg, 0.465 mmol) was dissolved in
CHCl.sub.3 (3.1 mL). Manganese dioxide (243 mg, 2.79 mmol) was
added and the reaction mixture was heated to 40.degree. C. After
heating overnight, the reaction mixture was filtered through celite
and concentrated in vacuo to give Intermediate 655C (88.3 mg, 0.392
mmol, 84%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.85 (s, 1H), 7.88-7.86 (m, 1H), 7.86-7.83 (m, 1H); LC-MS:
Method H, compound did not ionize.
Intermediate 655D:
3-(benzyloxy)-8-bromoquinoline-6-carbonitrile
##STR01569##
[3573] Intermediate 655C (88.3 mg, 0.392 mmol),
2-(benzyloxy)acetaldehyde (58.9 mg, 0.392 mmol), and sodium
methoxide (0.5 M, 863 .mu.L, 0.432 mmol) were dissolved in MeOH
(1.57 mL) and heated to reflux. After heating overnight, the
reaction mixture was diluted with saturated NH.sub.4Cl, partially
concentrated in vacuo and diluted with EtOAc. The layers were
separated and the organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 40 g silica
gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 655D (59.5 mg, 0.175 mmol, 45%) as a yellow
solid: LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 339/341
(M+H).sup.+.
Intermediate 655E: 8-bromo-3-hydroxyquinoline-6-carbonitrile,
HCl
##STR01570##
[3575] Intermediate 655D (59 mg, 0.174 mmol) and pentamethylbenzene
(181 mg, 1.218 mmol) were dissolved in DCM (3.48 mL) and cooled to
-78.degree. C. Boron trichloride (1 M in heptane, 452 .mu.L, 0.452
mmol) was added and the reaction mixture was allowed to slowly warm
to ambient temperature. After stirring overnight, the reaction
mixture was diluted with hexanes and 1 N HCl and allowed to stir
for 1 hour. The solid was collected by suction filtration to give
Intermediate 655E (24.5 mg, 0.086 mmol, 49%) as a white solid:
.sup.1H NMR (400 MHz, MeOH.sub.4) .delta. 8.73 (d, J=2.9 Hz, 1H),
8.27 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.59 (d, J=2.6 Hz,
1H); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 249/251
(M+H).sup.+.
Intermediate 655F: 8-bromo-3-methoxyquinoline-6-carbonitrile
##STR01571##
[3577] Intermediate 655E (24.5 mg, 0.086 mmol), K.sub.2CO.sub.3
(35.6 mg, 0.257 mmol), and methyl iodide (10.7 .mu.L, 0.172 mmol)
were dissolved in acetone (858 .mu.L) and heated to 50.degree. C.
in a sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 655F (21.5 mg, 0.082 mmol, 95%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92 (d, J=2.9 Hz, 1H),
8.12 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.43 (d, J=2.9 Hz,
1H), 4.03 (s, 3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z:
263/265 (M+H).sup.+.
Intermediate 655G:
3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinoline-6-carbonitrile
##STR01572##
[3579] Intermediate 655F (21 mg, 0.080 mmol), bispinacolatodiboron
(40.5 mg, 0.160 mmol), potassium acetate (19.6 mg, 0.200 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (5.21 mg, 6.39 .mu.mol)
were stored on HIVAC for 15 minutes then were dissolved in
1,4-dioxane (399 .mu.L) and degassed for 15 minutes by bubbling
with argon. The reaction mixture was heated to 130.degree. C. in
the microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 655G,
which was used directly in the subsequent reaction.
Example 655
[3580] Intermediate 655G (20 mg, 0.064 mmol), Intermediate I-130
(26.5 mg, 0.064 mmol) and PdCl.sub.2(dppf) (2.83 mg, 3.87 .mu.mol)
were dissolved in 1,4-dioxane (645 .mu.L) and Na.sub.2CO.sub.3 (2
M, 290 .mu.L, 0.580 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 45-90% B in 20 minutes) then repurified
by preparative HPLC (Method D, 40-80% B in 20 minutes) to give
Example 655 (1.3 mg, 0.0023 mmol, 3.6%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.95 (d, J=2.4 Hz, 1H),
8.80-8.69 (m, 3H), 8.60 (s, 1H), 8.05-7.98 (m, 2H), 7.93 (d, J=11.6
Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 4.01 (s,
3H), 3.41 (br. s., 3H), 1.41 (t, J=6.6 Hz, 6H); LC-MS: Method H,
compound did not ionize; Analytical HPLC Method B, 100% purity.
Example 656
(2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxybenzo[d]thiazol-4-yl)(1-(tri-
fluoromethyl)cyclobutyl)methanol
##STR01573##
[3581] Intermediate 656A:
(2-amino-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)
cyclobutyl)methanone
##STR01574##
[3583] Intermediate I-22 (1 g, 3.86 mmol) was dissolved in THF
(38.6 mL). NaH (0.170 g, 4.25 mmol) was added. After 15 minutes,
the reaction mixture was cooled to -78.degree. C. and BuLi (1.93
mL, 4.82 mmol) was added. After 30 minutes, ethyl
1-(trifluoromethyl) cyclobutanecarboxylate (2.27 g, 11.6 mmol) was
added and the reaction mixture was allowed to warm to ambient
temperature. After achieving ambient temperature, the reaction
mixture was diluted with EtOAc and washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to
give Intermediate 656A, which was used directly in the subsequent
step: LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 331.1
(M+H).sup.+.
Intermediate 656B:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)
cyclobutyl)methanone
##STR01575##
[3585] Intermediate 656A (1.28 g, 3.86 mmol), lithium chloride
(0.164 g, 3.86 mmol), copper(II) chloride (0.519 g, 3.86 mmol), and
tert-butyl nitrite (0.461 mL, 3.86 mmol) were dissolved in MeCN
(38.6 mL). After 3 hours, the reaction mixture was diluted with
EtOAc, washed with 1 N HCl, saturated NaHCO.sub.3, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 40 g
silica gel column, 19 minute gradient from 0 to 100% EtOAc in
hexanes) to give Intermediate 656B (386 mg, 1.1 mmol, 29% over 2
steps): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.36 (d, J=2.4
Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 3.91 (s, 3H), 3.01-2.89 (m, 2H),
2.66-2.56 (m, 2H), 2.23-2.09 (m, 1H), 2.06-1.92 (m, 1H); LC-MS:
Method H, RT=1.18 min, MS (ESI) m/z: 350.1 (M+H).sup.+.
Intermediate 656C:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)
cyclobutyl)methanol
##STR01576##
[3587] Intermediate 656B (386 mg, 1.104 mmol) was suspended in MeOH
(5.52 mL) and cooled to 0.degree. C. Sodium borohydride (84 mg,
2.21 mmol) was then added. After 45 minutes, the reaction mixture
was diluted with water and extracted with EtOAc. The organic layer
was washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 40 g silica gel column, 19 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 656C (314 mg,
0.891 mmol, 81%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.21 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 5.31 (d,
J=8.6 Hz, 1H), 4.28 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 2.69-2.59 (m,
1H), 2.39-2.25 (m, 2H), 2.24-2.14 (m, 1H), 1.99-1.86 (m, 1H),
1.69-1.59 (m, 1H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z:
352.1 (M+H).sup.+.
Intermediate 656D:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)
cyclobutyl)methanol
##STR01577##
[3589] Intermediate 656C (314 mg, 0.891 mmol) was purified by
chiral SFC (Chiralpak OJ-H, 30.times.250 mm, 5 micron, 5% MeOH/95%
CO.sub.2, 70 mL/min, 150 bar, 40.degree. C.) to give Intermediate
656D (136 mg, 0.386 mmol, 43%, 87.8% ee): .sup.1H NMR and LCMS data
was identical to Intermediate 656C.
Example 656
[3590] Intermediate I-121 (20 mg, 0.063 mmol), Intermediate 656D
(22 mg, 0.063 mmol) and PdCl.sub.2(dppf) (2.75 mg, 3.75 .mu.mol)
were dissolved in 1,4-dioxane (626 .mu.L) and Na.sub.2CO.sub.3 (2
M, 282 .mu.L, 0.563 mmol) and heated to 100.degree. C. After 2
hours, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 60-100% B in 20 minutes) to give
Example 656 (6.7 mg, 0.013 mmol, 21%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.88 (d, J=2.4 Hz, 1H), 8.58 (s, 1H), 8.18
(s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.69 (s, 1H), 7.33 (s, 1H), 5.94
(s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.42-3.36 (m, 1H), 2.70 (d,
J=8.5 Hz, 1H), 2.21-2.12 (m, 2H), 2.09 (d, J=5.8 Hz, 1H), 1.83 (d,
J=9.8 Hz, 1H), 1.56 (dd, J=10.5, 5.3 Hz, 1H); LC-MS: Method H,
RT=1.32 min, MS (ESI) m/z: 509.0 (M+H).sup.+; Analytical HPLC
Method B, 100% purity.
Example 657
(2R,3S)-3-((2-(3,6-dimethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)ox-
y)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01578##
[3591] Intermediate 657A: 5-methoxy-2-nitrobenzoyl chloride
##STR01579##
[3593] 5-methoxy-2-nitrobenzoic acid (3.9 g, 19.78 mmol) was
dissolved in DCM (39.6 mL). Oxalyl chloride (13.8 mL, 27.7 mmol)
and then DMF (0.153 mL, 1.98 mmol) were added at ambient
temperature. After 1.5 hours, the reaction mixture was concentrated
in vacuo to give Intermediate 657A, which was used directly in the
subsequent step.
Intermediate 657B: ethyl 5-methoxy-2-nitrobenzoate
##STR01580##
[3595] Intermediate 657A (4.26 g, 19.8 mmol) was dissolved in
sodium methoxide (0.5 M in MeOH, 59.3 mL, 29.6 mmol). THF (60 mL)
was added to aid solubility. After stirring overnight, the reaction
mixture was concentrated in vacuo, diluted with EtOAc and washed
with water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to give Intermediate 657B (3.43 g, 15.2 mmol,
77%) as a yellow oil (Note, final extraction solution was allowed
to sit overnight and the methyl ester swapped to the ethyl ester at
that point): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (d,
J=9.0 Hz, 1H), 7.06-7.04 (m, 1H), 7.04-6.99 (m, 1H), 4.41 (q, J=7.0
Hz, 2H), 3.92 (s, 3H), 1.37 (t, J=7.2 Hz, 3H)
Intermediate 657C: Ethyl 2-amino-5-methoxybenzoate
##STR01581##
[3597] Intermediate 657B (3.43 g, 15.2 mmol) was dissolved in EtOH
(21.8 mL). Palladium on carbon (0.324 g, 0.305 mmol) and then
ammonium formate (4.80 g, 76 mmol) were added and the reaction
mixture was heated to reflux. After 3 hours, the reaction mixture
was filtered through celite and concentrated in vacuo to give
Intermediate 657C (2.85 g, 14.6 mmol, 96%) as an orange oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.37 (d, J=3.1 Hz, 1H),
6.95 (dd, J=8.9, 3.0 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.40 (br. s.,
2H), 4.34 (q, J=7.3 Hz, 2H), 3.77 (s, 3H), 1.39 (t, J=7.2 Hz, 3H);
LC-MS: Method H, RT=0.76 min, MS (ESI) m/z: 196 (M+H).sup.+.
Intermediate 657D: ethyl 2-amino-3-bromo-5-methoxybenzoate
##STR01582##
[3599] Intermediate 657C (0.5 g, 2.56 mmol) and NBS (0.456 g, 2.56
mmol) were dissolved in AcOH (5.12 mL). After 3 hours, the reaction
was quenched with vigorous stirring with saturated NaHCO.sub.3. The
layers were separated and the organic layer was further washed with
water, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (ISCO, 40 g silica gel column, 27 minute gradient
from 0 to 100% EtOAc in hexanes) to give Intermediate 657D (236 mg,
0.861 mmol, 34%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.46 (d, J=2.8 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 5.98 (br.
s., 2H), 4.38 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz,
3H); LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 274/276
(M+H).sup.+.
Intermediate 657E: (2-amino-3-bromo-5-methoxyphenyl)methanol
##STR01583##
[3601] Intermediate 657D (236 mg, 0.861 mmol) was dissolved in THF
(2.87 mL). Lithium borohydride (37.5 mg, 1.72 mmol) was added and
the reaction mixture was heated to 50.degree. C. After 2 hours, the
reaction mixture was diluted with water and stirred for 30 minutes.
All of the lithium borohydride had not dissolved, so concentrated
HCl was added carefully to speed up the quenching process. The
reaction mixture was then extracted three times with EtOAc. The
combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 657E (188 mg, 0.808 mmol, 94%) as an orange solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (d, J=2.9 Hz, 1H),
6.71 (d, J=2.9 Hz, 1H), 4.68 (s, 2H), 4.35 (br. s., 2H), 3.76 (s,
3H), 1.72 (br. s., 1H); LC-MS: Method H, RT=0.68 min, MS (ESI) m/z:
232/234 (M+H).sup.+.
Intermediate 657F: 2-amino-3-bromo-5-methoxybenzaldehyde
##STR01584##
[3603] Intermediate 657E (186 mg, 0.801 mmol) was dissolved in
CHCl.sub.3 (5.34 mL). Manganese dioxide (418 mg, 4.81 mmol) was
added and the reaction mixture was heated to 40.degree. C. After
heating overnight, the reaction mixture was filtered through celite
and concentrated in vacuo to give Intermediate 657F (167 mg, 0.724
mmol, 90%) as a red solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.82 (s, 1H), 7.36 (d, J=2.9 Hz, 1H), 7.04 (d, J=2.9 Hz,
1H), 6.35 (br. s., 2H), 3.82 (s, 3H); LC-MS: Method H, RT=0.90 min,
MS (ESI) m/z: 230/232 (M+H).sup.+.
Intermediate 657G: 3-(benzyloxy)-8-bromo-6-methoxyquinoline
##STR01585##
[3605] Intermediate 657F (165 mg, 0.717 mmol),
2-(benzyloxy)acetaldehyde (108 mg, 0.717 mmol), and sodium
methoxide (0.5 M in MeOH, 1.58 mL, 0.789 mmol) were dissolved in
MeOH (2.87 mL) and heated to reflux. After heating overnight, the
reaction mixture was diluted with saturated NH.sub.4Cl, partially
concentrated in vacuo and diluted with EtOAc. The layers were
separated and the organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography (ISCO, 24 g silica
gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to
give Intermediate 657G (210 mg, 0.610 mmol, 85%): LC-MS: Method H,
RT=1.10 min, MS (ESI) m/z: 344/346 (M+H).sup.+.
Intermediate 657H: 8-bromo-6-methoxyquinolin-3-ol, HCl
##STR01586##
[3607] Intermediate 657G (210 mg, 0.610 mmol) and
pentamethylbenzene (633 mg, 4.27 mmol) were dissolved in DCM (12.2
mL) and cooled to -78.degree. C. Boron trichloride (1 M in heptane,
1.59 mL, 1.59 mmol) was then added and the reaction mixture was
allowed to warm slowly to ambient temperature. After stirring
overnight, the reaction mixture was diluted with hexanes and 1 N
HCl and allowed to stir for 1 hour. The solid was collected by
suction filtration to give Intermediate 657H (38.9 mg, 0.134 mmol,
22%) as a brown solid: .sup.1H NMR (400 MHz, MeOH.sub.4) .delta.
8.54 (d, J=2.6 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.4 Hz,
1H), 7.39 (d, J=2.4 Hz, 1H), 3.97 (s, 3H); LC-MS: Method H, RT=0.77
min, MS (ESI) m/z: 254/256 (M+H).sup.+.
Intermediate 657I: 8-bromo-3,6-dimethoxyquinoline
##STR01587##
[3609] Intermediate 657H (38.9 mg, 0.134 mmol), K.sub.2CO.sub.3
(55.5 mg, 0.402 mmol), and methyl iodide (16.7 .mu.L, 0.268 mmol)
were dissolved in acetone (1.34 mL) and heated to 50.degree. C. in
a sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 657I (32 mg, 0.119 mmol, 89%) as a tan solid: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (d, J=2.6 Hz, 1H), 7.51 (d,
J=2.6 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 6.93 (d, J=2.6 Hz, 1H), 3.88
(s, 3H), 3.84 (s, 3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z:
268/270 (M+H).sup.+.
Intermediate 657J:
3,6-dimethoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinoline
##STR01588##
[3611] Intermediate 657I (32 mg, 0.119 mmol), bispinacolatodiboron
(60.6 mg, 0.239 mmol), potassium acetate (29.3 mg, 0.298 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (7.80 mg, 9.55 .mu.mol)
were stored on HIVAC for 15 minutes, then were dissolved in
1,4-dioxane (597 .mu.L), and degassed for 15 minutes by bubbling
with argon. The reaction mixture was heated to 130.degree. C. in
the microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 657J,
which was used directly in the subsequent reaction: LC-MS: Method
H, RT=0.66 min, MS (ESI) m/z: 234.2 (boronic acid mass observed,
M+H).sup.+.
Example 657
[3612] Intermediate 657J (18 mg, 0.057 mmol), Intermediate I-130
(23.5 mg, 0.057 mmol) and PdCl.sub.2(dppf) (2.51 mg, 3.43 .mu.mol)
were dissolved in 1,4-dioxane (571 .mu.L) and Na.sub.2CO.sub.3 (2
M, 257 .mu.L, 0.514 mmol) and heated to 100.degree. C. After 2
hours, the reaction mixture was cooled to ambient temperature. The
reaction mixture was concentrated in vacuo. The crude material was
purified by preparative HPLC (Method D, 45-90% B in 20 minutes) to
give Example 657 (6.2 mg, 0.011 mmol, 19%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.96 (br. s., 1H), 8.82-8.64 (m, 3H), 8.33
(br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.96 (d, J=11.6 Hz, 1H), 7.87
(br. s., 1H), 7.55 (br. s., 1H), 5.12 (d, J=4.9 Hz, 1H), 4.81 (br.
s., 1H), 3.99 (s, 6H), 2.56 (s, 3H), 1.40 (d, J=5.8 Hz, 6H); LC-MS:
Method H, RT=1.12 min, MS (ESI) m/z: 565.9 (M+H).sup.+; Analytical
HPLC Method B, 100% purity.
Example 658
2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)-
benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate
##STR01589##
[3613] Intermediate 658A:
1-(2-chloro-6-(2-hydroxyethoxy)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-
-ol
##STR01590##
[3615] Intermediate 638D (19.4 mg, 0.055 mmol) was dissolved in
toluene (363 .mu.L) and THF (182 .mu.L) and cooled to -78.degree.
C. DIBAL-H (1 M in toluene, 164 .mu.L, 0.164 mmol) was then added
and the reaction mixture was allowed to warm slowly to ambient
temperature. After stirring overnight, another 50 .mu.L of DIBAL
was then added. After 2.5 hours, the reaction was quenched with a
saturated solution of Rochelle's salt. The reaction mixture was
extracted with EtOAc. The organic layer was further washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo to give Intermediate 658A (28.3 mg, 0.090 mmol, 100%) as an
orange oil, which was used directly in the subsequent reaction:
LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 316.2 (M+H).sup.+.
Intermediate 658B:
2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)eth-
yl carbonochloridate
##STR01591##
[3617] Intermediate 658A (24 mg, 0.076 mmol) and phosgene solution
(15% in toluene, 268 .mu.L, 0.380 mmol) were dissolved in THF (760
.mu.L). After 30 minutes, the reaction mixture was concentrated in
vacuo to give Intermediate 658B, which was used directly in the
subsequent reaction: LC-MS: Method H, RT=1.17 min, MS (ESI) m/z:
378.0 (M+H).sup.+.
Intermediate 658C:
2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)eth-
yl pyridin-4-ylcarbamate
##STR01592##
[3619] Intermediate 658B (14 mg, 0.037 mmol), pyridin-4-amine (12.2
mg, 0.130 mmol), and diisopropylethylamine (64.6 .mu.L, 0.370 mmol)
were dissolved in DCM (740 .mu.L.) After 30 minutes, the reaction
mixture was concentrated in vacuo to give Intermediate 658C, which
was used directly in the subsequent step: LC-MS: Method H, RT=0.87
min, MS (ESI) m/z: 436.1 (M+H).sup.+.
Example 658
[3620] Intermediate I-9 (13.2 mg, 0.044 mmol) and Intermediate 658C
(16 mg, 0.037 mmol) were dissolved in DMF (367 .mu.L).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.8 mg, 2.2 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Sodium carbonate (2 M, 22 .mu.L, 0.044 mmol) was
added and the reaction mixture was degassed for 5 minutes, then
sealed and heated to 100.degree. C. in the microwave for 30
minutes. The crude material was purified by preparative HPLC
(Method D, 55-100% B in 20 minutes) to give Example 658 (3.3 mg,
0.0057 mmol, 16%): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.29 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.38 (d, J=5.8 Hz, 2H),
7.81 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.45 (d, J=6.1 Hz, 2H), 7.15
(d, J=2.1 Hz, 1H), 5.42 (d, J=4.6 Hz, 1H), 5.31 (d, J=4.9 Hz, 1H),
4.53 (br. s., 2H), 4.42-4.23 (m, 2H), 4.07 (s, 3H), 3.35 (s, 1H),
2.64 (s, 3H), 0.94 (s, 9H); LC-MS: Method H, RT=1.08 min, MS (ESI)
m/z: 574.2 (M+H).sup.+; Analytical HPLC Method B, 99% purity.
Example 659
(2R,3S)-3-((2-(3-(difluoromethoxy)-6-methylquinolin-8-yl)-5-fluorobenzo[d]-
thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01593##
[3621] Intermediate 659A:
8-bromo-3-(difluoromethoxy)-6-methylquinoline
##STR01594##
[3623] Intermediate I-125E (100 mg, 0.42 mmol) and K.sub.2CO.sub.3
(290 mg, 2.1 mmol) were suspended in DMF (4.2 mL) and heated to
100.degree. C. Sodium 2-chloro-2,2-difluoroacetate (256 mg, 1.68
mmol) was then added. After 1.5 hours, the reaction mixture was
cooled to ambient temperature, diluted with water, and thrice
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
(ISCO, 24 g silica gel column, 19 minute gradient from 0 to 50%
EtOAc in hexanes) to give Intermediate 659A (58 mg, 0.201 mmol,
48%): .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.85 (d, J=2.5 Hz,
1H), 7.93 (d, J=1.7 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.56 (s, 1H),
6.88-6.47 (m, 1H), 2.56 (s, 3H); LC-MS: Method H, RT=1.08 min, MS
(ESI) m/z: 288/290 (M+H).sup.+.
Intermediate 659B:
3-(difluoromethoxy)-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)quinoline
##STR01595##
[3625] Intermediate 659A (58 mg, 0.201 mmol), bispinacolatodiboron
(102 mg, 0.403 mmol), potassium acetate (49.4 mg, 0.503 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (13.2 mg, 0.016 mmol) were
stored on HIVAC for 15 minutes then were dissolved in dry
1,4-dioxane (1.01 mL) and degassed for 15 minutes by bubbling with
argon. The reaction mixture was heated to 130.degree. C. in the
microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 659B,
which was used directly in the subsequent reaction: LC-MS: Method
H, RT=0.82 min, MS (ESI) m/z: 254.0 (boronic acid mass observed,
M+H).sup.+.
Example 659
[3626] Intermediate 659B (15 mg, 0.045 mmol), Intermediate I-130
(18.4 mg, 0.045 mmol) and PdCl.sub.2(dppf) (1.96 mg, 2.69 .mu.mol)
were dissolved in 1,4-dioxane (448 .mu.L) and Na.sub.2CO.sub.3 (2
M, 201 .mu.L, 0.403 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example
659 (8.7 mg, 0.015 mmol, 33%): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.95 (br. s., 1H), 8.98 (br. s., 1H), 8.77 (br. s., 1H),
8.74 (br. s., 2H), 8.29 (br. s., 1H), 8.06 (d, J=7.6 Hz, 1H), 8.00
(br. s., 1H), 7.96 (d, J=11.3 Hz, 1H), 7.66-7.32 (m, 1H), 5.12 (d,
J=6.4 Hz, 1H), 4.82 (d, J=5.8 Hz, 1H), 2.64 (s, 3H), 2.55 (s, 3H),
1.40 (br. s., 6H); LC-MS: Method H, compound did not ionize;
Analytical HPLC Method B, 100% purity.
Example 660
(2R,3S)-3-((2-(3-ethoxy-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-y-
l)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01596##
[3627] Intermediate 660A: 8-bromo-3-ethoxy-6-methylquinoline
##STR01597##
[3629] Intermediate I-125E (100 mg, 0.364 mmol), K.sub.2CO.sub.3
(151 mg, 1.09 mmol), and iodoethane (114 mg, 0.728 mmol) were
dissolved in acetone (3.64 mL) and heated to 50.degree. C. in a
sealed tube. After heating overnight, the reaction mixture was
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to give
Intermediate 660A (105 mg, 0.394 mmol, 100%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.73 (d, J=2.9 Hz, 1H),
7.76 (d, J=1.5 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=2.9 Hz, 1H), 4.19
(q, J=7.0 Hz, 2H), 2.52 (s, 3H), 1.54 (t, J=6.9 Hz, 3H); LC-MS:
Method H, RT=1.14 min, MS (ESI) m/z: 266/268 (M+H).sup.+.
Intermediate 660B:
3-ethoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinoline
##STR01598##
[3631] Intermediate 660A (100 mg, 0.376 mmol), bispinacolatodiboron
(191 mg, 0.752 mmol), potassium acetate (92 mg, 0.939 mmol), and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (24.6 mg, 0.030 mmol) were
stored on HIVAC for 15 minutes then were dissolved in dry
1,4-dioxane (1.88 mL) and degassed for 15 minutes by bubbling with
argon. The reaction mixture was heated to 130.degree. C. in the
microwave for 40 minutes. The reaction mixture was diluted with
EtOAc and washed with water then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo to give Intermediate 660B,
which was used directly in the subsequent reaction: LC-MS: Method
H, RT=0.70 min, MS (ESI) m/z: 232.0 (boronic acid mass observed,
M+H).sup.+.
Example 660
[3632] Intermediate 660B (15 mg, 0.048 mmol), Intermediate I-130
(19.7 mg, 0.048 mmol) and PdCl.sub.2(dppf) (2.1 mg, 2.87 .mu.mol)
were dissolved in 1,4-dioxane (479 .mu.L) and Na.sub.2CO.sub.3 (2
M, 216 .mu.L, 0.431 mmol) and heated to 100.degree. C. After 1
hour, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The crude material was purified by
preparative HPLC (Method D, 50-100% B in 15 minutes) to give
Example 660 (7.2 mg, 0.013 mmol, 27%): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.77 (br. s., 1H), 8.74
(br. s., 2H), 8.60 (br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.94 (d,
J=11.6 Hz, 1H), 7.85 (br. s., 2H), 5.11 (d, J=6.1 Hz, 1H), 4.80 (d,
J=5.5 Hz, 1H), 4.33-4.20 (m, 2H), 2.61 (s, 3H), 2.55 (s, 3H), 1.46
(t, J=6.6 Hz, 3H), 1.40 (d, J=5.5 Hz, 6H); LC-MS: Method H, RT=1.04
min, MS (ESI) m/z: 562.2 (M+H).sup.+; Analytical HPLC Method B,
100% purity.
Example 661
5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline
##STR01599##
[3633] Intermediate 661A: tert-butyl
N-(2-bromo-4-methyl-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
##STR01600##
[3635] 2-Bromo-4-methyl-6-nitroaniline (3 g, 12.98 mmol), DMAP
(0.159 g, 1.298 mmol), and Boc.sub.2O (7.54 ml, 32.5 mmol) were
dissolved in THF (21.64 ml) and allowed to stir overnight. The
reaction mixture was diluted with water and extracted with EtOAc.
The organic layer was washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography (ISCO, 80 g silica gel column, 29
minute gradient from 0 to 50% EtOAc in hexanes) to yield
Intermediate 661A (5.41 g, 12.54 mmol, 97% yield) as a yellow
solid. .sup.1H NMR (400 MHz, MeOH.sub.4) .delta. 7.90 (s, 2H), 2.47
(s, 3H), 1.36 (s, 18H). LC-MS: method H, RT=1.10 min, compound does
not ionize.
Intermediate 661B: methyl
2-((2-bromo-4-methyl-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
##STR01601##
[3637] Intermediate 661A (5.41 g, 12.54 mmol) was dissolved in DCM
(20.91 ml) and TFA (1.933 ml, 25.09 mmol) was added. The reaction
mixture was stirred at room temperature for 45 min. The reaction
mixture was diluted with DCM, quenched with saturated NaHCO.sub.3,
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude material was redissolved in DMF
(20.91 ml). Cs.sub.2CO.sub.3 (10.22 g, 31.4 mmol) was added and
stirred for 15 minutes. Methyl bromoacetate (1.387 ml, 15.05 mmol)
was added and stirred for an additional 15 min. The reaction
mixture was diluted with EtOAc, washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude material was purified by column chromatography (ISCO, 120 g
silica gel column, 29 minute gradient from 0 to 50% EtOAc in
hexanes) to yield Intermediate 661B (4.58 g, 11.36 mmol, 91% yield)
as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.79-7.54 (m, 2H), 4.55 (d, J=17.3 Hz, 1H), 4.00 (s, 1H), 3.68 (s,
3H), 2.43 (s, 3H), 1.56-1.53 (m, 3H), 1.42-1.33 (m, 9H). LC-MS:
method H, RT=1.02 min, compound does not ionize.
Intermediate 661C: methyl
2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate
##STR01602##
[3639] Intermediate 661B (4.58 g, 11.36 mmol) was dissolved in HCl
in dioxanes (14.20 ml, 56.8 mmol) and stirred at room temperature
for 5h. The reaction mixture was concentrated to yield Intermediate
661C (3.55 g, 11.71 mmol, 100% yield) as a yellow solid. Used
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.72 (d, J=2.8 Hz, 2H), 4.56 (d, J=17.3 Hz, 1H), 4.05 (d,
J=17.6 Hz, 1H), 3.69 (s, 3H), 2.43 (s, 3H). LC-MS: method H,
RT=0.97 min, MS (ESI) m/z: 303.1 (M+H).sup.+.
Intermediate 661D:
5-bromo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
##STR01603##
[3641] Intermediate 661C (3.55 g, 11.71 mmol) was dissolved in MeOH
(42.6 ml). Concentrated HCl (3.90 ml, 46.8 mmol) then tin(II)
chloride dihydrate (10.57 g, 46.8 mmol) were added and the reaction
heated to 65.degree. C. for 2.5 h. The reaction mixture was cooled
to ambient temperature, neutralized with 10 N NaOH and diluted with
brine and EtOAc. The mixture was filtered through celite and the
layers separated. The organic layer was washed with saturated
NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to yield Intermediate 661D (2.30 g, 9.54
mmol, 81%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.75 (br. s.,
1H), 6.95 (s, 1H), 6.52 (s, 1H), 4.29 (br. s., 1H), 4.04 (d, J=1.3
Hz, 2H), 2.22 (s, 3H). LC-MS: method H, RT=0.78 min, MS (ESI) m/z:
241.1 (M+H).sup.+.
Intermediate 661E: 5-bromo-7-methylquinoxalin-2(1H)-one
##STR01604##
[3643] Intermediate 661D (2.30 g, 9.54 mmol) was suspended in MeOH
(27.7 ml). NaOH (28.6 ml, 28.6 mmol) then H.sub.2O.sub.2 (5.01 ml,
57.2 mmol) were added and the reaction mixture was allowed to stir
at room temperature for 48 h. The reaction was quenched with
saturated Na.sub.2SO.sub.3. The reaction was then diluted with
saturated NaHCO.sub.3 and extracted thrice with EtOAc. The combined
organic layers were filtered through celite, washed with brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo.
Compound was then triturated with EtOAc to yield Intermediate 661E
(1.32 g, 5.52 mmol, 57.9% yield) as an off white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.16 (s, 1H), 7.49 (s, 1H), 7.09
(s, 1H), 2.40 (s, 3H). LC-MS: method H, RT=0.75 min, MS (ESI) m/z:
239.0 (M+H).sup.+.
Intermediate 661F: 5-bromo-2-ethoxy-7-methylquinoxaline
##STR01605##
[3645] Intermediate 661E (0.050 g, 0.209 mmol) was dissolved in DMF
(1 mL). To this solution was added Cs.sub.2CO.sub.3 (0.341 g, 1.046
mmol), and the reaction mixture was allowed to stir for 5 min.
Iodoethane (0.017 mL, 0.209 mmol) was then added, and the reaction
mixture was allowed to room temperature for 48 hours. The reaction
mixture was diluted with water and EtOAc. The layers were separated
and the organic layer was washed with brine, dried with sodium
sulfate and concentrated under reduced pressure. Purified on Prep
HPLC using Solvent A: 10% MeOH/90% H.sub.2O/0.1% TFA and Solvent B
90% MeOH/10% H.sub.2O/0.1% TFA on Phenomenex AXIA C18 30.times.100
mm with a 10 min gradient and 5 min hold time with a flow rate of
40 mL/min to yield Intermediate 661F (0.012 g, 0.045 mmol, 21.48%
yield) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.32 (s, 1H), 7.52-7.47 (m, 1H), 7.11 (s, 1H), 4.30 (q, J=7.2 Hz,
2H), 2.51 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=0.87
min, MS (ESI) m/z: 267.0 (M+H).sup.+.
Example 661
[3646] Intermediate 661F (0.012 g, 0.045 mmol) and
benzofuran-2-ylboronic acid (10.91 mg, 0.067 mmol) were dissolved
in toluene (0.674 ml) and EtOH (0.225 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.201 mg, 2.70 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3 (0.027 ml, 0.054 mmol) was added and the
reaction degassed for 5 minutes, then sealed and heated to
120.degree. C. in the microwave for 30 minutes. The reaction
mixture was diluted with EtOAc, filtered through a micron filter,
and concentrated in vacuo. The crude material was purified by Prep
LC (Axia Luna 5 u C18 30.times.100 mm column, 10 minute gradient
from 20 to 100% B in A, A=10:90:0.1 MeOH:H.sub.2O:TFA, B=90:10:0.1
MeOH:H.sub.2O:TFA) to yield Example 661 (0.88 mg, 2.75 .mu.mol,
6.11% yield) as a tan solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.50 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.07 (d, J=0.8 Hz,
1H), 7.67 (d, J=7.5 Hz, 1H), 7.60 (d, J=1.0 Hz, 1H), 7.56 (d, J=8.8
Hz, 1H), 7.35-7.29 (m, 1H), 7.28-7.22 (m, 1H), 4.56 (q, J=7.0 Hz,
2H), 2.62 (s, 3H), 1.50 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=1.31
min, MS (ESI) m/z: 305.1 (M+H).sup.+.
Example 662
4-methoxyphenyl
(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-
-5-yl)oxy)ethyl)carbamate
##STR01606##
[3647] Intermediate 662A: tert-butyl
(2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
##STR01607##
[3649] Intermediate I-138A (0.250 g, 0.729 mmol) was dissolved in
DMF (7.29 ml). tert-Butyl (2-bromoethyl)carbamate (0.196 g, 0.875
mmol) and Cs.sub.2CO.sub.3 (1.187 g, 3.64 mmol) were added and the
reaction mixture was stirred at 40.degree. C. overnight. The
reaction mixture was diluted with EtOAc and water and the layers
were separated. The organic layer was washed with brine, dried with
sodium sulfate, and concentrated under reduced pressure. The
reaction was purified on ISCO using a 40 g column with a 0-100%
EtOAc in hexanes gradient to yield Intermediate 662A (0.074 g,
0.228 mmol, 31.3% yield) as a pale yellow solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 6.54 (s, 1H), 5.01 (br. s., 2H), 4.33 (t,
J=5.2 Hz, 2H), 3.52 (d, J=4.8 Hz, 2H), 2.49 (d, J=0.7 Hz, 3H), 1.45
(s, 9H), 1.28-1.24 (m, 1H). LC-MS: method H, RT=0.83 min, MS (ESI)
m/z: 325.2 (M+H).sup.+.
Intermediate 662B: tert-butyl
(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
##STR01608##
[3651] Copper(II) bromide (0.087 g, 0.388 mmol) and t-butyl nitrite
(0.046 ml, 0.388 mmol) were dissolved in MeCN (0.912 ml) and
allowed to stir 10 minutes. Intermediate 662A (0.074 g, 0.228 mmol)
was dissolved in MeCN (1.369 ml) and the copper solution was added.
The reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na+SO.sub.4), filtered,
and concentrated in vacuo to yield Intermediate 662B (0.080 g,
0.206 mmol, 90% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
6.66 (d, J=0.9 Hz, 1H), 4.39 (t, J=5.3 Hz, 2H), 3.54 (d, J=5.1 Hz,
2H), 2.63 (d, J=0.9 Hz, 3H), 1.45 (s, 9H). LC-MS: method H, RT=1.13
min, MS (ESI) m/z: 388.1 (M+H).sup.+.
Intermediate 662C: tert-butyl
(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-
-5-yl)oxy)ethyl)carbamate
##STR01609##
[3653] Intermediate I-9 (0.062 g, 0.206 mmol) and Intermediate 662B
(0.080 g, 0.206 mmol) were dissolved in DMF (1 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (10.10 mg, 0.012 mmol) was
added and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 ml, 0.300
mmol) was added and the reaction degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
The reaction mixture was filtered and purified on 24 g ISCO column
with 0-100% EtOAc in hexanes gradient to yield Intermediate 662C
(0.048 g, 0.100 mmol, 48.4% yield) as a pale yellow solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (d, J=2.0 Hz, 1H), 8.54 (s,
1H), 7.77-7.72 (m, 1H), 6.70 (d, J=0.7 Hz, 1H), 4.47 (t, J=5.2 Hz,
2H), 4.12 (s, 3H), 3.58 (d, J=4.8 Hz, 2H), 2.79 (d, J=0.7 Hz, 3H),
2.66 (s, 3H), 1.53 (s, 9H). LC-MS: method H, RT=1.36 min, MS (ESI)
m/z: 482.1 (M+H).sup.+.
Intermediate 662D:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethanamine
##STR01610##
[3655] To a mixture of Intermediate 662C (0.048 g, 0.100 mmol) in
DCM (1) was added 2,6-lutidine (0.035 ml, 0.299 mmol) followed by
TMS-OTf (0.072 ml, 0.399 mmol) at room temperature. The mixture was
stirred at room temperature for 1 h. The mixture was diluted with
NaHCO.sub.3 and extracted by EtOAc. The combined organic layer was
washed by brine, dried by sodium sulfate and concentrated to yield
Intermediate 662D (0.036 g, 0.094 mmol, 95% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.60 (d, J=1.5 Hz, 1H), 8.53 (s, 1H),
7.74 (d, J=0.9 Hz, 1H), 6.72 (d, J=0.9 Hz, 1H), 4.44 (t, J=5.3 Hz,
2H), 4.12 (s, 3H), 3.12 (t, J=5.3 Hz, 2H), 2.79 (d, J=0.9 Hz, 3H),
2.66 (s, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 382.1
(M+H).sup.+.
Example 662
[3656] Intermediate 662D (0.020 g, 0.052 mmol) was dissolved in DCM
(0.350 ml) and THF (0.175 ml). To the solution was added
4-methoxyphenyl carbonochloridate (0.029 g, 0.157 mmol) followed by
DIEA (0.092 ml, 0.524 mmol). The solution was allowed to stir at
room temperature overnight. The reaction mixture was concentrated
and suspended in 2 mL of hot DMSO, filtered, and purified by
preparative HPLC (Method D, 70% to 100% B in 20 minutes) to yield
Example 662 (0.0027 g, 5.08 mol, 9.69% yield): MS (ESI) m/z: 532.2
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.76 (br.
s., 1H), 8.59 (br. s., 1H), 7.94-7.85 (m, 2H), 7.03 (d, J=8.0 Hz,
2H), 6.79-6.67 (m, 2H), 4.47 (br. s., 2H), 4.11 (br. s., 3H), 3.76
(br. s., 4H), 3.67 (br. s., 2H), 2.77 (br. s., 3H), 2.67 (br. s.,
3H). LC-MS: method H, RT=1.45 min, MS (ESI) m/z: 532.1 (M+H).sup.+.
Analytical HPLC Method B: 100% purity.
Example 663
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetr-
ahydro-2H-pyran-4-yl)methanol
##STR01611##
[3657] Intermediate 663A:
(2-amino-6-methoxybenzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)
methanol
##STR01612##
[3659] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1930 .mu.l). NaH (8.49 mg, 0.212 mmol) was added and the reaction
mixture was stirred for 5 min. The reaction mixture was cooled to
-78.degree. C. and BuLi (101 .mu.l, 0.232 mmol) was added and
allowed to stir for 30 min. Tetrahydro-2H-pyran-4-carbaldehyde
(44.0 mg, 0.386 mmol) was added and the reaction mixture was
allowed to warm to ambient temperature. The reaction mixture was
diluted with EtOAc and washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to yield
Intermediate 663A (0.05 g, 0.170 mmol, 88%). Used without further
purification. LC-MS: method H, RT=0.56 min, MS (ESI) m/z: 295.2
(M+H).sup.+.
Intermediate 663B:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methano-
l
##STR01613##
[3661] Copper(II) chloride (0.044 g, 0.329 mmol) and t-butyl
nitrite (0.039 ml, 0.329 mmol) were dissolved in MeCN (0.775 ml)
and allowed to stir 10 minutes. Intermediate 663A (0.057 g, 0.194
mmol) was dissolved in MeCN (1.162 ml) and the copper solution was
added. The reaction mixture was stirred for 2.5h at 60.degree. C.
The reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. Purified on ISCO using 0-100%
EtOAc in hexanes gradient on a 24 g column to yield Intermediate
663B (0.020 g, 0.064 mmol, 32.9% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.15 (d, J=2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H),
4.72 (t, J=7.6 Hz, 1H), 3.97 (d, J=6.6 Hz, 2H), 3.87 (s, 3H),
3.46-3.34 (m, 3H), 3.27 (td, J=11.8, 2.2 Hz, 1H), 1.28-1.23 (m,
2H), 0.94-0.81 (m, 2H). LC-MS: method H, RT=0.56 min, MS (ESI) m/z:
314.1 (M+H).sup.+.
Example 663
[3662] Intermediate I-9 (9.57 mg, 0.032 mmol) and Intermediate 663B
(0.010, 0.032 mmol) were dissolved in DMF (1 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.561 mg, 1.912 .mu.mol)
was added and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 ml, 0.300
mmol) was added and the reaction degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
The reaction mixture was concentrated and suspended in 2 mL of hot
DMSO, filtered, and purified by preparative HPLC (Method D, 30% to
70% B in 25 minutes) to yield Example 663 (0.0044 g, 9.45 .mu.mol,
29.7% yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.73 (br.
s., 1H), 8.54 (br. s., 1H), 7.82 (br. s., 1H), 7.59 (br. s., 1H),
7.16 (br. s., 1H), 5.48-5.31 (m, 2H), 4.08 (br. s., 3H), 3.88-3.86
(m, 3H), 3.78 (d, J=9.8 Hz, 1H), 3.27-3.16 (m, 2H), 2.64 (br. s.,
3H), 2.00 (br. s., 1H), 1.71 (d, J=11.8 Hz, 1H), 1.45 (t, J=12.6
Hz, 3H), 1.19 (d, J=12.5 Hz, 2H). LC-MS: method H, RT=1.45 min, MS
(ESI) m/z: 452.2 (M+H).sup.+. Analytical HPLC Method B: 97%
purity.
Example 664
(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetr-
ahydro-2H-pyran-4-yl)methanol
##STR01614##
[3663] Intermediate 664A:
(2-amino-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)met-
hanone
##STR01615##
[3665] Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF
(1930 .mu.l). NaH (8.49 mg, 0.212 mmol) was added and the reaction
mixture was stirred for 30 min. The reaction mixture was cooled to
-78.degree. C. and BuLi (101 .mu.l, 0.232 mmol) was added and the
reaction mixture was allowed to stir for 30 min. Methyl
1-(trifluoromethyl) cyclobutanecarboxylate (35.1 mg, 0.193 mmol)
was added and the reaction mixture was allowed to warm to ambient
temperature. The reaction mixture was stirred for 10 min and
diluted with water and EtOAc. The layers were separated and the
aqueous layer was back extracted with EtOAc. The combined organic
layer was washed with water, dried with sodium sulfate, and
concentrated under reduced pressure to yield Intermediate 664A
(0.023 g, 0.191 mmol, 33%). LC-MS: method H, RT=0.77 min, MS (ESI)
m/z: 331.2 (M+H).sup.+.
Intermediate 664B:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)
cyclobutyl)methanone
##STR01616##
[3667] Copper(II) chloride (0.042 g, 0.309 mmol) and t-butyl
nitrite (0.037 ml, 0.309 mmol) were dissolved in MeCN (0.727 ml)
and allowed to stir 10 minutes. Intermediate 664A (0.060 g, 0.182
mmol) was dissolved in MeCN (1.090 ml) and the copper solution was
added. The reaction mixture was stirred for 2.5 h at 60.degree. C.
The reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. Purified on ISCO using a 12 g
column with 0-100% gradient of EtOAc in hexanes to yield
Intermediate 664B (0.025 g, 0.036 mmol, 19.68% yield). LC-MS:
method H, RT=1.12 min, MS (ESI) m/z: 350.1 (M+H).sup.+.
Intermediate 664C:
(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)
cyclobutyl)methanol
##STR01617##
[3669] Intermediate 664B (0.035 g, 0.100 mmol) was dissolved in
MeOH (1.00 ml) and cooled to 0.degree. C. Sodium borohydride (3.79
mg, 0.100 mmol) was added to the flask, and the reaction mixture
was allowed to stir for 2h. The reaction mixture was diluted with
water and EtOAc. The layers were separated, and the aqueous layer
was back extracted with EtOAc.times.3. The combined organic layer
was washed with water, dried with sodium sulfate, and concentrated
under reduced pressure to yield Intermediate 664C (0.030 g, 0.085
mmol, 85% yield) as a white solid. Used without further
purification. LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 352.1
(M+H).sup.+.
Example 664
[3670] Intermediate I-9 (0.065 g, 0.216 mmol) and Intermediate 664B
(0.076 g, 0.216 mmol) were dissolved in DMF (2.160 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (10.59 mg, 0.013 mmol) was
added and the reaction degassed by bubbling with argon for 15
minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 ml, 0.300
mmol) was added and the reaction degassed for 5 minutes, then
sealed and heated to 90.degree. C. in the microwave for 30 minutes.
Enantiomers were separated using Lux 5 u Cellulose-4, 21.times.250
mm, 5 micron column with 35% EtOH/65% CO.sub.2, UV 220 nm to afford
Example 664 (10.7 mg, 0.021 mmol, 9.61% yield) as a single
enantiomer (99% enantiomeric excess). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.56 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.77 (s,
1H), 7.37 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 5.81 (d, J=9.2
Hz, 1H), 5.34 (d, J=9.2 Hz, 1H), 4.13 (s, 3H), 3.92 (s, 3H), 2.73
(s, 2H), 2.65 (s, 3H), 2.35 (s, 4H), 1.88 (s, 1H). LC-MS: method H,
RT=1.34 min, MS (ESI) m/z: 490.1 (M+H).sup.+. Analytical HPLC
Method B: 97% purity
Examples 665 to 677
[3671] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
663 or Example 664 and the examples above.
TABLE-US-00017 LCMS LCMS Ex. [M + H].sup.+ RT(Min)/ No. Structure
m/z Method NMR 665 ##STR01618## 498.2 1.37/H .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.41 (s, 1H), 7.78 (s, 1H),
7.46 (s, 1H), 7.11-7.07 (m, 2H), 6.99-6.94 (m, 1H), 6.90 (d, J =
7.3 Hz, 2H), 6.48 (s, 1H), 5.94 (d, J = 4.9 Hz, 1H), 5.59 (d, J =
4.9 Hz, 1H), 4.06 (s, 3H), 3.66 (s, 3H), 2.75 (d, J = 7.3 Hz, 1H),
2.65 (s, 4H), 2.25 (d, J = 9.2 Hz, 1H), 2.18-2.03 (m, 2H), 1.75
(br. s., 1H). 666 ##STR01619## 466.2 1.35/H .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.72 (br. s., 1H), 8.56 (br. s., 1H), 7.81
(br. s., 1H), 7.59 (br. s., 1H), 7.15 (br. s., 1H), 5.67 (br. s.,
1H), 5.36 (br. s., 1H), 4.07 (br. s., 3H), 3.86 (br. s., 3H),
3.43-3.38 (m, 2H), 3.17 (br. s., 3H), 2.63 (br. s., 3H), 2.35 (br.
s., 1H), 2.23-2.13 (m, 1H), 1.74 (br. s., 4H). 667 ##STR01620##
476.1 1.29/H .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.70 (s,
1H), 8.53 (s, 1H), 7.79 (s, 1H), 7.62 (s, 1H), 7.19 (s, 1H),
5.93-5.90 (m, 1H), 5.89-5.86 (m, 1H), 4.06 (s, 3H), 3.86 (s, 3H),
2.60 (s, 3H), 1.22 (br. s., 1H), 0.92 (br. s., 2H), 0.49 (d, J =
9.5 Hz, 1H). 668 ##STR01621## 484.2 1.27/H .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.68 (s, 1H), 8.45 (s, 1H), 7.78 (s, 1H),
7.48 (d, J = 1.7 Hz, 1H), 7.20-7.00 (m, 5H), 6.73 (s, 1H), 5.58 (d,
J = 4.4 Hz, 1H), 5.51 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 3.71 (s,
3H), 2.65 (s, 3H), 1.37 (d, J = 4.4 Hz, 1H), 1.00 (d, J = 4.0 Hz,
1H), 0.78- 0.65 (m, 2H). 669 ##STR01622## 490.1 1.34/H .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.45 (s, 1H), 7.78
(s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 5.98
(d, J = 5.2 Hz, 1H), 5.92 (d, J = 5.2 Hz, 1H), 4.05 (s, 3H), 3.86
(s, 3H), 2.58 (s, 3H), 2.21-2.01 (m, 2H), 1.80 (d, J = 10.4 Hz,
1H), 1.67-1.53 (m, 1H), 1.20 (br. s., 1H), 0.80 (br. s., 1H). 671
##STR01623## 476.1 1.29/H .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.55 (s, 1H), 8.49 (s, 1H), 7.77 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H),
7.01 (d, J = 2.4 Hz, 1H), 5.72-5.64 (m, 1H), 5.53 (s, 1H), 4.13 (s,
3H), 3.92 (s, 3H), 2.66 (s, 3H), 1.17 (br. s., 1H), 1.02 (dt, J =
18.2, 5.7 Hz, 2H), 0.58 (d, J = 8.8 Hz, 1H) 672 ##STR01624## 464.2
1.43 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (s, 1H), 8.47
(d, J = 1.5 Hz, 1H), 7.75 (dd, J = 1.8, 0.9 Hz, 1H), 7.31 (d, J =
2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 5.84 (d, J = 9.1 Hz, 1H),
4.79 (d, J = 9.5 Hz, 1H), 4.13 (s, 3H), 3.91 (s, 3H), 2.66 (s, 3H),
1.61 (br. s., 10H), 0.96 (s, 3H). 673 ##STR01625## 451.0 1.15/H
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.68 (s, 1H), 8.50 (s,
1H), 7.78 (s, 1H), 7.70-7.60 (m, 3H), 7.13 (s, 1H), 6.96 (br. s.,
1H), 6.91 (br. s., 1H), 4.06 (s, 3H), 3.84 (s, 3H), 2.61 (s, 3H).
674 ##STR01626## 466.2 1.23/H .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.67 (s, 1H), 8.49 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H),
7.13 (s, 1H), 5.58-5.42 (m, 2H), 4.05 (s, 3H), 3.85 (s, 3H),
3.77-3.59 (m, 3H), 3.42 (br. s., 1H), 2.61 (s, 3H), 1.93-1.73 (m,
2H), 1.44 (br. s., 1H), 0.98 (s, 3H), 0.89-0.82 (m, 1H). 675
##STR01627## 492.1 1.29/H .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.73 (s, 1H), 8.66 (s, 1H), 7.84 (s, 1H), 7.61 (d, J = 2.1
Hz, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 7.01 (d, J = 9.8 Hz, 1H),
6.72-6.64 (m, 2H), 6.32 (d, J = 4.3 Hz, 1H), 4.12 (s, 3H), 3.91 (s,
3H), 3.78 (s, 3H), 2.68 (s, 3H). 676 ##STR01628## 464.2 1.39/H
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.52 (s,
1H), 7.80 (s, 1H), 7.58 (br. s., 1H), 7.14 (br. s., 1H), 5.46 (br.
s., 1H), 5.32 (d, J = 4.0 Hz, 1H), 4.08 (s, 3H), 3.87 (s, 3H), 3.48
(br. s., 3H), 2.63 (s, 3H), 1.69-1.49 (m, 6H), 1.43-1.29 (m, 2H),
1.24-1.13 (m, 1H), 1.05 (d, J = 12.5 Hz, 1H). 677 ##STR01629##
382.1 1.19/H .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.55 (s, 1H), 7.80 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.23 (d,
J = 2.1 Hz, 1H), 5.72-5.59 (m, 1H), 4.08 (s, 3H), 3.88 (s, 3H),
3.39 (br. s., 1H), 2.64 (s, 3H), 2.56 (s, 3H).
Example 678
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01630##
[3673] To a solution of Intermediate I-132 (17 mg, 0.037 mmol) in
DCM (1 mL) and THF (0.5 mL) was added 2-methylpyrimidin-5-amine
(8.02 mg, 0.073 mmol) followed by pyridine (0.030 mL, 0.367 mmol).
The mixture was stirred at room temperature for 1 hour. The
reaction was quenched with 0.2 mL of MeOH. The reaction mixture was
concentrated and redissolved in DMF, filtered, and purified by
preparative HPLC (Method D, 25 to 100% B in 20 minutes) to yield
Example 678 (5.9 mg, 10.58 .mu.mol, 28.8% yield): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.97 (br. s., 1H), 8.71 (br. s., 2H),
8.63-8.59 (m, 1H), 8.44 (s, 1H), 8.37 (d, J=10.7 Hz, 1H), 7.77 (s,
1H), 5.26 (br. s., 1H), 4.79 (d, J=10.7 Hz, 1H), 4.57-4.44 (m, 1H),
4.05 (s, 3H), 3.44 (br. s., 3H), 2.58 (s, 3H), 1.40 (d, J=6.4 Hz,
3H). LC-MS: method H, RT=1.45 min, MS (ESI) m/z: 536.2 (M+H).sup.+.
Analytical HPLC Method B: 96% purity.
Examples 679 to 702
[3674] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
678 and the examples above. If necessary, removal of silyl
protecting groups was accomplished by treatment of the protected
compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or
MeOH/HCl (20/1) solution to afford the desired compound.
TABLE-US-00018 LCMS RT LCMS (Min) Ex. [M + H].sup.+ Method No.
Structure Amine m/z H NMR 679 ##STR01631## ##STR01632## 552.1 1.27
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.82 (br. s., 1H),
8.62-8.54 (m, 2H), 8.40 (br. s., 1H), 8.34 (d, J = 10.7 Hz, 1H),
7.73 (s, 1H), 5.24 (br. s., 1H), 4.79 (d, J = 11.3 Hz, 1H), 4.48
(t, J = 11.6 Hz, 1H), 4.04 (s, 3H), 3.45 (br. s., 1H), 2.57 (s,
3H), 2.54 (s, 3H), 1.46-1.37 (m, 3H). 680 ##STR01633## ##STR01634##
521.1 1.07 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.60- 8.56
(m, 1H), 8.42 (s, 1H), 8.35 (d, J = 9.5 Hz, 3H), 7.75 (s, 1H), 7.43
(d, J = 5.2 Hz, 2H), 5.28 (br. s., 1H), 4.78 (d, J = 10.1 Hz, 1H),
4.56-4.47 (m, 1H), 4.04 (s, 3H), 2.57 (s, 3H), 1.54-1.31 (m, 3H).
681 ##STR01635## ##STR01636## 535.1 1.06 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.80 (br. s., 1H), 8.62 (s, 1H), 8.45 (br.
s., 2H), 8.37 (d, J = 10.7 Hz, 1H), 7.77 (s, 2H), 7.16 (d, J = 7.9
Hz, 1H), 5.26 (br. s., 1H), 4.75 (d, J = 9.5 Hz, 1H), 4.50 (dd, J =
11.7, 6.0 Hz, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 2.35 (s, 3H), 1.39
(d, J = 6.4 Hz, 3H). 682 ##STR01637## ##STR01638## 539.1 1.27
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.21 (br. s., 1H),
8.60 (s, 1H), 8.46-8.34 (m, 3H), 8.17 (s, 1H), 7.94 (s, 1H), 7.76
(s, 1H), 5.28 (br. s., 1H), 4.78 (d, J = 10.4 Hz, 1H), 4.51 (dd, J
= 11.7, 5.6 Hz, 1H), 4.05 (s, 3H), 3.42 (br. s., 3H), 2.58 (s, 3H),
1.41 (d, J = 6.4 Hz, 3H). 683 ##STR01639## ##STR01640## 577.1 1.23
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.51 (d,
J = 1.7 Hz, 1H), 8.43 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H), 7.39-
7.33 (m, 1H), 7.09-7.04 (m, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.26
(td, J = 6.3, 3.0 Hz, 1H), 4.74 (dd, J = 11.7, 2.9 Hz, 1H), 4.54
(dd, J = 11.7, 6.2 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 1.40 (d, J
= 6.6 Hz, 3H). 684 ##STR01641## ##STR01642## 521.2 1.07 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.61 (s, 2H), 8.44 (s, 1H), 8.37
(d, J = 10.7 Hz, 1H), 8.19 (br. s., 1H), 7.89 (br. s., 1H), 7.76
(s, 1H), 7.32 (br. s., 1H), 5.28 (br. s., 1H), 4.75 (d, J = 9.8 Hz,
1H), 4.52 (dd, J = 11.4, 6.0 Hz, 1H), 4.05 (s, 3H), 2.58 (s, 3H),
1.41 (d, J = 6.4 Hz, 3H). 685 ##STR01643## I-97 582.2 1.15 .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.73- 8.51 (m, 4H), 8.01 (d, J =
9.7 Hz, 1H), 7.79 (br. s., 1H), 6.64 (br. s., 1H), 5.80 (br. s.,
1H), 5.41 (br. s., 1H), 4.83 (br. s., 1H), 4.50 (br. s., 2H), 4.15
(s, 3H), 4.00 (br. s., 2H), 2.67 (s, 3H), 1.52 (t, J = 6.1 Hz, 3H).
686 ##STR01644## I-98 566.2 1.13 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.96 (br. s., 1H), 8.76-8.65 (m, 3H), 8.51
(s, 2H), 8.42 (d, J = 10.7 Hz, 2H), 7.83 (s, 2H), 5.75-5.64 (m,
1H), 5.27 (br. s., 1H), 4.81 (d, J = 11.6 Hz, 1H), 4.58-4.46 (m,
1H), 4.07 (s, 3H), 3.77 (br. s., 2H), 2.91 (d, J = 6.7 Hz, 2H),
2.61 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 687 ##STR01645## I-99 631.2
1.27 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.69 (br. s., 1H),
8.58 (s, 1H), 8.42 (s, 1H), 8.33 (d, J = 10.7 Hz, 1H), 8.20 (br.
s., 1H), 7.85-7.78 (m, 1H), 7.74 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H),
5.72-5.59 (m, 1H), 5.26 (br. s., 1H), 4.75 (d, J = 9.8 Hz, 1H),
4.56-4.43 (m, 3H), 4.05 (s, 3H), 3.82-3.65 (m, 2H), 2.58 (s, 3H),
1.41 (d, J = 6.4 Hz, 3H). 688 ##STR01646## I-103 596.1 1.26 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.87- 9.76 (m, 1H), 8.65 (s,
1H), 8.60 (br. s., 2H), 8.48 (s, 1H), 8.41 (d, J = 10.7 Hz, 1H),
7.80 (s, 1H), 5.69 (d, J = 6.4 Hz, 1H), 5.31-5.23 (m, 1H),
4.86-4.76 (m, 1H), 4.53 (dd, J = 11.6, 6.1 Hz, 1H), 4.07 (s, 3H),
4.05-3.99 (m, 1H), 3.93 (br. s., 1H), 3.54 (d, J = 4.9 Hz, 1H),
2.61 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H).
689 ##STR01647## I-107 580.2 1.20 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.39 (br. s., 1H), 8.23 (br. s., 1H),
7.97-7.84 (m, 3H), 7.63 (d, J = 7.6 Hz, 2H), 7.34- 7.05 (m, 2H),
6.57 (d, J = 9.5 Hz, 1H), 5.75 (d, J = 6.1 Hz, 1H), 2.54 (s, 3H),
2.50 (br. s., 3H), 2.13 (br. s., 3H), 1.54 (d, J = 4.9 Hz, 3H). 690
##STR01648## ##STR01649## 579.2 1.23 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.65 (br. s., 2H), 8.54 (s, 1H), 8.46 (d, J =
10.7 Hz, 1H), 8.05 (br. s., 1H), 8.00 (s, 1H), 7.86 (s, 1H), 5.29
(br. s., 1H), 4.96 (d, J = 11.9 Hz, 1H), 4.53 (dd, J = 11.6, 5.2
Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H). 691
##STR01650## I-109 565.1 1.00 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.78 (br. s., 1H), 8.65 (s, 1H), 8.57-8.47 (m, 2H), 8.39
(d, J = 10.7 Hz, 1H), 7.90- 7.68 (m, 2H), 7.18 (d, J = 8.5 Hz, 1H),
5.66 (br. s., 1H), 5.28 (dt, J = 6.3, 3.3 Hz, 1H), 4.76 (dd, J =
11.7, 2.9 Hz, 1H), 4.53 (dd, J = 11.7, 6.3 Hz, 1H), 4.07 (s, 3H),
3.68 (d, J = 5.2 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.61 (s, 3H),
1.42 (d, J = 6.7 Hz, 3H). 692 ##STR01651## I-106 596.1 1.20 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80 (br. s., 1H), 8.64-8.62
(m, 1H), 8.60 (br. s., 2H), 8.47 (s, 1H), 8.39 (d, J = 10.7 Hz,
1H), 7.79 (s, 1H), 5.68 (br. s., 1H), 5.31-5.23 (m, 1H), 5.01 (d, J
= 5.2 Hz, 1H), 4.89-4.84 (m, 1H), 4.82-4.76 (m, 1H), 4.53 (dd, J =
11.7, 6.0 Hz, 2H), 4.07 (s, 3H), 2.60 (s, 3H), 1.48-1.39 (m, 3H),
1.25-1.18 (m, 3H). 693 ##STR01652## I-105 596.2 1.20 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.80 (br. s., 1H), 8.67-8.54 (m,
2H), 8.45 (s, 2H), 8.37 (d, J = 10.7 Hz, 1H), 7.77 (s, 1H), 5.68
(br. s., 1H), 5.27 (br. s., 2H), 5.00 (d, J = 5.2 Hz, 2H),
4.91-4.85 (m, 1H), 4.80 (d, J = 9.5 Hz, 1H), 4.52 (dd, J = 11.6,
5.8 Hz, 2H), 4.07 (s, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H),
1.20 (d, J = 6.4 Hz, 3H). 694 ##STR01653## 385B 551.1 1.01 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.87 (br. s., 1H), 8.65-8.60
(m, 1H), 8.55- 8.49 (m, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.37 (d, J =
10.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.39 (d, J =
8.5 Hz, 1H), 5.67 (br. s., 1H), 5.29 (dt, J = 6.4, 3.2 Hz, 1H),
4.76 (dd, J = 11.6, 2.7 Hz, 1H), 4.54 (dd, J = 11.9, 6.1 Hz, 1H),
4.49 (s, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 1.51-1.35 (m, 3H). 695
##STR01654## I-92 593.2 1.03 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.72 (br. s., 1H), 8.55 (s, 1H), 8.42 (br. s., 1H), 8.37
(s, 1H), 8.29 (d, J = 10.7 Hz, 1H), 7.69 (s, 2H), 7.12 (d, J = 8.5
Hz, 1H), 5.25-5.15 (m, 1H), 4.68 (dd, J = 11.6, 2.4 Hz, 1H), 4.59
(s, 1H), 4.46 (dd, J = 11.7, 6.3 Hz, 1H), 3.99 (s, 3H), 2.52 (s,
3H), 1.35 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 2.4 Hz, 6H). 696
##STR01655## I-94 565.2 1.02 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.63- 8.58 (m, 1H), 8.45 (s, 1H), 8.39-8.34 (m, 1H),
8.28-8.22 (m, 1H), 7.77 (s, 1H), 7.32 (s, 1H), 7.28 (d, J = 3.7 Hz,
2H), 5.72-5.61 (m, 1H), 5.33-5.26 (m, 1H), 4.78 (d, J = 9.2 Hz,
1H), 4.53 (dd, J = 11.7, 6.3 Hz, 1H), 4.07 (s, 3H), 3.68 (br. s.,
2H), 2.79-2.70 (m, 2H), 2.60 (s, 3H), 1.49-1.39 (m, 3H). 697
##STR01656## I-110 581.1 1.03 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.09 (br. s., 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.38 (d, J
= 11.0 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.04 (d, J
= 5.8 Hz, 1H), 6.88 (s, 1H), 5.29 (br. s., 1H), 4.80 (d, J = 11.9
Hz, 1H), 4.55- 4.50 (m, 2H), 4.22-4.14 (m, 4H), 4.07 (s, 3H), 2.61
(s, 3H), 1.42 (d, J = 6.7 Hz, 3H). 698 ##STR01657## ##STR01658##
522.1 1.03 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.43 (br.
s., 1H), 9.16-9.11 (m, 1H), 8.98 (d, J = 5.8 Hz, 1H), 8.68-8.63 (m,
1H), 8.52 (br. s., 1H), 8.47-8.39 (m, 1H), 7.85 (br. s., 1H), 7.76
(br. s., 1H), 5.37-5.24 (m, 1H), 4.98-4.88 (m, 1H), 4.54 (s, 1H),
4.39-4.28 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.53-1.41 (m, 3H).
699 ##STR01659## I-108 623.2 1.10 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.07 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H),
8.34 (d, J = 10.7 Hz, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.75 (s, 1H),
7.01 (d, J = 5.8 Hz, 1H), 6.85 (s, 1H), 5.28 (br. s., 1H), 4.80 (d,
J = 9.8 Hz, 1H), 4.50 (dd, J = 11.7, 5.6 Hz, 1H), 4.34-4.19 (m,
2H), 4.06 (s, 3H), 3.46 (br. s., 2H), 2.59 (s, 3H), 1.76 (t, J =
7.3 Hz, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.14-1.08 (m, 6H). 700
##STR01660## I-93 581.1 1.18 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.60 (br. s., 1H), 8.59 (s, 1H), 8.43 (br. s., 1H), 8.34
(d, J = 10.7 Hz, 1H), 8.16 (br. s., 1H), 7.75 (br. s., 2H), 6.75
(d, J = 8.9 Hz, 1H), 5.74-5.59 (m, 1H), 5.25 (br. s., 1H), 4.76 (d,
J = 10.1 Hz, 1H), 4.57- 4.44 (m, 1H), 4.16 (d, J = 4.3 Hz, 2H),
4.06 (s, 3H), 3.67 (br. s., 2H), 2.59 (s, 3H), 1.51-1.37 (m, 3H).
701 ##STR01661## I-104 596.1 1.26 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.82 (br. s., 1H), 8.70-8.65 (m, 1H), 8.63-
8.55 (m, 2H), 8.51 (s, 1H), 8.43 (d, J = 11.0 Hz, 1H), 7.82 (s,
1H), 5.70 (br. s., 1H), 5.27 (t, J = 6.1 Hz, 1H), 4.89-4.77 (m,
2H), 4.53 (dd, J = 11.6, 5.8 Hz, 1H), 4.08 (s, 3H), 4.03-3.89 (m,
1H), 3.58-3.34 (m, 1H), 2.62 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H),
1.11 (d, J = 5.8 Hz, 3H). 702 ##STR01662## I-100 624.2 1.30 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.79 (br. s., 1H), 8.69 (s,
1H), 8.59 (br. s., 2H), 8.53 (s, 1H), 8.44 (d, J = 10.7 Hz, 1H),
7.84 (s, 1H), 5.25 (br. s., 1H), 4.85 (br. s., 1H), 4.58-4.48 (m,
1H), 4.38 (s, 1H), 4.30 (d, J = 7.6 Hz, 2H), 4.09 (s, 3H),
3.43-3.33 (m, 2H), 2.63 (s, 3H), 1.41 (d, J = 6.7 Hz, 3H), 1.14 (s,
6H).
Example 708
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate
##STR01663##
[3676] To a solution of Intermediate I-134 (17 mg, 0.036 mmol) in
DCM (1 mL) and THF (0.5 mL), was added
6-aminobenzo[d]oxazol-2(3H)-one (10.70 mg, 0.071 mmol) followed by
pyridine (0.029 mL, 0.356 mmol). The mixture was stirred at room
temperature for 1 hour. The reaction was quenched with 0.2 mL of
MeOH. The reaction mixture was concentrated and redissolved in DMF,
filtered, and purified by preparative HPLC (Method D, 40 to 80% B
in 20 minutes) to yield Example 708 (6 mg, 9.96 .mu.mol, 27.9%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.56 (br. s.,
1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.35 (d, J=10.4 Hz, 1H), 7.75 (s,
1H), 7.39 (br. s., 1H), 7.09 (br. s., 1H), 6.91 (d, J=7.6 Hz, 1H),
5.64 (d, J=6.4 Hz, 1H), 5.13 (d, J=6.4 Hz, 1H), 4.06 (s, 3H),
3.54-3.38 (m, 1H), 2.59 (s, 3H), 1.45 (d, J=6.4 Hz, 3H), 1.40-1.35
(m, 3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 591.1
(M+H).sup.+. Analytical HPLC Method B: 98% purity.
Examples 709 to 731
[3677] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
708 and the examples above. If necessary, removal of silyl
protecting groups was accomplished by treatment of the protected
compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or
MeOH/HCl (20/1) solution to afford the desired compound.
TABLE-US-00019 LCMS LCMS RT [M + (Min) Ex. H].sup.+ Method No.
Structure Amine m/z H NMR 709 ##STR01664## ##STR01665## 535.2 1.01
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.81 (br. s., 1H),
8.61- 8.50 (m, 2H), 8.39 (br. s., 1H), 8.31 (d, J = 10.7 Hz, 1H),
8.16 (br. s., 1H), 7.87 (br. s., 1H), 7.72 (br. s., 1H), 7.30 (br.
s., 1H), 5.62 (d, J = 5.2 Hz, 1H), 5.16 (d, J = 6.1 Hz, 1H), 4.05
(s, 3H), 3.56 (br. s., 3H), 1.45 (d, J = 5.8 Hz, 3H), 1.39 (d, J =
5.8 Hz, 3H). 710 ##STR01666## ##STR01667## 549.1 1.11 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.76 (br. s., 1H), 8.60 (s, 1H),
8.46 (br. s., 2H), 8.38 (d, J = 10.7 Hz, 1H), 7.78 (br. s., 2H),
7.21 (br. s., 1H), 5.66 (d, J = 6.7 Hz, 1H), 5.14 (d, J = 6.1 Hz,
1H), 4.07 (s, 3H), 2.60 (s, 3H), 2.35 (s, 3H), 1.45 (d, J = 6.4 Hz,
3H), 1.39 (d, J = 6.4 Hz, 3H). 711 ##STR01668## ##STR01669## 566.0
1.31 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.70 (br. s., 1H),
8.60 (d, J = 9.2 Hz, 3H), 8.48 (s, 1H), 8.40 (d, J = 10.4 Hz, 1H),
7.80 (s, 1H), 5.73 (d, J = 5.2 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H),
4.08 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H),
1.38 (d, J = 6.7 Hz, 3H). 712 ##STR01670## I-107 594.2 1.18 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.28 (s, 1H), 8.91 (br. s.,
2H), 8.49-8.41 (m, 2H), 8.37 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H),
5.82 (d, J = 6.7 Hz, 1H), 5.14 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H),
3.83 (s, 3H), 2.58 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J =
6.4 Hz, 3H). 713 ##STR01671## ##STR01672## 535.2 1.01 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.04 (s, 1H), 8.50 (s, 1H), 8.39
(s, 1H), 8.34-8.29 (m, 3H), 7.72 (s, 1H), 7.39 (d, J = 5.2 Hz, 2H),
5.66 (d, J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.05 (s, 3H),
2.56 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
714 ##STR01673## ##STR01674## 553.2 1.25 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.07 (br. s., 1H), 8.51 (s, 1H), 8.40 (s,
1H), 8.36 (br. s., 1H), 8.32 (d, J = 10.7 Hz, 1H), 8.13 (br. s.,
1H), 7.83-7.76 (m, 1H), 7.72 (s, 1H), 5.67 (d, J = 6.4 Hz, 1H),
5.15 (d, J = 6.4 Hz, 1H), 4.05 (s, 3H), 2.58-2.56 (m, 3H), 1.44 (d,
J = 6.1 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 715 ##STR01675##
##STR01676## 593.2 1.21 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.06 (s, 1H), 8.54 (br. s., 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.33
(d, J = 10.7 Hz, 1H), 8.00 (br. s., 1H), 7.93 (d, J = 8.5 Hz, 1H),
7.74 (s, 1H), 5.81 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H),
4.06 (s, 3H), 3.77 (s, 3H), 2.58 (br. s., 3H), 1.44 (d, J = 6.4 Hz,
3H), 1.38 (d, J = 6.4 Hz, 3H). 716 ##STR01677## ##STR01678## 536.3
1.23 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.12-9.93 (m,
1H), 8.83 (br. s., 2H), 8.79 (s, 1H), 8.67 (s, 1H), 8.54 (d, J =
1.9 Hz, 1H), 8.44 (d, J = 10.7 Hz, 1H), 7.85 (s, 1H), 5.70 (dd, J =
6.7, 2.6 Hz, 1H), 5.16 (dd, J = 6.6, 2.5 Hz, 1H), 4.09 (s, 3H),
2.63 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.40 (d, J = 6.6 Hz, 3H).
717 ##STR01679## I-94 579.3 1.00 1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.00 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.40 (d, J =
11.0 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.80 (s, 1H), 7.29 (br. s.,
2H), 5.67 (d, J = 6.4 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.08 (s,
3H), 3.64 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.61 (s,
3H), 1.46 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H). 718
##STR01680## I-92 607.2 1.06 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.64 (br. s., 1H), 8.54 (s, 1H), 8.40 (s, 2H), 8.29 (d, J =
10.7 Hz, 1H), 7.74 (s, 2H), 7.22-7.13 (m, 1H), 5.65 (dd, J = 6.7,
2.4 Hz, 1H), 5.12 (dd, J = 6.7, 2.4 Hz, 1H), 4.05 (s, 3H),
3.71-3.70 (m, 1H), 2.67 (d, J = 9.2 Hz, 2H), 2.57 (s, 3H), 1.43 (d,
J = 6.7 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 8.9 Hz,
6H). 719 ##STR01681## I-110 595.1 1.07 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.93 (s, 1H), 8.55 (s, 1H), 8.46 (s, 1H),
8.36 (d, J = 10.7 Hz, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.77 (s, 1H),
7.00 (d, J = 5.5 Hz, 1H), 6.81 (s, 1H), 5.68 (dd, J = 6.6, 2.3 Hz,
1H), 5.14 (dd, J = 6.7, 2.1 Hz, 1H), 4.19-4.09 (m, 3H), 4.07 (s,
3H), 3.65-3.58 (m, 1H), 3.46 (br. s., 1H), 2.60 (s, 3H), 1.44 (d, J
= 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H). 720 ##STR01682## I-109
579.1 1.04 MS (ESI) m/z: 579.1 (M + H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.67 (br. s., 1H), 8.58 (s, 1H), 8.44 (s,
2H), 8.33 (d, J = 10.7 Hz, 1H), 7.76 (s, 2H), 7.16 (d, J = 7.9 Hz,
1H), 5.62 (dd, J = 6.4, 2.4 Hz, 1H), 5.14 (dd, J = 6.4, 2.4 Hz,
1H), 4.06 (s, 3H), 3.65 (t, J = 6.9 Hz, 1H), 3.48 (br. s., 1H),
2.76 (d, J = 4.0 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H),
1.38 (d, J = 6.7 Hz, 3H). 721 ##STR01683## I-97 596.1 1.21 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.71 (br. s., 1H), 8.62 (br.
s., 1H), 8.50 (s, 1H), 8.40 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H),
5.75 (d, J = 6.4 Hz, 1H), 5.17 (d, J = 6.7 Hz, 1H), 4.96 (t, J =
5.5 Hz, 1H), 4.28-4.16 (m, 2H), 4.12 (s, 3H), 3.72 (d, J = 5.2 Hz,
2H), 2.65 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.43 (d, J = 6.7 Hz,
3H). 722 ##STR01684## I-106 610.1 1.24 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.78-9.71 (m, 1H), 8.70-8.60 (m, 2H), 8.52
(s, 1H), 8.43 (d, J = 10.4 Hz, 1H), 7.84 (s, 1H), 5.73 (dd, J =
6.4, 2.4 Hz, 1H), 5.18 (dd, J = 6.6, 2.3 Hz, 1H), 5.02 (br. s.,
1H), 4.93-4.86 (m, 1H), 4.13 (s, 3H), 3.65-3.38 (m, 3H), 2.66 (s,
3H), 1.49 (d, J = 6.1 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H). 723
##STR01685## I-94 565.1 1.05 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.82-9.74 (m, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.53-8.46
(m, 2H), 8.39 (d, J = 11.0 Hz, 1H), 7.92-7.83 (m, 1H), 7.80 (s,
1H), 7.38 (d, J = 8.5 Hz, 1H), 5.64 (dd, J = 6.6, 2.6 Hz, 1H), 5.16
(dd, J = 6.6, 2.3 Hz, 1H), 4.47 (s, 2H), 4.08 (s, 3H), 2.61 (s,
3H), 1.46 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H). 724
##STR01686## I-105 610.1 1.23 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.68-9.57 (m, 1H), 8.57 (s, 1H), 8.52 (br. s., 1H), 8.43
(s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.75 (s, 1H), 5.65 (dd, J =
6.7, 2.4 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.91 (d, J = 5.5 Hz,
1H), 4.80 (t, J = 5.6 Hz, 1H), 4.03 (s, 3H), 3.54-3.38 (m, 3H),
2.56 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.7 Hz, 3H),
1.10 (d, J = 6.1 Hz, 3H). 725 ##STR01687## I-93 595.2 1.22 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.42 (br. s., 1H), 8.52 (br.
s., 1H), 8.40 (br. s., 1H), 8.34-8.24 (m, 1H), 8.14- 8.01 (m, 1H),
7.73 (br. s., 2H), 6.80-6.59 (m, 1H), 5.66 (br. s., 1H), 5.09 (d, J
= 6.1 Hz, 1H), 4.92 (s, 1H), 4.15- 4.08 (m, 1H), 4.05 (s, 3H),
3.72-3.57 (m, 4H), 2.59-2.55 (m, 3H), 1.42 (d, J = 6.1 Hz, 3H),
1.35 (d, J = 6.4 Hz, 3H). 726 ##STR01688## I-99 645.2 1.30 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.57 (br. s., 1H), 8.54 (s,
1H), 8.42 (s, 1H), 8.31 (d, J = 10.4 Hz, 1H), 8.17 (br. s., 1H),
7.85 (br. s., 1H), 7.75 (s, 1H), 6.88 (br. s., 1H), 5.79 (t, J =
6.1 Hz, 1H), 5.71 (d, J = 5.8 Hz, 1H), 5.17 (d, J = 5.8 Hz, 1H),
4.60-4.39 (m, 2H), 4.10 (s, 3H), 3.77 (br. s., 2H), 2.61 (s, 3H),
1.49 (d, J = 6.4 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H). 727
##STR01689## I-108 637.2 1.13 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.90 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.34 (d, J = 10.7
Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H), 6.99 (d, J = 5.2
Hz, 1H), 6.76 (s, 1H), 5.70 (d, J = 4.9 Hz, 1H), 5.13 (d, J = 6.4
Hz, 1H), 4.27-4.13 (m, 2H), 4.06 (s, 3H), 3.48 (s, 1H), 2.59 (s,
3H), 2.52 (br. s., 6H), 1.72 (t, J = 6.4 Hz, 2H), 1.44 (d, J = 6.4
Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H). 728 ##STR01690## I-103 610.2
1.29 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.72-9.62 (m, 1H),
8.63 (br. s., 1H), 8.57 (br. s., 2H), 8.50 (s, 1H), 8.41 (d, J =
10.4 Hz, 1H), 7.81 (s, 1H), 5.71 (d, J = 6.7 Hz, 1H), 5.12 (dd, J =
6.4, 2.1 Hz, 1H), 4.97 (d, J = 5.5 Hz, 1H), 4.84 (d, J = 4.9 Hz,
1H), 4.08 (s, 3H), 4.06-3.96 (m, 1H), 3.94-3.89 (m, 2H), 2.62 (s,
3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.10 (t, J
= 5.8 Hz, 3H). 729 ##STR01691## I-104 610.2 1.29 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.72-9.65 (m, 1H), 8.64 (br. s., 1H),
8.57 (br. s., 2H), 8.51 (s, 1H), 8.41 (d, J = 10.7 Hz, 1H), 7.82
(s, 1H), 5.71 (d, J = 6.4 Hz, 1H), 5.16-5.09 (m, 1H), 4.84 (d, J =
4.9 Hz, 1H), 4.08 (s, 3H), 4.06-3.97 (m, 1H), 3.91 (s, 2H), 2.62
(s, 3H), 1.44 (d, J = 6.1 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.10
(s, 3H). 730 ##STR01692## I-100 638.2 1.32 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.62 (s, 1H), 8.56 (br. s., 2H), 8.50 (s,
1H), 8.40 (d, J = 10.7 Hz, 1H), 7.81 (s, 1H), 5.73 (d, J = 4.9 Hz,
1H), 5.11 (dd, J = 6.4, 1.8 Hz, 1H), 4.34-4.16 (m, 2H), 4.08 (s,
3H), 2.61 (s, 3H), 1.78 (t, J = 7.3 Hz, 2H), 1.43 (d, J = 6.4 Hz,
3H), 1.38 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 2.7 Hz, 6H). 731
##STR01693## ##STR01694## 550.2 1.23 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.68 (br. s., 2H), 8.62 (s, 1H), 8.49 (s,
1H), 8.40 (d, J = 11.0 Hz, 1H), 7.81 (s, 1H), 5.69 (d, J = 6.4 Hz,
1H), 5.12 (d, J = 6.4 Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 2.46 (s,
3H), 1.43 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H).
Example 733
(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl pyridin-3-ylcarbamate
##STR01695##
[3679] To a solution of Intermediate I-138 (10 mg, 0.022 mmol) in
DCM (1 mL) and THF (0.5 mL) was added pyridin-3-amine (7.18 mg,
0.076 mmol) followed by DIEA (0.038 mL, 0.218 mmol). The mixture
was stirred at room temperature for 1 h. The reaction was quenched
with 0.2 mL of MeOH. The reaction mixture was concentrated,
redissolved in DMF, filtered, and purified by preparative HPLC
(Method D, 25 to 100% B in 15 minutes) to yield Example 733 (3.5
mg, 6.57 .mu.mol, 30.2% yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.70 (s, 1H), 8.62 (br. s., 1H), 8.54 (s, 1H), 8.19 (br.
s., 1H), 7.89 (br. s., 1H), 7.82 (s, 1H), 7.30 (d, J=7.9 Hz, 1H),
6.90 (s, 1H), 5.24 (br. s., 1H), 4.65-4.41 (m, 2H), 4.08 (s, 3H),
2.72 (s, 3H), 2.63 (s, 3H), 1.39 (d, J=6.4 Hz, 3H). LC-MS: method
H, RT=1.07 min, MS (ESI) m/z: 517.2 (M+H).sup.+. Analytical HPLC
Method B: 97% purity.
Examples 734 to 740
[3680] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
733 and the examples above
TABLE-US-00020 LCMS LCMS RT [M + (Min) Ex. H].sup.+ Method No.
Structure Amine m/z H NMR 734 ##STR01696## ##STR01697## 549.2 1.36
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.88 (br. s., 1H), 8.68
(s, 1H), 8.53 (s, 1H), 8.05 (br. s., 1H), 7.81 (s, 1H), 6.90 (s,
1H), 5.22 (br. s., 1H), 4.68-4.38 (m, 2H), 4.08 (s, 3H), 2.72 (s,
3H), 2.63 (s, 3H), 2.18 (s, 3H), 1.38 (d, J = 6.1 Hz, 4H). 735
##STR01698## ##STR01699## 542.2 1.30 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.30 (br. s., 1H), 8.81 (br. s., 1H), 8.66
(s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.26 (br. s., 1H), 7.80 (s,
1H), 6.89 (s, 1H), 5.26 (br. s., 1H), 4.74-4.34 (m, 2H), 4.07 (s,
3H), 2.71 (s, 3H), 2.62 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 736
##STR01700## ##STR01701## 553.1 1.35 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.77 (br. s., 2H), 8.59 (s, 1H), 8.44 (s,
1H), 7.73 (s, 1H), 6.85 (s, 1H), 5.22 (br. s., 1H), 4.68 (d, J =
9.5 Hz, 1H), 4.38 (dd, J = 11.9, 6.1 Hz, 1H), 4.04 (s, 3H), 2.67
(s, 3H), 2.58 (s, 3H), 1.39 (d, J = 6.7 Hz, 3H). 737 ##STR01702##
##STR01703## 532.2 1.25 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.73 (br. s., 2H), 8.59 (s, 1H), 8.43 (s, 1H), 7.73 (s, 1H), 6.84
(s, 1H), 5.22 (dd, J = 6.4, 3.4 Hz, 1H), 4.61 (dd, J = 11.7, 2.6
Hz, 1H), 4.39 (dd, J = 11.7, 6.3 Hz, 1H), 4.04 (s, 3H), 2.66 (s,
3H), 2.58 (s, 3H), 2.51 (br. s., 3H), 1.38 (d, J = 6.4 Hz, 3H). 738
##STR01704## ##STR01705## 548.2 1.30 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.61 (br. s., 2H), 8.52 (s,
1H), 7.80 (s, 1H), 6.89 (s, 1H), 5.19 (br. s., 1H), 4.66 (d, J =
9.5 Hz, 1H), 4.39 (dd, J = 11.7, 6.0 Hz, 1H), 4 06 (s, 3H),
3.86-3.79 (m, 3H), 2.70 (s, 3H), 2.62 (s, 3H), 1.37 (d, J = 6.4 Hz,
3H). 740 ##STR01706## ##STR01707## 530.2 1.12 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.80 (br. s., 1H), 8.62-8.57 (m, 1H), 8.55
(s, 1H), 8.42 (s, 1H), 8.18 (br. s., 1H), 7.88 (br. s., 1H), 7.72
(s, 1H), 7.38- 7.22 (m, 1H), 6.80 (s, 1H), 5.56-5.46 (m, 1H), 5.10
(dd, J = 6.4, 2.4 Hz, 1H), 4.04 (s, 3H), 2.66 (s, 3H), 2.58 (s,
3H), 1.37 (dd, J = 11.6, 6.4 Hz, 6H).
Example 741
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyrid-
in-5-yl)oxy) propan-2-yl
(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
##STR01708##
[3682] To a suspension of Example 689 (0.012 g, 0.021 mmol) in THF
(0.207 ml) was added 1-amino-2-methylpropan-2-ol (0.029 ml, 0.622
mmol) followed by magnesium chloride (0.020 g, 0.207 mmol). The
reaction vial was sealed and heated to 65.degree. C. overnight. The
reaction mixture was diluted with EtOAc and filtered through
Celite. The reaction mixture was concentrated, redissolved in DMF,
filtered, and purified by preparative HPLC (Method D, 50 to 100% B
in 21 minutes) to yield Example 741 (0.0011 g, 1.713 mol, 8.26%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.15 (br. s.,
1H), 8.60 (br. s., 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.35 (d, J=11.0
Hz, 1H), 8.26 (br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.5
Hz, 1H), 7.78 (s, 1H), 5.28 (br. s., 1H), 4.89 (d, J=10.1 Hz, 1H),
4.50 (dd, J=11.7, 5.6 Hz, 1H), 4.06 (s, 3H), 3.23 (dd, J=11.1, 6.3
Hz, 2H), 2.59 (s, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.08 (d, J=5.8 Hz,
6H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 636.2 (M+H).sup.+.
Analytical HPLC Method B: 99% purity.
Examples 742 to 749
[3683] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
741 and the examples above.
TABLE-US-00021 LCMS LCMS [M + RT Ex. H].sup.+ (Min)/ No. Structure
ester m/z Method NMR 742 ##STR01709## 689 632.2 2.17/B .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.16 (br. s., 2H), 8.61 (br. s.,
2H), 8.50 (br. s., 1H), 8.41 (d, J = 9.8 Hz, 1H), 8.03 (br. s.,
1H), 7.95 (d, J = 8.5 Hz, 1H), 7.82 (br. s., 1H), 5.83- 5.67 (m,
1H), 5.29 (br. s., 2H), 4.95-4.83 (m, 3H), 4.53 (br. s., 2H), 4.08
(br. s., 3H), 3.38 (br. s., 3H), 2.62 (br. s., 3H), 1.85-1.66 (m,
6H). 743 ##STR01710## 689 648.2 2.25/B .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.11 (d, J = 12.2 Hz, 1H), 8.58 (br. s.,
2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.1 Hz, 1H), 7.99 (br. s.,
1H), 7.74 (br. s., 1H), 7.51 (t, J = 10.2 Hz, 1H), 5.31 (br. s.,
1H), 5.06 (br. s., 1H), 4.78 (d, J = 10.1 Hz, 2H), 4.06 (s, 3H),
3.51 (s, 2H), 3.14 (br. s., 2H), 3.01-2.91 (m, 2H), 2.58 (s, 3H),
1.92-1.72 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H). 744 ##STR01711## 689
634.2 2.20/B .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.15-10.04 (m, 1H), 8.56 (d, J = 10.1 Hz, 2H), 8.42 (br. s., 1H),
8.33 (d, J = 10.4 Hz, 1H), 8.02 (br. s., 1H), 7.75 (br. s., 2H),
5.30 (br. s., 1H), 5.09-4.97 (m, 1H), 4.92-4.74 (m, 1H), 4.52 (br.
s., 1H), 4.28 (br. s., 1H), 4.05 (s, 3H), 3.80-3.67 (m, 1H),
3.52-3.36 (m, 2H), 2.58 (br. s., 3H), 1.95-1.84 (m, 1H), 1.77 (br.
s., 2H), 1.43 (d, J = 6.1 Hz, 3H). 745 ##STR01712## 689 634.2
2.20/B .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.15-10.04 (m,
1H), 8.56 (d, J = 10.1 Hz, 2H), 8.42 (br. s., 1H), 8.33 (d, J =
10.4 Hz, 1H), 8.02 (br. s., 1H), 7.75 (br. s., 2H), 5.30 (br. s.,
1H), 5.09-4.97 (m, 1H), 4.92-4.74 (m, 1H), 4.52 (br. s., 1H), 4.28
(br. s., 1H), 4.05 (s, 3H), 3.80-3.67 (m, 1H), 3.52-3.36 (m, 2H),
2.58 (br. s., 3H), 1.95-1.84 (m, 1H), 1.77 (br. s., 2H), 1.43 (d, J
= 6.1 Hz, 3H). 746 ##STR01713## 689 648.2 2.19/B .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.11 (br. s., 2H), 8.63- 8.53 (m, 2H),
8.45 (s, 1H), 8.36 (d, J = 10.7 Hz, 1H), 7.98 (br. s., 1H), 7.77
(s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 5.31 (br. s., 1H), 4.87-4.75 (m,
2H), 4.61-4.48 (m, 1H), 4.06 (s, 3H), 4.01 (br. s., 1H), 3.72 (br.
s., 1H), 3.60 (br. s., 1H), 3.22- 3.10 (m, 2H), 2.60 (s, 3H), 1.79
(br. s., 1H), 1.67 (br. s., 1H), 1.43 (d, J = 6.1 Hz, 3H),
1.40-1.24 (m, 2H). 747 ##STR01714## 689 622.1 1.17/H .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.16 (br. s., 2H), 8.62 (br. s.,
1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.41-8.34 (m, 2H), 8.03 (br. s.,
1H), 7.95 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 5.29 (br. s., 1H),
4.89 (d, J = 10.1 Hz, 1H), 4.52 (dd, J = 11.7, 5.3 Hz, 1H), 4.07
(s, 3H), 3.75 (br. s., 1H), 3.53 (s, 1H), 3.32- 3.25 (m, 1H),
3.18-3.10 (m, 1H), 2.61 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H),
1.10-0.99 (m, 3H). 748 ##STR01715## 689 622.2 1.17/H .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.17 (br. s., 2H), 8.63 (br. s.,
1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.43-8.33 (m, 2H), 8.03 (br. s.,
1H), 7.94 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 5.29 (br. s., 1H),
4.88 (d, J = 10.1 Hz, 1H), 4.52 (dd, J = 11.3, 5.5 Hz, 1H), 4.07
(s, 3H), 3.77 (br. s., 1H), 3.50-3.44 (m, 1H), 3.30 (br. s., 1H),
3.13 (d, J = 7.0 Hz, 1H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H),
1.05 (d, J = 5.8 Hz, 3H). 749 ##STR01716## 690 565.1 1.10/H .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.95 (br. s., 2H), 8.58 (s,
1H), 8.43 (s, 1H), 8.36 (d, J = 10.8 Hz, 1H), 8.19-8.01 (m, 2H),
7.75 (s, 1H), 7.65 (br. s., 1H), 5.35-5.26 (m, 1H), 4.84 (d, J =
9.8 Hz, 1H), 4.59-4.48 (m, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.44
(d, J = 6.4 Hz, 3H).
Example 750
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate
##STR01717##
[3685] To a suspension of Example 715 (0.030 g, 0.051 mmol) in THF
(0.506 ml) was added (S)-1-aminopropan-2-ol (0.114 g, 1.519 mmol)
followed by magnesium chloride (0.047 g, 0.510 mmol). The reaction
vial was sealed and heated to 65.degree. C. overnight. The reaction
mixture was diluted with EtOAc and filtered through Celite. The
reaction mixture was concentrated, redissolved in DMF, filtered,
and purified by preparative HPLC (Method D, 35 to 100% B in 20
minutes) to yield Example 750 (0.0129 g, 0.020 mmol, 40.1% yield
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.51
(d, J=8.2 Hz, 1H), 8.41 (s, 2H), 8.31 (d, J=10.7 Hz, 2H), 7.99 (br.
s., 1H), 7.89 (t, J=7.3 Hz, 1H), 7.73 (s, 1H), 5.77 (d, J=6.7 Hz,
1H), 5.12 (d, J=6.4 Hz, 1H), 4.91 (s, 1H), 4.05 (s, 3H), 3.77-3.69
(m, 1H), 3.38-2.96 (m, 2H), 2.57 (s, 3H), 1.44 (d, J=6.4 Hz, 3H),
1.38 (d, J=6.4 Hz, 3H), 1.08-0.98 (m, 3H). LC-MS: method H, RT=1.23
min,): MS (ESI) m/z: 636.1 (M+H).sup.+. Analytical HPLC Method B:
100% purity.
Examples 751 to 761
[3686] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
741 and the examples above.
TABLE-US-00022 LCMS LCMS RT Ex. [M + H].sup.+ (Min)/ No. Structure
ester m/z Method NMR 751 ##STR01718## 712 650.2 2.37/B .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.23-10.17 (m, 1H), 8.90 (br. s.,
2H), 8.48 (s, 1H), 8.43 (s, 1H), 8.37-8.30 (m, 2H), 7.75 (s, 1H),
5.78 (dd, J = 6.6, 2.3 Hz, 1H), 5.22-5.08 (m, 1H), 4.72 (s, 1H),
4.05 (s, 3H), 3.51-3.45 (m, 2H), 3.30-3.14 (m, 2H), 2.58 (s, 3H),
1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.08 (d, J =
10.4 Hz, 6H). 752 ##STR01719## 712 637.2 1.14/H .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.16 (br. s., 1H), 8.87 (br. s., 2H),
8.47 (s, 2H), 8.43 (s, 1H), 8.34 (d, J = 11.0 Hz, 1H), 7.75 (s,
1H), 5.78 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.86 (d, J
= 4.9 Hz, 1H), 4.04 (s, 3H), 3.81-3.71 (m, 1H), 3.47 (s, 3H),
3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.57 (s, 3H), 1.43 (d, J =
6.4 Hz, 2H), 1.38 (d, J = 6.4 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H).
753 ##STR01720## 712 637.2 1.14/H .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.16 (br. s., 1H), 8.87 (br. s., 2H), 8.47
(s, 2H), 8.43 (s, 1H), 8.34 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H),
5.78 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.86 (d, J =
4.9 Hz, 1H), 4.04 (s, 3H), 3.81-3.71 (m, 1H), 3.47 (s, 3H),
3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.57 (s, 3H), 1.43 (d, J =
6.4 Hz, 2H), 1.38 (d, J = 6.4 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H).
754 ##STR01721## 715 578.2 1.23/H .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.07 (s, 1H), 8.60 (br. s., 1H), 8.53 (s,
1H), 8.45 (s, 1H), 8.38 (d, J = 10.8 Hz, 1H), 8.02-7.97 (m, 1H),
7.95-7.88 (m, 2H), 7.76 (s, 1H), 7.42 (br. s., 1H), 5.69 (dd, J =
6.4, 2.4 Hz, 1H), 5.20-5.11 (m, 1H), 4.06 (s, 3H), 2.59 (s, 3H),
1.45 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H). 755
##STR01722## 712 579.0 1.14/H .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.27 (br. s., 1H), 8.92 (br. s., 2H), 8.59 (s, 1H), 8.48
(s, 1H), 8.41 (d, J = 10.8 Hz, 1H), 8.06 (br. s., 1H), 7.79 (s,
1H), 7.64 (br. s., 1H), 5.73 (d, J = 6.4 Hz, 1H), 5.18 (d, J = 4.4
Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H), 1.41
(d, J = 6.7 Hz, 3H). 756 ##STR01723## 715 678.2 2.56/B .sup.1H NMR
(500MHz, DMSO-d.sub.6) .delta. 10.01 (br. s., 1H), 8.64 (s, 1H),
8.59-8.53 (m, 1H), 8.51 (s, 1H), 8.41 (d, J = 11.0 Hz, 1H), 8.05-
7.93 (m, 1H), 7.82 (s, 1H), 7.59- 7.52 (m, 1H), 5.67 (br. s., 1H),
5.17 (d, J = 6.1 Hz, 1H), 4.36- 4.15 (m, 1H), 4.08 (s, 3H), 4.05-
3.99 (m, 1H), 3.91 (s, 2H), 3.75 (br. s., 2H), 3.66-3.31 (m, 3H),
3.33-2.97 (m, 1H), 2.62 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d,
J = 6.4 Hz, 3H). 757 ##STR01724## 715 648.2 2.41/B .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.99-9.88 (m, 1H), 8.52-8.48 (m, 1H),
8.42 (br. s., 1H), 8.38- 8.28 (m, 2H), 8.12-7.87 (m, 1H), 7.74 (br.
s., 1H), 7.69 (d, J = 7.9 Hz, 1H), 5.81-5.65 (m, 1H), 5.14 (br. s.,
1H), 5.05-4.92 (m, 1H), 4.24 (br. s., 1H), 4.05 (s, 3H), 3.58 (d, J
= 5.8 Hz, 3H), 3.51- 3.32 (m, 1H), 2.58 (s, 3H), 1.93- 1.65 (m,
2H), 1.45 (br. s., 3H), 1.39 (d, J = 6.1 Hz, 3H). 758 ##STR01725##
715 662.2 2.47/B .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.96
(d, J = 18.9 Hz, 1H), 8.54 (br. s., 2H), 8.41 (br. s., 1H), 8.32
(d, J = 10.7 Hz, 1H), 7.96 (br. s., 1H), 7.74 (s, 1H), 7.50 (d, J =
8.9 Hz, 1H), 5.67 (br. s., 2H), 5.18-5.09 (m, 2H), 4.90 (d, J = 4.9
Hz, 1H), 4.05 (s, 3H), 3.84 (br. s., 1H), 3.47 (br. s., 1H), 3.14
(br. s., 1H), 2.90 (s, 1H), 2.82-2.64 (m, 1H), 2.56 (s, 3H),
1.90-1.70 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz,
3H). 759 ##STR01726## 715 662.0 2.97/B .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.53 (s, 2H), 8.40 (s,
1H), 8.30 (d, J = 10.7 Hz, 1H), 8.04-7.90 (m, 1H), 7.72 (s, 1H),
7.49 (br. s., 1H), 5.67 (br. s., 1H), 5.15 (d, J = 6.4 Hz, 1H),
4.90 (br. s., 1H), 4.04 (s, 3H), 3.74-3.55 (m, 4H), 3.24-2.95 (m,
2H), 2.57 (br. s., 3H), 1.78 (br. s., 1H), 1.68-1.54 (m, 1H), 1.44
(d, J = 6.1 Hz, 3H), 1.39 (d, J = 6.1 Hz, 3H), 1.27 (br. s., 1H).
760 ##STR01727## 715 648.0 2.98/B .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.99-9.88 (m, 1H), 8.52-8.48 (m, 1H), 8.42
(br. s., 1H), 8.38- 8.28 (m, 2H), 8.12-7.87 (m, 1H), 7.74 (br. s.,
1H), 7.69 (d, J = 7.9 Hz, 1H), 5.81-5.65 (m, 1H), 5.14 (br. s.,
1H), 5.05-4.92 (m, 1H), 4.24 (br. s., 1H), 4.05 (s, 3H), 3.58 (d, J
= 5.8 Hz, 3H), 3.51-3.32 (m, 1H), 2.58 (s, 3H), 1.93- 1.65 (m, 2H),
1.45 (br. s., 3H), 1.39 (d, J = 6.1 Hz, 3H). 761 ##STR01728## 712
676.0 3.43/B .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.98 (br.
s., 1H), 8.51 (d, J = 7.0 Hz, 2H), 8.45 (d, J = 11.6 Hz, 2H), 8.33
(d, J = 10.7 Hz, 1H), 7.99 (br. s., 1H), 7.90 (d, J = 7.9 Hz, 1H),
7.75 (s, 1H), 5.76 (d, J = 6.4 Hz, 1H), 5.14 (br. s., 1H), 4.83
(br. s., 1H), 4.06 (s, 3H), 3.36 (d, J = 4.9 Hz, 2H), 2.58 (s, 3H),
1.83-1.62 (m, 8H), 1.45 (d, J = 6.1 Hz, 3H), 1.39 (d, J = 6.4 Hz,
3H).
Example 762
N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridi-
n-5-yl)oxy)ethyl)-4-methylbenzenesulfonamide
##STR01729##
[3688] To a solution of Intermediate 662D (15 mg, 0.039 mmol) in
DMF (1 mL) was added DIEA (0.069 mL, 0.393 mmol) and
4-methylbenzene-1-sulfonyl chloride (9.00 mg, 0.047 mmol). The
mixture was stirred at room temperature for 1 hour. The reaction
was quenched by 0.2 ml of MeOH. The reaction mixture was
concentrated, redissolved in DMF, filtered, and purified by
preparative HPLC (Method D, 65 to 100% B in 22 minutes) to yield
Example 762 (7.52 mg, 0.014 mmol, 35.7% yield): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.52 (s, 1H), 7.89 (t,
J=5.4 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0
Hz, 2H), 6.72 (s, 1H), 4.31 (t, J=5.5 Hz, 2H), 4.08 (s, 3H), 3.21
(d, J=5.5 Hz, 2H), 2.71 (s, 3H), 2.63 (s, 3H), 2.35 (s, 3H). LC-MS:
method H, RT=1.23 min,): MS (ESI) m/z: 536.1 (M+H).sup.+.
Analytical HPLC Method B: 100% purity.
Example 763
6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylt-
hiazolo[5,4-b]pyridine
##STR01730##
[3689] Intermediate 763A:
5-bromo-3-fluoro-2-methoxy-4-methylpyridine
##STR01731##
[3691] 3-fluoro-2-methoxy-4-methylpyridine (0.500 g, 3.54 mmol) was
dissolved in AcOH (17.71 ml). Next, bromine (0.219 ml, 4.25 mmol)
and sodium acetate (0.581 g, 7.09 mmol) were added, and the
reaction mixture was heated to 80.degree. C. overnight. The
reaction was carefully quenched with saturated NaHCO.sub.3 and
extracted with EtOAc. The organic layer was washed with 1 N NaOH,
water, then brine, then dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to yield Intermediate 763A (0.450 g, 2.045
mmol, 57.7% yield) as a white solid. LC-MS: Method H, RT=1.02 min,
MS (ESI) m/z: 220.1 (M+H).sup.+.
Intermediate 763B:
N-benzyl-5-fluoro-6-methoxy-4-methylpyridin-3-amine
##STR01732##
[3693] Intermediate 763A (0.450 g, 2.045 mmol), copper(I) iodide
(0.078 g, 0.409 mmol), potassium carbonate (0.424 g, 3.07 mmol),
and L-proline (0.094 g, 0.818 mmol) was added. The reaction mixture
was placed under vacuum and backfilled with argon. The solids were
dissolved in DMSO (20.45 ml) and stirred for 5 min. To the reaction
was added benzylamine (0.268 ml, 2.454 mmol) and the reaction
mixture was heated to 80.degree. C. overnight. The reaction mixture
was diluted with water and EtOAc. The layers were separated and the
organic layer was washed with water, washed with brine, dried with
sodium sulfate, and concentrated under reduced pressure. Purified
on ISCO using a 40 g column with 0-100% EtOAc in hexanes gradient
to yield Intermediate 763B (0.123 g, 0.499 mmol, 24.42% yield):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39-7.27 (m, 6H), 4.33
(d, J=5.1 Hz, 2H), 3.93 (s, 3H), 3.48 (br. s., 1H), 2.12 (d, J=2.2
Hz, 3H). LC-MS: method H, RT=0.99 min, MS (ESI) m/z: 247.2
(M+H).sup.+.
Intermediate 763C: 5-fluoro-6-methoxy-4-methylpyridin-3-amine
##STR01733##
[3695] Intermediate 763B (0.150 g, 0.609 mmol) was dissolved in
MeOH (6.09 ml) and palladium on carbon (0.130 g, 0.122 mmol) was
added. The reaction mixture was placed under vacuum and back filled
with argon three times. The reaction mixture was placed under
vacuum and back filled with hydrogen (1.228 mg, 0.609 mmol) three
times. The reaction mixture was allowed to stir at room temperature
for 3h. The reaction mixture was filtered and concentrated to yield
Intermediate 763C (0.074 g, 0.474 mmol, 78% yield) as a yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (s, 1H), 3.94
(s, 3H), 3.33 (br. s., 1H), 2.13 (d, J=2.0 Hz, 3H). LC-MS: method
H, RT=0.55 min, MS (ESI) m/z: MS (ESI) m/z: 157.0 (M+H).sup.+.
Intermediate 763D:
6-fluoro-5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-amine
##STR01734##
[3697] Potassium thiocyanate (0.046 g, 0.474 mmol) was dissolved in
acetic acid (1.137 ml) and cooled to 0.degree. C. Intermediate 763C
(0.074 g, 0.474 mmol) was dissolved in acetic acid (0.379 ml) and
added dropwise. Bromine (0.049 ml, 0.948 mmol) was dissolved in
acetic acid (0.379 ml) and added dropwise to the reaction mixture.
The reaction mixture was allowed to warm to room temperature and
stir overnight. The reaction mixture was concentrated under reduced
pressure. The resultant residue was diluted with water and
neutralized with 1 N NaOH. The aqueous solution was extracted with
EtOAc.times.3. The combined organic layer was washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure
to yield Intermediate 763D (0.099 g, 0.464 mmol, 98% yield). LC-MS:
Method H, RT=0.71 min, MS (ESI) m/z: MS (ESI) m/z: 214.1
(M+H).sup.+.
Intermediate 763E:
2-bromo-6-fluoro-5-methoxy-7-methylthiazolo[5,4-b]pyridine
##STR01735##
[3699] Copper(II)bromide (0.178 g, 0.797 mmol) and t-butyl nitrite
(0.095 ml, 0.797 mmol) were dissolved in MeCN (1.876 ml) and
allowed to stir 10 minutes. Intermediate 763D (0.100 g, 0.469 mmol)
was dissolved in MeCN (2.81 ml) and the copper solution was added.
The reaction mixture was stirred for 2.5h at 60.degree. C. The
reaction mixture was diluted with EtOAc, washed with 1 N HCl,
saturated NaHCO.sub.3, then brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. Purified on ISCO using a 12 g
column with 0-100% gradient of EtOAc in hexanes to yield
Intermediate 763E (0.098 g, 0.354 mmol, 75% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 4.06 (s, 1H), 2.60 (d, J=2.2 Hz, 1H).
LC-MS: method H, RT=1.13 min, MS (ESI) m/z: MS (ESI) m/z: 277.1
(M+H).sup.+.
Example 763
[3700] Intermediate I-2 (0.017 g, 0.054 mmol) and Intermediate 763E
(0.015 g, 0.054 mmol) were dissolved in DMF (1 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.65 mg, 3.25 .mu.mol)
was added and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Next, Na.sub.2CO.sub.3, 3 M aqueous solution
(0.100 ml, 0.300 mmol) was added and the reaction mixture was
degassed for 5 minutes, then sealed and heated to 90.degree. C. in
a microwave for 30 minutes. The reaction mixture was concentrated,
redissolved in DMF, filtered, and purified by preparative HPLC
(Method D, 60 to 100% B in 20 minutes) to yield Example 763 (0.0008
g, 1.831 .mu.mol, 3.38% yield): LC-MS: method H, RT=1.30 min, MS
(ESI) m/z: 385.2 (M+H).sup.+. Analytical HPLC Method B: 88%
purity.
Example 764
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01736##
[3702] Example 712 (50 mg, 0.084 mmol) was solvated in THF (1 mL)
and cooled to -78.degree. C. To this mixture was added
diisobutylaluminum hydride (1 M in toluene) (0.253 mL, 0.253 mmol)
and the reaction mixture was stirred for 30 min. The reaction was
quenched with 1 mL of a 1 M HCl solution at -78.degree. C. The
reaction mixture was allowed to thaw to room temperature and
stirred for a total of 30 min. The mixture was diluted with EtOAc
and washed with saturated NH.sub.4Cl before being dried over
MgSO.sub.4 and filtered over a pad of SiO.sub.2 gel. The filtrate
was concentrated and resubjected to identical reaction conditions.
The reaction mixture was diluted with sat'd Rochelle's salt and
allowed to stir overnight. The reaction mixture was diluted with
EtOAc and the layers were separated. The aqueous layer was back
extracted with EtOAc.times.3 and the combined organic layer was
washed with brine, dried with sodium sulfate, and concentrated
under reduced pressure to yield Example 764 (24.2 mg, 0.042 mmol,
49.8% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.91-8.84
(m, 2H), 8.58 (d, J=1.8 Hz, 1H), 8.55 (s, 1H), 8.01 (d, J=10.3 Hz,
1H), 7.85-7.74 (m, 1H), 6.69-6.53 (m, 1H), 5.75 (dd, 2.5 Hz, 1H),
5.27 (dd, 2.6 Hz, 1H), 4.82 (d, J=4.8 Hz, 2H), 4.16 (s, 3H), 3.49
(s, 1H), 2.67 (s, 3H), 1.50 (t, J=6.9 Hz, 6H). LC-MS: method H,
RT=1.23 min,): MS (ESI) m/z: 566.2 (M+H).sup.+. Analytical HPLC
Method B: 95% purity.
Example 765
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate
##STR01737##
[3704] A solution of Example 715 (0.045 g, 0.076 mmol) in THF (1
mL) was cooled to -78.degree. C. Methylmagnesium bromide (0.101 mL,
0.304 mmol) was added and the mixture was allowed to warm to room
temperature. The mixture was stirred for 1 h. The reaction mixture
was diluted with water and EtOAc. The layers were separated and the
organic layer was washed with brine, dried with sodium sulfate, and
concentrated under reduced pressure. Purified by ISCO using a 24 g
column eluting with 0-70% EtOAc in DCM to yield Example 765 (0.015
g, 0.025 mmol, 33.3% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.56 (d, J=1.8 Hz, 2H), 8.37 (s, 1H), 7.98 (d, J=10.3 Hz,
1H), 7.77 (s, 1H), 7.31 (s, 2H), 6.59 (br. s., 1H), 5.66 (br. s.,
1H), 5.23 (dd, J=6.5, 3.0 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 1.48
(d, J=6.6 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.25 (s, 6H). LC-MS:
method H, RT=1.08 min, MS (ESI) m/z: 593.2 (M+H).sup.+.
[3705] The methyl ketone
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)
thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl
(6-acetylpyridin-3-yl)carbamate was also isolated from the reaction
as Intermediate 765A (0.020 g, 0.035 mmol 35% yield), which will be
used below. LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 577.2
(M+H).sup.+. Analytical HPLC Method B: 99% purity.
Example 766
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(6-(1-hydroxyethyl)pyridin-3-yl)carbamate
##STR01738##
[3707] Intermediate 765A (0.020 g, 0.035 mmol) was dissolved in THF
(0.347 ml) and cooled to -78.degree. C. To the cooled reaction
mixture was added DIBAL-H in toluene (0.087 ml, 0.087 mmol), and
the reaction mixture was allowed to stir for 1 h. The reaction
mixture was allowed to warm to room temperature and saturated
solution of Rochelle's salt was added. The resulting mixture was
allowed to stir overnight. The reaction mixture was diluted with
EtOAc and water. The layers were separated and the organic layer
was washed with brine, dried with sodium sulfate and concentrated
under reduced pressure. The reaction mixture was concentrated,
redissolved in DMF, filtered, and purified by preparative HPLC
(Method D, 60 to 100% B in 15 minutes, then a 6 minute hold time)
to yield the racemic product. The reaction was further purified 35%
EtOH/65% CO.sub.2 in a 15 min run, Lux 5 u Cellulose-4,
21.times.250 mm, 5 micron column, flow rate 45 mL/min, 150 Bar,
40.degree. C. and UV detection was set to 220 nm to yield Example
766 (3.3 mg, 5.48 .mu.mol, 15.78% yield) as the first eluting
isomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.79 (br. s.,
1H), 8.63 (br. s., 1H), 8.48 (s, 2H), 8.37 (d, J=10.7 Hz, 1H), 7.80
(s, 2H), 5.64 (d, J=4.9 Hz, 1H), 5.15 (d, J=5.8 Hz, 1H), 4.07 (s,
3H), 3.56-3.48 (m, 3H), 2.61 (s, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.38
(d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z:
579.2 (M+H).sup.+. Analytical HPLC Method B: 99% purity.
Example 767
(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl
(6-(1-hydroxyethyl)pyridin-3-yl)carbamate
##STR01739##
[3709] Intermediate 765A (0.020 g, 0.035 mmol) was dissolved in THF
(0.347 ml) and cooled to -78.degree. C. To the cooled reaction, was
added DIBAL-H in toluene (0.087 ml, 0.087 mmol), and the reaction
mixture was allowed to stir for 1 h. The reaction mixture was
allowed to warm to room temperature and sat'd solution of
Rochelle's salt was added. The reaction mixture was allowed to stir
overnight. The reaction mixture was diluted with EtOAc and water.
The layers were separated and the organic layer was washed with
brine, dried with sodium sulfate and concentrated under reduced
pressure. The reaction mixture was concentrated, redissolved in
DMF, filtered, and purified by preparative HPLC (Method D, 60 to
100% B in 15 minutes, then a 6 minute hold time) to yield the
racemic product. The reaction was further purified as above 35%
EtOH/65% CO.sub.2 in a 15 min run, Lux 5 u Cellulose-4,
21.times.250 mm, 5 micron column, flow rate 45 mL/min, 150 Bar,
40.degree. C. and UV detection was set to 220 nm to yield Example
767 (2.9 mg, 4.66 .mu.mol, 13.4% yield) as the second eluting
isomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80-9.64 (m,
1H), 8.63 (s, 1H), 8.48 (s, 2H), 8.37 (d, J=10.7 Hz, 1H), 7.80 (s,
2H), 7.43-7.35 (m, 1H), 5.69-5.60 (m, 1H), 5.22-5.10 (m, 1H), 4.64
(d, J=6.4 Hz, 1H), 4.07 (s, 3H), 3.55 (br. s., 4H), 2.61 (s, 3H),
1.45 (d, J=6.7 Hz, 3H), 1.38 (d, J=6.7 Hz, 3H). LC-MS: method H,
RT=1.08 min, MS (ESI) m/z: 579.2 (M+H).sup.+. Analytical HPLC
Method B: 99% purity.
Example 768
(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01740##
[3711] Example 689 (50 mg, 0.086 mmol) was solvated in THF (1 mL)
and cooled to -78.degree. C. To this mixture was added
diisobutylaluminum hydride (1 M in toluene) (0.259 mL, 0.259 mmol)
and stirred for 30 min. The reaction was quenched with 1 mL of a 1
M HCl solution at -78.degree. C. The reaction mixture was allowed
to thaw to room temperature and stirred for a total of 30 min. The
mixture was diluted with EtOAc and washed with saturated NH.sub.4Cl
before being dried over MgSO.sub.4 and filtered over a pad of
SiO.sub.2 gel to remove aluminates. The filtrate was concentrated
and resubjected to identical reaction conditions. The reaction
mixture was diluted with sat'd Rochelle's salt and allowed to stir
overnight. The reaction mixture was diluted with EtOAc and the
layers were separated. The aqueous layer was back extracted with
EtOAc.times.3 and the combined organic layer was washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure.
The reaction was purified on ISCO using a 12 g column eluting with
0-100% EtOAc in hexanes to yield Example 768 (19.60 mg, 0.034 mmol,
39.1% yield) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.88 (br. s., 2H), 8.59 (s, 1H), 8.57 (s, 1H), 8.03 (d,
J=10.3 Hz, 1H), 7.81 (s, 1H), 6.67 (br. s., 1H), 5.44 (dt, J=6.3,
3.0 Hz, 1H), 4.89-4.78 (m, 3H), 4.57 (d, J=6.2 Hz, 1H), 4.16 (s,
3H), 3.50 (br. s., 1H), 2.68 (s, 3H), 1.53 (d, J=6.4 Hz, 3H). MS
(ESI) m/z: 552.1 (M+H).sup.+. LC-MS: method H, RT=1.12 min, MS
(ESI) m/z: 552.1 (M+H).sup.+. Analytical HPLC Method B: 95%
purity.
Example 769
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyr-
idin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01741##
[3713] Intermediate I-121 (15 mg, 0.047 mmol), Intermediate I-135
(21.26 mg, 0.052 mmol) and PdCl.sub.2(dppf) (2.061 mg, 2.82
.mu.mol) were dissolved in dioxane (469 .mu.l) and Na.sub.2CO.sub.3
(211 .mu.l, 0.422 mmol) and heated to 100.degree. C. in an oil bath
for 2 hours. The reaction mixture was cooled to ambient
temperature, diluted with EtOAc, washed with water, then brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
reaction mixture was concentrated, redissolved in DMF, filtered,
and purified by preparative HPLC (Method D, 25 to 100% B in 15
minutes) to yield Example 769 (7.2, 12.65 mmol, 2.70E+04% yield):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.81 (br. s., 1H), 8.77
(br. s., 1H), 8.68 (br. s., 2H), 8.55 (s, 1H), 8.41 (d, J=10.7 Hz,
1H), 8.19 (s, 1H), 7.93 (br. s., 1H), 5.73 (d, J=6.4 Hz, 1H), 5.13
(d, J=6.1 Hz, 1H), 4.00 (s, 3H), 2.46 (s, 3H), 1.44 (d, J=6.4 Hz,
3H), 1.38 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.42, MS (ESI)
m/z: 569.1 (M+H).sup.+. Analytical HPLC Method B: 100%
Examples 770 to 775
[3714] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
769 and the examples above. If necessary, removal of silyl
protecting groups was accomplished by treatment of the protected
compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or
MeOH/HCl (20/1) solution to afford the desired compound.
TABLE-US-00023 LCMS LCMS Ex. Boronic [M + H].sup.+ RT (Min) No.
Structure acid Chloride m/z Method H NMR 770 ##STR01742## I-121
I-139 555.1 1.40 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.03-9.92 (m, 1H), 8.82 (br. s., 1H), 8.73 (br. s., 2H), 8.56 (s,
1H), 8.44 (d, J = 10.7 Hz, 1H), 8.19 (s, 1H), 7.93 (br. s., 1H),
5.28 (br. s., 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.55 (dd, J = 11.7,
6.3 Hz, 1H), 4.00 (s, 3H), 2.50-2.50 (m, 3H), 1.43 (d, J = 6.4 Hz,
3H). 771 ##STR01743## I-124 I-139 535.2 1.03 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.73 (br. s., 2H), 8.58 (br. s., 1H),
8.47-8.38 (m, 1H), 7.89 (d, J = 9.8 Hz, 1H), 7.21- 6.97 (m, 2H),
5.28 (br. s., 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.62-4.50 (m, 1H),
4.00 (s, 3H), 2.61 (s, 3H), 1 48-1.40 (m, 3H). 772 ##STR01744##
I-136 I-130 552.2 1.09 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.77 (br. s., 1H), 8.66 (br. s., 2H), 8.41 (d, J = 9.5 Hz, 1H),
7.99 (d, J = 7.9 Hz, 1H), 7.93-7.82 (m, 3H), 5.04 (d, J = 6.4 Hz,
1H), 4.75 (d, J = 6.1 Hz, 1H), 3.93 (s, 3H), 2.48 (br. s., 3H),
1.33 (br. s., 6H). 773 ##STR01745## I-140 I-130 564.3 0.92 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.96 (br. s, 1H), 8.83 (br. s.,
1H), 8.75 (br. s., 2H), 8.06- 7.99 (m, 2H), 7.98-7.93 (m, 2H),
5.22-5.05 (m, 1H), 4.81 (br. s., 2H), 4.00 (br. s., 3H), 2.55 (br.
s., 5H), 1.40 (br. s., 6H). 774 ##STR01746## I-121 I-137 615.1 1.18
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.66 (br. s., 1H), 8.76
(br. s., 1H), 8.59-8.56 (m, 2H), 8.54 (d, J = 2.1 Hz, 1H), 8.40 (d,
J = 10.7 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.7 Hz,
1H), 5.72 (dd, J = 6.6, 2.3 Hz, 1H), 5.11 (dd, J = 6.4, 2.1 Hz,
1H), 4.87 (s, 1H), 4.22-4.10 (m, 2H), 3.99 (s, 3H), 3.66 (d, J =
5.5 Hz, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.7 Hz, 3H).
775 ##STR01747## I-124 I-137 595.0 1.08 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.71-9.54 (m, 1H), 8.65 (d, J = 2.1 Hz, 1H),
8.56-8.46 (m, 3H), 8.33 (d, J = 10.7 Hz, 1H), 7.83-7.72 (m, 2H),
5.63 (dd, J = 6.6, 2.3 Hz, 1H), 5.14-4.99 (m, 1H), 4.76 (s, 1H),
4.19-4.03 (m, 2H), 3.92 (s, 3H), 3.60 (d, J = 5.5 Hz, 2H), 2.53 (s,
3H), 1.36 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H).
Example 776
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyr-
idin-5-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate
##STR01748##
[3715] Intermediate 776A:
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-ol
##STR01749##
[3717] Intermediate I-121 (75 mg, 0.235 mmol), Intermediate I-133
(64.7 mg, 0.235 mmol) and PdCl.sub.2(dppf) (10.30 mg, 0.014 mmol)
were dissolved in dioxane (2347 .mu.l) and Na.sub.2CO.sub.3 (1056
.mu.l, 2.112 mmol) and heated to 100.degree. C. in an oil bath for
2 hours. The reaction mixture was cooled to ambient temperature,
diluted with EtOAc, washed with water, then brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Purified
on ISCO using 0-100% EtOAc in DCM on a 24 g column to yield
Intermediate 776A (0.054 g, 0.124 mmol, 53.0% yield) as a yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.80 (dd, J=16.2,
2.5 Hz, 2H), 8.02 (d, J=10.3 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.41
(d, J=2.9 Hz, 1H), 5.48-5.35 (m, 1H), 4.22-4.10 (m, 1H), 4.03 (s,
3H), 2.56-2.47 (m, 1H), 1.46 (d, J=6.4 Hz, 3H), 1.33 (d, J=6.6 Hz,
3H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 433.9
(M+H).sup.+.
Intermediate 776B:
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-yl carbonochloridate
##STR01750##
[3719] To a solution of Intermediate 776A (0.054 g, 0.124 mmol) in
THF (5 mL) at room temperature was added 15% phosgene in toluene
(0.439 mL, 0.622 mmol), and the mixture was stirred at room
temperature overnight. Solvent was completely removed to give
Intermediate 776B (0.062 g, 0.112 mmol, 90% yield) as a yellow
solid. LC-MS: method H, RT=1.39 min MS (ESI) m/z: 495.9
(M+H).sup.+.
Example 776
[3720] 5-fluoropyridin-3-amine (3.39 mg, 0.030 mmol) and pyridine
(0.016 mL, 0.201 mmol) were dissolved in DCM (2 mL). To this
solution was added Intermediate 776B (0.010 g, 0.020 mmol) as a
solution in DCM (1 mL). The reaction mixture was allowed to stir
for 1 h. The reaction mixture was concentrated under reduced
pressure, redissolved in DMF, filtered, and purified by preparative
HPLC (Method D, 25 to 100% B in 15 minutes) to yield Example 776
(0.0072 g, 0.013 mmol, 62.5% yield): .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.07 (br. s., 1H), 8.76 (s, 1H), 8.54 (s,
1H), 8.44-8.37 (m, 2H), 8.18 (s, 1H), 8.14 (s, 1H), 7.92 (d, J=2.4
Hz, 1H), 7.81 (br. s., 1H), 5.71 (d, J=6.1 Hz, 1H), 5.17 (d, J=5.2
Hz, 1H), 4.00 (s, 3H), 1.46 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.4 Hz,
3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 572.0 (M+H).sup.+.
Analytical HPLC Method B: 100% purity.
Examples 777 to 791
[3721] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
776 and the examples above. If necessary, removal of silyl
protecting groups was accomplished by treatment of the protected
compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or
MeOH/HCl (20/1) solution to afford the desired compound.
TABLE-US-00024 LCMS LCMS Ex. [M + H].sup.+ RT (Min) No. Structure
Amine m/z Method H NMR 777 ##STR01751## ##STR01752## 610.0 1.50
.sup.1H NMR (500 MHz, DMSO- d.sub.6) .delta. 11.39 (s, 1H), 9.53
(br. s., 1H), 8.70 (br. s., 1H), 8.52 (s, 1H), 8.37 (d, J = 11.0
Hz, 1H), 8.14 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.37 (br. s, 1H),
7.09 (br. s., 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.66 (d, J = 4.6 Hz,
1H), 5.13 (d, J = 4.3 Hz, 1H), 3.98 (s, 3H), 1.45 (d, J = 6.4 Hz,
3H), 1.38 (d, J = 6.4 Hz, 3H). 778 ##STR01753## ##STR01754## 656.0
1.08 .sup.1H NMR (500 MHz, DMSO- d.sub.6) .delta. 9.90 (s, 1H),
8.69 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 10.7 Hz, 1H),
8.13 (s, 1H), 7.94-7.84 (m, 2H), 7.00-6.95 (m, 1H), 6.76 (br. s,
1H), 5.77-5.64 (m, 1H), 5.23-5.09 (m, 1H), 4.19 (dt, J = 19.8, 7.4
Hz, 2H), 3.97 (s, 3H), 3.49 (s, 1H), 1.74-1.68 (m, 2H), 1.44 (d, J
= 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.10 (s, 6H). 779
##STR01755## ##STR01756## 614.1 1.06 .sup.1H NMR (500 MHz, DMSO-
d.sub.6) .delta. 9.49 (br. s., 1H), 8.79 (br. s., 1H), 8.56 (s,
1H), 8.42 (d, J = 10.7 Hz, 1H), 8.19 (s, 1H), 8.12 (br. s., 1H),
7.93 (br. s., 1H), 7.76 (br. s., 1H), 6.72 (br. s., 1H), 5.68 (d, J
= 6.7 Hz, 1H), 5.12 (d, J = 6.7 Hz, 1H), 4.18-4.06 (m, 2H), 4.00
(s, 3H), 3.65 (t, J = 4.9 Hz, 2H), 3.36 (br. s., 1H), 1.45 (d, J =
6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H). 780 ##STR01757##
##STR01758## 614.1 1.06 .sup.1H NMR (500 MHz, DMSO- d.sub.6)
.delta. 9.95 (s, 1H), 8.74 (d, J = 2.7 Hz, 1H), 8.55 (d, J = 2.1
Hz, 1H), 8.41 (d, J = 11.0 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H),
7.94-7.88 (m, 2H), 7.02 (d, J = 5.5 Hz, 1H), 6.82 (s, 1H), 5.70 (d,
J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.14 (dq, J = 19.5, 5.5
Hz, 2H), 4.00 (s, 3H), 3.61 (d, J = 4.0 Hz, 2H), 3.39 (s, 1H), 1.45
(d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 781 ##STR01759##
##STR01760## 598.1 1.06 .sup.1H NMR (500 MHz, DMSO- d6) .delta.
9.74 (br. s., 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.49
(br. s., 1H), 8.42 (d, J = 11.0 Hz, 1H), 8.19 (s, 1H), 7.93 (d, J =
2.4 Hz, 1H), 7.79 (br. s., 1H), 7.26-7.18 (m, 1H), 5.66 (d, J = 6.4
Hz, 1H), 5.16 (d, J = 7.3 Hz, 1H), 4.00 (s, 3H), 3.66 (t, J = 6.9
Hz, 2H), 3.38 (br. s., 1H), 2.77 (q, J = 6.1 Hz, 2H), 1.46 (d, J =
6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 782 ##STR01761##
##STR01762## 570.9 1.25 .sup.1H NMR (500 MHz, DMSO- d.sub.6)
.delta. 10.21-10.16 (m, 1H), 8.87 (d, J = 2.7 Hz, 1H), 8.63 (s,
1H), 8.47 (br. s., 1H), 8.20 (br. s., 2H), 8.06 (d, J = 8.2 Hz,
1H), 7.98 (d, J = 11.3 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.83 (d,
J = 12.2 Hz, 1H), 5.13 (br. s., 1H), 4.82 (br. s., 1H), 4.00 (s,
3H), 1.49-1.34 (m, 6H). 783 ##STR01763## ##STR01764## 622.9 1.31
.sup.1H NMR (500 MHz, DMSO- d.sub.6) .delta. 10.32 (s, 1H), 8.83
(d, J = 2.7 Hz, 1H), 8.77 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.17
(d, J = 1.8 Hz, 1H), 8.14-8.10 (m, 1H), 8.04 (d, J = 8.2 Hz, 1H),
7.95 (d, J = 11.6 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.81 (d, J =
8.9 Hz, 1H), 5.15 (dd, J = 6.6, 2.3 Hz, 1H), 4.84 (d, J = 4.0 Hz,
1H), 3.99 (s, 3H), 1.42 (dd, J = 6.0, 3.8 Hz, 6H). 784 ##STR01765##
##STR01766## 582.9 1.26 .sup.1H NMR (500 MHz, DMSO- d.sub.6)
.delta. 9.65-9.57 (m, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.61 (s, 1H),
8.23-8.20 (m, 1H), 8.18 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.96 (d,
J = 11.6 Hz, 1H), 7.93 (br. s., 1H), 7.82-7.73 (m, 1H), 6.76 (d, J
= 8.2 Hz, 1H), 5.09 (d, J = 4.6 Hz, 1H), 4.80 (d, J = 5.5 Hz, 1H),
3.99 (s, 3H), 3.78 (s, 3H), 1.39 (dd, J = 9.9, 6.6 Hz, 6H). 785
##STR01767## ##STR01768## 583.0 1.05 .sup.1H NMR (500 MHz, DMSO-
d.sub.6) d 9.91 (br. s., 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.61 (s,
1H), 8.24 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H),
7.99-7.91 (m, 3H), 7.55 (br. s., 1H), 5.12 (d, J = 4.6 Hz, 1H),
4.81 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 1.41 (t, J =
6.6 Hz, 6H). 786 ##STR01769## ##STR01770## 577.9 1.25 .sup.1H NMR
(500 MHz, DMSO- d.sub.6) d 10.28 (br. s., 1H), 8.87-8.81 (m, 2H),
8.60 (s, 2H), 8.25 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2 Hz,
1H), 7.96 (d, J = 11.3 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 5.14 (d,
J = 4.3 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.42 (d, J
= 4.9 Hz, 6H). 787 ##STR01771## ##STR01772## 582.8 1.02 .sup.1H NMR
(500 MHz, DMSO- d.sub.6) d 9.71 (br. s., 1H), 8.86 (d, J = 2.4 Hz,
1H), 8.62 (s, 1H), 8.33 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J =
8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.93 (br. s., 1H), 7.63
(br. s., 1H), 5.10 (d, J = 4.0 Hz, 1H), 4.81 (d, J = 4.3 Hz, 1H),
4.00 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H), 1.40 (t, J = 7.3 Hz, 6H).
788 ##STR01773## ##STR01774## 552.9 1.02 .sup.1H NMR (500 MHz,
DMSO- d.sub.6) .delta. 9.91 (br. s., 1H), 8.86 (d, J = 2.7 Hz, 1H),
8.65 (br. s., 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 4.3 Hz,
1H), 8.18 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz,
1H), 7.93 (d, J = 2.7 Hz, 1H), 7.92-7.88 (m, 1H), 7.33 (dd, J =
8.2, 4.6 Hz, 1H), 5.22-5.08 (m, 1H), 4.81 (d, J = 3.7 Hz, 1H), 4.00
(s, 3H), 1.41 (t, J = 6.7 Hz, 6H). 789 ##STR01775## ##STR01776##
571.0 1.27 .sup.1H NMR (500 MHz, DMSO- d.sub.6) d 10.01-9.90 (m,
1H), 8.85 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.27 (br.
s., 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.97
(d, J = 11.6 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 6.4
Hz, 1H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.81 (d, J = 3.7 Hz, 1H),
4.00 (s, 3H), 1.41 (t, J = 6.4 Hz, 6H). 790 ##STR01777##
##STR01778## 552.9 1.02 .sup.1H NMR (500 MHz, DMSO- d.sub.6)
.delta. 10.31 (s, 1H), 8.86 (d, J = 2.7 Hz, 1H), 8.62 (d, J = 1.8
Hz, 1H), 8.41 (d, J = 5.5 Hz, 2H), 8.19 (d, J = 1.8 Hz, 1H), 8.05
(d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.94 (d, J = 2.4
Hz, 1H), 7.52 (d, J = 5.8 Hz, 2H), 5.16 (d, J = 4.0 Hz, 1H), 4.82
(d, J = 3.7 Hz, 1H), 4.00 (s, 3H), 1.48-1.36 (m, 6H). 791
##STR01779## ##STR01780## 549.2 1.06 .sup.1H NMR (500 MHz, DMSO-
d.sub.6) .delta. 9.76 (br. s., 1H), 8.65 (br. s., 2H), 8.49 (s,
1H), 8.34 (d, J = 10.7 Hz, 1H), 7.80 (d, J = 9.8 Hz, 2H), 7.61-7.33
(m, 1H), 7.18-6.88 (m, 1H), 5.65 (d, J = 6.4 Hz, 1H), 5.06 (d, J =
6.4 Hz, 1H), 3.92 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H), 1.37 (d, J =
6.1 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H).
Example 792
(2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyr-
idin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01781##
[3722] Intermediate 792A: methyl
5-(((((2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,-
4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylat-
e
##STR01782##
[3724] Intermediate I-124 (6.56 mg, 0.022 mmol), Intermediate I-141
(10 mg, 0.022 mmol), and PdCl.sub.2(dppf) (0.963 mg, 1.316 .mu.mol)
were dissolved in dioxane (219 .mu.l) and 3 M aqueous
Na.sub.2CO.sub.3 (99 .mu.l, 0.197 mmol) was added. The reaction
mixture was heated to 100.degree. C. in an oil bath for 2 hours.
The reaction mixture was cooled to ambient temperature, diluted
with EtOAc, washed with water, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
reaction material was dissolved in DCM and filtered. Purified on
ISCO using 0-100% EtOAc in DCM on a 4 g column to yield
Intermediate 792A (7.5 mg, 0.013 mmol, 57.7% yield) as a yellow
solid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 593.1
(M+H).sup.+.
Example 792
[3725] Intermediate 792A (7.5 mg, 0.013 mmol) was dissolved in THF
(127 .mu.l) and lithium borohydride (0.276 mg, 0.013 mmol) was
added in one portion. The reaction mixture was allowed to stir at
room temperature for 3 h. Residue was dissolved in THF and air was
bubbled through the reaction until the solvent was evaporated. The
reaction material was dissolved in DMF, filtered, and purified by
preparative HPLC (Method D, 45 to 90% B in 15 minutes) to yield
Example 792 (1.7 mg, 2.95 .mu.mol, 23.32% yield): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.96 (br. s., 1H), 8.80 (br. s., 2H),
8.74 (br. s., 1H), 8.57 (br. s., 1H), 8.41 (d, J=10.7 Hz, 1H), 7.88
(d, J=10.4 Hz, 2H), 5.70 (br. s., 1H), 5.17 (br. s., 1H), 4.49 (br.
s., 2H), 4.00 (br. s., 3H), 3.84-3.34 (m, 1H), 2.61 (br. s., 3H),
1.54-1.34 (m, 6H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z:
565.2 (M+H).sup.+. Analytical HPLC Method B: 98% purity.
Example 793
(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyr-
idin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01783##
[3726] Intermediate 793A: methyl
5-(((((2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,-
4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylat-
e
##STR01784##
[3728] Intermediate I-121 (7.01 mg, 0.022 mmol), Intermediate I-141
(10 mg, 0.022 mmol), and PdCl.sub.2(dppf) (0.963 mg, 1.316 .mu.mol)
were dissolved in dioxane (219 .mu.l) and 3 M aqueous
Na.sub.2CO.sub.3 (99 .mu.l, 0.197 mmol) was added. The reaction
mixture was heated to 100.degree. C. in an oil bath for 2 hours.
The reaction mixture was cooled to ambient temperature, diluted
with EtOAc, washed with water, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
reaction material was dissolved in DCM and filtered. Purified on
ISCO using 0-100% EtOAc in DCM on a 4 g column to yield
Intermediate 793A (5.9 mg, 0.0096 mmol, 44% yield) as a yellow
solid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 613.1
(M+H).sup.+.
Example 793
[3729] Intermediate 793A (5.9 mg, 0.009 mmol) was dissolved in THF
(127 .mu.l) and lithium borohydride (0.276 mg, 0.013 mmol) was
added in one portion. The reaction mixture was allowed to stir at
room temperature for 3 h. Residue was dissolved in THF and air was
bubbled through the reaction until the solvent was evaporated. The
reaction material was dissolved in DMF, filtered, and purified by
preparative HPLC (Method D, 45 to 90% B in 15 minutes) to yield
Example 793 (1.1 mg, 1.79 .mu.mol, 19% yield): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.94 (br. s., 1H), 8.91-8.71 (m, 2H),
8.58 (br. s., 1H), 8.45 (d, J=10.1 Hz, 1H), 8.21 (br. s., 1H), 7.95
(br. s., 1H), 7.70 (d, J=14.3 Hz, 1H), 5.71 (br. s., 1H), 5.17 (br.
s., 1H), 4.48 (br. s., 2H), 4.00 (br. s., 3H), 3.43-3.28 (m, 1H),
1.52-1.36 (m, 6H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z:
585.1 (M+H).sup.+. Analytical HPLC Method B: 95% purity.
Example 794
(R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-
-5-yl)oxy)propan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01785##
[3730] Intermediate 794A: (R)-methyl
5-((((1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyri-
din-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
##STR01786##
[3732] Intermediate I-121 (7.23 mg, 0.022 mmol), Intermediate I-142
(10 mg, 0.022 mmol) and PdCl.sub.2(dppf) (0.963 mg, 1.316 .mu.mol)
were dissolved in dioxane (219 .mu.l) and 3M aqueous
Na.sub.2CO.sub.3 (99 .mu.l, 0.197 mmol) was added. The reaction
mixture was heated to 100.degree. C. in an oil bath for 2 hours.
The reaction mixture was cooled to ambient temperature, diluted
with EtOAc, washed with water, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
material was dissolved in DCM and filtered. Purified on ISCO using
0-100% EtOAc in DCM on a 4 g column to yield Intermediate 792A (4.5
mg, 0.0075 mmol, 33% yield) as a yellow solid. LC-MS: method H,
RT=1.23 min, MS (ESI) m/z: 599.1 (M+H).sup.+.
Example 794
[3733] Intermediate 794A (4.5 mg, 0.008 mmol) was dissolved in THF
(127 .mu.l) and lithium borohydride (0.276 mg, 0.013 mmol) was
added in one portion. The reaction mixture was allowed to stir at
room temperature for 3 h. Residue was dissolved in THF and air was
bubbled through the reaction mixture until the solvent was
evaporated. The mixture was dissolved in DMF, filtered, and
purified by preparative HPLC (Method D, 45 to 90% B in 15 minutes)
to yield Example 794 (0.8 mg, 1.33 .mu.mol, 18% yield). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.08 (br. s., 1H), 8.84 (d, J=18.0
Hz, 3H), 8.59 (br. s., 1H), 8.48 (d, J=9.8 Hz, 1H), 8.22 (br. s.,
1H), 7.96 (br. s., 1H), 5.30 (br. s., 1H), 4.84 (d, J=11.9 Hz, 1H),
4.60-4.54 (m, 1H), 4.51 (br. s., 2H), 4.01 (br. s., 3H), 3.41-3.23
(m, 1H), 1.43 (br. s., 3H). LC-MS: method H, RT=0.96 min, MS (ESI)
m/z: 571.1 (M+H).sup.+. Analytical HPLC Method B: 95% purity.
Example 795
(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]t-
hiazol-6-yl)oxy)butan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
##STR01787##
[3735] Intermediate I-97 (10.83 mg, 0.035 mmol) and pyridine (0.019
mL, 0.236 mmol) were dissolved in DCM (2 mL). To this solution was
added Intermediate I-143 (0.0125 g, 0.024 mmol) as a solution in
DCM (1 mL). The reaction mixture was allowed to stir for 30 min.
The reaction mixture was concentrated under reduced pressure and
dissolved in 2 mL of 1:1 THF:MeOH solution and CSA (5.48 mg, 0.024
mmol) was added. The reaction mixture was allowed to stir at room
temperature for 2 h. TEA (0.033 mL, 0.236 mmol) was added to quench
the CSA, and the reaction mixture was concentrated and dissolved in
2 mL of DMF, filtered, and purified by preparative HPLC (Method D,
50 to 100% B in 20 minutes) to yield Example 795 (0.0075 g, 0.012
mmol, 49.0% yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.80 (br. s., 1H), 8.82 (d, J=2.1 Hz, 1H), 8.59 (br. s., 3H), 8.18
(s, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.92 (br. s., 1H), 5.11 (d, J=4.9
Hz, 1H), 4.86 (br. s., 1H), 4.23 (br. s., 2H), 3.99 (s, 3H), 3.68
(d, J=4.9 Hz, 2H), 3.34 (br. s., 1H), 1.41 (dd, J=15.3, 6.1 Hz,
6H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 647.9 (M+H).sup.+.
Analytical HPLC Method B: 100% purity.
Examples 796 to 804
[3736] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
795 and the examples above.
TABLE-US-00025 LCMS LCMS Ex. [M + H].sup.+ RT (Min) No. Structure
Amine m/z Method H NMR 796 ##STR01788## ##STR01789## 663.9 1.26
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80 (br. s., 1H), 8.80
(br. s., 1H), 8.63- 8.54 (m, 3H), 8.16 (s, 1H), 8.04 (d, J = 7.3
Hz, 1H), 7.90 (br. s., 1H), 5.11 (d, J = 7.0 Hz, 1H), 4.85 (d, J =
7.0 Hz, 1H), 4.07 (d, J = 6.4 Hz, 1H), 4.02 (br. s., 1H), 3.99 (s,
3H), 3.96- 3.89 (m, 1H), 3.36 (d, J = 4.6 Hz, 1H), 1.41 (dd, J =
15.6, 6.1 Hz, 6H), 1.11 (d, J = 6.1 Hz, 3H). 797 ##STR01790##
##STR01791## 605.1 1.33 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.94 (br. s., 1H), 8.78 (d, J = 2.7 Hz, 1H), 8.55 (d, J = 2.1 Hz,
1H), 8.30-8.24 (m, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 7.3
Hz, 2H), 7.88 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 7.0 Hz, 1H), 5.13
(dd, J = 6.4, 2.4 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 3.98 (s, 3H),
1.42 (dd, J = 16.2, 6.4 Hz, 6H). 798 ##STR01792## ##STR01793##
588.8 1.10 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.00 (s,
1H), 8.82 (d, J = 2.7 Hz, 1H), 8.59 (d, J = 2.4 Hz, 3H), 8.18 (d, J
= 2.1 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H),
7.79 (d,J = 6.4 Hz, 2H), 5.22 (dd, J = 6.7, 2.4 Hz, 1H), 4.95-4.77
(m, 1H), 3.99 (s, 3H), 1.44 (t, J = 7.0 Hz, 6H). 799 ##STR01794##
##STR01795## 588.8 1.11 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.91 (br. s., 1H), 8.83 (d, J = 3.1 Hz, 1H), 8.65 (br. s., 1H),
8.61 (d, J = 2.1 Hz, 1H), 8.23- 8.17 (m, 2H), 8.07 (d, J = 7.6 Hz,
1H), 7.93 (d, J = 2.7 Hz, 2H), 7.33 (dd, J = 8.1, 4.7 Hz, 1H), 5.15
(dd, J = 6.4, 2.7 Hz, 1H), 4.92-4.77 (m, 1H), 4.00 (s, 3H), 1.42
(dd, J = 15.3, 6.4 Hz, 6H). 800 ##STR01796## ##STR01797## 616.8
1.12 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.15 (br. s.,
1H), 8.83 (d, J = 2.7 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.50 (br.
s., 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.97-
7.85 (m, 2H), 5.14 (d, J = 6.4 Hz, 1H), 4.87 (d, J = 4.0 Hz, 1H),
4.00 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 1.42 (dd, J = 14.2, 6.6
Hz, 6H). 801 ##STR01798## ##STR01799## 618.8 1.33 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.60 (br. s., 1H), 8.82 (d, J = 2.7 Hz,
1H), 8.60 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.1 Hz, 2H), 8.04 (d, J
= 7.3 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.76 (br. s., 1H), 6.75
(d, J = 7.9 Hz, 1H), 5.10 (dd, J = 6.6, 2.6 Hz, 1H), 4.83 (dd, J =
6.4, 2.7 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 1.42 (d, J = 6.1 Hz,
3H), 1.39 (d, J = 6.4 Hz, 3H). 802 ##STR01800## ##STR01801## 613.8
1.32 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.27 (br. s.,
1H), 8.81 (d, J = 2.7 Hz, 2H), 8.62-8.56 (m, 2H), 8.25 (br. s.,
1H), 8.17 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.91 (d, J
= 2.4 Hz, 1H), 5.15 (dd, J = 6.6, 2.3 Hz, 1H), 4.88 (d, J = 4.0 Hz,
1H), 3.99 (s, 3H), 1.43 (dd, J = 12.2, 6.4 Hz, 6H). 803
##STR01802## ##STR01803## 618.9 1.13 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.86 (br. s., 1H), 8.76 (d, J = 2.7 Hz, 1H),
8.53 (d, J = 2.1 Hz, 1H), 8.19 (br. s., 1H), 8.12 (d, J = 2.4 Hz,
1H), 8.00 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 2.7 Hz,
1H), 7.50 (br. s., 1H), 5.09 (dd, J = 6.6, 2.6 Hz, 1H), 4.89-4.68
(m, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.35
(d, J = 6.7 Hz, 3H). 804 ##STR01804## ##STR01805## 605.1 1.32
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.18 (br. s., 1H),
8.79 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.46 (br. s.,
1H), 8.19 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.04 (d, J
= 7.3 Hz, 1H), 7.89 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 10.4 Hz, 1H),
5.15 (dd, J = 6.6, 2.6 Hz, 1H), 4.85 (d, J = 3.7 Hz, 1H), 3.98 (s,
3H), 1.42 (dd, J = 14.2, 6.6 Hz, 6H).
Example 806
1-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-
-dimethylpropan-1-ol
##STR01806##
[3737] Intermediate 806A:
4-bromo-6-fluorobenzo[d]thiazol-2-amine
##STR01807##
[3739] 2-Bromo-4-fluoroaniline (0.54 g, 2.84 mmol) was dissolved in
MeCN (14.21 ml). Ammonium thiocyanate (0.324 g, 4.26 mmol) was
added to the reaction mixture followed by benzyltrimethylammonium
tribromide (1.108 g, 2.84 mmol), and the reaction mixture was
allowed to stir for 12 hours. The reaction mixture was diluted with
saturated aqueous NaHCO.sub.3, and the solids were collected by
suction filtration and washed with water to yield Intermediate 806A
(0.700 g, 2.84 mmol, 100%). .sup.1H NMR (400 MHz, MeOH.sub.4)
.delta. 7.41 (dd, J=8.0, 2.5 Hz, 1H), 7.26 (dd, 2.5 Hz, 1H). LC-MS:
method H, RT=0.81 min, MS (ESI) m/z: 247/249 (M+H).sup.+.
Intermediate 806B:
1-(2-amino-6-fluorobenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
##STR01808##
[3741] Intermediate 806A (50 mg, 0.202 mmol) was dissolved in THF
(2024 .mu.l). NaH (8.90 mg, 0.223 mmol) was added and the reaction
mixture was stirred for 30 min. The reaction mixture was cooled to
-78.degree. C. and BuLi (106 .mu.l, 0.243 mmol) was added. The
reaction mixture was allowed to stir for 30 min. Pivalaldehyde
(17.43 mg, 0.202 mmol) was added, and the reaction mixture was
allowed to warm to ambient temperature. The reaction mixture was
stirred for 10 min then diluted with water and EtOAc. The layers
were separated and the aqueous layer was back extracted with EtOAc.
The combined organic layer was washed with water, dried with sodium
sulfate, and concentrated under reduced pressure to yield
Intermediate 806B (0.064 g, 0.151 mmol, 75% yield). Used without
further purification as a 60% pure mixture. LC-MS: method H,
RT=0.56 min, MS (ESI) m/z: 255.2 (M+H).sup.+.
Intermediate 806C:
1-(2-chloro-6-fluorobenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
##STR01809##
[3743] Copper(II) chloride (0.058 g, 0.434 mmol) and t-butyl
nitrite (0.052 ml, 0.434 mmol) were dissolved in MeCN (1.022 ml)
and allowed to stir 10 minutes. Intermediate 806B (0.065 g, 0.256
mmol) was dissolved in MeCN (1.533 ml), and the copper solution was
added. The reaction mixture was stirred for 2.5 h at 60.degree. C.
The reaction mixture was diluted with EtOAc and water. The layers
were separated, and the organic layer was washed with 1 N HCl,
washed with saturated aqueous NaHCO.sub.3, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
material was purified on ISCO using a 12 g column with 0-100%
gradient of EtOAc in hexanes to yield Intermediate 806C (0.008 g,
0.029 mmol, 11.43% yield) as a white solid. LC-MS: method H,
RT=1.14 min, MS (ESI) m/z: 274.1 (M+H).sup.+.
Example 806
[3744] Intermediate I-9 (8.77 mg, 0.029 mmol) and Intermediate 806C
(0.008 g, 0.029 mmol) were dissolved in DMF (0.292 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.432 mg, 1.753 .mu.mol)
was added, and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
ml, 0.300 mmol) was added, and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction mixture was filtered and
purified by preparative HPLC (Method D, 20 to 100% B in 20 minutes)
to yield Example 806 (0.0032 g, 0.007 mmol, 24% % yield): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.55 (s, 1H),
7.92 (d, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.32 (d, J=10.4 Hz, 1H), 5.46
(br. s., 1H), 4.07 (s, 3H), 2.64 (s, 3H), 0.95 (s, 9H). LC-MS:
method H, RT=1.39 min, MS (ESI) m/z: 412.2 (M+H).sup.+. Analytical
HPLC Method B: 92% purity.
Example 807
1-(5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-
-yl)-2,2-dimethylpropan-1-ol
##STR01810##
[3745] Intermediate 807A:
2-bromo-7-(dibromomethyl)-5-methoxythiazolo[5,4-b]pyridine
##STR01811##
[3747] Intermediate I-16 (0.250 g, 0.965 mmol) was dissolved in
CCl.sub.4 (3 mL) and NBS (0.859 g, 4.82 mmol) was added followed by
AIBN (0.048 g, 0.289 mmol). The reaction mixture was allowed to
stir at reflux for 12 hours. The reaction mixture was cooled and
diluted with water and EtOAc. The layers were separated and the
organic layer was washed with 1 N HCl, washed with brine, dried
with sodium sulfate, and concentrated under reduced pressure to
yield Intermediate 807A (0.125 g, 0.300 mmol, 31%) which was used
without purification. LC-MS: method H, RT=1.14 min, MS (ESI) m/z:
416.9 (M+H).sup.+.
Intermediate 807B:
1-(2-bromo-5-methoxythiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol
##STR01812##
[3749] Intermediate 807A (0.125 g, 0.458 mmol) was dissolved in THF
(4.58 ml) and t-butyl magnesium chloride (0.267 g, 2.288 mmol) was
added at -78.degree. C. The reaction mixture was allowed to slowly
warm to room temperature. The reaction was quenched with saturated
aqueous NH.sub.4Cl and the reaction mixture was diluted with EtOAc.
The layers were separated, and the organic layer was washed with
brine, dried with sodium sulfate, and concentrated under reduced
pressure to yield Intermediate 807B (0.034 g, 0.103 mmol, 22.43%
yield): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.72 (s, 1H),
4.78 (d, J=8.1 Hz, 1H), 3.98 (s, 3H), 3.79 (d, J=8.4 Hz, 1H), 0.96
(s, 9H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 331.0
(M+H).sup.+.
Example 807
[3750] Intermediate I-9 (0.034 g, 0.115 mmol) and Intermediate 806B
(0.038 g, 0.115 mmol) were dissolved in DMF (1.147 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (5.62 mg, 6.88 .mu.mol)
was added, and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
ml, 0.300 mmol) was added and the reaction mixture was degassed for
5 minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was filtered and purified by
preparative HPLC (Method D, 60 to 100% B in 17 minutes) to yield
Example 807 (13.7 mg, 0.032 mmol, 27.8% yield): .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H), 8.52 (s, 1H), 7.84 (s,
1H), 6.95 (s, 1H), 5.53 (d, J=4.6 Hz, 1H), 5.32 (d, J=4.6 Hz, 1H),
4.09 (s, 3H), 3.99 (s, 3H), 2.65 (s, 3H), 0.97 (s, 9H). LC-MS:
method H, RT=1.23 min, MS (ESI) m/z: 425.1 (M+H).sup.+. Analytical
HPLC Method B: 99% purity.
Example 808
6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(methoxymethyl)benzo[d]t-
hiazole
##STR01813##
[3751] Intermediate 808A:
2-bromo-6-methoxy-4-(methoxymethyl)benzo[d]thiazole
##STR01814##
[3753] Intermediate I-20D (0.100 g, 0.365 mmol) was dissolved in
THF (3.65 ml) and sodium hydride (0.022 g, 0.547 mmol) was added.
The reaction mixture was allowed to stir for 10 min and MeI (0.034
ml, 0.547 mmol) was added. The reaction mixture was allowed to stir
at room temperature for 3 h. The reaction mixture was diluted with
water and EtOAc. The layers were separated, and the organic layer
was washed with brine, dried with sodium sulfate, and concentrated
under reduced pressure. The crude reaction mixture was purified on
ISCO using a 12 g column eluting with 0-100% EtOAc in hexanes to
yield Intermediate 808A (0.037 g, 0.129 mmol, 35.5% yield) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.20 (s,
2H), 4.96 (s, 2H), 3.90 (s, 3H), 3.53 (s, 3H). LC-MS: method H,
RT=1.28 min, MS (ESI) m/z: 287.9 (M+H).sup.+.
Example 808
[3754] Intermediate I-9 (10 mg, 0.033 mmol) and Intermediate 808A
(8.12 mg, 0.033 mmol) were dissolved in DMF (0.333 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.632 mg, 1.999 .mu.mol)
was added, and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
ml, 0.300 mmol) was added, and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction mixture was filtered and
purified by preparative HPLC (Method D, 70 to 100% B in 25 minutes)
to yield Example 808 (0.0046 g, 0.012 mmol, 36% yield): .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.58 (s, 1H), 7.83
(s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.14 (s, 1H), 5.04 (s, 2H), 4.09
(s, 3H), 3.89 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H). LC-MS: method H,
RT=1.31 min, MS (ESI) m/z: 382.12 (M+H).sup.+. Analytical HPLC
Method B: 100% purity.
Example 809
2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine
##STR01815##
[3755] Intermediate 809A: 2-chlorothiazolo[4,5-c]pyridine
##STR01816##
[3757] Copper(II) chloride (0.445 g, 3.31 mmol) and t-butyl nitrite
(0.669 ml, 5.62 mmol) were dissolved in MeCN (13.23 ml) and allowed
to stir 10 minutes. Thiazolo[4,5-c]pyridin-2-amine (0.500 g, 3.31
mmol) was dissolved in MeCN (19.84 ml) and the copper solution was
added. The reaction mixture was stirred for 1.5 h at 60.degree. C.
The reaction mixture was diluted with EtOAc and water. The layers
were separated, and the organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Purified
on ISCO using a 40 g column with 0-100% gradient of EtOAc in
hexanes to yield Intermediate 809A (0.125 g, 0.733 mmol, 22.15%
yield). LC-MS: method H, RT=0.51 min, MS (ESI) m/z: 170.9
(M+H).sup.+.
Example 809
[3758] Intermediate I-9 (17.59 mg, 0.059 mmol) and Intermediate
809A (10 mg, 0.059 mmol) were dissolved in DMF (0.586 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (2.87 mg, 3.52 .mu.mol)
was added, and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
ml, 0.300 mmol) was added, and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction mixture was filtered and
purified by preparative HPLC (Method D, 20 to 25% B in 25 minutes)
to yield Example 809 (1.3 mg, 4.22 .mu.mol, 7.19% yield): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.51 (br. s., 1H), 8.77 (s,
1H), 8.69 (s, 1H), 8.61 (br. s., 1H), 8.41 (br. s., 1H), 7.95 (s,
1H), 4.10 (s, 3H), 2.67 (s, 3H). LC-MS: method H, RT=0.86 min, MS
(ESI) m/z: 309.1 (M+H).sup.+. Analytical HPLC Method B: 100%
purity.
Example 810
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-
-yl)oxy)ethyl pyridin-3-ylcarbamate
##STR01817##
[3759] Intermediate 810A:
2-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR01818##
[3761] Intermediate I-131A (1.394 g, 4.02 mmol) was dissolved in
DMF (40.2 ml) and Cs.sub.2CO.sub.3 (7.85 g, 24.10 mmol) was added
followed by 2-bromoethyl acetate (0.805 g, 4.82 mmol). The reaction
mixture was stirred at room temperature for 3 hours. The reaction
mixture was then heated to 40.degree. C. and allow to stir for 12
hours. The reaction mixture was diluted with water and EtOAc. The
layers were separated, and the organic layer was washed with brine,
dried with sodium sulfate, and concentrated under reduced pressure
to yield Intermediate 810A (0.540 g, 1.991 mmol, 49.6% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.51 (d, J=10.6 Hz, 1H),
5.16 (br. s., 2H), 4.64-4.57 (m, 2H), 4.50-4.42 (m, 2H), 2.09 (s,
3H). LC-MS: method H, RT=0.69 min, MS (ESI) m/z: 272.1
(M+H).sup.+.
Intermediate 810B:
2-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR01819##
[3763] Copper(II) chloride (0.455 g, 3.38 mmol) and t-butyl nitrite
(0.403 ml, 3.38 mmol) were dissolved in MeCN (7.96 ml) and the
mixture was allowed to stir for 10 minutes. Intermediate 810A
(0.540 g, 1.991 mmol) was dissolved in MeCN (11.94 ml), and the
copper solution was added. The reaction mixture was stirred for 2.5
hours at 60.degree. C. The reaction mixture was diluted with EtOAc
and water. The layers were separated, and the organic layer was
washed with 1 N HCl, washed with saturated aqueous NaHCO.sub.3,
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. Purified on ISCO using a 12 g column with
0-100% gradient of EtOAc in hexanes to yield Intermediate 810B
(0.306 g, 1.053 mmol, 52.9% yield) as a yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.86 (d, J=9.7 Hz, 1H), 4.71-4.64 (m,
2H), 4.52-4.45 (m, 2H), 2.10 (s, 3H). LC-MS: method H, RT=1.01 min,
MS (ESI) m/z: 291.0 (M+H).sup.+.
Intermediate 810C:
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl acetate
##STR01820##
[3765] Intermediate I-9 (20.65 mg, 0.069 mmol) and Intermediate
810B (20 mg, 0.069 mmol) were dissolved in DMF (0.688 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (3.37 mg, 4.13 .mu.mol)
was added, and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
ml, 0.300 mmol) was added, and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. Purified on ISCO using a 12 g column
eluting with 0-100% EtOAc in DCM to yield Intermediate 810C (0.039
g, 0.055 mmol, 79% yield) as a yellow solid. LC-MS: method H,
RT=1.28 min, MS (ESI) m/z: 428.9 (M+H).sup.+.
Intermediate 810D:
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethanol
##STR01821##
[3767] To a suspension of Intermediate 810C (0.039 g, 0.091 mmol)
in THF (1 mL) and MeOH (0.333 mL) was added NaOH (0.273 mL, 0.273
mmol) at room temperature. The mixture was stirred at room
temperature for 1 hour. The mixture was diluted by EtOAc and 1N
HCl. The layers were separated, and the organic layer was washed
with water, washed with brine, dried with sodium sulfate, and
concentrated to yield Intermediate 810D (0.050 g, 0.129 mmol, 100%
yield) as a white solid. Used without further purification in the
next step. LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 386.9
(M+H).sup.+.
Intermediate 810E:
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl carbonochloridate
##STR01822##
[3769] To a solution of Intermediate 810D (0.050 g, 0.129 mmol) in
THF (5 mL) at room temperature was added 15% phosgene in toluene
(0.456 mL, 0.647 mmol), and the mixture was stirred for 3 h.
Solvent was completely removed to yield Intermediate 810E (0.058 g,
0.129 mmol, 100% yield) as a yellow solid. The material was used
immediately in the next step without purification. LC-MS: method H,
RT=1.30 min, MS (ESI) m/z: 448.8 (M+H).sup.+.
Example 810
[3770] Pyridin-3-amine (0.012 g, 0.129 mmol) and pyridine (0.105
mL, 1.292 mmol) were dissolved in DCM (2 mL). Intermediate 810E
(0.058 g, 0.129 mmol) was added as a solution in DCM (1 mL). The
reaction mixture was allowed to stir for 30 min. The reaction
mixture was concentrated under reduced pressure and purified on
ISCO using 0-100% EtOAc in hexanes on a 12 g column. The reaction
mixture was further purified by preparative HPLC (Method D, 35 to
75% B in 25 minutes, 4 min hold time at 75%) to yield Example 810
(0.0052 g, 10.06 .mu.mol, 7.79% yield) as a pale yellow solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.00 (s, 1H), 8.73 (s,
1H), 8.62 (br. s., 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.20 (br. s.,
1H), 7.88 (br. s., 2H), 7.33 (br. s., 1H), 4.79 (br. s., 2H), 4.57
(br. s., 2H), 4.10 (s, 3H), 2.64 (br. s., 3H). LC-MS: method H,
RT=0.98 min, MS (ESI) m/z: 507.1 (M+H).sup.+. Analytical HPLC
Method B: 98% purity.
Example 811
2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-
-yl)oxy) ethyl (6-fluoro-5-methylpyridin-3-yl)carbamate
##STR01823##
[3772] To a solution of Intermediate 810E (7.5 mg, 0.017 mmol) in
DCM (1 mL) and THF (0.5 mL) was added
6-fluoro-5-methylpyridin-3-amine (7.38 mg, 0.058 mmol) followed by
DIPEA (0.029 mL, 0.167 mmol). The mixture was stirred at room
temperature for 1 hour. The reaction was quenched with 0.2 mL of
MeOH. The reaction mixture was concentrated, dissolved in DMF, and
filtered. The reaction was purified by preparative HPLC (Method D,
50 to 100% B in 20 minutes, 5 min hold time at 100%) to yield
Example 811 (0.0052 g, 9.37 .mu.mol, 56.1% yield): LC-MS: method H,
RT=1.22 min, MS (ESI) m/z: 539.2 (M+H).sup.+. Analytical HPLC
Method B: 97% purity.
Example 812
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-
-yl)oxy) ethyl (6-(thiophen-2-yl)pyridin-3-yl)carbamate
##STR01824##
[3773] Intermediate 812A:
2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR01825##
[3775] 2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate (0.050 g, 0.146 mmol) was dissolved in DMF. 2-Bromomethyl
acetate (0.058 g, 0.350 mmol) and Cs.sub.2CO.sub.3 (0.237 g, 0.729
mmol) were added and the reaction mixture was stirred at 40.degree.
C. for 18 h. The reaction mixture was diluted with EtOAc and water.
The layers were separated. The organic layer was washed with brine
dried with sodium sulfate, and concentrated under reduced pressure.
The reaction mixture was purified on ISCO using a 24 g column with
a 0-100% EtOAc in hexanes gradient to yield Intermediate 812A
(0.044 g, 0.165 mmol, 56.5% yield) as a pale yellow solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 6.53-6.53 (m, 1H), 5.01 (br. s.,
2H), 4.52-4.48 (m, 2H), 4.44-4.39 (m, 2H), 2.49 (d, J=0.7 Hz, 3H),
2.09 (s, 3H). LC-MS: method H, RT=0.72 min, MS (ESI) m/z: 268.2
(M+H).sup.+.
Intermediate 812B:
2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl
acetate
##STR01826##
[3777] Copper(II) bromide (0.063 g, 0.280 mmol) and t-butyl nitrite
(0.033 mL, 0.280 mmol) were dissolved in MeCN (0.658 mL) and
allowed to stir 10 minutes. Intermediate 812A (0.044 g, 0.165 mmol)
was dissolved in MeCN (0.988 mL) and the copper solution was added.
The reaction mixture was diluted with EtOAc and water. The organic
layer was washed with 1 N HCl, washed with saturated aqueous
NaHCO.sub.3, washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo to yield Intermediate 812B (0.046 g,
0.139 mmol, 84% yield): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
6.69 (d, J=0.9 Hz, 1H), 4.57-4.53 (m, 2H), 4.44-4.41 (m, 2H), 2.63
(d, J=0.9 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=1.07 min, MS
(ESI) m/z: 331.0 (M+H).sup.+.
Intermediate 812C:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl acetate
##STR01827##
[3779] Intermediate I-9 (0.042 g, 0.140 mmol) and Intermediate 812B
(0.046 g, 0.140 mmol) were dissolved in DMF (1 mL).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (6.86 mg, 8.40 .mu.mol) was
added and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 mL,
0.300 mmol) was added and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction was purified on ISCO using 24 g column
with a 0-100% EtOAc in hexanes gradient to yield Intermediate 812C
(0.021 g, 0.049 mmol, 35.4% yield) as an off white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (d, J=2.0 Hz, 1H), 8.54 (s,
1H), 7.75 (s, 1H), 6.74 (s, 1H), 4.63 (dd, J=5.8, 3.6 Hz, 2H),
4.51-4.43 (m, 2H), 4.13 (s, 3H), 2.79 (s, 3H), 2.66 (s, 3H), 2.11
(s, 3H). LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 425.1
(M+H).sup.+.
Intermediate 812D:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethanol
##STR01828##
[3781] To a suspension of Intermediate 812C (0.143 g, 0.337 mmol)
in THF (3 mL) and MeOH (1 mL) was added NaOH (1.011 mL, 1.011 mmol)
at room temperature. The mixture was stirred at room temperature
for 1 hour. The mixture was diluted with EtOAc and 1N HCl. The
organic layer was washed with water, washed with brine, dried with
sodium sulfate, and concentrated to yield Intermediate 812D (0.120
g, 0.314 mmol, 93% yield) as a tan solid. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. 8.61 (s, 1H), 8.58 (s, 1H), 7.78 (s, 1H),
6.82 (s, 1H), 4.48-4.45 (m, 2H), 4.40-4.36 (m, 1H), 4.13 (s, 3H),
3.94-3.90 (m, 2H), 2.77 (s, 3H), 2.66 (s, 3H). LC-MS: method H,
RT=1.15 min, MS (ESI) m/z: 383.9 (M+H).sup.+.
Intermediate 812E:
2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin--
5-yl)oxy)ethyl carbonochloridate
##STR01829##
[3783] To a solution of Intermediate 812D (0.025 g, 0.065 mmol) in
THF (3 mL) at was added 15% phosgene in toluene (0.231 mL, 0.327
mmol) and the mixture was stirred at for 1 h. The reaction mixture
was concentrated under vacuum to give Intermediate 812E (0.030 g,
0.067 mmol, 100% yield) as a yellow solid. It was used for the next
step without any purification. LC-MS: method H, RT=1.35 min, MS
(ESI) m/z: 444.7 (M+H).sup.+.
Example 812
[3784] To a solution of Intermediate 812E (20 mg, 0.045 mmol) in
DCM (1 mL) and THF (0.5 mL) was added
6-(thiophen-2-yl)pyridin-3-amine (14.81 mg, 0.157 mmol) followed by
DIEA (0.079 mL, 0.450 mmol). The mixture was stirred at for 1 hour.
The reaction mixture was diluted with EtOAc and water. The combined
organic layer was washed with brine and concentrated under vacuum.
The reaction mixture was diluted with DMSO, filtered, and purified
by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to
yield Example 812 (0.0057 g, 5.61 .mu.mol, 12.48% yield): .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.05 (br. s., 1H), 8.63 (s,
1H), 8.56 (br. s., 1H), 8.50 (s, 1H), 7.92 (br. s., 1H), 7.83 (d,
J=8.8 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J=3.3 Hz, 1H), 7.55 (d, J=4.8
Hz, 1H), 7.12 (t, J=3.9 Hz, 1H), 6.90 (s, 1H), 4.66 (br. s., 2H),
4.52 (br. s., 2H), 4.06 (s, 3H), 2.72 (s, 3H), 2.62 (s, 3H). LC-MS:
method H, RT=1.21 min, MS (ESI) m/z: 585.5 (M+H).sup.+. Analytical
HPLC Method B: 97% purity.
Example 813
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridi-
n-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01830##
[3785] Intermediate 813A:
(R)-1-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-fluorothiazolo[-
5,4-b]pyridin-5-yl)oxy)propan-2-ol
##STR01831##
[3787] Intermediate I-1(0.483 g, 1.903 mmol) and Intermediate I-131
(0.500 g, 1.903 mmol) were dissolved in DMF (19.03 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.093 g, 0.114 mmol) was
added, and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 ml,
0.300 mmol) was added, and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with water and
EtOAc. The layers were separated and the organic layer was washed
with brine, dried with sodium sulfate, and concentrated under
reduced pressure to yield a brown oil. Purified by ISCO using 0-70%
gradient of EtOAc in hexanes on a 120 g column over 15 min to yield
Intermediate 813A (0.591 g, 1.354 mmol, 71.1% yield): .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.74 (d, J=1.7 Hz, 1H), 8.71 (s, 1H),
8.04 (d, J=10.2 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.83-7.53
(m, 1H), 4.58 (dd, J=10.7, 2.8 Hz, 1H), 4.47-4.37 (m, 1H), 4.34
(br. s., 1H), 2.71 (s, 3H), 1.61-1.53 (m, 1H), 1.38 (d, J=6.3 Hz,
3H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 437.1
(M+H).sup.+.
Intermediate 813B:
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-ol
##STR01832##
[3789] Intermediate 813A (0.035 g, 0.080 mmol) was dissolved in THF
(2 ml) and sodium ethoxide (0.040 ml, 0.080 mmol, 2 M in EtOH) was
added. The reaction mixture was allowed to stir at for 2 hours. The
reaction mixture was diluted with water and EtOAc. The layers were
separated, and the organic layer was washed with brine, dried with
sodium sulfate, and concentrated under reduced pressure to yield
Intermediate 813B (0.030 g, 0.058 mmol, 80% yield). Used without
further purification in the next step. LC-MS: method H, RT=1.30
min, MS (ESI) m/z: 415.1 (M+H).sup.+.
Intermediate 813C:
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl carbonochloridate
##STR01833##
[3791] To a solution of Intermediate 813B (0.030 g, 0.058 mmol) in
THF (3 mL) at was added 15% phosgene in toluene (0.511 mL, 0.724
mmol), and the mixture was stirred at for 12 hours. Solvent was
completely removed, and the sample was stored under vacuum
overnight to yield Intermediate 813C (0.035 g, 0.066 mmol, 91%
yield) as a yellow solid. LC-MS: method H, RT=1.42 min, MS (ESI)
m/z: 477.1 (M+H).sup.+.
Example 813
[3792] 2-Methylpyrimidin-5-amine (13.73 mg, 0.126 mmol) and
pyridine (0.068 mL, 0.839 mmol) were dissolved in DCM (3 mL).
Intermediate 813C (40 mg, 0.084 mmol) was added as a solution in
DCM (1 mL). The reaction mixture was allowed to stir for 1 hour.
The reaction mixture was concentrated under reduced pressure and
purified by ISCO using a 12 g column with a 0-100% EtOAc in hexanes
gradient to yield Example 813 (0.0203 g, 0.035 mmol, 41.8% yield)
as a yellow solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.74
(br. s., 2H), 8.55 (t, J=2.3 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.01
(s, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.74 (s, 1H), 6.55 (br. s., 1H),
5.75 (dd, J=6.5, 3.4 Hz, 1H), 5.39 (dd, J=6.5, 3.4 Hz, 1H), 4.57
(d, J=7.0 Hz, 3H), 2.64 (s, 3H), 1.52 (d, J=1.5 Hz, 3H), 1.50 (s,
3H), 1.48 (d, J=1.5 Hz, 3H). LC-MS: method H, RT=1.27 min, MS (ESI)
m/z: 550.1 (M+H).sup.+. Analytical HPLC Method B: 95% purity.
Example 814
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridi-
n-5-yl)oxy)propan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
##STR01834##
[3793] Intermediate 814A:
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl
(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
##STR01835##
[3795] Intermediate I-97 (16.95 mg, 0.063 mmol) and pyridine (0.034
mL, 0.419 mmol) were dissolved in DCM (3 mL). Intermediate 813C (20
mg, 0.042 mmol) was added as a solution in DCM (1 mL). The reaction
mixture was allowed to stir for 1 hour. The reaction mixture was
concentrated under reduced pressure. Used without further
purification in the next step. LC-MS: method H, RT=1.56 min, MS
(ESI) m/z: 710.3 (M+H).sup.+.
Example 814
[3796] Intermediate 814A (0.009 g, 0.013 mmol) was dissolved in THF
(2 mL) and 2 mL of 90% MeOH, 10% water, 0.1% TFA was added. The
reaction mixture was allowed to stir for 12 hours. The reaction
mixture was concentrated, dissolved in DMF, filtered, and purified
by preparative HPLC (Method D, 50% to 100% B in 19 minutes, 6 min
hold time) to yield Example 814 (7.7 mg, 0.013 mmol, 100% yield):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.81-9.74 (m, 1H),
8.61-8.52 (m, 3H), 8.41 (br. s., 1H), 8.33 (d, J=10.7 Hz, 1H), 7.71
(s, 1H), 5.67 (br. s., 1H), 5.24 (br. s., 1H), 4.93-4.87 (m, 1H),
4.80 (d, J=9.8 Hz, 1H), 4.48 (q, J=6.8 Hz, 5H), 4.20 (d, J=5.2 Hz,
3H), 2.57 (s, 3H), 1.45-1.38 (m, 6H). LC-MS: method H, RT=1.20 min,
MS (ESI) m/z: 596.2 (M+H).sup.+. Analytical HPLC Method B: 100%
purity.
Example 815
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridi-
n-5-yl)oxy) propan-2-yl
(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
##STR01836##
[3797] Intermediate 815A:
(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyrid-
in-5-yl)oxy)propan-2-yl
(2-(((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)
pyrimidin-5-yl)carbamate
##STR01837##
[3799] Intermediate I-103 (0.020 g, 0.069 mmol) and pyridine (0.051
mL, 0.629 mmol) were dissolved in DCM (2 mL) Intermediate 813C
(0.030 g, 0.063 mmol) was added as a solution in DCM (1 mL). The
reaction mixture was allowed to stir for 1 hour. The reaction
mixture was concentrated under reduced pressure and purified on
ISCO using 24 g column eluting with 0-100% EtOAc in hexanes over 15
min to yield Intermediate 815A (28.3 mg, 0.039 mmol, 62.1% yield)
as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.08-9.05 (m, 2H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.01 (d,
J=10.3 Hz, 1H), 7.77 (s, 1H), 6.80 (s, 1H), 5.87-5.73 (m, 1H), 5.28
(dd, J=6.6, 2.9 Hz, 1H), 4.68-4.54 (m, 1H), 4.09 (s, 2H), 2.67 (s,
3H), 1.54-1.48 (m, 9H). LC-MS: method H, RT=1.58 min, MS (ESI) m/z:
724.0 (M+H).sup.+.
Example 815
[3800] Intermediate 815A (0.0283 g, 0.039 mmol) was dissolved in
THF (1 mL) and EtOH (1 mL). To the solution was added 4 M HCl in
dioxane (1 mL, 110 mmol), and the reaction mixture was allowed to
stir at room temperature for 3 hours. The reaction mixture was
concentrated under reduced pressure, dissolved in DMF, filtered,
and purified by preparative HPLC (Method D, 50% to 100% B in 20
minutes, 10 min hold time) to yield Example 815 (0.0145 g, 0.024
mmol, 60.8% yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.86-9.73 (m, 1H), 8.62-8.53 (m, 3H), 8.44 (br. s., 1H), 8.36 (d,
J=10.7 Hz, 1H), 7.74 (s, 1H), 5.69 (br. s., 1H), 5.26 (br. s., 2H),
4.83 (d, J=10.1 Hz, 1H), 4.50 (q, J=7.0 Hz, 4H), 4.29 (d, J=7.6 Hz,
1H), 4.04 (d, J=12.8 Hz, 1H), 3.93 (br. s., 1H), 3.52-3.46 (m, 3H),
2.59 (s, 3H), 1.47-1.40 (m, 6H). LC-MS: method H, RT=1.23 min, MS
(ESI) m/z: 610.1 (M+H).sup.+. Analytical HPLC Method B: 100%
purity.
Example 816
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]py-
ridin-5-yl)oxy)butan-2-yl
(2-(hydroxymethyl)pyrimidin-5-yl)carbamate
##STR01838##
[3801] Intermediate 816A:
(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-fluorothiaz-
olo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
##STR01839##
[3803] Intermediate I-1(0.075 g, 0.285 mmol) and Intermediate I-133
(0.082 g, 0.285 mmol) were dissolved in DMF (2.95 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.012 g, 0.018 mmol) was
added, and the reaction mixture was degassed by bubbling with argon
for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100 ml,
0.300 mmol) was added, and the reaction mixture was degassed for 5
minutes, then sealed and heated to 90.degree. C. in the microwave
for 30 minutes. The reaction mixture was diluted with water and
EtOAc. The layers were separated and the organic layer was washed
with brine, dried with sodium sulfate, and concentrated under
reduced pressure to yield a brown oil. Purified by ISCO using
0-100% gradient of EtOAc in hexanes on a 24 g column over 15 min to
yield Intermediate 816A (0.050 g, 0.111 mmol, 37.6% yield): .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.74 (d, J=1.8 Hz, 1H), 8.71 (s,
1H), 8.03 (d, J=10.1 Hz, 1H), 7.89-7.49 (m, 2H), 5.41 (dd, J=6.5,
3.0 Hz, 1H), 4.26-4.08 (m, 1H), 2.49 (d, J=4.6 Hz, 1H), 1.46 (d,
J=6.4 Hz, 3H), 1.33 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.27
min, MS (ESI) m/z: 451.1 (M+H).sup.+.
Intermediate 816B:
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-ol
##STR01840##
[3805] Intermediate 816A (0.100 g, 0.222 mmol) was dissolved in THF
(2 ml) and sodium ethoxide (0.111 ml, 0.222 mmol, 2 M in EtOH) was
added. The reaction mixture was allowed to stir at room temperature
for 2 hours. The reaction mixture was diluted with water and EtOAc.
The layers were separated, and the organic layer was washed with
brine, dried with sodium sulfate, and concentrated under reduced
pressure to yield Intermediate 816B (0.090 g, 0.210 mmol, 95%
yield). Used without further purification in the next step. LC-MS:
method H, RT=1.25 min, MS (ESI) m/z: 429.1 (M+H).sup.+.
Intermediate 816C:
(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]p-
yridin-5-yl)oxy)butan-2-yl carbonochloridate
##STR01841##
[3807] To a solution of Intermediate 816B (0.025 g, 0.058 mmol) in
THF (5 mL) at room temperature was added 15% phosgene in toluene
(0.206 mL, 0.292 mmol), and the mixture was stirred at room
temperature for 12 hours. Solvent was completely removed, and the
sample was stored under vacuum overnight to yield Intermediate 816C
(0.029 g, 0.053 mmol, 90% yield) as a yellow solid. LC-MS: method
H, RT=1.43 min, MS (ESI) m/z: 490.0 (M+H).sup.+.
Intermediate 816D: methyl
5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5-
,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxyla-
te
##STR01842##
[3809] Methyl 5-aminopyrimidine-2-carboxylate (10.29 mg, 0.067
mmol) and pyridine (0.049 mL, 0.611 mmol) were dissolved in DCM (2
mL) Intermediate 816C (0.030 g, 0.061 mmol) was added as a solution
in DCM (1 mL). The reaction mixture was allowed to stir for 1 hour.
The reaction mixture was concentrated under reduced pressure and
purified on ISCO using 24 g column eluting with 0-100% EtOAc over
15 min to yield Intermediate 816D (24.6 mg, 0.040 mmol, 66.3%
yield) as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.47 (d, J=1.8 Hz, 3H), 8.44 (s, 1H), 7.91 (d, J=10.3 Hz,
1H), 7.66 (s, 1H), 7.13 (s, 1H), 5.70-5.60 (m, 1H), 5.31 (br. s.,
1H), 2.56 (s, 3H), 1.41 (d, J=6.8 Hz, 5H), 1.17 (s, 3H), 0.07-0.11
(m, 6H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 608.0
(M+H).sup.+.
Example 816
[3810] Intermediate 816D (39 mg, 0.064 mmol) was solvated in THF (1
mL) and cooled to -78.degree. C. Diisobutylaluminum hydride (1 M in
toluene) (0.193 mL, 0.193 mmol) was added to the cooled mixture,
and the reaction mixture was stirred for 30 min. The reaction
mixture was quenched with 1 mL of a 1 M HCl solution at -78.degree.
C. The resulting thick, orange sludge was allowed to thaw to room
temperature and stirred for a total of 30 min until the solution
became fluid and bright yellow. The mixture was diluted with EtOAc
and washed with saturated NH.sub.4Cl before being dried over sodium
sulfate and filtered over a pad of SiO.sub.2 gel to remove
aluminates. The filtrate was concentrated and resubjected to
identical reaction conditions to those described above. This second
reaction mixture was quenched with saturated Rochelle's salt and
allowed to stir at room temperature for 1 hour. The resulting
mixture was diluted with EtOAc and the layers were separated. The
aqueous layer was back extracted with EtOAc 3.times., and the
combined organic layer was washed with brine, dried with sodium
sulfate, and concentrated under reduced pressure. The crude
material was dissolved in DMF, filtered, and purified by
preparative HPLC (Method D, 50% to 100% B in 22 minutes, 5 min hold
time) to yield Example 816 (0.0078 g, 0.013 mmol, 20.97% yield):
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.79
(br. s., 2H), 8.61 (s, 1H), 8.49 (s, 1H), 8.41 (d, J=10.7 Hz, 1H),
7.79 (s, 1H), 5.68 (d, J=6.4 Hz, 1H), 5.17 (d, J=5.2 Hz, 1H), 4.53
(q, J=7.0 Hz, 2H), 4.49 (s, 2H), 2.61 (s, 3H), 1.47-1.43 (m, 6H),
1.40 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=0.98 min, MS (ESI) m/z:
580.0 (M+H).sup.+. Analytical HPLC Method B: 100% purity.
Example 817
1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-
-dimethylpropan-1-ol
##STR01843##
[3811] Intermediate 817A:
2-ethoxy-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
quinoxaline
##STR01844##
[3813] In a sealed tube, Intermediate 661F (290 mg, 1.086 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (551
mg, 2.171 mmol), and potassium acetate (213 mg, 2.171 mmol) were
mixed in 1,4-dioxane (5 mL). After degassing with bubbling argon
for 10 minutes, Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (44.3 mg, 0.054
mmol) was added. The vial was sealed and heated at 120.degree. C.
for 60 minutes in the microwave. The reaction mixture was cooled to
room temperature, loaded on celite and was purified on ISCO (40 g
column, 0-50% EtOAc/Hexane in 18 minutes) to yield Intermediate
817A (0.311 g, 0.990 mmol, 91% yield): .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.53 (s, 1H), 7.91 (s, 1H), 7.68 (s, 1H),
4.47 (q, J=7.2 Hz, 2H), 3.26 (br. s., 3H), 1.41 (t, J=7.0 Hz, 3H),
1.34 (s, 12H). LC-MS: method H, RT=0.94 min, MS (ESI) m/z: 233.0
(M+H).sup.+ (mass of the boronic acid).
Example 817
[3814] Intermediate 817A (10 mg, 0.032 mmol) and Intermediate 628A
(9.10 mg, 0.032 mmol) were dissolved in DMF (1 ml).
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.560 mg, 1.910 .mu.mol)
was added, and the reaction mixture was degassed by bubbling with
argon for 15 minutes. Na.sub.2CO.sub.3, 3 M aqueous solution (0.100
ml, 0.300 mmol) was added, and the reaction mixture was degassed
for 5 minutes, then sealed and heated to 90.degree. C. in the
microwave for 30 minutes. The reaction mixture was filtered and
purified by preparative HPLC (Method D, 45% to 80% B in 25 minutes,
7 min hold time) to yield Example 817 (4.5 mg, 9.87 .mu.mol, 31.0%
yield): .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.68 (s, 1H),
8.51 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 5.41 (d,
J=4.6 Hz, 1H), 5.36 (br. s., 1H), 4.53 (q, J=7.0 Hz, 2H), 3.86 (s,
3H), 2.63 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 0.94 (s, 9H). LC-MS:
method H, RT=1.39 min, MS (ESI) m/z: 438.2 (M+H).sup.+. Analytical
HPLC Method B: 96% purity.
Example 818
(R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)-
oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate
##STR01845##
[3815] Intermediate 818A
(R)-1-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-ol
##STR01846##
[3817] In a flask charged with a stirring bar, Intermediate I-60
(215 mg, 0.867 mmol) was suspended in (R)-2-methyloxirane (1 mL,
0.867 mmol). Potassium carbonate (144 mg, 1.040 mmol) was added,
followed by tetrabutylammonium bromide (335 mg, 1.040 mmol). The
mixture was allowed to stir at 60.degree. C. for 18 hours. On the
next day, the reaction mixture was diluted by adding 20 mL of DCM
and silica gel was added. The solvent was removed on the rotavapor
and sample was dry loaded on ISCO (24 g silica gel column, 0-60%
EtOAc/Hexane). Collection of the desired fraction and removal of
solvent gave Intermediate 818A (245.4 mg, 0.802 mmol, 92% yield) as
colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.93 (d,
J=1.3 Hz, 1H), 7.97-7.89 (m, 1H), 4.96 (d, J=4.8 Hz, 1H), 4.07-3.98
(m, 1H), 3.98-3.89 (m, 2H), 1.18 (d, J=6.2 Hz, 3H); .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -133.79 (s, 1F); LC-MS: method E,
RT=0.85 min, MS (ESI) m/z: 306.0, 308.0 (M+H).sup.+.
Intermediate 818B:
(R)-1-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl
carbonochloridate
##STR01847##
[3819] Intermediate 818A (110 mg, 0.359 mmol) was dissolved in THF
(5 mL) under N.sub.2. Phosgene (2.56 mL, 3.59 mmol, 15% by wt.) in
toluene solution was added. The resulting mixture was stirred at
room temperature for 5 hours, then the solvent was removed on
rotavapor and residue was dried on HVAC for 30 minutes. The crude
product was used in the next step without purification. LC-MS:
method E, RT=1.08 min, MS (ESI) m/z: 365.0, 366.9 (M+H).sup.+.
Intermediate 818C:
(R)-1-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl
(6-cyanopyridin-3-yl)carbamate
##STR01848##
[3821] Intermediate 818B (66 mg, 0.179 mmol) was dissolved in DCM
(3 mL) and mixed with 5-aminopicolinonitrile (85 mg, 0.716 mmol).
Anhydrous pyridine (0.072 mL, 0.895 mmol) was added. The mixture
was allowed to stir at room temperature for 2 hours. The solvent
was removed on rotavapor and the residue was purified on ISCO
column (24 g silica gel, 0-100% EtOAc/Hexane). The desired
fractions were collected and removing solvent gave Intermediate
818C (59 mg, 0.145 mmol, 81% yield) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.51 (s, 1H), 8.75 (d, J=2.6 Hz,
1H), 8.08 (dd, 2.5 Hz, 1H), 8.01-7.87 (m, 3H), 5.26 (td, J=6.4, 3.1
Hz, 1H), 4.37-4.32 (m, 1H), 4.23 (dd, J=11.0, 6.2 Hz, 1H), 1.41 (d,
J=6.6 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -133.72
(s, 1F); LC-MS: method E, RT=0.97 min, MS (ESI) m/z: 407.0
(M+H).sup.+.
Example 818
[3822] In a vial charged with a stirring bar, Intermediate 818C (14
mg, 0.034 mmol) was mixed with Intermediate I-38 (12.7 mg, 0.041
mmol) in 1,4-dioxane (1 mL). PdCl.sub.2(dppf)-DCM (2.81 mg, 3.44
.mu.mol) was added, followed by Na.sub.2CO.sub.3 (0.5 ml, 1.0
mmol). The reaction mixture was allowed to stir at 100.degree. C.
for 30 minutes. After cooling down to room temperature, the layers
were separated and the aqueous layer was extracted by EtOAc (2
mL.times.2). Then organic phases were combined and concentrated on
Rotavapor. The residue was dissolved in DMF and purified by
prep-HPLC, Method B to afford Example 818 (3.8 mg, 0.007 mmol, 20%
yield) as the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.92 (s, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H),
8.08 (d, J=8.2 Hz, 1H), 8.03-7.90 (m, 3H), 5.29 (br. s., 1H), 4.40
(d, J=8.5 Hz, 1H), 4.29 (dd, J=10.7, 5.8 Hz, 1H), 4.11 (s, 3H),
3.35 (s, 1H), 1.44 (d, J=6.4 Hz, 3H); LC-MS: method L, RT=2.26 min,
MS (ESI) m/z: 556.15 (M+H).sup.+.
Example 819
(R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)-
oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
##STR01849##
[3823] Intermediate 819A:
(R)-1-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl
(2-methylpyrimidin-5-yl)carbamate
##STR01850##
[3825] Intermediate 819A was synthesized by the method described in
Intermediate 818C, using 2-methylpyrimidin-5-amine instead of
5-aminopicolinonitrile. LC-MS: method E, RT=0.86 min, MS (ESI) m/z:
397.1 (M+H).sup.+.
Example 819
[3826] Example 819 (2.2 mg, 0.004 mmol, 16% yield) was made from
Intermediate 819A (9.0 mg, 0.023 mmol) by the method described for
Example 818. LC-MS: method L, RT=2.03 min, MS (ESI) m/z: 546.10
(M+H).sup.+.
Example 820
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (2-methoxypyrimidin-5-yl)carbamate
##STR01851##
[3827] Intermediate 820A:
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-ol
##STR01852##
[3829] In a vial charged with a stirring bar, Intermediate I-72A
(228 mg, 0.713 mmol) was mixed with Intermediate I-28 (170 mg,
0.713 mmol) in 1,4-dioxane (5 mL). Na.sub.2CO.sub.3 (2 mL, 4.00
mmol) was added, followed by Pd(dppf)Cl.sub.2-DCM (29.1 mg, 0.036
mmol). The mixture was stirred at 100.degree. C. for 30 min. After
cooling down to room temperature, the reaction mixture was diluted
by adding 30 mL of EtOAc and 20 mL of water. After separation, the
aqueous layer was extracted by EtOAc (20 mL.times.2). Then the
organic phases were combined and washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified on CombiFlash (40 g silica gel column, 0-100%
EtOAc/Hexane). Removing solvent gave Intermediate 820A (296 mg,
0.682 mmol, 96% yield) as a yellow solid. LC-MS: method E, RT=1.09
min, MS (ESI) m/z: 434.1 (M+H).sup.+.
Intermediate 820B:
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-
-6-yl)oxy)butan-2-yl carbonochloridate
##STR01853##
[3831] Intermediate 820A (0.290 g, 0.668 mmol) was dissolved in
anhydrous THF (7 mL) and was treated with phosgene (4.77 mL, 6.68
mmol, 15% by wt. in toluene) at room temperature overnight. On the
next day, LCMS showed a clean reaction. Then solvent was removed on
the rotavapor and the residue was dried on high vacuum for 1 hour.
The crude product was used in the next step as is. LC-MS: method E,
RT=1.34 min, MS (ESI) m/z: 496.1 (M+H).sup.+.
Example 820
[3832] In a round bottom flask charged with a stirring bar,
Intermediate 820B (60 mg, 0.121 mmol) was dissolved in DCM (2 mL)
and mixed with 2-methoxypyrimidin-5-amine (60.5 mg, 0.484 mmol).
Pyridine (0.049 mL, 0.604 mmol) was added and the mixture was
stirred at room temperature for 4 hours. Solvent was removed on a
rotavapor and the residue was loaded on silica gel and purified by
CC (40 g silica gel, 0-100% EtOAc/Hexane gradient). The desired
fractions were removed and freeze-dried to give Example 820 (55.8
mg, 0.093 mmol, 77% yield) as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.69-9.87 (1H, m), 8.82 (1H, s), 8.63
(1H, d, J=2.42 Hz), 8.61 (1H, br. s.), 8.08 (1H, d, J=2.42 Hz),
8.06 (1H, d, J=8.14 Hz), 8.00 (1H, d, J=11.44 Hz), 5.09 (1H, dd,
J=6.60, 2.64 Hz), 4.82 (1H, dd, J=6.38, 2.86 Hz), 4.10 (3H, s),
3.83 (3H, s), 3.57 (1H, s), 1.36-1.42 (6H, m); .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. ppm -132.98 (1F, s); LC-MS: method G,
RT=1.14 min, MS (ESI) m/z: 585.1 (M+H).sup.+.
Examples 821 to 830
[3833] The following additional examples have been prepared,
isolated and characterized using the methods described for Example
820 and the examples above, from corresponded quinoxaline boronic
acids and aniline intermediates.
TABLE-US-00026 LCMS LCMS [M + RT Ex. H].sup.+ (Min)/ No. Structure
m/z Method NMR 821 ##STR01854## 584.15 2.66/L .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.61 (1 H, br. s.), 8.79 (1 H, s), 8.58
(1 H, d, J = 1.83 Hz), 8.19 (1 H, br. s.), 8.01-8.06 (2 H, m), 7.97
(1 H, d, J = 11.29 Hz), 7.74 (1 H, br. s.), 6.74 (1 H, d, J = 7.63
Hz), 5.07 (1 H, d, J = 4.27 Hz), 4.79 (1 H, d, J = 3.97 Hz), 4.08
(3 H, s), 3.76 (3 H, s), 1.38 (6 H, dd, J = 11.14, 6.26 Hz) 822
##STR01855## 568.15 2.22/L .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.82 (1 H, br. s.), 8.82 (1 H, s), 8.62 (1 H, d, J =
2.44 Hz), 8.50 (1 H, br. s.), 8.04-8.10 (2 H, m), 8.00 (1 H, d, J =
11.29 Hz), 7.77 (1 H, br. s.), 7.20 (1 H, br. s.), 5.09 (1 H, d, J
= 6.71 Hz), 4.80 (1 H, br. s.), 4.10 (3 H, s), 2.37 (3 H, s),
1.33-1.46 (6 H, m).sup.) 823 ##STR01856## 559.2 1.90/L .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 9.78 (1 H, br. s.), 8.85 (1 H,
s), 8.73 (1 H, s), 8.48 (1 H, br. s.), 8.45 (1 H, s), 8.02 (1 H, d,
J = 7.93 Hz), 7.92 (1 H, d, J = 11.29 Hz), 7.75 (1 H, br. s.), 7.15
(1 H, d, J = 8.24 Hz), 5.10 (1 H, d, J = 6.41 Hz), 4.79 (1 H, d, J
= 3.97 Hz), 4.09 (3 H, s), 2.36 (3 H, s), 1.39 (6 H, dd, J = 11.29,
6.41 Hz) 824 ##STR01857## 569.0 1.26/E .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.93 (1 H, br. s.), 8.84 (1 H, s), 8.72
(2 H, br. s.), 8.64 (1 H, d, J = 2.42 Hz), 8.09 (1 H, d, J = 2.42
Hz), 8.07 (1 H, d, J = 8.36 Hz), 8.01 (1 H, d, J = 11.44 Hz), 5.11
(1 H, dd, J = 6.49, 2.75 Hz), 4.77- 4.93 (1 H, m), 4.10 (3 H, s),
2.51-2.52 (3 H, m), 1.39 (6 H, dd, J = 6.49, 3.41 Hz). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. ppm -132.97 (1 F, s) 825
##STR01858## 560.2 2.11/L .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.95 (1 H, br. s.), 8.94 (1 H, s), 8.84 (1 H, s), 8.71
(2 H, br. s.), 8.53 (1 H, s), 8.06 (1 H, d, J = 8.24 Hz), 7.99 (1
H, d, J = 11.60 Hz), 5.10 (1 H, d, J = 6.41 Hz), 4.83 (1 H, d, J =
5.19 Hz), 4.11 (3 H, s), 2.50 (3 H, s), 1.39 (6 H, t, J = 6.26 Hz)
826 ##STR01859## 579.1 1.15/E .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.26 (1 H, s), 8.83 (1 H, s), 8.81 (1 H, s), 8.64 (1
H, d, J = 2.20 Hz), 8.60 (1 H, s), 8.23 (1 H, br. s.), 8.06-8.12 (2
H, m), 8.01 (1 H, d, J = 11.44 Hz), 5.12 (1 H, d, J = 6.82 Hz),
4.85 (1 H, s), 4.11 (3 H, s), 1.40 (6 H, d, J = 6.60 Hz) .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta. ppm -132.95 (1 F, s) 827
##STR01860## 599.1 0.90/J .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.85-10.06 (1 H, m), 8.80 (1 H, s), 8.72 (2 H, br. s.),
8.57 (1 H, s), 8.02 (1 H, d, J = 8.24 Hz), 7.93 (1 H, d, J = 11.29
Hz), 7.81 (1 H, s), 6.39- 6.65 (1 H, m), 5.10 (1 H, dd, J = 6.56,
2.29 Hz), 4.68-4.89 (3 H, m), 2.61 (3 H, s), 2.54 (3 H, s), 1.38 (6
H, t, J = 5.65 Hz) 828 ##STR01861## 570.20 2.36/L .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 8.85 (1 H, s), 8.73 (1 H, s), 8.66
(1 H, br. s.), 8.45 (1 H, s), 8.00 (2 H, d, J = 7.93 Hz), 7.82-7.95
(2 H, m), 5.09 (1 H, d, J = 6.41 Hz), 4.81 (1 H, d, J = 4.27 Hz),
4.06 (3 H, s), 1.37 (7 H, t, J = 5.34 Hz) 829 ##STR01862## 579.15
2.69/M .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 10.40 (1 H,
s), 8.66- 8.77 (2 H, m), 8.51 (1 H, d, J = 2.14 Hz), 7.85-8.12 (5
H, m), 5.13 (1 H, dd, J = 6.41, 2.14 Hz), 4.84 (1 H, d, J = 3.97
Hz), 4.06 (3 H, s), 1.35-1.45 (6H, m) 830 ##STR01863## 612.2 2.69/G
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.24 (s, 1H), 8.82 (s,
1H), 8.70 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.3 Hz, 1H), 8.16-7.83
(m, 5H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.86 (d, J = 6.6 Hz, 1H),
4.10 (s, 3H), 3.80 (s, 3H), 1.41 (dd, J = 6.5, 2.8 Hz, 6H)
Example 831
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
##STR01864##
[3835] Example 830 (10 mg, 0.016 mmol) was dissolved in anhydrous
THF (1 mL) and cooled to -78.degree. C. under an atmosphere of
N.sub.2. DIBAL-H (0.082 mL, 0.082 mmol) was then added drop wise.
After 2 min of stirring at -78.degree. C., the reddish solution was
allowed to thaw to room temperature. Next, 1 mL of saturated
Rochelle's Salt solution was added to quench the reaction, causing
the solution to return to a yellow color. The reaction mixture was
stirred vigorously for 3 h before being diluted with EtOAc and
washed with saturated NH.sub.4Cl (aq.). The organic phase was dried
over Na.sub.2SO.sub.4, filtered, concentrated. The crude product
was purified by prep-HPLC, Method D to afford Example 831 (2.4 mg,
0.004 mmol, 24% yield) as the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.81 (1H, br. s.), 8.64 (1H, s), 8.50
(1H, br. s.), 8.44 (1H, s), 7.77-8.03 (4H, m), 7.34 (1H, d, J=8.54
Hz), 5.36-5.45 (1H, m), 5.10 (1H, d, J=5.19 Hz), 4.76 (1H, br. s.),
4.45 (2H, d, J=5.19 Hz), 4.03 (3H, s), 1.38 (6H, dd, J=12.36, 6.26
Hz); .sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta. ppm -132.94 (1F,
s.); LC-MS: method L, RT=2.24 min, MS (ESI) m/z: 584.25
(M+H).sup.+.
Example 832
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (6-(methylcarbamoyl)pyridin-3-yl)carbamate
##STR01865##
[3837] To a vial charged with Example 830 (8 mg, 0.013 mmol) were
added THF (0.4 mL), followed by methylamine (0.6 mL, 0.013 mmol).
The reaction mixture was sealed and heated at 60.degree. C. for 30
minutes. The solvent was removed and the residue was redissolved in
DMF, before being purified by prep-HPLC, Method D to afford Example
832 (4.9 mg, 0.008 mmol, 59% yield) as the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 10.11 (1H, br. s.), 8.61
(1H, br. s.), 8.54 (1H, d, J=4.58 Hz), 8.43 (1H, s), 7.61-8.11 (6H,
m), 5.11 (1H, d, J=6.10 Hz), 4.83 (1H, d, J=6.10 Hz), 4.03 (3H, s),
2.75 (3H, d, J=4.58 Hz), 1.40 (6H, dd, J=8.85, 7.02 Hz); .sup.19F
NMR (471 MHz, DMSO-d.sub.6) .delta. ppm -132.95 (1F, br. s.);
LC-MS: method L, RT=2.57 min, MS (ESI) m/z: 611.15 (M+H).sup.+.
Example 833
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy) butan-2-yl (6-carbamoylpyridin-3-yl)carbamate
##STR01866##
[3839] Example 830 (8 mg, 0.013 mmol) was dissolved in THF (0.5
mL). NH.sub.3 (2 mL, 14.00 mmol) in methanol (7N) was added. The
reaction mixture was sealed and heated at 60.degree. C. for 20
hours. On the next day, solvent was removed and the residue was
purified by prep-HPLC, Method D to afford Example 833 (4.5 mg,
0.007 mmol, 55% yield) as the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.16 (1H, br. s.), 8.50-8.70 (2H, m),
8.39 (1H, br. s.), 7.75-8.09 (6H, m), 7.43 (1H, br. s.), 5.12 (1H,
d, J=6.10 Hz), 4.78 (1H, d, J=4.58 Hz), 4.01 (3H, s), 1.33-1.46
(6H, m); .sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta. ppm -132.98
(1F, br. s.); LC-MS: method L, RT=2.50 min, MS (ESI) m/z: 597.10
(M+H).sup.+.
Example 834
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl
(6-(dimethylcarbamoyl)pyridin-3-yl)carbamate
##STR01867##
[3841] To a vial charged with Example 830 (8 mg, 0.013 mmol) was
added THF (0.5 mL). The resulting solution was cooled to 0.degree.
C. and magnesium chloride (6.22 mg, 0.065 mmol) was added. The
mixture was allowed to stir for 30 min before dimethylamine (0.196
mL, 0.392 mmol) was added. The ice bath was allowed to expire and
the reaction mixture was stirred at 60.degree. C. for 2 hours.
After cooling down to room temperature, solvent was removed and the
residue was dissolved in DMF. The remaining solids were removed by
filtration and the resulting solution was purified by prep-HPLC,
Method D to afford Example 834 (0.8 mg, 0.001 mmol, 10% yield) as
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
10.07 (1H, br. s.), 8.80 (1H, s), 8.60 (2H, d, J=2.48 Hz),
8.03-8.10 (2H, m), 7.92-8.02 (2H, m), 7.52 (1H, d, J=8.53 Hz), 5.13
(1H, dd, J=6.60, 2.75 Hz), 4.83 (1H, dd, J=6.33, 2.75 Hz), 4.09
(3H, s), 2.96 (6H, d, J=6.33 Hz), 1.40 (6H, dd, J=6.33, 5.23 Hz);
.sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta. ppm -138.05 (1F, br.
s.); LC-MS: method L, RT=2.52 min, MS (ESI) m/z: 625.15
(M+H).sup.+.
Example 835
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl
(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate
##STR01868##
[3843] 1-(5-aminopyridin-2-yl)-2-methylpropan-2-ol (2.95 mg, 0.018
mmol) was dissolved in DCM (0.5 mL) and pyridine (1.955 .mu.l,
0.024 mmol) was added. A solution of Intermediate 820B (8 mg, 0.016
mmol) in DCM (0.5 mL) was added dropwise to the reaction mixture.
The mixture was stirred at room temperature overnight. On the next
day, solvent was removed and the residue was purified by prep-HPLC,
Method D to afford Example 835 (6.8 mg, 0.010 mmol, 63% yield).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.76 (1H, br. s.),
8.65 (1H, s), 8.49 (1H, br. s.), 8.46 (1H, d, J=2.14 Hz), 7.94 (1H,
d, J=8.24 Hz), 7.92 (1H, d, J=2.14 Hz), 7.87 (1H, d, J=11.60 Hz),
7.75 (1H, br. s.), 7.19 (1H, d, J=8.24 Hz), 5.09 (1H, dd, J=6.41,
2.75 Hz), 4.77 (1H, dd, J=6.26, 2.59 Hz), 4.04 (3H, s), 3.53 (1H,
s), 2.72 (2H, s), 1.38 (6H, dd, J=12.66, 6.56 Hz), 1.02 (6H, s);
NMR (471 MHz, DMSO-d.sub.6) .delta. ppm -132.92 (1F, br. s.);
LC-MS: method L, RT=2.29 min, MS (ESI) m/z: 626.15 (M+H).sup.+.
Example 836
(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol--
6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
##STR01869##
[3845] Intermediate I-93 (7.83 mg, 0.031 mmol) was dissolved in DCM
(0.5 mL) and pyridine (3.42 .mu.l, 0.042 mmol) was added. Then
Intermediate 820B (14 mg, 0.028 mmol) in DCM (0.5 mL) was added
dropwise to the reaction mixture. The mixture was stirred at room
temperature overnight. On the next day, TBAF (0.282 mL, 0.282 mmol)
solution was added. After stirring for 3 hours, HCl (0.071 mL,
0.282 mmol) was added. The reaction mixture was stirred at room
temperature for an additional 30 minutes. Then solvent was removed
on the rotavapor and the residue was purified by prep-HPLC, Method
D to afford Example 836 (4.8 mg, 0.008 mmol, 27% yield). .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.75 (1H, br. s.), 8.64
(1H, s), 8.49 (1H, br. s.), 8.45 (1H, s), 7.93 (1H, d, J=8.24 Hz),
7.91 (1H, s), 7.85 (1H, d, J=11.60 Hz), 7.71-7.79 (1H, m), 7.18
(1H, d, J=8.54 Hz), 5.09 (1H, d, J=6.41 Hz), 4.76 (1H, d, J=5.80
Hz), 4.03 (3H, s), 3.66 (1H, t, J=6.71 Hz), 3.56 (1H, d, J=2.75
Hz), 2.77 (2H, t, J=6.71 Hz), 1.37 (7H, dd, J=13.43, 6.41 Hz);
.sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta. ppm -132.95 (1F, br.
s.); LC-MS: method L, RT=2.19 min, MS (ESI) m/z: 598.15
(M+H).sup.+.
Example 837
2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole
##STR01870##
[3847] In a vial charged with a stirring bar, Intermediate I-28 (17
mg, 0.053 mmol) was dissolved in 1,4-dioxane (1 mL), mixed with
2-bromo-6-methoxy-4-methylbenzo[d]thiazole (17.80 mg, 0.069 mmol).
Na.sub.2CO.sub.3 (1 mL, 2.0 mmol) was added, followed by
PdCl.sub.2(dppf)-DCM (4.33 mg, 5.30 .mu.mol). The reaction mixture
was stirred at 100.degree. C. for 1 hour. After cooling down to
room temperature, the reaction mixture was diluted by adding 20 ml
of EtOAc and 20 mL of water. After shaking and separation, the
organic phase was passed through Na.sub.2SO.sub.4 and concentrated
on rotavapor. The residue was purified by prep-HPLC, Method D to
afford Example 837 (2.0 mg, 0.005 mmol, 10% yield). .sup.1H NMR
(500 MHz, CDCl.sub.3-d) .delta. 8.80 (d, J=2.5 Hz, 1H), 8.59 (s,
1H), 7.92 (d, J=2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 6.95 (s, 1H),
4.14 (s, 3H), 3.90 (s, 3H), 2.83 (s, 3H); LC-MS: method L, RT=2.934
min, MS (ESI) m/z: 372.10 (M+H).sup.+.
* * * * *