U.S. patent application number 14/051339 was filed with the patent office on 2014-04-17 for amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use.
The applicant listed for this patent is Amgen Inc.. Invention is credited to Jennifer R. ALLEN, Yuan CHENG, Deborah CHOQUETTE, Oleg EPSTEIN, Angel GUZMAN-PEREZ, Paul E. HARRINGTON, Zihao HUA, Jason Brooks HUMAN, Randall W. HUNGATE, Ted JUDD, Richard T. LEWIS, Qingyian LIU, Patricia LOPEZ, Ana Elena MINATTI, Philip OLIVIERI, Karina ROMERO, Shannon RUMFELT, Robert M. RZASA, Laurie SCHENKEL, John STELLWAGEN, Ryan WHITE, Qiufen XUE, Xiao ZHENG, Wenge ZHONG.
Application Number | 20140107109 14/051339 |
Document ID | / |
Family ID | 49546609 |
Filed Date | 2014-04-17 |
United States Patent
Application |
20140107109 |
Kind Code |
A1 |
LEWIS; Richard T. ; et
al. |
April 17, 2014 |
AMINO-DIHYDROTHIAZINE AND AMINO-DIOXIDO DIHYDROTHIAZINE COMPOUNDS
AS BETA-SECRETASE ANTAGONISTS AND METHODS OF USE
Abstract
The present invention provides a new class of compounds useful
for the modulation of beta-secretase enzyme (BACE) activity. The
compounds have a general Formula I: ##STR00001## wherein variables
A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.1, R.sup.2, R.sup.3,
R.sup.7 and n of Formula I, independently, are defined herein. The
invention also provides pharmaceutical compositions comprising the
compounds, and corresponding uses of the compounds and compositions
for treatment of disorders and/or conditions related to A-beta
plaque formation and deposition, resulting from the biological
activity of BACE. Such BACE mediated disorders include, for
example, Alzheimer's Disease, cognitive deficits, cognitive
impairments, schizophrenia and other central nervous system
conditions. The invention further provides compounds of Formula II
and sub-formula embodiments thereof, intermediates and processes
and methods useful for the preparation of compounds of Formulas
I-II.
Inventors: |
LEWIS; Richard T.;
(Framingham, MA) ; ALLEN; Jennifer R.; (Newbury
Park, CA) ; CHENG; Yuan; (Newbury Park, CA) ;
CHOQUETTE; Deborah; (Medford, MA) ; EPSTEIN;
Oleg; (Belmont, MA) ; GUZMAN-PEREZ; Angel;
(Belmont, MA) ; HARRINGTON; Paul E.; (Camarillo,
CA) ; HUA; Zihao; (Andover, MA) ; HUNGATE;
Randall W.; (Camarillo, CA) ; HUMAN; Jason
Brooks; (Boston, MA) ; JUDD; Ted; (Granada
Hills, CA) ; LIU; Qingyian; (Camarillo, CA) ;
LOPEZ; Patricia; (Woodland Hills, CA) ; MINATTI; Ana
Elena; (Santa Monica, CA) ; OLIVIERI; Philip;
(Charlestown, MA) ; ROMERO; Karina; (Arlington,
MA) ; RUMFELT; Shannon; (Camarillo, CA) ;
RZASA; Robert M.; (Ventura, CA) ; SCHENKEL;
Laurie; (Boston, MA) ; STELLWAGEN; John;
(Beverly, MA) ; WHITE; Ryan; (Somerville, MA)
; XUE; Qiufen; (Newbury Park, CA) ; ZHENG;
Xiao; (Natick, MA) ; ZHONG; Wenge; (Thousand
Oaks, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amgen Inc. |
Thousand Oaks |
CA |
US |
|
|
Family ID: |
49546609 |
Appl. No.: |
14/051339 |
Filed: |
December 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61783656 |
Mar 14, 2013 |
|
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61713413 |
Oct 12, 2012 |
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Current U.S.
Class: |
514/224.2 ;
514/227.5; 514/227.8; 544/47; 544/48; 544/58.2; 544/6 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 513/04 20130101; C07D 241/44 20130101; C07D 213/79 20130101;
C07D 417/14 20130101; C07D 279/12 20130101; C07D 239/74 20130101;
C07D 513/10 20130101; C07D 279/14 20130101; C07D 498/04 20130101;
C07D 519/00 20130101; C07D 471/04 20130101; C07D 417/12 20130101;
C07D 495/04 20130101; A61P 25/18 20180101; C07D 417/04
20130101 |
Class at
Publication: |
514/224.2 ;
514/227.5; 514/227.8; 544/6; 544/47; 544/48; 544/58.2 |
International
Class: |
C07D 513/04 20060101
C07D513/04; C07D 513/10 20060101 C07D513/10; C07D 279/12 20060101
C07D279/12; C07D 498/04 20060101 C07D498/04; C07D 417/12 20060101
C07D417/12; C07D 417/14 20060101 C07D417/14; C07D 471/04 20060101
C07D471/04; C07D 495/04 20060101 C07D495/04; C07D 279/14 20060101
C07D279/14; C07D 417/04 20060101 C07D417/04 |
Claims
1. A compound of Formula I ##STR00329## or a stereoisomer,
tautomer, hydrate, solvate or pharmaceutically acceptable salt
thereof, wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or
N; A.sup.6 is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided
that no more than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is
N; each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH; alternatively, each R.sup.1 taken
together with the carbon atom to which they are attached form a
C.sub.3-6 spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a substituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
alternatively, each R.sup.2 taken together with the carbon atom to
which they are attached form a C.sub.3-6 spirocarbocyclic ring
optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom; R.sup.3 is C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH, C.sub.1-4haloalkyl or
cyclopropyl, wherein each of the C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and cyclopropyl is
optionally substituted with 1-4 F atoms; alternatively, one R.sup.2
and R.sup.3 taken together with the carbon atoms to which they are
attached form a C.sub.3-6-carbocyclic ring optionally including 1-2
heteroatoms selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8, independently, is H,
halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl, CN, OH,
OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9 or
--S--R.sup.9; R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10; each
R.sup.10, independently, is H, halo, haloalkyl, CN, OH, NO.sub.2,
NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and n is 0, 1 or 2.
2. The compound according to claim 1, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein n is 2.
3. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9,
--O--R.sup.9, --S--R.sup.9; or R.sup.7 is ##STR00330## wherein V is
NR.sup.10, O or S; and each W, independently, is CH, CF, CCl or
N.
4. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and
R.sup.2, independently, is H, F, Cl, CF.sub.3, OCF.sub.3,
methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3,
C(O)CH.sub.3 or CH.sub.2OCHF.sub.2; R.sup.3 is C.sub.1-4alkyl,
C.sub.1-4haloalkyl, CH.sub.2OH, CH.sub.2OCHF.sub.2 or cyclopropyl;
and each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8, independently,
is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3.
5. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, R.sup.7 is --NH--R.sup.9,
--O--R.sup.9, S--R.sup.9, --NH--C(.dbd.O)--R.sup.9 or ##STR00331##
wherein V is NR.sup.10, O or S; and each W, independently, is CH,
CF, CCl or N.
6. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
7. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--R.sup.9, --O--R.sup.9 or S--R.sup.9.
8. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
##STR00332## wherein V is NR.sup.10 or S; and each W,
independently, is CH, CF, CCl or N.
9. The compound according to claim 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4; A.sup.5 is CR.sup.5; A.sup.6 is CR.sup.6; and A.sup.8 is
CR.sup.8; wherein each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, CF.sub.3, CF.sub.2H, CH.sub.2F or
CH.sub.3.
10. A compound according to claim 1, or a stereoisomer, tautomer,
hydrate, solvate or pharmaceutically acceptable salt thereof,
having a Formula II: ##STR00333## wherein A.sup.4 is CR.sup.4 or N;
A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N; A.sup.8 is
CR.sup.8 or N, provided that no more than two of A.sup.4, A.sup.5,
A.sup.6 and A.sup.8 is N; each of R.sup.1 and R.sup.2,
independently, is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH; alternatively,
each R.sup.1 taken together with the carbon atom to which they are
attached form a C.sub.3-6-spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-4 F atoms on the carbon atoms and a subsituent
of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom; alternatively, each R.sup.2 taken together with
the carbon atom to which they are attached form a C.sub.3-6
spirocarbocyclic ring optionally including one heteroatom selected
from O and N and optionally substituted with 1-4 F atoms on the
carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
alternatively, one R.sup.2 and R.sup.3 taken together with the
carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8, independently, is H,
halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl, CN, OH,
OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9,
S--R.sup.9; or R.sup.7 is ##STR00334## wherein V is NR.sup.10, O or
S; and each W, independently, is CH, CF, CCl or N; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and each R.sup.10, independently, is H, halo, haloalkyl,
CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3,
oxo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6allynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
11. The compound according to claim 10, or a stereoisomer, tautomer
or pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, provided no more than one of A.sup.4,
A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and R.sup.2,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl,ethyl, CN,
OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3, C(O)CH.sub.3 or
CH.sub.2OCHF.sub.2; R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl,
CH.sub.2OH, CH.sub.2OCHF.sub.2 or cyclopropyl; and each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3.
12. The compound according to claim 10, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4; A.sup.5 is CR.sup.5; A.sup.6 is CR.sup.6; and A.sup.8 is
CR.sup.8; wherein each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, CF.sub.3, CF.sub.2H, CH.sub.2F or CH.sub.3;
R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H, or cyclopropyl, wherein each of the
C.sub.1-4alkyl and cyclopropyl is optionally substituted with 1-2 F
atoms; and R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or ##STR00335##
wherein V is NR.sup.10, O or S; and each W, independently, is CH,
CF, CCl or N.
13. The compound according to claim 12, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
14. The compound according to claim 12, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
##STR00336## wherein V is NR.sup.10, O or S; and each W,
independently, is CH, CF, CCl or N.
15. The compound according to claim 10, or a stereoisomer, tautomer
or pharmaceutically acceptable salt thereof, having a Formula II-A
##STR00337## wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5
or N; A.sup.6 is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided
that no more than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is
N; each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-3-alkyl, --OC.sub.1-3-alkyl, wherein each of the
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
C.sub.1-4-alkyl portion of --CH.sub.2OC.sub.1-3-alkyl and
--OC.sub.1-3-alkyl are optionally substituted with 1-4 substituents
of F; alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom; alternatively, each
R.sup.2 taken together with the carbon atom to which they are
attached form a C.sub.3-6 spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-4 F atoms on the carbon atoms and a subsituent
of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom; R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms; alternatively, one R.sup.2 and R.sup.3 taken together
with the carbon atoms to which they are attached form a C.sub.3-6
carbocyclic ring optionally including 1-2 heteroatoms selected from
O and N and optionally substituted with 1-4 F atoms on the carbon
atoms and a subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl
or C.sub.1-3haloalkyl on the nitrogen atom; each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H or F; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; each R.sup.10, independently, is H, halo, haloalkyl, CN,
OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
16. The compound according to claim 15, or a stereoisomer, tautomer
or pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4; A.sup.5 is CR.sup.5; A.sup.6 is CR.sup.6; A.sup.8 is
CR.sup.8; wherein each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl, CN,
OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3; each of
R.sup.1 and R.sup.2, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3; alternatively, each
R.sup.1 taken together with the carbon atom to which they are
attached form a C.sub.3-6 spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-3 F atoms; alternatively, each R.sup.2 taken
together with the carbon atom to which they are attached form a
C.sub.3-6 spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-3 F atoms;
R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or CH.sub.2F;
R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
ring is optionally substituted, independently, with 1-5
substituents of R.sup.10; each R.sup.10, independently, is H, halo,
haloalkyl, CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl,
--C(O)NHCH.sub.3, oxo, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6allynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6allyl, C.sub.2-6alkenyl,
C.sub.2-6allynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl.
17. The compound according to claim 15, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5, R.sup.6
and R.sup.8, independently, is H or F and provided no more than one
of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and
R.sup.2, independently, is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H
or CH.sub.2F; and R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F.
18. The compound according to claim 10, or a stereoisomer,
tautomer, hydrate, solvate or pharmaceutically acceptable salt
thereof, having a Formula II-B: ##STR00338## wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and
R.sup.2, independently, is H, F, Cl, C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-3-alkyl,
--OC.sub.1-3-alkyl, wherein each of the C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and C.sub.1-4-alkyl portion of
--CH.sub.2OC.sub.1-3-alkyl and --OC.sub.1-3-alkyl are optionally
substituted with 1-4 substituents of F; alternatively, each R.sup.1
taken together with the carbon atom to which they are attached form
a C.sub.3-6 spirocarbocyclic ring optionally including one
heteroatom selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
alternatively, each R.sup.2 taken together with the carbon atom to
which they are attached form a C.sub.3-6 spirocarbocyclic ring
optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom; R.sup.3 is C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH, C.sub.1-4haloalkyl or
cyclopropyl, wherein each of the C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and cyclopropyl is
optionally substituted with 1-4 F atoms; alternatively, one R.sup.2
and R.sup.3 taken together with the carbon atoms to which they are
attached form a C.sub.3-6 carbocyclic ring optionally including 1-2
heteroatoms selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8, independently, is H
or F; each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and each W, independently, is CH, CF, CCl or N.
19. The compound according to claim 18, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4; A.sup.5 is CR.sup.5; A.sup.6 is CR.sup.6; A.sup.8 is
CR.sup.8; wherein each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl, CN,
OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3; each of
R.sup.1 and R.sup.2, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3; alternatively, each
R.sup.1 taken together with the carbon atom to which they are
attached form a C.sub.3-6 spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-3 F atoms; alternatively, each R.sup.2 taken
together with the carbon atom to which they are attached form a
C.sub.3-6 spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-3 F atoms;
and R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or
CH.sub.2F.
20. The compound according to claim 18, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5, R.sup.6
and R.sup.8, independently, is H or F and provided no more than one
of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and
R.sup.2, independently, is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H
or CH.sub.2F; and R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F.
21. The compound according to claim 10, or a stereoisomer,
tautomer, hydrate, solvate or pharmaceutically acceptable salt
thereof, having a Formula II-C: ##STR00339## wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and
R.sup.2, independently, is H, F, Cl, C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-3-alkyl,
--OC.sub.1-3-alkyl, wherein each of the C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and C.sub.1-4-alkyl portion of
--CH.sub.2OC.sub.1-3-alkyl and --OC.sub.1-3-alkyl are optionally
substituted with 1-4 substituents of F; alternatively, each R.sup.1
taken together with the carbon atom to which they are attached form
a C.sub.3-6 spirocarbocyclic ring optionally including one
heteroatom selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
alternatively, each R.sup.2 taken together with the carbon atom to
which they are attached form a C.sub.3-6 spirocarbocyclic ring
optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom; R.sup.3 is C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH, C.sub.1-4haloalkyl or
cyclopropyl, wherein each of the C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and cyclopropyl is
optionally substituted with 1-4 F atoms; alternatively, one R.sup.2
and R.sup.3 taken together with the carbon atoms to which they are
attached form a C.sub.3-6 carbocyclic ring optionally including 1-2
heteroatoms selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8, independently, is H
or F; each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxyl, ethyl,
ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl or oxetan-3yl; V is
NR.sup.10, O or S; and each W, independently, is CH, CF, CCl or
N.
22. The compound according to claim 21, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4; A.sup.5 is CR.sup.5; A.sup.6 is CR.sup.6; A.sup.8 is
CR.sup.8; wherein each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl, CN,
OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3; each of
R.sup.1 and R.sup.2, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3; alternatively, each
R.sup.1 taken together with the carbon atom to which they are
attached form a C.sub.3-6 spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-3 F atoms; alternatively, each R.sup.2 taken
together with the carbon atom to which they are attached form a
C.sub.3-6 spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-3 F atoms;
R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or CH.sub.2F.
23. The compound according to claim 21, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6 is CR.sup.6 or N;
A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5, R.sup.6
and R.sup.8, independently, is H or F and provided no more than one
of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each of R.sup.1 and
R.sup.2, independently, is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H
or CH.sub.2F; and R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F.
24. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, as defined by Formula III-B-1:
##STR00340## wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5
or N; A.sup.6 is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided
that no more than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is
N; each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH; alternatively, each R.sup.1 taken
together with the carbon atom to which they are attached form a
C.sub.3-6-spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
alternatively, each R.sup.2 taken together with the carbon atom to
which they are attached form a C.sub.3-6 spirocarbocyclic ring
optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom; R.sup.3 is C.sub.1-4alkyl,
CH.sub.2OH, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or
cyclopropyl, wherein each of the C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and cyclopropyl is
optionally substituted with 1-4 F atoms; alternatively, one R.sup.2
and R.sup.3 taken together with the carbon atoms to which they are
attached form a C.sub.3-6-carbocyclic ring optionally including 1-2
heteroatoms selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8, independently, is H,
halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl, CN, OH,
OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl; each R.sup.10, independently, is H, halo,
haloalkyl, CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl,
--C(O)NHCH.sub.3, oxo, cyclopropylmethoxy, 2-butynyloxy,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkyllyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and each W, independently, is CH, CF, CCl or N.
25. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, as defined by Formula III-E ##STR00341##
wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6
is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided that no more
than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; R is a
C.sub.3-6-spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and/or a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
each of R.sup.1, independently, is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH; alternatively,
each R.sup.1 taken together with the carbon atom to which they are
attached form a C.sub.3-6-spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-4 F atoms on the carbon atoms and a subsituent
of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom; R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms; each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9,
--S--R.sup.9; or R.sup.7 is ##STR00342## wherein V is NR.sup.10, O
or S; and each W, independently, is CH, CF, CCl or N; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and each R.sup.10, independently, is H, halo, haloalkyl,
CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3,
oxo, cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
26. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, as defined by Formula III-E-1 ##STR00343##
wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6
is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided that no more
than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each
R.sup.a, independently, is H, F, C.sub.1-3-alkyl or
C.sub.1-3haloalkyl; each of R.sup.1, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3 or CH.sub.2OCHF.sub.2; alternatively, each
R.sup.1 taken together with the carbon atom to which they are
attached form a C.sub.3-6-spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-4 F atoms on the carbon atoms and a subsituent
of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom; R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl,
CH.sub.2OH, CH.sub.2OCHF.sub.2 or cyclopropyl; each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9,
--S--R.sup.9; or R.sup.7 is ##STR00344## wherein V is NR.sup.10, O
or S; and each W, independently, is CH, CF, CCl or N; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and each R.sup.10, independently, is H, halo, haloalkyl,
CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3,
oxo, cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
27. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, as defined by Formula III-F ##STR00345##
wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6
is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided that no more
than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; M is a
C.sub.3-6-carbocyclic ring optionally including one or two
heteroatoms selected from O and N and optionally substituted with
1-4 F atoms on the carbon atoms and/or a subsituent of
C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on a
nitrogen atom; each of R.sup.1, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH; alternatively, each R.sup.1 taken
together with the carbon atom to which they are attached form a
C.sub.3-6-spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH; each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9,
--S--R.sup.9; or R.sup.7 is ##STR00346## wherein V is NR.sup.10, O
or S; and each W, independently, is CH, CF, CCl or N; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and each R.sup.10, independently, is H, halo, haloalkyl,
CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3,
oxo, cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
28. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, as defined by Formula III-F-1 ##STR00347##
wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6
is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided that no more
than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each
R.sup.a, independently, is H, F, C.sub.1-3-alkyl or
C.sub.1-3haloalkyl; each R.sup.1, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH; alternatively, each R.sup.1 taken
together with the carbon atom to which they are attached form a
C.sub.3-6-spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH; each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9,
--S--R.sup.9; or R.sup.7 is ##STR00348## wherein V is NR.sup.10, O
or S; and each W, independently, is CH, CF, CCl or N; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; each R.sup.10, independently, is H, halo, haloalkyl, CN,
OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl; and p is 0, 1, 2 or 3.
29. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, as defined by Formula III-F-2 ##STR00349##
wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or N; A.sup.6
is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided that no more
than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; each
R.sup.a, independently, is H, F, C.sub.1-3-alkyl or
C.sub.1-3haloalkyl; each R.sup.1, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH; alternatively, each R.sup.1 taken
together with the carbon atom to which they are attached form a
C.sub.3-6-spirocarbocyclic ring optionally including one heteroatom
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen atom;
R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH; each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl; R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9,
--S--R.sup.9; or R.sup.7 is ##STR00350## wherein V is NR.sup.10, O
or S; and each W, independently, is CH, CF, CCl or N; R.sup.9 is
acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl or a
ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and each R.sup.10, independently, is H, halo, haloalkyl,
CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3,
oxo, cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
30. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophen-
yl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; Racemic
mixture of
N-(3-((3R,6R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Racemic mixture of
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyrazinecarboxamide;
Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridine carboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; Racemic
mixture of
N-(4-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thia-
zin-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide and
N-(4-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
N-(6-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine-
; Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-am-
ine;
N-(3-((8R)-10-amino-8-methyl-6,6-dioxido-6-thia-9-azaspiro[4.5]dec-9--
en-8-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile;
(5R)-(2-fluoro-5-(1-naphthalenylsulfanyl)phenyl)-2,2,5-trimethyl-5,6-dihy-
dro-2H-1,4-thiazin-3-amine 1,1-dioxide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
8-((3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1-
,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-7-methoxy-4-quinazolinamine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxy-5-quinoxalinamine;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihy-
dro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amin-
e;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiaz-
in-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-amine;
5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
5-((3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine,
benzamide; and
3-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-th-
iazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile.
31. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
8-((5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-6-fluoro-3-pyridinyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitr-
ile;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thi-
azin-3-yl)-6-fluoro-3-pyridinyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-ami-
ne;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-
-1,4-thiazin-3-yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-1,7-naphthyridin-8--
amine;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-ami-
ne;
4-((3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2-
H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carboni-
trile;
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-
-en-7-yl)-6-fluoro-3-pyridinyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-7-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8--
amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin--
4-amine;
4-((3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-
-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-
-7-carbonitrile;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-ethoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-2-ethoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
8-((3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-7-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitri-
le;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]-
non-8-en-7-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
Mixture of
N-(3-((7R)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
8-((3-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-
-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
8-((3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]n-
on-8-en-7-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-(cyclopropylmethoxy)-1,7-naphthyridin-8-amine;
8-((3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitri-
le;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-
-1,4-thiazin-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine-
;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin--
8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)-2-(2-fluoroethoxy)pyrido[3,4-b]pyrazin-5-am-
ine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thi-
azin-3-yl)-4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[3,4-b]pyrazin-5-
-amine;
((5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1-
,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,4-b]pyrazin-2-yl)oxy)aceton-
itrile;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-5-
-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(2-butyn-1-yloxy)pyrido[3,4-b]pyrazin-5-am-
ine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thi-
azin-3-yl)-4-fluorophenyl)-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4--
amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-
-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-3-bromopyrido[2,3-d]pyridazin-8-amine;
and
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine.
32. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from
N-(3-((4aR,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-
-amine;
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-f-
uro[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]py-
razin-5-amine;
5-((3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,-
4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H-
)-one;
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.-
5]oct-6-en-8-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
6-en-8-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
6-en-8-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxam-
ide;
N-(3-((1R,6R)-4-amino-3,3-dimethyl-2,2-dioxido-2-thia-5-azabicyclo[4.-
1.0]hept-4-en-6-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamid-
e; Mixture of
N-(3-((4aR,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2--
pyridinecarboxamide and
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2--
pyridinecarboxamide; Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide
and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo-
[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxam-
ide; Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecar-
boxamide and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecar-
boxamide; Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridineca-
rboxamide and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridineca-
rboxamide; Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-ami-
ne and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-fu-
ro[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-
-8-amine;
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-
-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-p-
yridinecarboxamide; and
N-(3-((1R,6R)-4-amino-3,3-dimethyl-2,2-dioxido-2-thia-5-azabicyclo[4.1.0]-
hept-4-en-6-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine.
33. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from
(5R)-5-(2-fluoro-5-((3-fluoro-2-pyridinyl)oxy)phenyl)-2,2,5-trimethyl-5,6-
-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide;
2-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenoxy)-4-pyridinecarbonitrile; and
(5R)-(5-((4-bromo-2-pyridinyl)oxy)-2-fluorophenyl)-2,2,5-trimethyl-5,6-di-
hydro-2H-1,4-thiazin-3-amine 1,1-dioxide.
34. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)-2-pyrazinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecar-
boxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihy-
dro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarbox-
amide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazine-
carboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethyl)-2-pyridinecarb-
oxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-cyano-2-pyridinecarboxa-
mide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridine-
carboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecar-
boxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihy-
dro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarbo-
xamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarbo-
xamide
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazine-
carboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridinecarbo-
xamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-methoxy-2-pyridinecarbox-
amide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxa-
mide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-th-
iazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethenyl)-2-pyridinecarboxa-
mide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-th-
iazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethenyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-ethyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethyl-2-pyridinecarboxamid-
e;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethyl)-2-pyridi-
necarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-5-(difluoromethyl)-2-pyridinecarboxa-
mide;
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8--
en-7-yl)-6-fluoro-3-pyridinyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-pyridi-
necarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-bromo-5-chloro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxamide;
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-6-fluoro-3-pyridinyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxam-
ide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thi-
azin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxam-
ide;
N-(3-((7R)-9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azaspir-
o[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridi-
necarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamidel;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-((4-fluoro-2-butyn-1-yl)oxy)-2-pyri-
dinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-chloro-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-fluoro-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarbox-
amide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-6-fluoro-3-pyridinyl)-5-methoxy-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxami-
de;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thia-
zin-3-yl)-6-fluoro-3-pyridinyl)-5-cyano-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinec-
arboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethenyl)-2-pyridi-
necarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxami-
de;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarbox-
amide; Mixture of
N-(3-((7R)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxa-
mide and
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro-
[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridin-
ecarboxamide;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxa-
mide;
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspir-
o[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarbox-
amide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]-
pyridine-2-carboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)-5-(difluoromethoxy)-3-methy-
l-2-pyridinecarboxamide;
N-(5-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-6-fluoro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxami-
de;
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[-
2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methyl-2-pyridinec-
arboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridine-
carboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
and
N-(3-((6S)-8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-
-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide.
35. A pharmaceutical composition comprising a compound according to
claim 2 and a pharmaceutically acceptable excipient.
36. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject an effective dosage amount of a
compound according to claim 2.
37. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject an effective dosage amount of a
compound to claim 2.
38. A method of treating a neurological disorder selected from the
group consisting of mild cognitive impairment, Down's syndrome,
Hereditary cerebral hemorrhage with dutch-type amyloidosis,
cerebral amyloid angiopathy, degenerative dementia, dementia
associated with Parkinson's disease, dementia associated with
supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse lewy body type of Alzheimer's disease or a
combination thereof in a subject, the method comprising
administering to the subject an effective dosage amount of a
compound according to claim 2.
39. A method of reducing the formation of plaque on the brain of a
subject, the method comprising administering to the subject an
effective dosage amount of a compound according to claim 2.
40. A process for preparing a compound according to claim 1, the
process comprising the step of reacting a compound 20 ##STR00351##
wherein R.sup.1, R.sup.2, R.sup.3, A.sup.4, A.sup.5, A.sup.6 and
A.sup.8 of compound 20 are as defined in claim 1, with a compound
having the structure or R.sup.9--C(.dbd.O)Cl or R.sup.9--Br,
wherein R.sup.9 is as defined in claim 1 to prepare the compound
according to claim 1.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/713,413, filed on Oct. 12, 2012 and U.S.
Provisional Patent Application No. 61/783,656, filed on Mar. 14,
2013, both specifications of which are hereby incorporated herein
by reference in its entireties.
FIELD OF THE INVENTION
[0002] The invention relates generally to pharmaceutically active
compounds, pharmaceutical compositions and methods of use thereof,
to treat beta-secretase mediated diseases and conditions,
including, without limitation, Alzheimer's disease, plaque
formation and associated central nervous system (CNS)
disorders.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) affects greater than 12 million
aging people worldwide, and importantly, the number affected
continues to grow. AD accounts for the majority of dementias
clinically diagnosed after the age of 60. AD is generally
characterized by the progressive decline of memory, reasoning,
judgement and orientation. As the disease progresses, motor,
sensory, and vocal abilities are affected until there is global
impairment of multiple cognitive functions. The loss of cognitive
function occurs gradually, typically leading to a diminished
cognition of self, family and friends. Patients with severe
cognitive impairment and/or diagnosed as end-stage AD are generally
bedridden, incontinent, and dependent on custodial care. The AD
patient eventually dies in about nine to ten years, on average,
after initial diagnosis. Due to the incapacitating, generally
humiliating and ultimately fatal effects of AD, there is a need to
treat AD effectively upon diagnosis.
[0004] AD is characterized by two major physiological changes in
the brain. The first change, beta amyloid plaque formation,
supports the "amyloid cascade hypothesis" which conveys the thought
that AD is caused by the formation of characteristic beta amyloid
peptide (A-beta), or A-beta fragments thereof, deposits in the
brain (commonly referred to as beta amyloid "plaques" or "plaque
deposits") and in cerebral blood vessels (beta amyloid angiopathy).
A wealth of evidence suggests that beta-amyloid and accompanying
amyloid plaque formation is central to the pathophysiology of AD
and is likely to play an early role in this intractable
neurodegenerative disorder. The second change in AD is the
formation of intraneuronal tangles, consisting of an aggregate form
of the protein tau. Besides being found in patients with AD,
intraneuronal tangles are also found in other dementia-inducing
disorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34
(1992).
[0005] Several lines of evidence indicate that progressive cerebral
deposition of A-beta plays a seminal role in the pathogenisis of AD
and can precede cognitive symptoms by years or even decades.
Selkoe, Neuron, 6:487 (1991). Release of A-beta from neuronal cells
grown in culture and the presence of A-beta in cerebrospinal fluid
(CSF) of both normal individuals and AD patients has been
demonstrated. Seubert et al., Nature, 359:325-327 (1992). Autopsies
of AD patients have revealed large numbers of lesions comprising
these 2 factors in areas of the human brain believed to be
important for memory and cognition.
[0006] Smaller numbers of these lesions in a more restricted
anatomical distribution are found in the brains of most aged humans
who do not have clinical AD. Amyloid containing plaques and
vascular amyloid angiopathy were also found in the brains of
individuals with Down's Syndrome, Hereditary Cerebral Hemorrhage
with Amyloidosis of the Dutch-type (HCHWA-D), and other
neurodegenerative disorders.
[0007] It has been hypothesized that A-beta formation is a
causative precursor or factor in the development of AD. More
specifically, deposition of A-beta in areas of the brain
responsible for cognitive factors is believed to be a major factor
in the development of AD. Beta amyloid plaques are primarily
composed of amyloid beta peptide (A-beta peptide). A-beta peptide
is derived from the proteolytic cleavage of a large transmembrane
amyloid precursor protein (APP), and is a peptide comprised of
about 39-42 amino acid residues. A-beta 42 (42 amino acids long) is
thought to be the major component of these plaque deposits in the
brains of Alzheimer's Disease patients. Citron, Trends in
Pharmacological Sciences, 25(2):92-97 (2004).
[0008] Similar plaques appear in some variants of Lewy body
dementia and in inclusion body myositis, a muscle disease. A.beta.
also forms aggregates coating cerebral blood vessels in cerebral
amyloid angiopathy. These plaques are composed of a tangle of
regularly ordered fibrillar aggregates called amyloid fibers, a
protein fold shared by other peptides such as prions associated
with protein misfolding diseases. Research on laboratory rats
suggest that the dimeric, soluble form of the peptide is a
causative agent in the development of Alzheimer's and is the
smallest synaptotoxic species of soluble amyloid beta oligomer.
Shankar, G. M., Nature Medicine (Jun. 22, 2008) online doi 10:1038
nm 1782.
[0009] Several aspartyl proteases, including beta-secretase and
gamma-secretase, are thought to be involved in the processing or
cleavage of APP, resulting in the formation of A-beta peptide. Beta
secretase (BACE, also commonly referred to as memapsin) is thought
to first cleave APP to generate two fragments: (1) a first
N-terminus fragment (beta APP) and (2) a second C-99 fragment,
which is subsequently cleaved by gamma secretase to generate the
A-beta peptide. APP has also found to be cleaved by alpha-secretase
to produce alpha-sAPP, a secreted form of APP that does not result
in beta-amyloid plaque formation. This alternate pathway precludes
the formation of A-beta peptide. A description of the proteolytic
processing fragments of APP is found, for example, in U.S. Pat.
Nos. 5,441,870, 5,712,130 and 5,942,400.
[0010] BACE is an aspartyl protease enzyme comprising 501 amino
acids and responsible for processing APP at the beta-secretase
specific cleavage site. BACE is present in two forms, BACE 1 and
BACE 2, designated as such depending upon the specific cleavage
site of APP. Beta secretase is described in Sinha et al., Nature,
402:537-554 (1999) (p510) and PCT application WO 2000/17369. It has
been proposed that A-beta peptide accumulates as a result of APP
processing by BACE. Moreover, in vivo processing of APP at the beta
secretase cleavage site is thought to be a rate-limiting step in
A-beta production. Sabbagh, M. et al., Alz. Dis. Rev. 3:1-19
(1997). Thus, inhibition of the BACE enzyme activity is desirable
for the treatment of AD.
[0011] Studies have shown that the inhibition of BACE may be linked
to the treatment of AD. The BACE enzyme is essential for the
generation of beta-amyloid or A-beta. BACE knockout mice do not
produce beta-amyloid and are free from Alzheimer's associated
pathologies including neuronal loss and certain memory deficits.
Cole, S. L., Vasser, R., Molecular Degeneration 2:22, 2007. When
crossed with transgenic mice that over express APP, the progeny of
BACE deficient mice show reduced amounts of A-beta in brain
extracts as compares with control animals (Luo et al., Nature
Neuroscience, 4:231-232 (2001)). The fact that BACE initiates the
formation of beta-amyloid, and the observation that BACE levels are
elevated in this disease provide direct and compelling reasons to
develop therapies directed at BACE inhibition thus reducing
beta-amyloid and its associated toxicities. To this end, inhibition
of beta secretase activity and a corresponding reduction of A-beta
in the brain should provide a therapeutic method for treating AD
and other beta amyloid or plaque related disorders.
[0012] Consequently, the approach of regulating or reducing the
formation of A-beta peptide formation and deposition as a potential
treatment for AD has received tremendous attention, support and
commitment from both researchers and investors alike. A small
molecule gamma-secretase inhibitor, LY450139 ("Semagacestat"), an
A-beta lowering agent, is in phase II clinical trials for the
treatment of Alzheimer's Disease. The pharmacokinetics of
semagacestat in plasma, as well as the plasma and cerebral spinal
fluid (CSF) A-Beta peptide levels as pharmacodynamic responses to
semagacestat administration were evaluated in healthy human
subjects in single and multiple doses, and pharmacokinetic and
pharmacodynamic changes were also assessed in mild to moderate AD
patients in two (2) clinical trials (Expert Opin. Pharmacother.
(2009), 10 (10); Clin. Neuropharmacol. 2007; 30 (pgs 317-325); and
Neurology, 2006, 66 (pgs 602-624)).
[0013] Additional approaches have been taken in attempts to treat
AD and plaque-related disorders. One such approach to reduce the
formation of plaque deposits in the brain involves the inhibition
of and, therefore, the reduction of BACE activity. For example,
each of the following PCT publications: WO12/006,953, WO12/139,425,
WO11/069,934, WO11/070,029, WO11/029,803, WO11/020,806, WO
11/009,943, WO11/138,293, WO07/049,532, WO08/133,273, WO08/133,274,
WO11/071,057, WO11/071,135, WO11/070,781, WO11/058,763,
WO11/077,726, WO13/028,670 and WO11/154,431 describe inhibitors of
BACE, useful for treating AD and other beta-secretase mediated
disorders. For Example, WO2011009943 describes BACE inhibitors for
the treatment of neurological disorders of the general formula:
##STR00002##
while WO2011138293 describes BACE1 and BACE2 inhibiting compounds
of the general formula:
##STR00003##
[0014] The lysosomal aspartic protease Cathepsin D (CatD) is
ubiquitously expressed in eukaryotic organisms. CatD activity is
essential to accomplish the acid-dependent extensive or partial
proteolysis of protein substrates within endosomal and lysosomal
compartments therein delivered via endocytosis, phagocytosis or
autophagocytosis. CatD may also act at physiological pH on
small-size substrates in the cytosol and in the extracellular
milieu. Mouse and fruit fly CatD knock-out models have highlighted
the multi-pathophysiological roles of CatD in tissue homeostasis
and organ development.
[0015] Inhibition of protein Cathepsin D has been implicated in
undesirable side effects. For instance, the inhibition of Cathepsin
D is believed to be linked to adverse retinal development and
retinal atrophy. Particularly, in mice it was found that cathepsin
D is essential for the metabolic maintenance of retinal
photoreceptor cells and that its deficiency induces apoptosis of
the cells, while the loss of INL neurons is mediated by nitrc oxide
release from microglial cells. However, in the very same mice, it
was also found that no atrophic change was detected in the retina
of mice deficient in cathepsin B or L. Mol. Cell. Neurosci, 2003,
February 22(2):146-161. Further, Animal models of cathepsin D
(CatD) deficiency are characterized by a progressive and relentless
neurodegenerative phenotype similar to that observed in Neuronal
Ceroid Lipofuscinoses (NCL), a group of pediatric neurodegenerative
diseases known collectively as Batten Disease. It has been shown
that the targeted deletion of the pro-apoptotic molecule Bax
prevents apoptotic markers but not neuronal cell death and
neurodegeneration induced by CatD deficiency, which suggests that
alterations in the macroautophagy-lysosomal degradation pathway can
mediate neuronal cell death in NCL/Batten Disease in the absence of
apoptosis. Autophagy, 2007, September-October; 3(5):474-476.
Finally, an adverse effect of the inhibition of Cat D is evident
from the data presented in PLoS One, 2011; 6(7):e21908, published
Jul. 1, 2011. The authors of the PLoS One paper found that
knock-down of cathepsin D affects the retinal pigment epithelium,
impairs swim-bladder ontogenesis and causes premature death in
zebrafish. The main phenotypic alterations produced by CatD
knock-down in zebrafish were: 1. abnormal development of the eye
and of retinal pigment epithelium; 2. absence of the swim-bladder;
3. skin hyper-pigmentation; 4. reduced growth and premature death.
Rescue experiments confirmed the involvement of CatD in the
developmental processes leading to these phenotypic
alterations.
[0016] Moreover, such toxicity findings which, in view of the
literature, may have played a role in the termination of a human
Bace-mediated Alzheimer's Disease clinical trial. Eli Lilly
terminated a phase I clinical trial of LY 2811376 after rat
toxicology studies showed that a higher compound dose given for
three months damaged the pigment epithelium of the rat's eye. The
retinal layer had inclusions and extensive damage. The Ph I dosing
trial was terminated and people brought in for eye assessments did
not show any abnormalities (Alzheimer's Research Forum News, Mar.
31, 2011 reporting on Martin Citron's presentation at the AD/PD
Conference March 2011 in Barcelona, Spain)
[0017] Hence, it is desirable to provide compounds which modulate
the activity of and are reasonably selective for BACE, while not
suffering from undesirable side effects possibly due to
intervention with or the reduction and/or direct or indirect
inhibition of the expression and/or function of other proteins or
biological pathways.
BRIEF DESCRIPTION OF THE INVENTION
[0018] The present invention provides a new class of compounds
useful for the modulation of beta secretase activity, and as
treatment of AD. Particularly, the compounds of the invention are
useful for the regulation or reduction of the formation of A-beta
peptide and, consequently, the regulation and/or reduction of
formation of beta amyloid plaque both on the brain, as well as in
the CNS. To this end, the compounds are useful for the treatment of
AD and other beta secretase and/or plaque-related and/or mediated
disorders. For example, the compounds are useful for the
prophylaxis and/or treatment, acute and/or chronic, of AD and other
diseases or conditions involving the deposition or accumulation of
beta amyloid peptide, and formation of plaque, on the brain.
[0019] The compounds provided by the invention, including
stereoisomers, tautomers, hydrates, solvates and pharmaceutically
acceptable salts thereof, are generally defined by Formula I
##STR00004##
wherein each of A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.1,
R.sup.2, R.sup.3, R.sup.7 and n of Formula I are defined below. The
invention also provides procedures for making compounds of Formula
I, and sub-Formulas thereof, as well as intermediates useful in
such procedures.
[0020] The invention further provides pharmaceutical compositions
comprising compounds of the invention, and uses of these
compositions in the treatment of beta secretase mediated diseases.
For example, and in one embodiment, the invention provides a
pharmaceutical composition comprising an effective dosage amount of
a compound of Formula I in association with at least one
pharmaceutically acceptable excipient.
[0021] The foregoing merely summarizes certain aspects of the
invention and is not intended, nor should it be construed, as
limiting the invention in any way. All patents and other
publications recited herein are hereby incorporated by reference in
their entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0022] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula I:
##STR00005##
or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically
acceptable salt thereof, wherein
[0023] A.sup.4 is CR.sup.4 or N;
[0024] A.sup.5 is CR.sup.5 or N;
[0025] A.sup.6 is CR.sup.6 or N;
[0026] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0027] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0028] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
substituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0029] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
substituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0030] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0031] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a substituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0032] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0033] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9 or --S--R.sup.9;
[0034] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0035] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and
[0036] n is 0, 1 or 2.
[0037] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula I:
##STR00006##
or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically
acceptable salt thereof, wherein
[0038] A.sup.4 is CR.sup.4 or N;
[0039] A.sup.5 is CR.sup.5 or N;
[0040] A.sup.6 is CR.sup.6 or N;
[0041] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0042] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0043] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
substituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0044] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
substituent of C.sub.1-3allyl, CH.sub.2OC.sub.1-2allyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0045] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4allyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0046] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0047] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0048] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0049] or R.sup.7 is
##STR00007## [0050] wherein V is NR.sup.10, O or S; and [0051] each
W, independently, is CH, CF, CCl or N;
[0052] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4allynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0053] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and
[0054] n is 0, 1 or 2.
[0055] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula II:
##STR00008##
wherein
[0056] A.sup.4 is CR.sup.4 or N;
[0057] A.sup.5 is CR.sup.5 or N;
[0058] A.sup.6 is CR.sup.6 or N;
[0059] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0060] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0061] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0062] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3allyl, CH.sub.2OC.sub.1-2allyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0063] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4allyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0064] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0065] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0066] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0067] or R.sup.7 is
##STR00009## [0068] wherein V is NR.sup.10, O or S; and [0069] each
W, independently, is CH, CF, CCl or N;
[0070] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4allynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0071] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0072] In another embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are also
generally defined by Formula II:
##STR00010##
wherein
[0073] A.sup.4 is CR.sup.4 or N;
[0074] A.sup.5 is CR.sup.5 or N;
[0075] A.sup.6 is CR.sup.6 or N;
[0076] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0077] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0078] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0079] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2allyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0080] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4allyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0081] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3allyl,
CH.sub.2OC.sub.1-2allyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0082] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0083] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0084] or R.sup.7 is
##STR00011## [0085] wherein V is NR.sup.10, O or S; and [0086] each
W, independently, is CH, CF, CCl or N;
[0087] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4allynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0088] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6allyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl.
[0089] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula II-A:
##STR00012##
wherein
[0090] A.sup.4 is CR.sup.4 or N;
[0091] A.sup.5 is CR.sup.5 or N;
[0092] A.sup.6 is CR.sup.6 or N;
[0093] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0094] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-3-alkyl, --OC.sub.1-3-alkyl, wherein each of the
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
C.sub.1-4-alkyl portion of --CH.sub.2OC.sub.1-3-alkyl and
--OC.sub.1-3-alkyl are optionally substituted with 1-4 substituents
of F;
[0095] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0096] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0097] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0098] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a C.sub.3-6
carbocyclic ring optionally including 1-2 heteroatoms selected from
O and N and optionally substituted with 1-4 F atoms on the carbon
atoms and a subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl
or C.sub.1-3haloalkyl on the nitrogen atom;
[0099] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H or F;
[0100] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0101] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0102] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula II-B:
##STR00013##
wherein
[0103] A.sup.4 is CR.sup.4 or N;
[0104] A.sup.5 is CR.sup.5 or N;
[0105] A.sup.6 is CR.sup.6 or N;
[0106] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0107] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-3-alkyl, --OC.sub.1-3-alkyl, wherein each of the
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
C.sub.1-4-alkyl portion of --CH.sub.2OC.sub.1-3-alkyl and
--OC.sub.1-3-alkyl are optionally substituted with 1-4 substituents
of F;
[0108] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0109] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0110] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0111] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a C.sub.3-6
carbocyclic ring optionally including 1-2 heteroatoms selected from
O and N and optionally substituted with 1-4 F atoms on the carbon
atoms and a subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl
or C.sub.1-3haloalkyl on the nitrogen atom;
[0112] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H or F;
[0113] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, acetyl, --C(O)NHCH.sub.3, oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and
[0114] each W, independently, is CH, CF, CCl or N.
[0115] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula II-C:
##STR00014##
wherein
[0116] A.sup.4 is CR.sup.4 or N;
[0117] A.sup.5 is CR.sup.5 or N;
[0118] A.sup.6 is CR.sup.6 or N;
[0119] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0120] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-3-alkyl, --OC.sub.1-3-alkyl, wherein each of the
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
C.sub.1-4-alkyl portion of --CH.sub.2OC.sub.1-3-alkyl and
--OC.sub.1-3-alkyl are optionally substituted with 1-4 substituents
of F;
[0121] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0122] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0123] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0124] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a C.sub.3-6
carbocyclic ring optionally including 1-2 heteroatoms selected from
O and N and optionally substituted with 1-4 F atoms on the carbon
atoms and a subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl
or C.sub.1-3haloalkyl on the nitrogen atom;
[0125] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H or F;
[0126] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxyl, ethyl,
ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl or oxetan-3yl;
[0127] V is NR.sup.10, O or S; and
[0128] each W, independently, is CH, CF, CCl or N.
[0129] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III:
##STR00015##
wherein
[0130] A.sup.4 is CR.sup.4 or N;
[0131] A.sup.5 is CR.sup.5 or N;
[0132] A.sup.6 is CR.sup.6 or N;
[0133] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0134] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0135] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0136] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0137] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0138] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0139] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0140] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0141] or R.sup.7 is
##STR00016## [0142] wherein V is NR.sup.10, O or S; and [0143] each
W, independently, is CH, CF, CCl or N;
[0144] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0145] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0146] Similarly, the invention provides compounds of sub-formulas
III-A, III-B, III-C and III-D, respectively, as described
below.
##STR00017##
in conjunction with any of the above or below embodiments,
including those described in embodiments A, A-1 to A-4, B, B-1 to
B-10, C, C-1 to C-10, D, D-1 to D-4, E, E-1 to E-4, F, F-1 to F-4,
G, G-1 to G-4, H, H-1 to H-4, I, I-1 to 1-9, J, J-1 to J-8, K, K-1
to K-2, L, M, N-1 to N-2, O-1 to O-2 and P-1 to P-2 described
herein.
[0147] In another embodiment, the invention provides compounds of
Formulas III-B, wherein each W, independently, is CH, CF, CCl or N,
provided
##STR00018##
is not
##STR00019##
wherein each R.sup.11, independently, is H, F of Cl.
[0148] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-B-1:
##STR00020##
wherein
[0149] A.sup.4 is CR.sup.4 or N;
[0150] A.sup.5 is CR.sup.5 or N;
[0151] A.sup.6 is CR.sup.6 or N;
[0152] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0153] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0154] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0155] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0156] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0157] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0158] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0159] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl; and
[0160] each W, independently, is CH, CF, CCl or N.
[0161] In another embodiment, the invention provides compounds of
Formulas III-B, III-C and III-D, wherein the sum of the number of
heteroatoms, selected from N, O and S, at positions corresponding
to each V and W in Formulas III-B, III-C and III-D is at least
4.
[0162] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-E:
##STR00021##
wherein
[0163] A.sup.4 is CR.sup.4 or N;
[0164] A.sup.5 is CR.sup.5 or N;
[0165] A.sup.6 is CR.sup.6 or N;
[0166] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0167] R is a C.sub.3-6-spirocarbocyclic ring optionally including
one heteroatom selected from O and N and optionally substituted
with 1-4 F atoms on the carbon atoms and/or a subsituent of
C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom;
[0168] each of R.sup.1, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0169] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0170] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0171] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0172] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0173] or R.sup.7 is
##STR00022## [0174] wherein V is NR.sup.10, O or S; and [0175] each
W, independently, is CH, CF, CCl or N;
[0176] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4allynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0177] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl.
[0178] In another embodiment, the invention includes compounds of
Formula III-E, wherein R is a cyclopropyl ring optionally
substituted with 1-4 F atoms.
[0179] In another embodiment, the invention includes compounds of
Formula III-E, wherein R is a cyclobutyl ring optionally
substituted with 1-4 F atoms.
[0180] In another embodiment, the invention includes compounds of
Formula III-E, wherein R is a cyclopentyl ring optionally
substituted with 1-4 F atoms.
[0181] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-E-1:
##STR00023##
wherein
[0182] A.sup.4 is CR.sup.4 or N;
[0183] A.sup.5 is CR.sup.5 or N;
[0184] A.sup.6 is CR.sup.6 or N;
[0185] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0186] each R.sup.a, independently, is H, F, C.sub.1-3-alkyl or
C.sub.1-3haloalkyl;
[0187] each of R.sup.1, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3,
C(O)CH.sub.3 or CH.sub.2OCHF.sub.2;
[0188] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0189] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl;
[0190] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl, CN,
OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3;
[0191] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0192] or R.sup.7 is
##STR00024## [0193] wherein V is NR.sup.10, O or S; and [0194] each
W, independently, is CH, CF, CCl or N;
[0195] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0196] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl.
[0197] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-F:
##STR00025##
wherein
[0198] A.sup.4 is CR.sup.4 or N;
[0199] A.sup.5 is CR.sup.5 or N;
[0200] A.sup.6 is CR.sup.6 or N;
[0201] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0202] M is a C.sub.3-6-carbocyclic ring optionally including one
or two heteroatoms selected from O and N and optionally substituted
with 1-4 F atoms on the carbon atoms and/or a subsituent of
C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on a
nitrogen atom;
[0203] each of R.sup.1, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0204] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0205] R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH;
[0206] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0207] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0208] or R.sup.7 is
##STR00026## [0209] wherein V is NR.sup.10, O or S; and [0210] each
W, independently, is CH, CF, CCl or N;
[0211] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0212] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl.
[0213] In another embodiment, the invention includes compounds of
Formula III-F, wherein M is a tetrahydrofuran ring optionally
substituted with 1-4 F atoms.
[0214] In another embodiment, the invention includes compounds of
Formula III-F, wherein M is a tetrahydropyran ring optionally
substituted with 1-4 F atoms.
[0215] In another embodiment, the invention includes compounds of
Formula III-F, wherein M is a cyclopentyl ring optionally
substituted with 1-4 F atoms.
[0216] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-F-1:
##STR00027##
wherein
[0217] A.sup.4 is CR.sup.4 or N;
[0218] A.sup.5 is CR.sup.5 or N;
[0219] A.sup.6 is CR.sup.6 or N;
[0220] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0221] each R.sup.a, independently, is H, F, C.sub.1-3-alkyl or
C.sub.1-3haloalkyl;
[0222] each R.sup.1, independently, is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH;
[0223] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0224] R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH;
[0225] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0226] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0227] or R.sup.7 is
##STR00028## [0228] wherein V is NR.sup.10, O or S; and [0229] each
W, independently, is CH, CF, CCl or N;
[0230] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0231] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkyllyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl; and
[0232] p is 0, 1, 2 or 3.
[0233] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-F-2:
##STR00029##
wherein
[0234] A.sup.4 is CR.sup.4 or N;
[0235] A.sup.5 is CR.sup.5 or N;
[0236] A.sup.6 is CR.sup.6 or N;
[0237] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0238] each R.sup.a, independently, is H, F, C.sub.1-3-alkyl or
C.sub.1-3haloalkyl;
[0239] each R.sup.1, independently, is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH;
[0240] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0241] R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH;
[0242] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0243] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, --S--R.sup.9;
[0244] or R.sup.7 is
##STR00030## [0245] wherein V is NR.sup.10, O or S; and [0246] each
W, independently, is CH, CF, CCl or N;
[0247] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0248] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl.
[0249] In yet another embodiment, the invention provides compounds,
and tautomers, stereoisomers, hydrates and pharmaceutically
acceptable salts thereof, of sub-formula III-G:
##STR00031##
wherein, A.sup.4 is CR.sup.4 or N;
[0250] A.sup.5 is CR.sup.5 or N;
[0251] A.sup.6 is CR.sup.6 or N;
[0252] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0253] L.sup.1 is --NH-- or --C(.dbd.O)NH--;
[0254] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0255] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6-spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0256] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0257] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0258] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0259] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0260] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,
pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or
dioxolyl, wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,
oxetan-3-yl or dioxolyl, is optionally substituted independently
with 1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy,
isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl or oxetan-3yl; and
[0261] each W, independently, is CH, CF, CCl or N.
[0262] The present invention contemplates that the various
different embodiments of Formulas I, II and III, and sub-Formulas
II-A, II-B and II-C thereof, described herein, may comprise the
following embodiments with respect to individual variables of
A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.1, R.sup.2, R.sup.3,
R.sup.7, V and W, where applicable, as described below. Hence,
these embodiments with respect to individual variables A.sup.4,
A.sup.5, A.sup.6, A.sup.8, R.sup.1, R.sup.2, R.sup.3, R.sup.7, V
and W where applicable, may be applied "in conjunction with any of
the other {above and below} embodiments" to create various
embodiments of general Formulas I, II and III, and each sub-formula
thereof, which are not literally or identically described herein.
More specifically, the term "in conjunction with any of the above
or below embodiments" includes embodiments A, A-1 to A-4, B, B-1 to
B10, C, C-1 to C-10, D, D-1 to D-4, E, E-1 to E-4, F, F-1 to F-4,
G, G-1 to G-4, H, H-1 to H-4, I, I-1 to 1-9, J, J-1 to J-9, K, K-1
to K-2, L, M, N-1 to N-2, O-1 to O-2 and P-1 to P-2 described
herein, as it applies to general Formulas I and II, and
sub-formulas II-A, II-B and II-C, also described herein.
[0263] In another embodiment A, the invention includes compounds of
Formula I, wherein n is 0, 1 or 2, in conjunction with any of the
above or below embodiments.
[0264] In another embodiment A-1, the invention includes compounds
of Formula I, wherein n is 1 or 2, in conjunction with any of the
above or below embodiments.
[0265] In another embodiment A-2, the invention includes compounds
of Formula I, wherein n is 2, in conjunction with any of the above
or below embodiments.
[0266] In another embodiment A-3, the invention includes compounds
of Formula I, wherein n is 1, in conjunction with any of the above
or below embodiments.
[0267] In another embodiment A-4, the invention includes compounds
of Formula I, wherein n is 0, in conjunction with any of the above
or below embodiments.
[0268] In another embodiment B, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4allynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH, in conjunction
with any of the above or below embodiments.
[0269] In another embodiment B-1, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-3-alkyl,
--OC.sub.1-3-alkyl, wherein each of the C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and C.sub.1-4-alkyl portion of
--CH.sub.2OC.sub.1-3-alkyl and --OC.sub.1-3-alkyl are optionally
substituted with 1-4 substituents of F, in conjunction with any of
the above or below embodiments.
[0270] In another embodiment B-2, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3,
C(O)CH.sub.3 or CH.sub.2OCHF.sub.2, in conjunction with any of the
above or below embodiments.
[0271] In another embodiment B-3, the invention includes compounds
wherein each R.sup.1, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3, in conjunction with any of
the above or below embodiments.
[0272] In another embodiment B-4, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CF.sub.2H or CH.sub.2F, in conjunction with any of the
above or below embodiments.
[0273] In another embodiment B-5, the invention includes compounds
wherein each R.sup.1, independently, is H, F, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F, in conjunction with any of the above or
below embodiments.
[0274] In another embodiment B-6, the invention includes compounds
wherein each R.sup.1, independently, is H, F, CF.sub.3 or CH.sub.3,
in conjunction with any of the above or below embodiments.
[0275] In another embodiment B-7, the invention includes compounds
wherein each R.sup.1, independently, is H or F, in conjunction with
any of the above or below embodiments.
[0276] In another embodiment B-8, the invention includes compounds
wherein each R.sup.1, taken together with the carbon atom to which
they are attached form a C.sub.3-6 spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-4 F atoms on the carbon atoms and a subsituent
of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom, in conjunction with any of the above or below
embodiments.
[0277] In another embodiment B-9, the invention includes compounds
wherein each R.sup.1, taken together with the carbon atom to which
they are attached form a cyclopropyl, cyclobutyl or cyclopentyl
ring optionally substituted with 1-4 F atoms on the carbon atoms,
in conjunction with any of the above or below embodiments.
[0278] In another embodiment B-10, the invention includes compounds
wherein each R.sup.1, taken together with the carbon atom to which
they are attached form a cyclopropyl or cyclopentyl ring optionally
substituted with 1-4 F atoms on the carbon atoms, in conjunction
with any of the above or below embodiments.
[0279] In another embodiment C, the invention includes compounds
wherein each R.sup.2, independently, is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH, in conjunction
with any of the above or below embodiments.
[0280] In another embodiment C-1, the invention includes compounds
wherein each R.sup.2, independently, is H, F, Cl, C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-3-alkyl,
--OC.sub.1-3-alkyl, wherein each of the C.sub.1-4-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and C.sub.1-4-alkyl portion of
--CH.sub.2OC.sub.1-3-alkyl and --OC.sub.1-3-alkyl are optionally
substituted with 1-4 substituents of F, in conjunction with any of
the above or below embodiments.
[0281] In another embodiment C-2, the invention includes compounds
wherein each R.sup.2, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3,
C(O)CH.sub.3 or CH.sub.2OCHF.sub.2, in conjunction with any of the
above or below embodiments.
[0282] In another embodiment C-3, the invention includes compounds
wherein each R.sup.2, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3, in conjunction with any of
the above or below embodiments.
[0283] In another embodiment C-4, the invention includes compounds
wherein each R.sup.2, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CF.sub.2H or CH.sub.2F, in conjunction with any of the
above or below embodiments.
[0284] In another embodiment C-5, the invention includes compounds
wherein each R.sup.2, independently, is H, F, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F, in conjunction with any of the above or
below embodiments.
[0285] In another embodiment C-6, the invention includes compounds
wherein each R.sup.2, independently, is H, F, CF.sub.3 or CH.sub.3,
in conjunction with any of the above or below embodiments.
[0286] In another embodiment C-7, the invention includes compounds
wherein each R.sup.2, independently, is H or F, in conjunction with
any of the above or below embodiments.
[0287] In another embodiment C-8, the invention includes compounds
wherein each R.sup.2, taken together with the carbon atom to which
they are attached form a C.sub.3-6 spirocarbocyclic ring optionally
including one heteroatom selected from O and N and optionally
substituted with 1-4 F atoms on the carbon atoms and a subsituent
of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on
the nitrogen atom, in conjunction with any of the above or below
embodiments.
[0288] In another embodiment C-9, the invention includes compounds
wherein each R.sup.2, taken together with the carbon atom to which
they are attached form a cyclopropyl, cyclobutyl or cyclopentyl
ring optionally substituted with 1-4 F atoms on the carbon atoms,
in conjunction with any of the above or below embodiments.
[0289] In another embodiment C-10, the invention includes compounds
wherein each R.sup.2, taken together with the carbon atom to which
they are attached form a cyclopropyl or cyclopentyl ring optionally
substituted with 1-4 F atoms on the carbon atoms, in conjunction
with any of the above or below embodiments.
[0290] In another embodiment D, the invention includes compounds
wherein R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms, in
conjunction with any of the above or below embodiments.
[0291] In another embodiment D-1, the invention includes compounds
wherein R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl, wherein each of the
C.sub.1-4alkyl, C.sub.1-4haloalkyl and cyclopropyl is optionally
substituted with 1-4 F atoms, in conjunction with any of the above
or below embodiments.
[0292] In another embodiment D-2, the invention includes compounds
wherein R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H, or cyclopropyl, wherein each of the
C.sub.1-4alkyl and cyclopropyl is optionally substituted with 1-2 F
atoms, in conjunction with any of the above or below
embodiments.
[0293] In another embodiment D-3, the invention includes compounds
wherein R.sup.3 is CH.sub.3, CF.sub.3, C.sub.2H.sub.5, CF.sub.2H or
CH.sub.2F, in conjunction with any of the above or below
embodiments.
[0294] In another embodiment D-4, the invention includes compounds
wherein R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F, in
conjunction with any of the above or below embodiments.
[0295] In another embodiment E, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0296] In another embodiment E-1, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3, in conjunction with any of the above or below
embodiments.
[0297] In another embodiment E-2, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0298] In another embodiment E-3, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H or F, in
conjunction with any of the above or below embodiments.
[0299] In another embodiment E-4, the invention includes compounds
wherein A.sup.4 is N, in conjunction with any of the above or below
embodiments.
[0300] In another embodiment F, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0301] In another embodiment F-1, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3, in conjunction with any of the above or below
embodiments.
[0302] In another embodiment F-2, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0303] In another embodiment F-3, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H or F, in
conjunction with any of the above or below embodiments.
[0304] In another embodiment F-4, the invention includes compounds
wherein A.sup.5 is N, in conjunction with any of the above or below
embodiments.
[0305] In another embodiment G, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0306] In another embodiment G-1, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3, in conjunction with any of the above or below
embodiments.
[0307] In another embodiment G-2, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0308] In another embodiment G-3, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H or F, in
conjunction with any of the above or below embodiments.
[0309] In another embodiment G-4, the invention includes compounds
wherein A.sup.6 is N, in conjunction with any of the above or below
embodiments.
[0310] In another embodiment H, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0311] In another embodiment H-1, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3, in conjunction with any of the above or below
embodiments.
[0312] In another embodiment H-2, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0313] In another embodiment H-3, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H or F, in
conjunction with any of the above or below embodiments.
[0314] In another embodiment H-4, the invention includes compounds
wherein A.sup.8 is N, in conjunction with any of the above or below
embodiments.
[0315] In another embodiment I, the invention includes compounds
wherein no more than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8
is N, in conjunction with any of the above or below
embodiments.
[0316] In another embodiment I-1, the invention includes compounds
wherein no more than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8
is N, in conjunction with any of the above or below
embodiments.
[0317] In another embodiment 1-2, the invention includes compounds
wherein A.sup.4 is CR.sup.4 or N, A.sup.5 is CR.sup.5 or N, A.sup.6
is CR.sup.6 or N and A.sup.8 is CR.sup.8 or N, provided that no
more than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N, in
conjunction with any of the above or below embodiments.
[0318] In another embodiment, the invention includes compounds
wherein A.sup.4 is CR.sup.4 or N, A.sup.5 is CR.sup.5, A.sup.6 is
CR.sup.6 and A.sup.8 is CR.sup.8, in conjunction with any of the
above or below embodiments.
[0319] In another embodiment 1-3, the invention includes compounds
wherein A.sup.4 is N, A.sup.5 is CR.sup.5, A.sup.6 is CR.sup.6 and
A.sup.8 is CR.sup.8, in conjunction with any of the above or below
embodiments.
[0320] In another embodiment 1-4, the invention includes compounds
wherein A.sup.4 is CR.sup.4, A.sup.5 is N, A.sup.6 is CR.sup.6, and
A.sup.8 is CR.sup.8, in conjunction with any of the above or below
embodiments.
[0321] In another embodiment 1-5, the invention includes compounds
wherein A.sup.4 is CR.sup.4, A.sup.5 is CR.sup.5, A.sup.6 is N, and
A.sup.8 is CR.sup.8, in conjunction with any of the above or below
embodiments.
[0322] In another embodiment 1-6, the invention includes compounds
wherein A.sup.4 is CR.sup.5, A.sup.5 is CR.sup.5, A.sup.6 is
CR.sup.6, and A.sup.8 is N, in conjunction with any of the above or
below embodiments.
[0323] In another embodiment 1-7, the invention includes compounds
wherein
[0324] A.sup.4 is CR.sup.4 or N;
[0325] A.sup.5 is CR.sup.5 or N;
[0326] A.sup.6 is CR.sup.6 or N;
[0327] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; and
[0328] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl, CN,
OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in
conjunction with any of the above or below embodiments.
[0329] In another embodiment 1-8, the invention includes compounds
wherein
[0330] A.sup.4 is CR.sup.4;
[0331] A.sup.5 is CR.sup.5;
[0332] A.sup.6 is CR.sup.6; and
[0333] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, CF.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.3, in conjunction with any of the above or
below embodiments.
[0334] In another embodiment 1-9, the invention includes compounds
wherein A.sup.4 is CH, CF or N, A.sup.5 is CH, CF or N, A.sup.6 is
CH, CF or N, A.sup.8 is CH, CF or N, one of A.sup.4, A.sup.5,
A.sup.6 and
[0335] A.sup.8 is N, in conjunction with any of the above or below
embodiments.
[0336] In another embodiment J, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9, S--R.sup.9; or R.sup.7 is
##STR00032## [0337] wherein V is NR.sup.10, O or S; and [0338] each
W, independently, is CH, CF, CCl or N, in conjunction with any of
the above or below embodiments.
[0339] In another embodiment J-1, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9 or
##STR00033##
[0340] wherein V is NR.sup.10, O or S; and
[0341] each W, independently, is CH, CF, CCl or N, in conjunction
with any of the above or below embodiments.
[0342] In another embodiment J-2, the invention includes compounds
wherein R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00034##
[0343] wherein V is NR.sup.10, O or S; and
[0344] each W, independently, is CH, CF, CCl or N, in conjunction
with any of the above or below embodiments.
[0345] In another embodiment J-3, the invention includes compounds
wherein R.sup.7 is --NH--C(.dbd.O)--R.sup.9, in conjunction with
any of the above or below embodiments.
[0346] In another embodiment J-4, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, in conjunction with any of the
above or below embodiments.
[0347] In another embodiment J-5, the invention includes compounds
wherein R.sup.7 is
##STR00035## [0348] wherein V is NR.sup.10, O or S; and [0349] each
W, independently, is CH, CF, CCl or N, in conjunction with any of
the above or below embodiments.
[0350] In another embodiment J-6, the invention includes compounds
wherein R.sup.7 is
##STR00036##
[0351] wherein V is NR.sup.10, O or S; and
[0352] each W, independently, is CH, CF, CCl or N, in conjunction
with any of the above or below embodiments.
[0353] In another embodiment J-7, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, --O--R.sup.9 or in conjunction
with any of the above or below embodiments.
[0354] In another embodiment J-8, the invention includes compounds
wherein R.sup.7 is --O--R.sup.9 or in conjunction with any of the
above or below embodiments.
[0355] In another embodiment J-9, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9 or wherein R.sup.9 is acetyl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4allynyl or a fully or
partially unsaturated 5-, 6- or 7-membered monocyclic or 8-, 9- or
10-membered bicyclic ring formed of carbon atoms, said ring
optionally including 1-4 heteroatoms if monocyclic or 1-5
heteroatoms if bicyclic, said heteroatoms selected from O, N or S,
wherein the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4allynyl and
ring are optionally substituted, independently, with 1-5
substituents of R.sup.10, in conjunction with any of the above or
below embodiments.
[0356] In another embodiment K, the invention includes compounds
wherein R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10, in
conjunction with any of the above or below embodiments.
[0357] In another embodiment K-1, the invention includes compounds
wherein each R.sup.9, independently, is acetyl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl or a ring selected from phenyl,
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10, in
conjunction with any of the above or below embodiments.
[0358] In another embodiment K-2, the invention includes compounds
wherein each R.sup.10, independently, is H, halo, haloalkyl, CN,
OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
cyclopropylmethoxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is
optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3thioalkoxyl or oxetan-3yl, in
conjunction with any of the above or below embodiments.
[0359] In another embodiment L, the present invention provides
compounds, and solvates, tautomers, hydrates, stereoisomers and
pharmaceutically acceptable salts thereof, as defined by Formulas
I, II, II-A, II-B or II-C, wherein
[0360] A.sup.4 is CR.sup.4 or N;
[0361] A.sup.5 is CR.sup.5 or N;
[0362] A.sup.6 is CR.sup.6 or N;
[0363] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0364] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3 or CH.sub.2OCHF.sub.2;
[0365] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl; and
[0366] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl,
[0367] CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in
conjunction with any of the above or below embodiments.
[0368] In another embodiment M, the present invention provides
compounds, and solvates, tautomers, hydrates, stereoisomers and
pharmaceutically acceptable salts thereof, as defined by Formulas I
and II, wherein
[0369] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9 or
##STR00037## [0370] wherein V is NR.sup.10, O or S; and
[0371] each W, independently, is CH, CF, CCl or N, in conjunction
with any of the above or below embodiments.
[0372] In another embodiment N-1, the invention includes compounds
of Formula II-A wherein A.sup.4 is CR.sup.4 or N;
[0373] A.sup.5 is CR.sup.5 or N;
[0374] A.sup.6 is CR.sup.6 or N;
[0375] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0376] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-3-alkyl, --OC.sub.1-3-alkyl, wherein each of the
C.sub.1-4-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
C.sub.1-4-alkyl portion of --CH.sub.2OC.sub.1-3-alkyl and
--OC.sub.1-3-alkyl are optionally substituted with 1-4 substituents
of F;
[0377] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0378] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-4 F atoms on the carbon atoms and a
subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl or
C.sub.1-3haloalkyl on the nitrogen atom;
[0379] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH,
CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl or cyclopropyl, wherein
each of the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
C.sub.1-4haloalkyl and cyclopropyl is optionally substituted with
1-4 F atoms;
[0380] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a C.sub.3-6
carbocyclic ring optionally including 1-2 heteroatoms selected from
O and N and optionally substituted with 1-4 F atoms on the carbon
atoms and a subsituent of C.sub.1-3alkyl, CH.sub.2OC.sub.1-2alkyl
or C.sub.1-3haloalkyl on the nitrogen atom;
[0381] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H or F;
[0382] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10;
[0383] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0384] In another embodiment N-2, the invention includes compounds
of Formula II-A wherein A.sup.4 is CR.sup.4;
[0385] A.sup.5 is CR.sup.5;
[0386] A.sup.6 is CR.sup.6;
[0387] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3;
[0388] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3;
[0389] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-3 F atoms;
[0390] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-3 F atoms;
[0391] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or
CH.sub.2F;
[0392] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the
ring is optionally substituted, independently, with 1-5
substituents of R.sup.10;
[0393] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0394] In another embodiment 0-1, the invention includes compounds
of Formula II-B wherein A.sup.4 is CR.sup.4;
[0395] A.sup.5 is CR.sup.5;
[0396] A.sup.6 is CR.sup.6;
[0397] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3;
[0398] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3;
[0399] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-3 F atoms;
[0400] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-3 F atoms; and
[0401] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or CH.sub.2F,
in conjunction with any of the above or below embodiments with
respect to Formula II-B.
[0402] In another embodiment O-2, the invention includes compounds
of Formula II-B wherein A.sup.4 is CR.sup.4 or N;
[0403] A.sup.5 is CR.sup.5 or N;
[0404] A.sup.6 is CR.sup.6 or N;
[0405] A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H or F and provided no more
than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0406] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F; and
[0407] R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F, in
conjunction with any of the above or below embodiments with respect
to Formula II-B.
[0408] In another embodiment P-1, the invention includes compounds
of Formula II-C wherein A.sup.4 is CR.sup.4;
[0409] A.sup.5 is CR.sup.5;
[0410] A.sup.6 is CR.sup.6;
[0411] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3;
[0412] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, C.sub.2H.sub.5, CF.sub.2H, CH.sub.2F, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3;
[0413] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-3 F atoms;
[0414] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a C.sub.3-6 spirocarbocyclic
ring optionally including one heteroatom selected from O and N and
optionally substituted with 1-3 F atoms; and
[0415] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or CH.sub.2F,
in conjunction with any of the above or below embodiments with
respect to Formula II-C.
[0416] In another embodiment P-2, the invention includes compounds
of Formula II-C wherein A.sup.4 is CR.sup.4 or N;
[0417] A.sup.5 is CR.sup.5 or N;
[0418] A.sup.6 is CR.sup.6 or N;
[0419] A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H or F and provided no more
than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0420] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F; and
[0421] R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F, in
conjunction with any of the above or below embodiments with respect
to Formula II-C.
[0422] In one embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula II:
##STR00038##
[0423] A.sup.4 is CH, CF or N;
[0424] A.sup.5 is CH, CF or N;
[0425] A.sup.6 is CH, CF or N;
[0426] A.sup.8 is CH, CF or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0427] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3,
C(O)CH.sub.3 or CH.sub.2OCHF.sub.2;
[0428] alternatively, each R.sup.1 taken together with the carbon
atom to which they are attached form a spirocyclopropyl,
spirocyclobutyl, spirocyclopentyl or spirocyclohexyl ring, said
ring optionally substituted with 1-4 F atoms;
[0429] each R.sup.2, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, methyl,ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3,
C(O)CH.sub.3 or CH.sub.2OCHF.sub.2;
[0430] alternatively, each R.sup.2 taken together with the carbon
atom to which they are attached form a spirocyclopropyl,
spirocyclobutyl, spirocyclopentyl or spirocyclohexyl ring, said
ring optionally substituted with 1-4 F atoms;
[0431] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl; and
[0432] alternatively, one R.sup.2 and R.sup.3 taken together with
the carbon atoms to which they are attached form a
C.sub.3-6-carbocyclic ring optionally including 1-2 heteroatoms
selected from O and N and optionally substituted with 1-4 F atoms
on the carbon atoms and a subsituent of C.sub.1-3alkyl,
CH.sub.2OC.sub.1-2alkyl or C.sub.1-3haloalkyl on the nitrogen
atom;
[0433] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9 or
--S--R.sup.9;
[0434] or R.sup.7 is
##STR00039## [0435] wherein V is NH, N(CH.sub.3), O or S; and
[0436] each W, independently, is CH, CF, CCl or N;
[0437] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, furanyl,
thienyl or pyrrolyl, wherein the ring is optionally substituted,
independently, with 1-5 substituents of R.sup.10; and
[0438] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0439] In another embodiment, the invention provides one or more of
the compounds, or a pharmaceutically acceptable salt thereof, of
Formulas I and II, and sub-formulas thereof, as taught and
described herein.
[0440] In another embodiment, the invention provides the compound
of Formula I, II or II-A, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0441]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0442]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0443]
N-(3-((3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophen-
yl)-5-methoxy-2-pyrazinecarboxamide; [0444]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0445]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-2-pyridinecarboxamide; [0446]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0447]
Racemic mixture of
N-(3-((3R,6R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0448]
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0449] Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0450] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0451]
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0452] Racemic mixture of
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
[0453]
N-(3-((3R,6S)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0454]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
[0455]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyrazinecarboxamide;
[0456] Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0457]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
[0458]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide; [0459]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
[0460]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0461]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
[0462]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxamide; [0463]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0464]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0465]
Racemic mixture of
N-(4-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide and
N-(4-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide; and
[0466]
N-(6-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide.
[0467] In another embodiment, the invention provides the compound
of Formula I, II, II-B, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0468]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0469]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0470]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0471]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0472]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0473]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0474]
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine-
; [0475] Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-am-
ine; [0476]
N-(3-((8R)-10-amino-8-methyl-6,6-dioxido-6-thia-9-azaspiro[4.5]dec-9-en-8-
-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0477]
N-(3-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0478]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0479]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
[0480] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and
[0481]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0482]
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0483]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonit-
rile; [0484]
(5R)-5-(2-fluoro-5-(1-naphthalenylsulfanyl)phenyl)-2,2,5-trimethyl-5,6-di-
hydro-2H-1,4-thiazin-3-amine 1,1-dioxide; [0485]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0486]
8-((3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonit-
rile; [0487]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
[0488]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0489]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
[0490]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-7-methoxy-4-quinazolinamine; [0491]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0492]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxy-5-quinoxalinamine; [0493]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0494] Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihy-
dro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amin-
e; [0495]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0496]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0497]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-am-
ine; [0498]
5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
and [0499]
5-((3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one.
[0500] In another embodiment, the invention provides the compound
of Formula I, II or II-C, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0501] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine,
benzamide; and [0502]
3-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile.
[0503] In another embodiment, the invention provides the compound
of Formula II, or a stereoisomer or pharmaceutically acceptable
salt thereof, selected from [0504]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-2-methyl[1,3]thiazolo[4,5-c]pyridin-4-amine; [0505]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methyl[1,3]thiazolo[4,5-c]pyridin-4-amine;
[0506]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0507]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0508]
N-(3-((3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophen-
yl)-5-methoxy-2-pyrazinecarboxamide; [0509]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0510]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-2-pyridinecarboxamide; [0511]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0512]
Racemic mixture of
N-(3-((3R,6R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0513]
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0514] Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0515] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0516]
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0517] Racemic mixture of
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0518]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
[0519]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyrazinecarboxamide;
[0520] Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0521]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
[0522]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide; [0523]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
[0524]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0525]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
[0526]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxamide; [0527]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0528]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0529]
Racemic mixture of
N-(4-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide and
N-(4-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
[0530]
N-(6-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide.
[0531]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0532]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0533]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0534]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0535]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0536]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0537]
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine-
; [0538] Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-am-
ine; [0539]
N-(3-((8R)-10-amino-8-methyl-6,6-dioxido-6-thia-9-azaspiro[4.5]dec-9-en-8-
-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0540]
N-(3-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0541]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0542]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
[0543] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0544]
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0545]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonit-
rile; [0546]
(5R)-5-(2-fluoro-5-(1-naphthalenylsulfanyl)phenyl)-2,2,5-trimethyl-5,6-di-
hydro-2H-1,4-thiazin-3-amine 1,1-dioxide; [0547]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0548]
8-((3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonit-
rile; [0549]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
[0550]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0551]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
[0552]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-7-methoxy-4-quinazolinamine; [0553]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0554]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxy-5-quinoxalinamine; [0555]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0556] Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihy-
dro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amin-
e; [0557]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0558]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0559]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-am-
ine; [0560]
5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
[0561]
5-((3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
[0562] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine,
benzamide; and [0563]
3-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile.
[0564] In another embodiment, the invention provides the compound
of Formula II, or a stereoisomer or pharmaceutically acceptable
salt thereof, selected from [0565]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0566]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0567]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0568]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0569]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0570]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-2-pyridinecarboxamide; [0571]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0572]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0573]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0574]
N-(3-((3R,6R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0575]
N-(3-((3R,6S)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0576]
N-(3-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0577]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0578]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0579]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0580]
N-(3-((3R,6S)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0581]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
[0582]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
[0583]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0584]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0585]
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0586]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-a-
mine; [0587]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide; [0588]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide; [0589]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
[0590]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide; and
[0591]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide.
[0592] In another embodiment, the invention provides the compound
of Formula II, or a stereoisomer or pharmaceutically acceptable
salt thereof, selected from [0593]
4-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenoxy)benzonitrile; [0594]
(5R)-5-(2-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenoxy)phenyl)-2,2,5-tri-
methyl-5,6-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide; [0595]
(5R)-5-(5-(3-ethylphenoxy)-2-fluorophenyl)-2,2,5-trimethyl-5,6-dihydro-2H-
-1,4-thiazin-3-amine 1,1-dioxide; [0596]
(5R)-5-(5-(4-chloro-3-ethylphenoxy)-2-fluorophenyl)-2,2,5-trimethyl-5,6-d-
ihydro-2H-1,4-thiazin-3-amine 1,1-dioxide; [0597]
(5R)-5-(2-fluoro-5-(2-naphthalenyloxy)phenyl)-2,2,5-trimethyl-5,6-dihydro-
-2H-1,4-thiazin-3-amine 1,1-dioxide; and [0598]
(5R)-5-(2-fluoro-5-(2-pyridinyloxy)phenyl)-2,2,5-trimethyl-5,6-dihydro-2H-
-1,4-thiazin-3-amine-1,1-dioxide.
[0599] In another embodiment, the invention provides the compound
of Formula I, II or III, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0600]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0601]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0602]
N-(3-((3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophen-
yl)-5-methoxy-2-pyrazinecarboxamide; [0603]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0604]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-2-pyridinecarboxamide; [0605]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0606]
Racemic mixture of
N-(3-((3R,6R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; [0607]
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0608] Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0609] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0610]
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0611] Racemic mixture of
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and
N-(3-((3R,6S)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0612]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
[0613]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyrazinecarboxamide;
[0614] Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0615]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
[0616]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide; [0617]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
[0618]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0619]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
[0620]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxamide; [0621]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0622]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0623]
Racemic mixture of
N-(4-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide and
N-(4-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
[0624]
N-(6-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
[0625]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0626]
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)--
4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0627]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0628]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0629]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0630]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0631]
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine-
; [0632] Racemic mixture of
N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-am-
ine; [0633]
N-(3-((8R)-10-amino-8-methyl-6,6-dioxido-6-thia-9-azaspiro[4.5]dec-9-en-8-
-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0634]
N-(3-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine; [0635]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0636]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
[0637] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0638]
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0639]
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonit-
rile; [0640]
(5R)-5-(2-fluoro-5-(1-naphthalenylsulfanyl)phenyl)-2,2,5-trimethyl-5,6-di-
hydro-2H-1,4-thiazin-3-amine 1,1-dioxide; [0641]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0642]
8-((3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonit-
rile; [0643]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
[0644]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0645]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
[0646]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-fluoro-7-methoxy-4-quinazolinamine; [0647]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0648]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-methoxy-5-quinoxalinamine; [0649]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0650] Racemic mixture of
N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine
and
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihy-
dro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amin-
e; [0651]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0652]
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0653]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-am-
ine; [0654]
5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2 (1H)-one;
[0655]
5-((3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
[0656] Racemic mixture of
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine and
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine,
benzamide; and [0657]
3-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile.
[0658] In another embodiment, the invention provides the compound
of Formula I, II or III, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0659]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
[0660]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-a-
mine; [0661]
8-((5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazi-
n-3-yl)-6-fluoro-3-pyridinyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitr-
ile; [0662]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0663]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-1,7-naphthyridin-8-amine;
[0664]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-ami-
ne; [0665]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dih-
ydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-1,7-naphthyr-
idin-8-amine; [0666]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
[0667]
4-((3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihyd-
ro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-car-
bonitrile; [0668]
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-6-fluoro-3-pyridinyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0669]
N-(3-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; [0670]
N-(3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-7-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0671]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8--
amine; [0672]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amin-
e; [0673]
4-((3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,-
6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-
e-7-carbonitrile; [0674]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-ethoxypyrido[3,4-b]pyrazin-5-amine;
[0675]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[-
3.5]non-8-en-7-yl)-4-fluorophenyl)-2-ethoxypyrido[3,4-b]pyrazin-5-amine;
[0676]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[-
3.5]non-8-en-7-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
[0677]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[-
3.5]non-8-en-7-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
[0678]
8-((3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro-
[3.5]non-8-en-7-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-car-
bonitrile; [0679]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0680] Mixture of
N-(3-((7R)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0681]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
[0682]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0683]
8-((3-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-
-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile; [0684]
8-((3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]n-
on-8-en-7-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0685]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-1,7-naphthyridin-8-amine-
; [0686]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)-3-(cyclopropylmethoxy)-1,7-naphthyridin-8-a-
mine; [0687]
8-((3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitri-
le; [0688]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dih-
ydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin--
4-amine; [0689]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-
-amine; [0690]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-(2-fluoroethoxy)pyrido[3,4-b]pyrazin-5-amine;
[0691]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[3,4-b]pyrazi-
n-5-amine; [0692]
((5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thia-
zin-3-yl)-4-fluorophenyl)amino)pyrido[3,4-b]pyrazin-2-yl)oxy)acetonitrile;
[0693]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-5-
-amine; [0694]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-2-(2-butyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine;
[0695]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-
-4-amine; [0696]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine-
; [0697]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)-3-bromopyrido[2,3-d]pyridazin-8-amine;
and [0698]
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azasp-
iro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-ami-
ne.
[0699] In another embodiment, the invention provides the compound
of Formula I, II or III, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0700]
N-(3-((4aR,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-
-amine; [0701]
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-
-amine; [0702]
5-((3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,-
4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H-
)-one; [0703]
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
6-en-8-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0704]
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
6-en-8-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0705]
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
6-en-8-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxam-
ide; [0706]
N-(3-((1R,6R)-4-amino-3,3-dimethyl-2,2-dioxido-2-thia-5-azabicyclo[4.1.0]-
hept-4-en-6-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0707] Mixture of
N-(3-((4aR,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2--
pyridinecarboxamide and
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2--
pyridinecarboxamide; [0708] Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide
and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo-
[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxam-
ide; [0709] Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecar-
boxamide and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecar-
boxamide; [0710] Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridineca-
rboxamide and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridineca-
rboxamide; [0711] Mixture of
N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-ami-
ne and
N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-fu-
ro[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-
-8-amine; [0712]
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-
-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridineca-
rboxamide; and [0713]
N-(3-((1R,6R)-4-amino-3,3-dimethyl-2,2-dioxido-2-thia-5-azabicyclo[4.1.0]-
hept-4-en-6-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine
[0714] In another embodiment, the invention provides the compound
of Formula I, II or III, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0715]
(5R)-5-(2-fluoro-5-((3-fluoro-2-pyridinyl)oxy)phenyl)-2,2,5-trimethyl-5,6-
-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide; [0716]
2-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenoxy)-4-pyridinecarbonitrile; and [0717]
(5R)-5-(5-((4-bromo-2-pyridinyl)oxy)-2-fluorophenyl)-2,2,5-trimethyl-5,6--
dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide.
[0718] In another embodiment, the invention provides the compound
of Formula I, II or III, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyrazinecarboxamide;
[0719]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)-2-pyrazinecarboxamide;
[0720]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarbo-
xamide; [0721]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
[0722]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
[0723]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxa-
mide; [0724]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecar-
boxamide; [0725]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxamide;
[0726]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazin-
ecarboxamide; [0727]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethyl)-2-pyridinecarb-
oxamide; [0728]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-cyano-2-pyridinecarboxamide;
[0729]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridi-
necarboxamide; [0730]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
[0731]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyri-
dinecarboxamide; [0732]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0733]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarbo-
xamide [0734]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarbox-
amide; [0735]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
[0736]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridi-
necarboxamide; [0737]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-methoxy-2-pyridinecarboxamide;
[0738]
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarbox-
amide; [0739]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethenyl)-2-pyridinecarboxamide;
[0740]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethenyl-2-pyridinecarboxamide;
[0741]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethyl-2-pyridinecarboxamide;
[0742]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethyl-2-pyridinecar-
boxamide; [0743]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethyl)-2-pyridine-
carboxamide; [0744]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyridinecarboxamide;
[0745]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-2-pyrazinecarboxamide;
[0746]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
[0747]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-5-(difluoromethyl)-2-pyridine-
carboxamide; [0748]
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-6-fluoro-3-pyridinyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-pyridinecar-
boxamide; [0749]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-3-bromo-5-chloro-2-pyridinecarboxamide;
[0750]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxamide;
[0751]
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-6-fluoro-3-pyridinyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0752]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxam-
ide; [0753]
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
[0754]
N-(3-((7R)-9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azas-
piro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0755]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-
-pyridinecarboxamide; [0756]
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,-
4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamidel;
[0757]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-((4-fluoro-2-butyn-1-yl)oxy)-
-2-pyridinecarboxamide; [0758]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-chloro-2-pyridinecarboxamide; [0759]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-fluoro-2-pyridinecarboxamide; [0760]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarbox-
amide; [0761]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-methoxy-2-pyridinecarboxamide;
[0762]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazine
carboxamide; [0763]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-cyano-2-pyridinecarboxamide; [0764]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethyl)-2-pyridine
carboxamide; [0765]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-py-
razinecarboxamide; [0766]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide;
[0767]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethenyl)-2-pyridi-
necarboxamide; [0768]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxami-
de; [0769]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,-
6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridin-
ecarboxamide; [0770] Mixture of
N-(3-((7R)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxa-
mide and
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro-
[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridin-
ecarboxamide; [0771]
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-
-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxa-
mide; [0772]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5-
]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0773]
N-(3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarbox-
amide; [0774]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridi-
ne-2-carboxamide; [0775]
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)-5-(difluoromethoxy)-3-methy-
l-2-pyridinecarboxamide; [0776]
N-(5-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-6-fluoro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxami-
de; [0777]
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-az-
aspiro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methyl-2-py-
ridinecarboxamide; [0778]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
[0779]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-p-
yridinecarboxamide; [0780]
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
and [0781]
N-(3-((6S)-8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[-
2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide-
.
[0782] All of the possible embodiments described herein for various
of the R groups of the compounds of Formula I may be applied, as
appropriate, to compounds of Formula II and any sub-formulas
thereof.
[0783] In another embodiment, the invention provides each of the
Exemplary compounds, and stereoisomers, tautomers, solvates,
pharmaceutically acceptable salts, derivatives or prodrugs thereof,
and related intermediates, described herein.
[0784] In another embodiment, the invention provides the
exemplified compounds described herein, and pharmaceutically
acceptable salt forms of each thereof.
DEFINITIONS
[0785] The following definitions should assist in understanding the
metes and bounds of the invention.
[0786] The term "comprising" is meant to be open ended, i.e., all
encompassing and non-limiting. It may be used herein synonymously
with "having." Comprising is intended to include each and every
indicated or recited component or element(s) while not excluding
any other components or elements.
[0787] The term "C.sub..alpha.-.beta.alkyl", when used either alone
or within other terms such as "haloalkyl" and "alkylamino",
embraces linear or branched radicals having .alpha. to .beta.
number of carbon atoms (such as C.sub.1-C.sub.10; C.sub.1-C.sub.6;
or C.sub.1-C.sub.4). Unless otherwise specified, one or more carbon
atoms of the "alkyl" radical may be substituted, such as with a
cycloalkyl moiety. Examples of "alkyl" radicals include methyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl,
cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl,
isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isoamyl, hexyl and the like.
[0788] The term "C.sub..alpha.-.beta.alkenyl", when used alone or
in combination, embraces linear or branched radicals having at
least one carbon-carbon double bond in a moiety having a number of
carbon atoms in the range from .alpha. and .beta.. Included within
alkenyl radicals are "lower alkenyl" radicals having two to about
six carbon atoms and, for example, those radicals having two to
about four carbon atoms. Examples of alkenyl radicals include,
without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace
radicals having "cis" and "trans" orientations, or alternatively,
"E" and "Z" orientations, as appreciated by those of ordinary skill
in the art.
[0789] The term "C.sub..alpha.-.beta.alkynyl", when used alone or
in combination, denotes linear or branched radicals having at least
one carbon-carbon triple bond in a moiety having a number of carbon
atoms in the range from .alpha. and .beta.. Examples of alkynyl
radicals include "lower alkynyl" radicals having two to about six
carbon atoms and, for example, lower alkynyl radicals having two to
about four carbon atoms. Examples of such radicals include, without
limitation, ethynyl, propynyl (propargyl), butynyl, and the
like.
[0790] The term "C.sub..alpha.-.beta.-alkyl",
"C.sub..alpha.-.beta.-alkenyl" and "C.sub..alpha.-.beta.-alkynyl",
when used with other terms such as "wherein 1, 2 or 3 carbon atoms
of said C.sub..alpha.-.beta.-alkyl, C.sub..alpha.-.beta.-alkenyl or
C.sub.2.alpha.-.beta.-alkynyl is optionally replaced with a
heteroatom selected from O, S, S(O), S(O).sub.2 and N" embraces
linear or branched radicals wherein one or more of the carbon atoms
may be replaced with a heteroatom. Examples of such "alkyl"
radicals include --O-methyl, --O-ethyl, --CH.sub.2--O--CH.sub.3,
--CH.sub.2CH.sub.2--O--CH.sub.3, --NH--CH.sub.2,
--CH.sub.2CH.sub.2--N(CH.sub.3)--CH.sub.3,
--S--(CH.sub.2).sub.3CH.sub.2, --CH.sub.2CH.sub.2--S--CH.sub.3 and
the like. Accordingly, such radicals also include radicals
encompassed by --OR.sup.7 where R.sup.7 may be defined as a
C.sub..alpha.-.beta.-alkyl. Examples of such "alkenyl" radicals
include --NH--CH.sub.2CH.dbd.CH.sub.2,
--S--CH.sub.2CH.sub.2CH.dbd.CHCH.sub.3 and the like. Similar
examples exist for such "alkynyl" radicals, as appreciated by those
skilled in the art.
[0791] The term "C.sub..alpha.-.beta.alkoxyl" or
"--OC.sub..alpha.-.beta.alkyl" when used alone or in combination,
embraces linear or branched oxygen-containing alkyl radicals each
having .alpha. to .beta. number of carbon atoms (such as
C.sub.1-C.sub.10). The terms "alkoxy" and "alkoxyl", when used
alone or in combination, embraces linear or branched
oxygen-containing radicals each having alkyl and substituted alkyl
portions of one or more carbon atoms. Examples of such radicals
include methoxy, ethoxy, propoxy, butoxy, tert-butoxy and
neopentoxy. Alkoxy radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxy" radicals or with other substitution. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,
trifluoroethoxy, fluoroethoxy and fluoropropoxy.
[0792] The term "aryl", when used alone or in combination, means a
carbocyclic aromatic moiety containing one, two or even three rings
wherein such rings may be attached together in a fused manner.
Every ring of an "aryl" multi-ring system need not be aromatic, and
the ring(s) fused to the aromatic ring may be partially or fully
unsaturated and include one or more heteroatoms selected from
nitrogen, oxygen and sulfur. Thus, the term "aryl" embraces
aromatic radicals such as phenyl, naphthyl, indenyl,
tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,
benzodioxazinyl, and the like. The "aryl" group may be substituted,
such as with 1 to 5 substituents including lower alkyl, hydroxyl,
halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the
like. Phenyl substituted with --O--CH.sub.2--O-- or
--O--CH.sub.2--CH.sub.2--O-- forms an aryl benzodioxolyl
substituent.
[0793] The term "C.sub..alpha.-.beta.-cycloalkyl", also referred to
herein as "carbocyclic", when used alone or in combination, denotes
a partially or fully saturated ring radical having a number of
carbon atoms in the range from .alpha. and .beta.. The "cycloalkyl"
may contain one ("monocyclic"), two ("bicyclic") or even three
("tricyclic") rings wherein such rings may be attached together in
a fused manner and each formed from carbon atoms. Examples of
saturated carbocyclic radicals include saturated 3 to 6-membered
monocyclic groups such as cyclopropane, cyclobutane, cyclopentane
and cyclohexane. Cycloalkyls may be substituted as described
herein.
[0794] The terms "ring" and "ring system" refer to a ring
comprising the delineated number of atoms, the atoms being carbon
or, where indicated, a heteroatom such as nitrogen, oxygen or
sulfur. Where the number of atoms is not delineated, such as a
"monocyclic ring system" or a "bicyclic ring system", the numbers
of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The
ring itself, as well as any substitutents thereon, may be attached
at any atom that allows a stable compound to be formed. The term
"nonaromatic" ring or ring system refers to the fact that at least
one, but not necessarily all, rings in a bicyclic or tricyclic ring
system is nonaromatic.
[0795] The terms "partially or fully saturated or unsaturated" and
"saturated or partially or fully unsaturated" with respect to each
individual ring, refer to the ring either as fully aromatic (fully
unsaturated), partially aromatic (or partially saturated) or fully
saturated (containing no double or triple bonds therein). If not
specified as such, then it is contemplated that each ring
(monocyclic) in a ring system (if bicyclic or tricyclic) may either
be fully aromatic, partially aromatic or fully saturated, and
optionally substituted with up to 5 substituents. This includes
carbocyclics, heterocyclics, aryl and heteroaryl rings.
[0796] The term "halo", when used alone or in combination, means
halogens such as fluorine, chlorine, bromine or iodine atoms.
[0797] The term "haloalkyl", when used alone or in combination,
embraces radicals wherein any one or more of the alkyl carbon atoms
is substituted with halo as defined above. For example, this term
includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such
as a perhaloalkyl. A monohaloalkyl radical, for example, may have
either an iodo, bromo, chloro or fluoro atom within the radical.
Dihalo and polyhaloalkyl radicals may have two or more of the same
halo atoms or a combination of different halo radicals. Examples of
haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl. "Perfluoroalkyl", as used herein, refers to
alkyl radicals having all hydrogen atoms replaced with fluoro
atoms. Examples include trifluoromethyl and pentafluoroethyl.
[0798] The term "heteroaryl", as used herein, either alone or in
combination, means a fully unsaturated (aromatic) ring moiety
formed from carbon atoms and having one or more heteroatoms
selected from nitrogen, oxygen and sulfur. The ring moiety or ring
system may contain one ("monocyclic"), two ("bicyclic") or even
three ("tricyclic") rings wherein such rings are attached together
in a fused manner. Every ring of a "heteroaryl" ring system need
not be aromatic, and the ring(s) fused thereto (to the
heteroaromatic ring) may be partially or fully saturated and
optionally include one or more heteroatoms selected from nitrogen,
oxygen and sulfur. The term "heteroaryl" does not include rings
having ring members of --O--O--, --O--S-- or --S--S--.
[0799] Examples of unsaturated heteroaryl radicals, include
unsaturated 5- to 6-membered heteromonocyclyl groups containing 1
to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl,
pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] and tetrazole; unsaturated
7- to 10-membered heterobicyclyl groups containing 1 to 4 nitrogen
atoms, including for example, quinolinyl, isoquinolinyl,
quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and the like;
unsaturated 5- to 6-membered heteromonocyclic group containing an
oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl,
etc.; unsaturated 5 to 6-membered heteromonocyclic group containing
a sulfur atom, for example, 2-thienyl, 3-thienyl, benzothienyl,
etc.; unsaturated 5- to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for
example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];
unsaturated 5 to 6-membered heteromonocyclic group containing 1 to
2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,
isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[0800] The terms "heterocycle" or "heterocyclic", when used alone
or in combination, means a partially or fully saturated ring moiety
containing one, two or even three rings wherein such rings may be
attached together in a fused manner, formed from carbon atoms and
including one or more heteroatoms selected from N, O or S. Examples
of saturated heterocyclic radicals include saturated 3 to
6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms
[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,
piperazinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of partially saturated heterocyclyl
radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and
dihydrothiazolyl.
[0801] The term "heterocycle" also embraces radicals where
heterocyclic radicals are fused/condensed with aryl radicals:
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,
benzoxadiazolyl]; unsaturated condensed heterocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
benzothiazolyl, benzothiadiazolyl]; and saturated, partially
unsaturated and unsaturated condensed heterocyclic group containing
1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,
2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples of
heterocyclic radicals include five to ten membered fused or unfused
radicals.
[0802] Examples of partially saturated and fully saturated
heterocyclyls include, without limitation, pyrrolidinyl,
imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl,
isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl,
chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihydro-1H-1.lamda.'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl and dihydrothiazolyl, and the like.
[0803] The term "a 3-8 membered monocyclic or 6-12 membered
bicyclic ring system, said ring system formed of carbon atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,
wherein said ring system is optionally substituted" refers to a
single ring of 3-, 4-, 5-, 6-, 7- or 8-atom membered or a 6-, 7-,
8-, 9-, 10-, 11 or 12-atom membered bicyclic ring system comprising
the delineated number of atoms, the atoms being carbon or, where
indicated, a heteroatom such as nitrogen (N), oxygen (O) or sulfur
(S). Where the number of atoms is not delineated, such as a
"monocyclic ring system" or a "bicyclic ring system", the numbers
of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The
ring or ring system may contain substitutents thereon, attached at
any atom that allows a stable compound to be formed. A bicyclic
ring is intended to include fused ring systems as well as
spiro-fused rings. This phrase encompasses carbocyclics,
heterocyclics, aryl and heteroaryl rings.
[0804] The term "alkylamino" includes "N-alkylamino" where amino
radicals are independently substituted with one alkyl radical.
Preferred alkylamino radicals are "lower alkylamino" radicals
having one to six carbon atoms. Even more preferred are lower
alkylamino radicals having one to three carbon atoms. Examples of
such lower alkylamino radicals include N-methylamino, and
N-ethylamino, N-propylamino, N-isopropylamino and the like.
[0805] The term "dialkylamino" includes "N,N-dialkylamino" where
amino radicals are independently substituted with two alkyl
radicals. Preferred alkylamino radicals are "lower alkylamino"
radicals having one to six carbon atoms. Even more preferred are
lower alkylamino radicals having one to three carbon atoms.
Examples of such lower alkylamino radicals include
N,N-dimethylamino, N,N-diethylamino, and the like.
[0806] The term "carbonyl", whether used alone or with other terms,
such as "aminocarbonyl", denotes --(C.dbd.O)--. "Carbonyl" is also
used herein synonymously with the term "oxo".
[0807] The term "alkylthio" or "thioalkoxy" embraces radicals
containing a linear or branched alkyl radical, of one to ten carbon
atoms, attached to a divalent sulfur atom. An example of
"alkylthio" or "thioalkoxy" is methylthio, (CH.sub.3S--).
[0808] The term "Formula I" includes any sub formulas, such as
Formulas II and III. Similar with Formulas II and III, in that they
include sub-formulas where described.
[0809] The term "pharmaceutically-acceptable" when used with
reference to a compound of Formulas I-III is intended to refer to a
form of the compound that is safe for administration. For example,
a salt form, a solvate, a hydrate, a prodrug or derivative form of
a compound of Formulas I-III, which has been approved for mammalian
use, via oral ingestion or other routes of administration, by a
governing body or regulatory agency, such as the Food and Drug
Administration (FDA) of the United States, is pharmaceutically
acceptable.
[0810] Included in the compounds of Formulas I-III are the
pharmaceutically acceptable salt forms of the free-base compounds.
The term "pharmaceutically-acceptable salts" embraces salts
commonly used to form alkali metal salts and to form addition salts
of free acids or free bases. As appreciated by those of ordinary
skill in the art, salts may be formed from ionic associations,
charge-charge interactions, covalent bonding, complexation,
coordination, etc. The nature of the salt is not critical, provided
that it is pharmaceutically acceptable.
[0811] Suitable pharmaceutically acceptable acid addition salts of
compounds of Formulas I-III may be prepared from an inorganic acid
or from an organic acid. Examples of such inorganic acids are
hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric,
carbonic, sulfuric and phosphoric acid. Appropriate organic acids
may be selected from aliphatic, cycloaliphatic, aromatic,
arylaliphatic, heterocyclic, carboxylic and sulfonic classes of
organic acids, examples of which include, without limitation,
formic, acetic, adipic, butyric, propionic, succinic, glycolic,
gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic,
maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,
benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,
toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric,
camphorsulfonic, digluconic, cyclopentanepropionic,
dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic,
hexanoic, 2-hydroxy-ethanesulfonic, nicotinic,
2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric,
2-phenylpropionic, picric, pivalic propionic, succinic, thiocyanic,
undecanoic, stearic, algenic, .beta.-hydroxybutyric, salicylic,
galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of
Formulas I-III include metallic salts, such as salts made from
aluminum, calcium, lithium, magnesium, potassium, sodium and zinc,
or salts made from organic bases including, without limitation,
primary, secondary and tertiary amines, substituted amines
including cyclic amines, such as caffeine, arginine, diethylamine,
N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine,
morpholine, N-ethyl morpholine, piperazine, piperidine,
triethylamine, disopropylethylamine and trimethylamine. All of
these salts may be prepared by conventional means from the
corresponding compound of the invention by reacting, for example,
the appropriate acid or base with the compound of Formulas
I-III.
[0812] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0813] Additional examples of such salts can be found in Berge et
al., J. Pharm. Sci., 66:1 (1977). Conventional methods may be used
to form the salts. For example, a phosphate salt of a compound of
the invention may be made by combining the desired compound free
base in a desired solvent, or combination of solvents, with
phosphoric acid in a desired stoichiometric amount, at a desired
temperature, typically under heat (depending upon the boiling point
of the solvent). The salt can be precipitated upon cooling (slow or
fast) and may crystallize (i.e., if crystalline in nature), as
appreciated by those of ordinary skill in the art. Further, hemi-,
mono-, di, tri- and poly-salt forms of the compounds of the present
invention are also contemplated herein. Similarly, hemi-, mono-,
di, tri- and poly-hydrated forms of the compounds, salts and
derivatives thereof, are also contemplated herein.
[0814] The term "pharmaceutically-acceptable derivative" as used
herein, denotes a derivative which is pharmaceutically
acceptable.
[0815] The compound(s) of Formulas I-III may be used to treat a
subject by administering the compound(s) as a pharmaceutical
composition. To this end, the compound(s) can be combined with one
or more excipients, including without limitation, carriers,
diluents or adjuvants to form a suitable composition, which is
described in more detail herein.
[0816] The term "excipient", as used herein, denotes any
pharmaceutically acceptable additive, carrier, adjuvant, or other
suitable ingredient, other than the active pharmaceutical
ingredient (API), which is typically included for formulation
and/or administration purposes. "Diluent" and "adjuvant" are
defined hereinafter.
[0817] The terms "treat", "treating," "treatment," and "therapy" as
used herein refer to therapy, including without limitation,
curative therapy, prophylactic therapy, and preventative therapy.
Prophylactic treatment generally constitutes either preventing the
onset of disorders altogether or delaying the onset of a
pre-clinically evident stage of disorders in individuals.
[0818] The phrase "effective dosage amount" is intended to quantify
the amount of each agent, which will achieve the goal of
improvement in disorder severity and the frequency of incidence
over treatment of each agent by itself, while avoiding adverse side
effects typically associated with alternative therapies.
Accordingly, this term is not limited to a single dose, but may
comprise multiple dosages required to bring about a therapeutic or
prophylactic response in the subject. For example, "effective
dosage amount" is not limited to a single capsule or tablet, but
may include more than one capsule or tablet, which is the dose
prescribed by a qualified physician or medical care giver to the
subject.
[0819] The term "leaving group" (also denoted as "LG") generally
refers to groups that are displaceable by a nucleophile. Such
leaving groups are known in the art. Examples of leaving groups
include, but are not limited to, halides (e.g., I, Br, F, Cl),
sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH.sub.3),
N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
Nucleophiles are species that are capable of attacking a molecule
at the point of attachment of the leaving group causing
displacement of the leaving group. Nucleophiles are known in the
art. Examples of nucleophilic groups include, but are not limited
to, amines, thiols, alcohols, Grignard reagents, anionic species
(e.g., alkoxides, amides, carbanions) and the like.
General Synthetic Procedures
[0820] The present invention further comprises procedures for the
preparation of compounds of Formulas I-III. The compounds of
Formulas I-III can be synthesized according to the procedures
described in the following Schemes 1, 2, 3a, 3b, 4 and 5, wherein
the substituents are as defined for Formulas I-III above, except
where further noted. The synthetic methods described below are
merely exemplary, and the compounds of the invention may also be
synthesized by alternate routes utilizing alternative synthetic
strategies, as appreciated by persons of ordinary skill in the
art.
[0821] The following list of abbreviations used throughout the
specification represent the following and should assist in
understanding the invention:
ACN, MeCN--acetonitrile Aq., aq.--aqueous Ar--argon (gas)
BOC--tert-butoxycarbonyl BOP--benzotriazol-1-yl-oxy
Hexafluorophosphate
BuLi--Butyllithium
[0822] Cs.sub.2CO.sub.3--cesium carbonate CHCl.sub.3--chloroform
CH.sub.2Cl.sub.2, DCM--dichloromethane, methylene chloride
Cu(1)I--copper(1) iodide DCC--dicyclohexylcarbodiimide
DEA--diethylamine DIC--1,3-diisopropylcarbodiimide DIEA,
DIPEA--diisopropylethylamine DME--dimethoxyethane
DMF--dimethylformamide DMAP--4-dimethylaminopyridine
DMSO--dimethylsulfoxide EDC,
EDCI--1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
Et.sub.2O--diethyl ether EtOAc--ethyl acetate g, gm--gram h,
hr--hour H.sub.2--hydrogen (gas) H.sub.2O--water
HATU--O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoroph-
osphate HBr--hydrobromic acid HCl--hydrochloric acid
HOBt--1-hydroxybenzotriazole hydrate HOAc--acetic acid HPLC--high
pressure liquid chromatography IPA, IpOH--isopropyl alcohol
K.sub.2CO.sub.3--potassium carbonate KI--potassium iodide
LG--leaving group LDA--Lithium diisopropylamide LiOH--lithium
hydroxide MgSO.sub.4--magnesium sulfate MS--mass spectrum
MeOH--methanol N.sub.2--nitrogen (gas) NaCNB H.sub.3--sodium
cyanoborohydride Na.sub.2CO.sub.3--sodium carbonate
NaHCO.sub.3--sodium bicarbonate NaH--sodium hydride NaI--sodium
iodide NaBH.sub.4--sodium borohydride NaOH--sodium hydroxide
Na.sub.2SO.sub.4--sodium sulfate NH.sub.4Cl--ammonium chloride
NH.sub.4OH--ammonium hydroxide
P(t-bu).sub.3--tri(tert-butyl)phosphine
Ph.sub.3P--triphenylphosphine Pd/C--palladium on carbon
Pd(PPh.sub.3).sub.4--palladium(0)triphenylphosphine tetrakis
Pd(dppf)Cl.sub.2--palladium(1,1-bisdiphenylphosphinoferrocene)
[0823] II chloride Pd(PhCN).sub.2Cl.sub.2--palladium di-cyanophenyl
dichloride Pd(OAc).sub.2--palladium acetate
Pd.sub.2(dba).sub.3--tris(dibenzylideneacetone) dipalladium
PyBop--benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium
hexafluorophosphate RT, rt--room temperature RBF, rbf--round bottom
flask TLC, tlc--thin layer chromatography TBAF--Tetrabutylammonium
flouride TBTU--O-benzotriazol-1-yl-N,N,N,N'-tetramethyluronium
tetrafluoroborate TEA, Et.sub.3N--triethylamine
TFA--trifluoroacetic acid THF--tetrahydrofuran UV--ultraviolet
light
##STR00040##
[0824] Scheme 1-A describes an exemplary method for preparing
racemic compounds 6 of Formulas I, II and III, wherein n is 2,
A.sup.4 is CR.sup.4, each of A.sup.5, A.sup.6 and A.sup.8 is,
independently, CH and each R.sup.1, independently, is CH.sub.3.
Beginning with compound 1, one of ordinary skill in the art may BOC
protect the amino group via conventional techniques and reagents
known in the art, as described herein, under suitable conditions,
to afford carbamate compound 2. The alcohol group of the carbamate
2 may be converted to the corresponding thio-acetyl using
thioacetic acid under suitable conditions as described hereinabove,
to generate compound intermediate 3. The thiol group liberated from
intermediate 3 may be used to displace the bromide of the
cyano-reagent shown above, to afford the corresponding methyl-cyano
thio-intermediate 4. Intermediate 4 may be oxidized and methylated
under appropriate conditions, to provide compounds 5. Intermediate
5 can then be treated with a suitable acid under appropriate
conditions to provide the ring closed desired intermediate 6.
##STR00041##
[0825] Scheme 1-B describes an exemplary, alternative method for
preparing stereospecific, boc-protected compounds 18 of Formulas I,
II and III, wherein n is 2, A.sup.4 is CR.sup.4 and R.sup.4 is F,
each of A.sup.5, A.sup.6 and A.sup.8 is as defined, such as CH, and
each R.sup.1, independently, is CH.sub.3. Beginning with compound
13 (may be commercially available depending upon R.sup.3) one of
ordinary skill in the art may generate the corresponding
sulfinamide 14 via known techniques and reagents such as Ellman
chemistry, or as described herein (see also Example 7 herein),
under suitable conditions. The intermediate 15 can be generated
using conditions as described hereinabove, followed by deprotection
of the amine with acid, such as HCl, to provide intermediate 16.
Intermediate 16 may be treated with trimethyl aluminum, or other
suitable metal reagent, to effectively close the ring and afford
the corresponding stereospecific intermediate 17. The primary amine
of intermediate 17 may be protected with Boc under appropriate
conditions, to provide useful intermediates 18, as shown.
Intermediate 18 may be reacted in synthesis taught herein to
provide desired compounds of Formulas I, II, III and sub-Formulas
thereof
##STR00042##
[0826] The bromide of compound 6 can be used as the handle by which
desired R.sup.7 groups, of Formulas I, II and III and sub-formulas
thereof, may be introduced to afford the finally desired compounds
of the invention, as shown in scheme 2 and described below.
Specifically, primary amino group of bromide 6 can be protected
with BOC using known methods. The bromide of the boc-protected
intermediate can be converted to the corresponding azide using
conventional techniques, such as those described herein. The azido
intermediate (not shown) can be reduced to the corresponding amine
compound 7 by treatment with a suitable phosphine, such as
trimethylphosphine under suitable conditions.
##STR00043##
[0827] As shown, desired R.sup.9-amide-linked compounds 9 can be
prepared as desired, such as by treatment with an activated acid in
conjunction with an activating reagent, such as HATU or DMTMM (see
Method A and B for Examples 17-35 in Table 1) to afford the desired
boc-protected amide-linked adduct. Compound 9 can be deprotected
using known conditions, such as with an acid, like TFA, to afford
final compounds of Formula II-A.
[0828] Acid activating groups convert the OH of the acid into a
strong leaving group "LG." A "leaving group" which may be a halide
such as an iodide, bromide, chloride or fluoride. LG may also be a
non-halide moiety such as an alkylsulfonate or other known groups
which generally form an electrophilic species (E.sup.+). Coupling
reactions generally occur more readily in one or a combination of
solvents and a base. Suitable solvents include, without limitation,
generally non-nucleophilic, anhydrous solvents such as toluene,
CH.sub.2Cl.sub.2, THF, DMF, N,N-dimethylacetamide and the like. The
solvent may range in polarity, as appreciated by those skilled in
the art. Suitable bases include, for example, tertiary amine bases
such as DIEA, TEA, carbonate bases such as Na.sub.2CO.sub.3,
K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, hydrides such as NaH, KH and the
like, alkoxides such as NaOCH.sub.3, and the like. The base itself
may also serve as a solvent. These coupling reactions are generally
fast and conversion occurs typically in ambient conditions.
However, depending upon the particular substrate, such reactions
may require heat, as appreciated by those skilled in the art.
##STR00044##
[0829] As shown, desired compounds 12 of Formula II-B can be
prepared by treatment of intermediate amine 10 with a desired
bicyclic R.sup.7 group having a suitable leaving group, such as a
chloride (Cl) or other aromatic leaving group, in the presence of a
suitable acid, such as in the presence of sulfuric acid. This
allows coupling of the bicyclic heteroaromatic R7 group to the
amine to form boc-protected intermediate 11. Intermediate 11 can
then be treated with acid, such as TFA, to afford the desired
amine-linked compounds of Formula II.
##STR00045##
[0830] Alternatively, desired compounds 12 of Formula II-B can be
prepared by as shown in scheme 5. The bromide of intermediate 13
(can be prepared in a manner similar to that described in scheme 1
above) may be first converted to the corresponding palladium (Pd)
adduct, using a Pd source such as Pd zero or other suitable Pd
reagent(s), and then treatment with an amine intermediate 14 to
provide the desired bicyclic R.sup.7 coupled boc-protected
intermediate 11. Intermediate 11 can then be treated with acid,
such as TFA, to afford the desired amine-linked compounds of
Formula II.
Examples
[0831] The Examples, described herein below, represent various
exemplary starting materials, intermediates and compounds of
Formulas I-III, which should assist in a better understanding and
appreciation of the scope of the present invention and of the
various methods which may be used to synthesize compounds of
Formulas I-III. It should be appreciated that the general methods
above and specific examples below are illustrative only, for the
purpose of assistance and of understanding the present invention,
and should not be construed as limiting the scope of the present
invention in any manner.
Chromatography:
[0832] Unless otherwise indicated, crude product-containing
residues were purified by passing the crude material or concentrate
through either a Biotage or Isco brand silica gel column
(pre-packed or individually packed with SiO.sub.2) and eluting the
product off the column with a solvent gradient as indicated. For
example a description of (330 g SiO.sub.2, 0-40% EtOAc/Hexane)
means the product was obtained by elution from the column packed
with 330 gms of silica, with a solvent gradient of 0% to 40% EtOAc
in Hexanes.
Preparative HPLC Method:
[0833] Where so indicated, the compounds described herein were
purified via reverse phase HPLC using one of the following
instruments: Shimadzu, Varian, Gilson; utilizing one of the
following two HPLC columns: (a) a Phenomenex Luna or (b) a Gemini
column (5 micron or 10 micron, C18, 150.times.50 mm)
[0834] A typical run through the instrument included: eluting at 45
ml/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v
TFA) in water (0.1% TFA) over 10 minutes; conditions can be varied
to achieve optimal separations.
Proton NMR Spectra:
[0835] Unless otherwise indicated, all .sup.1H NMR spectra were run
on a Bruker series 300 MHz instrument or a Bruker series 400 MHz
instrument. Where so characterized, all observed protons are
reported as parts-per-million (ppm) downfield from
tetramethylsilane (TMS) or other internal reference in the
appropriate solvent indicated.
Mass Spectra (MS)
[0836] Unless otherwise indicated, all mass spectral data for
starting materials, intermediates and/or exemplary compounds are
reported as mass/charge (m/z), having an (M+H.sup.+) molecular ion.
The molecular ion reported was obtained by electrospray detection
method (commonly referred to as an ESI MS) utilizing a PE SCIEX API
150EX MS instrument instrument or an Agilent 1100 series LC/MSD
system. Compounds having an isotopic atom, such as bromine and the
like, are generally reported according to the detected isotopic
pattern, as appreciated by those skilled in the art.
[0837] The compounds disclosed and described herein have been named
using either (1) the naming convention provided with Chem-Draw
Ultra 11.0 software, available in Chem Office, or (2) by the ISIS
database software (Advanced Chemistry Design Labs or ACD
software).
Example 1
##STR00046##
[0838] Synthesis of
(R)-5-Amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide
Step 1: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-hydroxypropan-2-yl)carbamate
[0839] To a suspension of
(R)-2-amino-2-(5-bromo-2-fluorophenyl)propan-1-ol HCl (25 g, 88
mmol) in dioxane (150 mL) was added a solution of sodium
bicarbonate (22.1 g, 264 mmol) in water (100 mL), followed by
di-tert-butyl dicarbonate (21.1 g, 97 mmol). The reaction was
stirred overnight at ambient temperature. After 16 hours, the
reaction mixture was partitioned between water and ether. The
organic layer was washed with water and brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated to generate the title
intermediate as a white solid (35.5 g, quantitative yield).
Step 2: (R)--S-(2-(5-Bromo-2-fluorophenyl)-2-((tert-butoxy
carbonyl)amino)propyl) ethanethioate
[0840] To a solution of triphenylphosphine (9.0 g, 34.5 mmol) in
THF (100 mL) at 0.degree. C. was added diisopropyl azodicarboxylate
(6.8 mL, 34.5 mmol) dropwise. The mixture was stirred for 30
minutes at 0.degree. C., and then a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-hydroxypropan-2-yl)carbamate (10 g,
29 mmol) in THF (30 mL) and thioacetic acid (2.5 mL, 34.5 mmol)
were added. The reaction was allowed to warm slowly to ambient
temperature and stirred overnight. After 16 hours, the reaction
mixture was concentrated, rediluted with DCM (100 mL), and passed
through a silica-gel pad, eluting with DCM. The filtrate was
concentrated and purified by silica-gel chromatography, eluting
with 50-100% dichloromethane in heptanes, to provide the title
intermediate (5.2 g, 12.8 mmol, 44% yield) as yellow oil.
Step 3: tert-Butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)thio)propan-2-yl)carbam-
ate
[0841] To a solution of
(R)--S-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propyl)e-
thanothioate (7.0 g, 17 2 mmol) in ethanol (115 mL) was added a
0.5-M solution of sodium methoxide in MeOH (34.5 mL, 17.2 mmol).
The mixture was stirred for 10 minutes at ambient temperature, and
then 2-bromopropionitrile (1.8 mL, 20.7 mmol) was added. The
reaction was stirred at ambient temperature for 20 minutes, and
then concentrated. The crude product was partitioned between water
and 1:1 ethyl acetate/heptanes. The organic layer was washed with
brine and concentrated to give the title intermediate (7.2 g, 17.2
mmol, quantitative yield), which was used in the next reaction
without further purification.
Step 4: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)propan-2-yl)c-
arbamate
[0842] To a solution of tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)thio)propan-2-yl)carbam-
ate (5.3 g, 12.8 mmol) in MeOH (85 mL) at 0.degree. C. was added a
solution of ammonium molybdate tetrahydrate (3.16 g, 2.56 mmol) in
30% aqueous hydrogen peroxide (19.6 mL, 640 mmol). The mixture was
stirred at ambient temperature overnight, quenched with saturated
aqueous sodium bicarbonate, and extracted with ethyl acetate. The
organic layer was washed with water and brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated.
[0843] The crude product was dissolved in DMF (30 mL). The solution
was degassed with nitrogen, and potassium carbonate (2.63 g, 19.1
mmol) and iodomethane (1.18 mL, 19.1 mmol) were added. The reaction
was stirred at ambient temperature for one hour. The reaction was
diluted with water (200 mL), and the precipitate was collected by
vacuum filtration. The precipitate was dissolved in ethyl acetate,
washed with brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated to provide the title intermediate (3.4
g, 7.3 mmol, 58% yield) as a light-yellow solid.
Step 5:
(R)-5-Amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-
-2H-1,4-thiazine 1,1-dioxide
[0844] A solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)propan-2-yl)c-
arbamate (3.4 g, 7.3 mmol) in dioxane (25 mL) was transferred to a
pressure vessel. To the reaction was added 4 M HCl in dioxane (18.3
mL, 73 mmol), and the vessel was sealed and stirred at 110.degree.
C. overnight. After 16 hours, the reaction mixture was
concentrated, and the residue was partitioned between ethyl acetate
and saturated aqueous sodium bicarbonate. The organic layer was
concentrated and purified by silica-gel chromatography, eluting
with 0-10% methanol in DCM, to provide the title compound (2.3 g,
6.3 mmol, 86% yield) as an off-white solid. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.61 (dd, J=2.6, 7.2 Hz, 1H), 7.44-7.48 (m,
1H), 7.16 (dd, J=8.6, 12.1 Hz, 1H), 6.20 (bs, 2H), 3.66 (d, J=15.2
Hz, 1H), 3.55 (d, J=15.5 Hz, 1H), 1.57 (s, 6H), 1.44 (s, 3H). LC/MS
(ESI.sup.+) m/z=363.0, 365.0 (M+H; 2 bromine isotopes).
Intermediate 1
##STR00047##
[0845] Synthesis of
R,S-5-Amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide
Step 1: 2-Methyl-2-(methylsulfonyl)propanenitrile
[0846] To a solution of 2-(methylsulfonyl)acetonitrile (60 g, 504
mmol) in DMF (252 mL) at 0.degree. C. was added potassium carbonate
(209 g, 1511 mmol) portion-wise, followed by iodomethane (136 mL,
1511 mmol). After 15 minutes, the ice bath was removed and the
reaction was stirred at RT for 48 hours. The reaction mixture was
filtered through a Celite.RTM. pad, and the filter cake was rinsed
with ethyl acetate and ether. The combined filtrates were
concentrated and partitioned between ether and water. The organic
portion was dried over sodium sulfate, filtered, and concentrated
in vacuo to afford the title intermediate (58 g, 78% yield) as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.27
(s, 3H) 1.71 (s, 6H).
Step 2:
(E)-N-(1-(5-Bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sul-
finamide
[0847] A mixture of 2-methylpropane-2-sulfinamide (14 g, 115 mmol),
1-(5-bromo-2-fluorophenyl)ethanone (25 g, 115 mmol), and titanium
(IV) ethoxide (60.3 mL, 288 mmol) in 2-methyltetrahydrofuran (230
mL) was stirred at 65.degree. C. for 16 hours. The reaction was
cooled to RT and poured into brine. The resulting mixture was
filtered through a Celite.RTM. pad, and the filter cake was rinsed
with EtOAc. The organic portion was dried over sodium sulfate,
filtered, and concentrated in vacuo to afford an oily residue. The
crude product was purified by silica-gel chromatography, eluting
with 0-100% ethyl acetate in heptanes, to afford the title
intermediate (31 g, 84% yield) as a light yellow solid. LC/MS
(ESI.sup.+) m/z=320 (M+H).
Step 3:
N-(2-(5-Bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)prop-
an-2-yl)-2-methylpropane-2-sulfinamide
[0848] To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile
(368 mg, 2.5 mmol) in THF (3.9 mL) at -78.degree. C. was added BuLi
(1.6 M in hexane) (1.56 mL, 2.5 mmol) dropwise via syringe. The
reaction was stirred for 20 minutes and then a mixture of
(E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamid-
e (400 mg, 1.25 mmol) and trimethylaluminum (2.0 M in heptane)
(0.63 mL, 1.3 mmol) in toluene (3.9 mL) at -78.degree. C. was
added. The reaction was stirred at -78.degree. C. for 2 hours, and
then partitioned between water and DCM. The organic portion was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford a yellow residue. The crude product was purified by
silica-gel chromatography, eluting with 10-100% dichloromethane in
heptanes, to afford the title intermediate (292 mg, 50% yield) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60-7.67
(m, 2H), 7.16-7.21 (m, 1H), 5.54 (s, 1H), 4.12-4.20 (m, 2H), 2.01
(s, 3H), 1.65 (s, 6H), 1.12 (s, 9H). LC/MS (ESI.sup.+) m/z=467
(M+H).
Step 4:
5-Amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H--
1,4-thiazine 1,1-dioxide
[0849] To a solution of
N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)propan-2-yl-
)-2-methylpropane-2-sulfinamide (46.4 mg, 0.1 mmol) in DCM (0.5 mL)
and EtOH (0.5 mL) was added 4 N HCl in dioxane (0.1 mL, 0.4 mmol).
The reaction was stirred at RT for 1 hour, and then partitioned
between aqueous sodium carbonate and DCM. The organic layer was
dried over anhydrous sodium sulfate, filtered, and concentrated to
provide
2-((2-amino-2-(5-bromo-2-fluorophenyl)propyl)sulfonyl)-2-methylpropanenit-
rile (36.1 mg, 100% yield). LC/MS (ESI.sup.+) m/z=363 (M+H).
[0850] A suspension of
2-((2-amino-2-(5-bromo-2-fluorophenyl)propyl)sulfonyl)-2-methylpropanenit-
rile (36.1 mg, 0.1 mmol) in 4 N HCl in dioxane (0.99 mL, 4.0 mmol)
was stirred at 105.degree. C. overnight. The reaction was cooled to
RT and poured slowly into a cold solution of aqueous sodium
bicarbonate. The mixture was diluted with DCM, and the organic
portion was dried over anhydrous sodium sulfate, filtered, and
concentrated to give a tan residue. The crude product was suspended
in DCM and filtered through a Celite.RTM. pad. The filter cake was
rinsed with 5% methanol in DCM, and the combined filtrates were
concentrated in vacuo to afford the title compound (35 mg, 97%
yield) as a tan solid. LC/MS (ESI.sup.+) m/z=363, 365 (M+H; 2
bromine isotopes).
Intermediate 2
##STR00048##
[0851] Synthesis of (R)-tert-Butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate
Step 1: (R)-tert-Butyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate
[0852] To a solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (0.34 g, 0.93 mmol) in dioxane (6.2 mL) was
added di-tert-butyl dicarbonate (0.323 mL, 1.392 mmol) and a
saturated aqueous solution of sodium bicarbonate (6.2 mL). The
reaction was stirred at ambient temperature for 16 hours and then
partitioned between water and ethyl acetate. The organic layer was
concentrated in vacuo to generate the title compound (430 mg, 0.93
mmol, quantitative yield).
Step 2: (R)-tert-Butyl
(5-(5-azido-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate
[0853] To a solution of (R)-tert-butyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (1.85 g, 3.99 mmol) in ethanol (13.91 mL)
and water (6.05 mL) were added sequentially copper (I) iodide
(0.304 g, 1.60 mmol), sodium azide (2.08 g, 31.9 mmol), (+)-sodium
1-ascorbate (0.32 g, 1.60 mmol) and
(1R,2R)--N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (0.50 mL,
3.19 mmol). The reaction was stirred at 50.degree. C. for 45
minutes and then partitioned between water and EtOAc. The organic
layer was concentrated to generate the title intermediate (1.70 g,
3.99 mmol, quantitative yield), which was used in the next reaction
without further purification. LC/MS (ESI.sup.+) m/z=426 (M+H).
Step 3: (R)-tert-Butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate
[0854] To a solution of (R)-tert-butyl
(5-(5-azido-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (1.70 g, 3.99 mmol) in THF (26.7 mL) and
water (8.91 mL) was added trimethylphosphine (1 M in THF, 4.39 mL,
4.39 mmol). The reaction was stirred at RT for 20 minutes and then
partitioned between water and DCM. The organic layer was
concentrated to generate a brown residue. The crude product was
purified by silica-gel chromatography, eluting with 20-100% EtOAc
in heptanes, to generate the title compound (1.25 g, 3.13 mmol, 78%
yield) as a tan solid. LC/MS (ESI.sup.+) m/z=400 (M+H).
Example 2
##STR00049##
[0855] Synthesis of
(R)-5-Amino-3-(5-bromo-2-fluorophenyl)-3-methyl-3,6-dihydro-2H-1,4-thiazi-
ne 1,1-dioxide
Step 1: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)thio)propan-2-yl)carbamate
[0856] In an analogous reaction to that described in Example 1,
step 3,
(R)--S-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propyl)e-
thanethioate was condensed with bromoacetonitrile to generate the
title intermediate (1.03 g, 2.55 mmol, quantitative yield) as a
clear oil.
Step 2: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e
[0857] In an analogous reaction to that described in Example 1,
step 4, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)thio)propan-2-yl)carbamate
was oxidized to generate the title compound (380 mg, 0.87 mmol,
quantitative yield) as white foam.
Step 3:
(R)-5-Amino-3-(5-bromo-2-fluorophenyl)-3-methyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide
[0858] In an analogous sequence to that described for Example 1,
step 5, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e was converted to the title compound (294 mg, 0.88 mmol, 76%
yield) as an off-white foam. LC/MS (ESI.sup.+) m/z=335, 337 (M+H; 2
bromine isotopes).
Intermediate 3
##STR00050##
[0859] Synthesis of (R)-tert-Butyl
(5-(5-amino-2-fluorophenyl)-5-methyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiaz-
in-3-yl)carbamate
[0860] In an analogous sequence of reactions to those described for
Intermediate 2, steps 1-3,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3-methyl-3,6-dihydro-2H-1,4-thiazi-
ne 1,1-dioxide was converted to the title compound in 88% overall
yield. LC/MS (ESI.sup.+) m/z=372 (M+H).
Example 3
##STR00051##
[0861] Synthesis of
(3R,6R)-5-Amino-3-(5-bromo-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3,6-dihy-
dro-2H-1,4-thiazine 1,1-dioxide
Route A
Step 1:
(3R)-5-Amino-3-(5-bromo-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2-
H-1,4-thiazine 1,1-dioxide
[0862] In an analogous sequence of reactions to those described in
Example 1, steps 4 and 5, tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)thio)propan-2-yl)carbam-
ate was converted to the title intermediate in 86% overall
yield.
Step 2:
(3R,6R)-5-Amino-3-(5-bromo-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0863] To a solution of
(3R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-t-
hiazine 1,1-dioxide (2.28 g, 6.53 mmol) in DMF (32.6 ml) at
-40.degree. C. was added N-fluorobenzenesulfonimide (2.26 g, 7.18
mmol) and cesium carbonate (3.19 g, 9.79 mmol). The reaction
mixture was stirred at -40.degree. C. for 1.5 hours, and then
warmed to RT. The mixture was diluted with water and extracted with
EtOAc. The organic layer was washed with water and brine and
concentrated. The crude material was purified by silica-gel
chromatography, eluting with 20-100% EtOAc in heptane, to provide
the title intermediate (2.03 g, 5.53 mmol, 85% yield) as a white
solid. LC/MS (ESI.sup.+) m/z=367, 369 (M+H; 2 bromine
isotopes).
Route B
Step 1: (R)-tert-Butyl
4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide
[0864] A solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-hydroxypropan-2-yl)carbamate (33.16
g, 95 mmol) in DCM (317 mL) was added dropwise to pre-cooled
mixture of pyridine (38.8 ml, 476 mmol) and thionyl chloride (13.89
ml, 190 mmol) at 0.degree. C. The reaction mixture was removed from
the ice-water bath and allowed to stir at RT for 2 hours. The
reaction was neutralized by the addition of 2 N aqueous HCl (240
mL), the organic phase was separated, and the aqueous phase was
extracted with DCM. The combined organic layers were washed with
water and brine and concentrated. The residue was dissolved in ACN
(300 mL), and ruthenium (III) chloride hydrate (10.73 mg, 0.048
mmol) was added, followed by a solution of sodium metaperiodate
(20.37 g, 95 mmol) in water (200 mL). The mixture was stirred for
20 minutes at RT and then diluted with water, and extracted with
DCM. The combined extracts were washed with brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo to yield
(R)-tert-butyl
4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide (33.95 g, 83 mmol, 87% yield) as an off-white solid,
which was used without further purification.
Step 2:
(R)--S-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)p-
ropyl) ethanethioate
[0865] A mixture of potassium ethanethioate (9.98 g, 87 mmol) and
(R)-tert-butyl
4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide (32.6 g, 79 mmol) in DMF (306 mL) was stirred at
50.degree. C. for 1 hour. The mixture was cooled, diluted with
water and extracted with EtOAc. The combined extracts were washed
with 1 N aqueous HCl, water, and brine and concentrated. The
residue was purified by silica-gel chromatography, eluting with
5-40% ethyl acetate in heptanes, to afford
(R)--S-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)
propyl)ethanethioate (26.2 g, 64.5 mmol, 81% yield) as an off-white
solid.
Step 3: tert-Butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)sulfonyl)propan-2-yl)ca-
rbamate
[0866] To a solution of
(R)--S-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)
amino)propyl)ethanethioate (5.13 g, 12.63 mmol) in ethanol (84 mL)
was added sodium methoxide (0.5 M solution in methanol, 25.3 mL,
12.63 mmol). The mixture was stirred at RT for 10 minutes, and then
(+/-)-2-bromopropionitrile (1.310 ml, 15.15 mmol) was added. The
reaction was stirred at RT for 20 minutes, concentrated, and
partitioned between water and 1:1 ethyl acetate/heptane. The
aqueous layer was extracted with EtOAc, and the combined organic
layers were washed with brine and concentrated.
[0867] The residue was dissolved in MeOH (63.2 mL) and cooled in an
ice-water bath. To this solution was added a solution of ammonium
molybdate (3.12 g, 2.53 mmol) in 30% hydrogen peroxide in water
(19.35 mL, 632 mmol). The mixture was stirred at RT for 16 hours,
quenched with saturated aqueous sodium bicarbonate, and extracted
with DCM. The combined organic layers were washed with water and
brine and concentrated. The crude material was purified by
silica-gel chromatography, eluting with 20-100% ethyl acetate in
heptane, to provide the title intermediate (3.92 g, 8.72 mmol,
69.1% yield) as a white solid.
Step 4:
(3R,6R)-5-Amino-3-(5-bromo-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0868] The tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)sulfonyl)propan-2-yl)ca-
rbamate was converted to the title compound as described in Example
3, steps 2 and 3. LC/MS (ESI.sup.+) m/z=367, 369 (M+H; 2 bromine
isotopes).
Intermediate 4
##STR00052##
[0869] Synthesis of tert-Butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate
[0870] In a sequence of reactions analogous to those described for
Intermediate 2, steps 1-3, (3R,
6R)-5-amino-3-(5-bromo-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide was converted to the title compound in
87% overall yield. LC/MS (ESI.sup.+) m/z=426 (M+Na).
Example 4
##STR00053##
[0871] Synthesis of
(2S,3R)-5-amino-3-(5-bromo-2-fluorophenyl)-2-fluoro-3,6,6-trimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: tert-Butyl
((5R,6S)-5-(5-bromo-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[0872] To a solution of potassium 2-methylpropan-2-olate (6.20 g,
55.2 mmol) in tetrahydrofuran (175 ml) at -78.degree. C. was added
DIPA (7.87 mL, 55.2 mmol) and the solution was stirred for 15
minutes. A solution of n-butyllithium (2.7 M in heptane) (18.54 ml,
50.1 mmol) was added, and the solution was stirred at -78.degree.
C. for 5 minutes, then ((R)-tert-butyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate) (8 g, 17.3 mmol) in THF (25 mL) was added
dropwise and the solution was stirred at -78.degree. C. for one
hour. A solution of N-fluorobenzenesulfonimide (28.3 g, 90 mmol) in
THF (100 mL) was then added and the solution was allowed to warm to
RT and sonicated for 30 minutes. The solution was quenched with
water (250 mL), extracted with ethyl acetate (2.times.300 mL), and
the extracts were concentrated. The product was purified by
silica-gel chromatography, eluting with 5-25% ethyl acetate in
heptanes, to provide the title intermediate (5.1 g, 12.46 mmol,
61.5% yield). LC/MS (ESI.sup.+) m/z=505 (M+Na).
Step 2:
(2S,3R)-5-amino-3-(5-bromo-2-fluorophenyl)-2-fluoro-3,6,6-trimethy-
l-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0873] To a solution of tert-butyl
((5R,6S)-5-(5-bromo-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (312 mg, 0.648 mmol) in
DCM (25 mL) was added TFA (1.25 mL, 16.2 mmol). The solution was
stirred for 2 hours, quenched with saturated aqueous sodium
carbonate, extracted with ethyl acetate, and the extracts were
concentrated. The product was purified by silica-gel
chromatography, eluting with 0-100% (90/10/1
dichloromethane/methanol/ammonium hydroxide) in dichloromethane, to
afford the title compound (125 mg, 0.328 mmol, 50.6% yield). LC/MS
(ESI.sup.+) m/z=383, 385 (M+H; 2 bromine isotopes).
Example 5
##STR00054##
[0874] Synthesis of
5-Amino-3-(5-bromo-2-fluorophenyl)-3-(fluromethyl)-6,6-dimethyl-3
6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: 1-(5-Bromo-2-fluorophenyl)-2-fluoroethanone
[0875] A 2.0 M solution of LDA in heptane/THF/ethylbenzene (100 mL,
200 mmol) was added dropwise via syringe to a solution of
1-bromo-4-fluorobenzene (20 mL, 182 mmol) in THF (600 mL) at
-78.degree. C. After stirring for 2.5 hours at -78.degree. C.,
ethyl monofluoroacetate (18.47 mL, 191 mmol) was added dropwise via
syringe, and the reaction was stirred at -78.degree. C. for 20
minutes and then stirred at -45.degree. C. for 30 minutes before
being quenched with saturated aqueous ammonium chloride at
-45.degree. C. The mixture was diluted with water and ethyl
acetate. The layers were separated and the aqueous layer was
extracted with ethyl acetate. The combined organic extracts were
washed with saturated aqueous ammonium chloride, water, and
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The crude product was
dissolved in a minimal amount of methanol and placed in a
-20.degree. C. freezer overnight. The resulting solid was collected
and washed with cold methanol to afford the title intermediate
(12.07 g, 51.6 mmol, 28% yield) as a white solid.
Step 2:
(R,Z)--N-(1-(5-Bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylp-
ropane-2-sulfinamide
[0876] Titanium (IV) ethoxide (4.05 mL, 19 6 mmol) was added via
syringe to a solution of
1-(5-bromo-2-fluorophenyl)-2-fluoroethanone (2.3 g, 9.79 mmol) and
(R)-(+)-2-methyl-2-propanesulfinamide (2.37 g, 19.57 mmol) in
tetrahydrofuran (20 ml) at RT. The reaction was stirred for 18
hours and then the reaction was slowly poured into a vigorously
stirred water/EtOAc mixture. After stirring 15 minutes, the mixture
was filtered through a Celite.RTM. pad, which was rinsed with ethyl
acetate, and the phases were separated. The aqueous layer was
extracted with ethyl acetate; the combined organic extracts were
washed with brine, dried over anhydrous sodium sulfate, filtered
and concentrated. The crude product was purified by silica-gel
chromatography, eluting with 10% EtOAc in hexanes, to provide the
title compound (2.81 g, 8.31 mmol, 85% yield) as a yellow oil.
LC/MS (ESI.sup.+) m/z=338, 340 (M+H; 2 bromine isotopes).
Step 3:
(R)--N-(2-(5-Bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl-
)-3-fluoropropan-2-yl)-2-methylpropane-2-sulfinamide
[0877] To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile
(1.654 g, 11.24 mmol) in THF (14 mL) at -78.degree. C. was added a
2.5 M solution of n-butyllithium in hexanes (4.49 mL, 11.24 mmol)
dropwise via syringe. After 30 minutes at -78.degree. C., a
0.degree. C. solution of
(R,E)-N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-
-sulfinamide (1.9 g, 5.62 mmol) in THF (14.00 mL), which had been
pretreated with boron trifluoride diethyl etherate (0.693 mL, 5.62
mmol) at 0.degree. C. for 15 minutes, was added dropwise via
cannula. The reaction was stirred for 2 hours at -78.degree. C.,
and then quenched with saturated aqueous ammonium chloride at
-78.degree. C. and diluted with water and ethyl acetate. The layers
were separated and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with water and saturated
aqueous sodium chloride, and dried over sodium sulfate. The
solution was filtered, concentrated, and purified by silica-gel
chromatography, eluting with 25% ethyl acetate in hexanes followed
by 40% ethyl acetate hexane to provide the title compound. The
product was isolated as a 2:1 mixture of diastereomers. LC/MS
(ESI.sup.+) m/z=485, 487 (M+H; 2 bromine isotopes).
Step 4:
2-((2-Amino-2-(5-bromo-2-fluorophenyl)-3-fluoropropyl)sulfonyl)-2--
methylpropanenitrile hydrochloride
[0878] A 4.0 M solution of hydrogen chloride in 1,4-dioxane (2.4
mL, 9.60 mmol) was added via syringe to a solution of
(R)--N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-flu-
oropropan-2-yl)-2-methylpropane-2-sulfinamide (1.14 g, 2.349 mmol)
in dichloromethane (12 mL) at RT. After stirring for 2 hours, the
reaction was filtered and the solid was washed with DCM and
air-dried to afford the title intermediate (0.754 g, 1.805 mmol,
77% yield) as a white solid. LC/MS (ESI.sup.+) m/z=381, 383 (M+H; 2
bromine isotopes).
Step 5:
5-Amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0879] A solution of
2-((2-amino-2-(5-bromo-2-fluorophenyl)-3-fluoropropyl)sulfonyl)-2-methylp-
ropanenitrile hydrochloride (0.489 g, 1.171 mmol) in 4 M HCl in
1,4-dioxane (12 mL, 48.0 mmol) was stirred at reflux for 48 hours.
After cooling, the solvent was removed and the resulting product
was partitioned between DCM and 10% aqueous sodium carbonate. The
layers were separated and the aqueous layer was extracted with DCM
and then EtOAc. The combined organic extracts were washed with
saturated aqueous sodium chloride, dried over anhydrous sodium
sulfate, filtered and concentrated. The crude product was purified
by silica-gel chromatography, eluting with 40% EtOAc in hexane, to
provide the title compound as a white solid. LC/MS (ESI.sup.+)
m/z=381, 383 (M+H; 2 bromine isotopes).
Intermediate 5
##STR00055##
[0880] Synthesis of
5-Amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihy-
dro-2H-1,4-thiazine 1,1-dioxide
[0881]
5-Amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,-
6-dihydro-2H-1,4-thiazine 1,1-dioxide (0.183 g, 0.480 mmol) was
converted to the title compound using a sequence of reactions
analogous to those described in Intermediate 2, steps 2 and 3, as a
2:1 ratio of enantiomers. LC/MS (ESI.sup.+) m/z=318 (M+H).
[0882] Alternatively, intermediate 5 may be prepared using a
different ring closure method, as shown and described
##STR00056##
[0883] To a solution of
N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-fluoropr-
opan-2-yl)-2-methylpropane-2-sulfinamide (45 g, 93 mmol) in dioxane
(800 mL) was added HCl (4.0 M in 1,4-dioxane, 107 mL, 428 mmol, 4.6
eq.). The reaction mixture was heated to 100.degree. C. for 2 d,
cooled to RT, concentrated, and dried under high vacuum to give
5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihy-
dro-2H-1,4-thiazine 1,1-dioxide hydrochloride as as light brown
solid. The product could be resolved into its constituent
enantiomers by Chiral supercritical fluid chromatography under the
following conditions: Column: Chiralpak AD-H, 30.times.250 mm, 20
.mu.m; Mobile Phase A: CO2; Mobile Phase B: Methanol (20 mM NH3);
Isocratic: 30% B; Flow Rate: 150 g/min; Detection: 270 nm
Example 6
##STR00057##
[0884] Synthesis of
R,S-5-amino-3-(5-bromo-2-fluorophenyl)-3-(difluoromethyl)-6,6-dimethyl-3,-
6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1:
R,S--N-(2-(5-Bromo-2-fluorophenyl)-3-((2-cyanopropan-2-yl)sulfonyl-
)-1,1-difluoropropan-2-yl)-2-methylpropane-2-sulfinamide
[0885] To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile
(0.612 g, 4.15 mmol) in THF (6.5 mL) at -78.degree. C. was added
n-butyllithium, 1.6 M solution in hexane (2.60 mL, 4.15 mmol)
dropwise. The resulting mixture was stirred for 20 minutes, and a
to -78.degree. C. solution of
(E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-
-2-sulfinamide (0.74 g, 2.077 mmol) in toluene (6.49 ml) which had
been pretreated with trimethylaluminum, 2.0M solution in toluene
(1.039 mL, 2.077 mmol) for 10 minutes, was added dropwise via
canula. The resulting mixture was stirred for 2 hours at
-78.degree. C., quenched with water at -78.degree. C., and
extracted with DCM. The combined organic layers were dried over
sodium sulfate, filtered, and concentrated. The crude product was
purified by silica-gel chromatography, eluting with a gradient of
0% to 20% 90:10:1 dichloromethane/methanol/ammonium hydroxide in
dichloromethane, to provide the title compound (0.936 g, 1.859
mmol, 90% yield) as white solid.
Step 2:
R,S-2-((2-Amino-2-(5-bromo-2-fluorophenyl)-3,3-difluoropropyl)sulf-
onyl)-2-methylpropanenitrile hydrochloride
[0886] To a solution of
R,S--N-(2-(5-bromo-2-fluorophenyl)-3-((2-cyanopropan-2-yl)sulfonyl)-1,1-d-
ifluoropropan-2-yl)-2-methylpropane-2-sulfinamide (829 mg, 1.647
mmol) in DCM (8.23 mL) was added HCl (4 N in 1,4-dioxane) (1.65 mL,
6.59 mmol), and the reaction was stirred at RT for 2 hours. The
resulting white precipitate was collected by vacuum filtration,
washed with DCM, and dried in air to give the title compound (0.66
g, 1.515 mmol, 92% yield) as white solid.
Step 3:
R,S-5-amino-3-(5-bromo-2-fluorophenyl)-3-(difluoromethyl)-6,6-dime-
thyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0887] To a suspension of
R,S-2-((2-amino-2-(5-bromo-2-fluorophenyl)-3,3-difluoropropyl)sulfonyl)-2-
-methylpropanenitrile hydrochloride (0.66 g, 1.515 mmol) in toluene
(15.15 mL) was added trimethylaluminum, 2.0M solution in toluene
(0.909 ml, 1.818 mmol). The mixture was stirred at 90.degree. C.
for 1 hour, cooled to 0.degree. C., and diluted with saturated
aqueous sodium carbonate. The aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The crude product was purified by silica-gel chromatography,
eluting with a gradient of 0% to 80% 90:10:1 DCM/MeOH/ammonium
hydroxide in DCM, to provide the title compound (0.473 g, 1.185
mmol, 78% yield) as white solid. LC/MS (ESI.sup.+) m/z=399, 401
(M+H; 2 bromine isotopes).
Intermediate 6
##STR00058##
[0888] Synthesis of R,S-tert-Butyl
(5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2,2-dimethyl-1,1-dioxido-5-
,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[0889] Using the sequence of steps described for Intermediate 2,
R,S-5-amino-3-(5-bromo-2-fluorophenyl)-3-(difluoromethyl)-6,6-dimethyl-3,-
6-dihydro-2H-1,4-thiazine 1,1-dioxide (0.452 g, 1.132 mmol) was
converted to the title compound in 89% yield as a light-yellow
solid. LC/MS (ESI.sup.+) m/z=484 (M+H).
Example 7
##STR00059##
[0890] Synthesis of
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone
[0891] To a solution of LDA, 2.0 M in heptane/THF/ethylbenzene (79
ml, 157 mmol) in THF (50 mL) at -78.degree. C. was added a solution
of 1-bromo-4-fluorobenzene (15.69 ml, 143 mmol) in THF (50 mL)
dropwise. The mixture was stirred at -78.degree. C. for 1 hour, and
a solution of ethyl trifluoroacetate (18.70 mL, 157 mmol) in THF
(50 mL) was added. The resulting mixture was stirred at 0.degree.
C. for 2 hours, quenched with saturated aqueous ammonium chloride,
and extracted with ethyl acetate. The combined organics were dried
over anhydrous sodium sulfate, filtered, concentrated and purified
by silica-gel chromatography, eluting with using 0-30% ethyl
acetate in hexanes, to afford the title intermediate (27.6 g, 102
mmol, 71.3% yield) as a brown oil.
Step 2:
(R,Z)--N-(1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethylidene)-2--
methylpropane-2-sulfinamide
[0892] A mixture of
1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (27.6 g, 102
mmol), (R)-2-methylpropane-2-sulfinamide (24.69 g, 204 mmol) and
titanium (IV) ethoxide (52.7 mL, 255 mmol) in THF (100 mL) was
heated at reflux for 2 hours. The mixture was brought to RT, and
brine was added and stirred for 10 min. The suspension was filtered
through silica gel; the organic phase was separated and the aqueous
phase was extracted with ethyl acetate. The combined organics were
washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated. The crude product was purified by silica-gel
chromatography, eluting with 0-5% ethyl acetate in hexanes, to
provide the title compound (20.66 g, 55.2 mmol, 54.2% yield) as a
yellow oil.
Step 3:
N--((S)-2-(5-bromo-2-fluorophenyl)-3-((2-cyanopropan-2-yl)sulfonyl-
)-1,1,1-trifluoropropan-2-yl)-2-methylpropane-2-sulfinamide
[0893] To a -78.degree. C. solution of
2-methyl-2-(methylsulfonyl)propanenitrile (11.53 g, 78 mmol) in THF
(100 mL) was added a 2.5 M solution of n-butyllithium in hexanes
(31.3 ml, 78 mmol) dropwise. The resulting mixture was stirred at
-78.degree. C. for 40 minutes, and then a solution of
(R,Z)--N-(1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethylidene)-2-methylp-
ropane-2-sulfinamide (19.54 g, 52.2 mmol) in THF (100 mL) was added
dropwise. The resulting mixture was stirred at -78.degree. C. for 1
hour, quenched with saturated aqueous ammonium chloride, and
extracted with EtOAc. The combined organics were dried over
anhydrous sodium sulfate, filtered, concentrated and purified by
silica-gel chromatography, eluting with 0-10% EtOAc in hexanes, to
afford the title intermediate (27 g, 51.8 mmol) as a pale yellow
oil. LC/MS (ESI.sup.+) m/z=417, 419 (M+H).
Step 4:
(5)-5-amino-3-(5-bromo-2-fluorophenyl)-6,6-dimethyl-3-(trifluorome-
thyl)-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0894] To a solution of
N--((S)-2-(5-bromo-2-fluorophenyl)-3-((2-cyanopropan-2-yl)sulfonyl)-1,1,1-
-trifluoropropan-2-yl)-2-methylpropane-2-sulfinamide (27 g, 51.8
mmol) in methanol (100 mL) was added a 4 M solution of HCl in
1,4-dioxane (64.7 ml, 259 mmol). The reaction was stirred at
ambient temperature for 2 hours, concentrated, and diluted with
DCM. The organic phase was washed with 10% aqueous sodium carbonate
and 1 N aqueous sodium hydroxide, dried over anhydrous sodium
sulfate, filtered and concentrated.
[0895] The crude product was dissolved in DCM (100 mL) and a 2 M
solution of trimethylaluminum in toluene (41.4 ml, 83 mmol) was
added dropwise. The resulting mixture was stirred at ambient
temperature for 17 hours, cooled to 0.degree. C., and 1 N HCl
(21.40 mL, 21.40 mmol) was added dropwise. After stirring at
ambient temperature, the aqueous solution was extracted with DCM.
The pH of the aqueous phase was adjusted to pH>10 with 10 N
aqueous sodium hydroxide and extracted with DCM. The combined
organic extracts were washed with brine, dried over anhydrous
sodium sulfate, filtered, and concentrated. The crude product was
purified by silica-gel chromatography to afford the title compound
(15.83 g, 37.9 mmol, 73.3% yield) as a pale yellow solid.
Example 8
##STR00060##
[0896] Synthesis of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0897] The title compound was prepared as described for Example 7,
substituting (S)-2-methylpropane-2-sulfinamide for the (R) isomer
in step 2. LC/MS (ESI.sup.+) m/z=417, 419 (M+H; 2 bromine
isotopes).
Example 9
##STR00061##
[0898] Synthesis of
(S)-5-amino-3-(5-amino-2-fluorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0899] To a mixture of
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide (7.0 g, 16.8 mmol), sodium
azide (3.27 g, 50.3 mmol), copper (I) iodide (0.639 g, 3.36 mmol)
and (+)-sodium 1-ascorbate (0.33 g, 1.68 mmol), under a nitrogen
atmosphere, were added
(1R,2R)-(-)--N,N'-dimethylcyclohexane-1,2-diamine (0.794 mL, 5.03
mmol), ethanol (40 mL), and water (20 mL). The resulting mixture
was stirred at reflux for 2 hours, quenched with a mixture of 9:1
saturated aqueous ammonium chloride/ammonium hydroxide, and
extracted with ethyl acetate. The combined organic layers were
washed with a 9:1 mixture of saturated aqueous ammonium
chloride/ammonium hydroxide, dried over anhydrous sodium sulfate,
filtered, and concentrated.
[0900] The crude product was dissolved in methanol (50 mL), and
sodium borohydride (1.90 g, 50.3 mmol) was added in small portions.
The reaction was stirred at RT for 1 hour, carefully quenched with
saturated aqueous ammonium chloride, and extracted with DCM. The
organic layer was dried over anhydrous sodium sulfate, filtered,
concentrated, and purified by silica-gel chromatography, eluting
with 0-4% MeOH in DCM, to afford the title compound (2.0 g, 5.66
mmol, 33.7% yield) as an off-white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.42 (s, 3H) 1.63 (s, 3H) 3.81-4.05 (m,
2H) 4.93 (s, 2H) 6.45-6.57 (m, 1H) 6.68 (br. s., 2H) 6.75-6.88 (m,
2H). LC/MS (ESI.sup.+) m/z=354 (M+H).
Example 10
##STR00062##
[0901] Synthesis of
(R)-5-amino-3-(5-amino-2-fluorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0902] The title compound was prepared from
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide as described for Example 9.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.42 (s, 3H) 1.63
(s, 3H) 3.80-4.06 (m, 2H) 4.93 (s, 2H) 6.52 (m, J=8.60, 3.40, 3.40
Hz, 1H) 6.67 (br. s., 2H) 6.76-6.88 (m, 2H). LC/MS (ESI.sup.+)
m/z=354 (M+H).
Example 11
##STR00063##
[0903] Synthesis of
R,S-5-Amino-3-(5-bromo-2,3-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-
-1,4-thiazine 1,1-dioxide
Step 1: 5-Bromo-2,3-difluoro-N-methoxy-N-methylbenzamide
[0904] To a solution of 5-bromo-2,3-difluorobenzoic acid (5.00 g,
21.10 mmol) in DCM (68 mL) and DMF (0.686 mL, 8.86 mmol), cooled to
0.degree. C., was added oxalyl chloride (5.54 mL, 63.3 mmol)
dropwise via syringe, and the reaction mixture was stirred at
0.degree. C. for 15 minutes then warmed to 18.degree. C. and
stirred for 1 hour. The reaction mixture was concentrated, and the
residue was dissolved in DCM (58 mL). To this solution was added
N,O-dimethyl hydroxylamine HCl (4.12 g, 42.2 mmol). The mixture was
cooled to 0.degree. C., and TEA (14.70 mL, 105 mmol) and
4-dimethylaminopyridine (0.103 g, 0.844 mmol) were added. The
reaction was stirred for 1.5 hours at 0.degree. C., and then
quenched with 1 N aq. HCl (20 mL) at 0.degree. C. The mixture was
diluted with DCM, washed with water and brine, dried over anhydrous
sodium sulfate, filtered, and concentrated to yield the title
intermediate (5.91 g, 21.10 mmol, 100% yield) as a light orange
crystalline solid. LC/MS (ESI.sup.+) m/z=280, 282 (M+H; 2 bromine
isotopes).
Step 2: 1-(5-Bromo-2,3-difluorophenyl)ethanone
[0905] To a solution of
5-bromo-2,3-difluoro-N-methoxy-N-methylbenzamide (5.91 g, 21.10
mmol) in THF (75 mL) at -78.degree. C. was added 3 M
methylmagnesium bromide in diethyl ether (21.10 mL, 63.3 mmol)
dropwise via an addition funnel. The mixture was slowly warmed to
0.degree. C. then stirred for 30 minutes. The reaction mixture was
quenched with 1 N aq. HCl (40 mL) at 0.degree. C. and diluted with
water and ethyl acetate. The mixture was filtered through a pad of
Celite.RTM., and the filtrate was washed with 1 N aq. HCl and
brine. The organic layer was dried over sodium sulfate and
concentrated to yield the title compound (4.70 g, 20.0 mmol, 95%
yield) as a yellow crystalline solid. LC/MS (ESI.sup.+) m/z=235,
237 (M+H; 2 bromine isotopes).
Step 3:
(E)-N-(1-(5-Bromo-2,3-difluorophenyl)ethylidene)-2-methylpropane-2-
-sulfinamide
[0906] To a solution of 1-(5-bromo-2,3-difluorophenyl)ethanone
(4.70 g, 20.00 mmol) in 2-methyltetrahydrofuran (40 mL) was added
2-methyl-2-propanesulfinamide (2.67 g, 22.00 mmol) and titanium
(IV) ethoxide (10.48 mL, 50.0 mmol). The reaction mixture was
heated at 70.degree. C. for 4.5 hours, cooled to room temperature,
and poured onto ice. DCM was added and the slurry was stirred
vigorously at RT until the ice melted. The mixture was filtered
through a pad of Celite.RTM., which was rinsed with DCM. The
combined organic filtrates were washed with water and brine and
concentrated. The crude product was purified by silica gel
chromatography, eluting with 1-100% ethyl acetate in heptane, to
afford the title intermediate (5.85 g, 17.30 mmol, 86% yield) as a
yellow oil. LC/MS (ESI.sup.+) m/z=338, 340 (M+H; 2 bromine
isotopes).
Step 4:
N-(2-(5-bromo-2,3-difluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-
propan-2-yl)-2-methylpropane-2-sulfinamide
[0907] To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile
(4.13 g, 28.1 mmol) in THF (50 mL) at -78.degree. C. was added a
solution of 1.6 M n-butyllithium in hexane (17.56 mL, 28.1 mmol)
dropwise via an addition funnel. The mixture was stirred at
-78.degree. C. for 45 minutes. A separate solution of
(E)-N-(1-(5-bromo-2,3-difluorophenyl)ethylidene)-2-methylpropane-2-sulfin-
amide (4.75 g, 14.04 mmol) in toluene (50 mL) was cooled to
-78.degree. C. and 2.0M trimethylaluminum in toluene (7.02 mL,
14.04 mmol) was added dropwise via syringe. After stirring for 10
minutes, this solution was added to the
2-methyl-2-(methylsulfonyl)propanenitrile solution dropwise via
cannula. The final reaction mixture was stirred at -78.degree. C.
for 2.5 hours. The reaction was quenched with water (40 mL) at
-78.degree. C. then warmed to room temperature. The mixture was
diluted with ethyl acetate and washed with water and brine. The
organic layer was concentrated, and the crude was purified by
silica gel chromatography, eluting with 0-100% ethyl acetate in
heptanes, to afford the title compound (5.94 g, 12.24 mmol, 87%
yield) as a white waxy solid. LC/MS (ESI.sup.+) m/z=485, 487 (M+H;
2 bromine isotopes).
Step 5:
2-((2-Amino-2-(5-bromo-2,3-difluorophenyl)propyl)sulfonyl)-2-methy-
lpropanenitrile hydrochloride
[0908] To a solution of
N-(2-(5-bromo-2,3-difluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)propan--
2-yl)-2-methylpropane-2-sulfinamide (5.94 g, 12.24 mmol) in
methanol (24 mL) at 0.degree. C. was added 4 N HCl in dioxane
(18.36 mL, 73.4 mmol). The reaction mixture was warmed to
18.degree. C. and stirred for 2 hours. The resulting precipitate
was collected by vacuum filtration, washed with ethyl acetate, and
dried under high vacuum to yield the title intermediate (4.07 g,
9.74 mmol, 80% yield) as a white solid. LC/MS (ESI.sup.+) m/z=381,
383 (M+H; 2 bromine isotopes).
Step 6:
5-Amino-3-(5-bromo-2,3-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-
-2H-1,4-thiazine 1,1-dioxide
[0909] To a suspension of
2-((2-amino-2-(5-bromo-2,3-difluorophenyl)propyl)sulfonyl)-2-methylpropan-
enitrile hydrochloride (4.84 g, 11.59 mmol) in toluene (40 mL) was
added 2 M trimethylaluminum in toluene (6.95 mL, 13.90 mmol). The
mixture was heated at 100.degree. C. for 2 hours, cooled to
0.degree. C., and quenched with saturated aqueous sodium carbonate
(8 mL). The reaction was diluted with ethyl acetate and extracted
with EtOAc and DCM. The combined organic layers were dried over
sodium sulfate, filtered and concentrated to yield the title
compound (3.75 g, 9.84 mmol, 85% yield) as a pale yellow solid.
LC/MS (ESI.sup.+) m/z=381, 383 (M+H; 2 bromine isotopes).
Intermediate 7
##STR00064##
[0910] Synthesis of tert-Butyl
(5-(5-amino-2,3-difluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2-
H-1,4-thiazin-3-yl)carbamate
[0911] Using the sequence of steps described for Intermediate
2,5-amino-3-(5-bromo-2,3-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1-
,4-thiazine 1,1-dioxide (0.100 g, 0.262 mmol) was converted to the
title compound in 65% yield as a white solid. LC/MS (ESI.sup.+)
m/z=418 (M+H).
Example 12
##STR00065##
[0912] Synthesis of
R,S-5-Amino-3-(3-bromo-2,6-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-
-1,4-thiazine 1,1-dioxide
Step 1: 1-(3-Bromo-2,6-difluorophenyl)ethanol
[0913] To a solution of 3-bromo-2,6-difluorobenzaldehyde (6.70 g,
30.3 mmol) in THF (100 mL) at -78.degree. C. was added an ether
solution of methylmagnesium bromide (3.0 M, 14.15 mL, 42.4 mmol)
dropwise over 5 minutes. The reaction was stirred at -78.degree. C.
for 30 minutes, then at 0.degree. C. for 1.5 hours. The reaction
was quenched with 50 mL of saturated aqueous ammonium chloride and
diluted with 600 mL of 7:3 EtOAc/hexane. The organic layer was
separated and extracted with brine, dried over anhydrous magnesium
sulfate and concentrated to afford the crude title intermediate
(7.2 g, quantitative), which was used in the next step without
further purification. .sup.1H NMR in CDCl.sub.3 .delta.: 7.43 (ddd,
1H, J=8.9, 7.8, 5.7), 6.82 (td, 1H, J=9.3, 9.3, 1.8), 5.26
(quintet, 1H, J=7.6), 2.20 (m, 1H), 1.64 (d, 3H, J=6.7).
Step 2: 1-(3-Bromo-2,6-difluorophenyl)ethanone
[0914] To a solution of 1-(3-bromo-2,6-difluorophenyl)ethanol (7.20
g, 30.4 mmol) in DCM (250 mL) was added water (0.657 mL, 36 4
mmol), followed by Dess-Martin periodinane (19.32 g, 45.6 mmol) in
portions over 3 minutes. The resulting thick white suspension was
stirred at RT for 2 hours. The reaction was filtered through a
Celite pad, which was rinsed with dichloromethane. The filtrate was
extracted with 1 M aqueous sodium carbonate and 10% aqueous sodium
sulfite, dried over anhydrous magnesium sulfate, and concentrated.
The residue was purified by silica gel chromatography, eluting with
11% ethyl acetate in hexanes, to afford the title compound (6.198
g, 26.4 mmol). .sup.1H NMR in CDCl3 .delta.: 7.61 (ddd, 1H, J=8.9,
7.6, 5.8), 6.90 (td, 1H, J=8.9, 8.9, 1.6), 2.61 (s, 3H).
Step 3:
(.+-.)-(E)-N-(1-(3-Bromo-2,6-difluorophenyl)ethylidene)-2-methylpr-
opane-2-sulfinamide
[0915] To a solution of 1-(3-bromo-2,6-difluorophenyl)ethanone
(6.198 g, 26.4 mmol) and 2-methylpropane-2-sulfinamide (3.36 g,
27.7 mmol) in THF (60 mL) was added titanium (IV) ethoxide (13.67
mL, 65.9 mmol), and the reaction was stirred at 70.degree. C. for 2
days. The reaction was poured into saturated brine (250 mL), and
the resulting suspension was filtered through a Celite pad, which
was rinsed with ethyl acetate. The phases of the filtrate were
separated, and the organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified by silica gel chromatography, eluting with 16% ethyl
aceate in hexanes, to provide the title compound (5.927 g, 17.52
mmol). MS m/z=338, 340 (M+H; 2 bromine isotopes). .sup.1H NMR in
CDCl.sub.3 showed an approximately 1:1 ratio of (E) and (Z)-isomers
6:7.53 (m, 1H), 6.86 (m, 1H), 2.70 (s, 1.5H), 2.48 (s, 1.5H), 1.31
(s, 4.5H), 1.25 (s, 4.5H).
Step 4:
N-(2-(3-bromo-2,6-difluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-
propan-2-yl)-2-methylpropane-2-sulfinamide
[0916] To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile
(1.78 g, 12.09 mmol) in THF in (13 mL) at -78.degree. C. was added
2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride
complex (1 M in tetrahydrofuran, 12.0 mL, 12.0 mmol) dropwise.
Immediately after the addition, a solution of
(E)-N-(1-(3-bromo-2,6-difluorophenyl)ethylidene)-2-methylpropane-2-sulfin-
amide (2.27 g, 6.71 mmol) in toluene (15 mL) at -78.degree. C. was
added dropwise. The reaction mixture was stirred at -78.degree. C.
for 1 hour and quenched with saturated ammonium chloride. The
mixture was warmed to room temperature and partitioned between
EtOAc and water. The aqueous phase was extracted with ethyl
acetate, and the combined organic extracts were washed with brine,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The crude product was purified by silica-gel chromatography,
eluting with 30-70% ethyl acetate in heptanes, to provide the title
intermediate (2.27 g, 6.71 mmol, 24% yield) as a white solid.
Step 5:
2-((2-amino-2-(3-bromo-2,6-difluorophenyl)propyl)sulfonyl)-2-methy-
lpropanenitrile hydrochloride
[0917] To a solution of
N-(2-(3-bromo-2,6-difluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)propan--
2-yl)-2-methylpropane-2-sulfinamide (0.392 g, 0.808 mmol) in DCM (3
mL) at RT was added hydrogen chloride (1 M in diethyl ether, 3.0
mL, 3.0 mmol). The reaction mixture was stirred at RT for 20 min,
diluted with hexanes, and partially concentrated until a
precipitate formed. The precipitate was collected by filtration,
washed with hexanes, and dried under high vacuum to give the title
intermediate (0.321 g, 0.768 mmol, 95% yield) as a white solid.
Step 6:
5-amino-3-(3-bromo-2,6-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-
-2H-1,4-thiazine 1,1-dioxide
[0918] To a suspension of
2-((2-amino-2-(3-bromo-2,6-difluorophenyl)propyl)sulfonyl)-2-methylpropan-
enitrile hydrochloride (0.310 g, 0.742 mmol) in toluene (3.7 mL) at
RT was added trimethylaluminum (2 M in toluene, 0.450 mL, 0.900
mmol). The reaction mixture was stirred at RT for 30 minutes and
then heated to 70.degree. C. After 40 minutes, the solution was
cooled to 0.degree. C., quenched with saturated aqueous sodium
bicarbonate, and partitioned between ethyl acetate and water. The
aqueous phase was extracted with ethyl acetate, and the combined
organic extracts were washed with brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The crude product
was purified by silica-gel chromatography, eluting with 3.5%
methanol in dichloromethane, to provide the title compound (0.184
g, 0.483 mmol, 65% yield) as a white solid. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.66 (ddd, J=8.8, 7.7, 5.5 Hz, 1H), 7.03
(ddd, J=11.9, 8.8, 1.3 Hz, 1H), 5.93 (s br, 2H), 3.64 (d, J=15.0
Hz, 1H), 3.55 (d, J=15.1 Hz, 1H), 1.75 (s, 3H), 1.58 (s, 3H), 1.51
(s, 3H). LC/MS (ESI.sup.+) m/z=383, 385 (M+H; 2 bromine
isotopes).
Example 13
##STR00066##
[0919] Synthesis of
(R)-5-Amino-3-(6-bromo-3-fluoropyridin-2-yl)-3,6,6-trimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide
Step 1. 1-(6-Bromo-3-fluoropyridin-2-yl)ethanol
[0920] To a solution of 6-bromo-3-fluoro-2-formylpyridine (1.05 g,
5.15 mmol) in THF (15 mL) at -78 C. was added dropwise
methylmagnesium bromide, 3 M solution in diethyl ether (2.5 mL).
The reaction was allowed to gradually warm up to RT and stirred
overnight. To this was added solid ammonium chloride (5 g) and
water (0.5 mL). The slurry was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give the title intermediate (1.13 g,
5.14 mmol).
Step 2. 1-(6-Bromo-3-fluoropyridin-2-0ethanone
[0921] To a solution of 1-(6-bromo-3-fluoropyridin-2-yl)ethanol
(1.13 g, 5.14 mmol) in dichloromethane (20 mL) was added manganese
(IV) oxide (2.68 g, 30.8 mmol). After stirring at RT overnight, the
solvent was evaporated. The residue was redissolved in toluene (15
mL), manganese (IV) oxide (2 g) was added, and the reaction was
heated at 100.degree. C. for 1 hour. The mixture was then filtered
through a silica gel pad, which was washed with ethyl acetate. The
filtrate was concentrated to provide the title compound (1.2 g) as
a yellow oil which was used directly in the next step.
Step 3.
(R)--N-(1-(6-Bromo-3-fluoropyridin-2-yl)-ethylidene)-2-methylpropa-
ne-2-sulfinamide
[0922] To a solution of 1-(6-bromo-3-fluoropyridin-2-yl)ethanone
(1.1 g, 5.05 mmol) and (R)-2-methylpropane-2-sulfinamide (1.223 g,
10.09 mmol) in THF (30 mL) was added titanium (IV) ethoxide (2.61
mL, 12.61 mmol) and the reaction was stirred at 80.degree. C. for 4
hours. After cooling to RT, 5 g of solid sodium bicarbonate was
added, followed by 0.5 mL of water. After stirring at RT for 30
minutes, the resulting slurry was filtered, and the precipitate was
rinsed with EtOAc. The filtrate was concentrated and the residue
was purified by silica-gel chromatography, eluting with 0-25% ethyl
acetate in DCM, to give the title intermediate (850 mg, 2.65 mmol).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.54 (dd, J=3.0, 8.5 Hz,
1H), 7.37 (t, J=9.1 Hz, 1H), 2.81 (s, 3H), 1.32 (s, 9H)
Step 4.
(R)-2-((2-Amino-2-(6-bromo-3-fluoropyridin-2-yl)propyl)sulfonyl)-2-
-methylpropanenitrile
[0923] To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile
(532 mg, 3.62 mmol) (azeotroped with toluene) in THF (10 mL) at
-78.degree. C. was added n-butyllithium, 1.6 M in hexanes (1.45 mL,
3.62 mmol). The reaction was stirred -78.degree. C. for 20 minutes,
and then a solution of
(R)--N-(1-(6-bromo-3-fluoropyridin-2-yl)ethylidene)-2-methylpropane-2-sul-
finamide (830 mg, 2.58 mmol) in toluene (10 mL) at -78.degree. C.,
which had been pretreated with a 2 M solution of trimethylaluminum
in toluene (1.29 mL, 2.58 mmol) for 10 minutes, was added dropwise.
The reaction was stirred at -78.degree. C. for 3 hours, and then
quenched with saturated aqueous ammonium chloride and extracted
with ethyl acetate. The combined organics were dried over sodium
sulfate, filtered, concentrated, and purified by silica-gel
chromatography, eluting with 10-20% ethyl acetate in
dichloromethane. The isolated product was dissolved in methanol (5
mL) of and treated with 4 N hydrogen chloride in dioxane (2 mL, 8
mmol). After stirring overnight, the solvents were evaporated, and
the residue was redissolved in ethyl acetate and washed with
saturated aqueous sodium bicarbonate, dried over sodium sulfate,
filtered and evaporated to provide the title intermediate (190 mg,
0.522 mmol).
Step 5.
(R)-5-amino-3-(6-bromo-3-fluoropyridin-2-yl)-3,6,6-trimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide
[0924] To a solution of
(R)-2-((2-amino-2-(6-bromo-3-fluoropyridin-2-yl)propyl)sulfonyl)-2-methyl-
propanenitrile (160 mg, 0.439 mmol) in toluene (10 mL) was added a
2 M solution of trimethylaluminum in toluene (439 .mu.L, 0.879
mmol) and the reaction was stirred at RT overnight. The solvent was
evaporated, and the residue was purified by silica-gel
chromatography, eluting with 2-5% methanol in DCM, to provide the
title compound (80 mg, 0.22 mmol). LC/MS (ESI.sup.+) m/z 364, 366
(M+H; 2 bromine isotopes).
Example 14
##STR00067##
[0925] Synthesis of
(R)-5-Amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide
Step 1: 1-(5-Bromo-2-fluoropyridin-3-yl)ethanol
[0926] To a solution of 5-bromo-2-fluoronicotinaldehyde (10 g, 49.0
mmol) in tetrahydrofuran (100 mL) at -78.degree. C. was added a 3 M
solution of methylmagnesium bromide in diethyl ether (24.51 ml,
73.5 mmol) dropwise. After the addition, the reaction was warmed
slowly to RT and stirred for 17 hours. The mixture was quenched
with saturated aqueous ammonium chloride and extracted with EtOAc.
The combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by silica-gel chromatography, eluting with
0-10% EtOAc in hexanes, to afford the title compound (10.80 g, 49.1
mmol) as a yellow oil.
Step 2: 1-(5-Bromo-2-fluoropyridin-3-yl)ethanone
[0927] To a solution of pyridinium dichromate (55.4 g, 147 mmol) in
dichloromethane (100 mL) at 0.degree. C. was added of
1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.80 g, 49.1 mmol) in
dichloromethane (30 mL). The reaction was allowed to warm up to RT
and stirred for two days. The mixture was filtered through
Celite.RTM., washed with DCM, and concentrated to afford the title
intermediate (11 g) as a light yellow solid.
Step 3:
(R)-5-Amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide
[0928] In an analogous sequence of reactions to those described for
Example 7, steps 1-4, 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (11
g, 50 5 mmol) was converted to the title compound in 20% yield.
LC/MS (ESI.sup.+) m/z=364, 366 (M+H; 2 bromine isotopes).
Example 15
##STR00068##
[0929] Synthesis of
(R)-5-Amino-3-(5-amino-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide
[0930] In an analogous reaction to that described for Example 9,
(R)-5-amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide (1.0 g, 2.75 mmol) was converted to the
title compound (0.172 g, 0.573 mmol) as a yellow-green oil. LC/MS
(ESI.sup.+) m/z=301 (M+H).
Example 16
##STR00069##
[0931] Synthesis of
5-amino-3-(2-bromo-5-fluoropyridin-4-yl)-3,6,6-trimethyl-3,6-dihydro-2H-1-
,4-thiazine 1,1-dioxide
[0932] In an analogous sequence of reactions to those described for
Example 7, steps 1-4, 1-(2-bromo-5-fluoropyridin-4-yl)ethanone
(11.63 g, 53 3 mmol) was converted to the title compound in 40%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (d, J=2.93
Hz, 1H), 7.61 (s, 1H), 4.70 (br. s., 2H), 3.44-3.61 (m, 2H),
1.68-1.82 (m, 6H), 1.61 (s, 3H). LC/MS (ESI.sup.+) m/z=364, 366
(M+H; 2 bromine isotopes).
Intermediate 8
##STR00070##
[0933] Synthesis of 3,8-Dichloro-1,7-naphthyridine
Step 1: 3-Bromo-5-chloropicolinonitrile
[0934] A microwave vial was charged with copper (I) cyanide (1.089
g, 12.16 mmol), 2,3-dibromo-5-chloropyridine (3 g, 11.06 mmol), and
propionitrile (15 mL). The vial was capped and irradiated in a
microwave reactor at 150.degree. C. for 2.5 hours. The solution was
concentrated, diluted with DCM (25 mL), and filtered. The filtrate
was concentrated, and the residue was purified by silica gel
chromatography, eluting with 0-30% EtOAc in heptanes, to afford the
title compound (2 g, 9.20 mmol). MS m/z=219 (M+H).
Step 2: 5-Chloro-3-((trimethylsilyl)ethynyl)picolinonitrile
[0935] A pressure vessel was charged with triethylamine (7.65 mL,
55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I)
iodide (0.263 g, 1.380 mmol), palladium (0)
tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol),
3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and
N,N-dimethylformamide (50 ml). The vessel was flushed with argon,
sealed, stirred at ambient temperature for 15 minutes, and then
heated at 50.degree. C. for 4 hours. The solution was diluted with
water and extracted with ethyl acetate. The combined organic layers
were concentrated, and the residue was purified by silica-gel
chromatography, eluting 0-50% ethyl acetate in hexane, to afford
the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H).
Step 3: 5-Chloro-3-(2,2-dimethoxyethyl)picolinonitrile
[0936] A pressure vessel was charged with
5-chloro-3-((trimethylsilyl)ethynyl)picolinonitrile (2 g, 8.52
mmol) and sodium methoxide (0.5 M in methanol, 42.6 mL, 21.30
mmol), sealed, and stirred at 55.degree. C. for one hour. The
solution was concentrated, and the residue was purified via silica
gel chromatography, eluting with 10% methanol in DCM to afford the
title compound (1.7 g, 7.50 mmol). MS m/z=227 (M+H).
Step 4: 3-Chloro-1,7-naphthyridin-8(7H)-one
[0937] To a solution of
5-chloro-3-(2,2-dimethoxyethyl)picolinonitrile (1.7 g, 7.50 mmol)
in acetone (50 mL) and water (150 mL) was added aqueous saturated
sodium carbonate (37.5 mL, 113 mmol) and 30% aqueous hydrogen
peroxide (38.3 mL, 375 mmol). The reaction was stirred at RT for
one hour, concentrated to remove most of the acetone, and extracted
with dichloromethane. The combined organic layers were
concentrated.
[0938] To a solution of this intermediate (1.8 g, 7.36 mmol) in
benzene (20 mL) was added p-toluenesulfonic acid (0.350 g, 1.839
mmol) and the reaction was sonicated for 10 minutes. The solution
was stirred overnight at 80.degree. C. and concentrated. The crude
product was purified via silica gel, eluting with 0-100% (80/20/1
ethyl acetate/methanol/ammonium hydroxide) in ethyl acetate, to the
title intermediate (1.1 g, 6.1 mmol). MS m/z=181 (M+H).
Step 5: 3,8-Dichloro-1,7-naphthyridine
[0939] A suspension of -chloro-1,7-naphthyridin-8(7H)-one (250 mg,
1.384 mmol) in phosphorus oxychloride (1.94 mL, 20.8 mmol) was
stirred at 95.degree. C. for one hour. The solution was
concentrated to afford the title compound (276 mg, 1.39 mmol). MS
m/z=199 (M+H).
Intermediate 9
##STR00071##
[0940] Synthesis of 8-Chloro-3-methoxy-1,7-naphthyridine
Step 1: 3-chloro-5-methoxypicolinonitrile
[0941] To a solution of 3,5-dichloropicolinonitrile (22.5 g, 130
mmol) in DMF (500 mL) at 0.degree. C. was added sodium methoxide
(6.67 g, 124 mmol) slowly. The reaction was stirred for 5 minutes
at 0.degree. C., then allowed to warm to RT and stir for 30
minutes. The solution was partitioned between water and EtOAc. The
organic layer was washed with water and concentrated. The crude
product was purified via silica gel chromatography, eluting with
0-75% ethyl acetate in heptanes, to afford a 1:1 ratio of the
desired isomer 3-chloro-5-methoxypicolinonitrile and
5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material
was used without further purification. MS m/z=169 (M+H).
Step 2: 5-Methoxy-3-((triethylsilyl)ethynyl)picolinonitrile
[0942] A sealed vessel was charged with bis(acetonitrile)palladium
(II) chloride (0.154 g, 0.593 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.848 g, 1.780 mmol), cesium carbonate (25.1 g, 77 mmol), the
product of Intermediate 9, step 1 (5 g, 29.7 mmol), and ACN (60
mL). The vessel was flushed with argon, sealed, and stirred at RT
for 25 minutes. To the reaction was added triethyl(ethynyl)silane
(5.41 g, 38.6 mmol), and the vessel was resealed and stirred at
90.degree. C. for 3 hours. The solution was concentrated, and the
residue was purified via silica gel chromatography, eluting with
0-50% ethyl acetate in heptanes, to afford the title compound (3.8
g, 13.9 mmol). MS m/z=273 (M+H).
Step 3: 3-(2,2-Dimethoxyethyl)-5-methoxypicolinonitrile
[0943] A pressure vessel was charged with
5-methoxy-3-((triethylsilyl)ethynyl)picolinonitrile (3.8 g, 13.95
mmol) and sodium methoxide (0.5 M in methanol, 69.7 mL, 34.9 mmol).
The vessel was sealed and stirred at 55.degree. C. for 2 hours. The
reaction was concentrated to afford the title intermediate (3.1 g,
13.95 mmol).
Step 4: 8-chloro-3-methoxy-1,7-naphthyridine
[0944] Using an analogous sequence of reactions to those described
in Intermediate 8, steps 4-5,
3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile (3.4 g, 15.30 mmol)
was converted to the title compound (552 mg, 2.84 mmol). MS m/z=195
(M+H).
Intermediate 10
##STR00072##
[0945] Synthesis of 5-Chloro-2-methoxypyrido[3,4-b]pyrazine
Step 5-Chloropyrido[3,4-b]pyrazin-2(1H)-one
[0946] A suspension 2-chloropyridine-3,4-diamine (2.5 g, 17.41
mmol) and a 50% solution of ethyl glyoxalate in toluene (3.45 mL,
17.41 mmol) in ethanol (34.8 mL) was stirred at reflux for 24
hours. The solution was cooled to -20.degree. C. for 16 hours, and
the resulting precipitate was collected by vacuum filtration and
rinsed with ethanol. The crude product was purified via
reverse-phase HPLC, eluting with 5-50% acetonitrile/0.1%
trifluoroacetic acid in water/0.1% trifluoroacetic acid, to afford
the title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H).
Step 2: 2,5-Dichloropyrido[3,4-b]pyrazine
[0947] A suspension of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one (0.57
g, 3.14 mmol) in phosphorus oxychloride (10.24 mL, 110 mmol) was
stirred at 110.degree. C. for two hours, and then concentrated. The
residue was dissolved in dichloromethane, washed with saturated
sodium bicarbonate, dried over anhydrous sodium sulfate, filtered,
and concentrated to afford the title compound (580 mg, 2.90 mmol).
MS m/z=200 (M+H).
Step 3: 5-Chloro-2-methoxypyrido[3,4-b]pyrazine
[0948] To a solution of 2,5-dichloropyrido[3,4-b]pyrazine (580 mg,
2.90 mmol) in N,N-dimethylformamide (10 mL) was added a 0.5-M
solution of sodium methoxide in methanol (6.09 mL, 3.04 mmol), and
the reaction was stirred at room temperature for 5 minutes. The
solution was diluted with water and extracted with ethyl acetate.
The organic layer was dried with sodium sulfate, filtered and
concentrated to afford the title compound (550 mg, 2.81 mmol). MS
m/z=196 (M+H).
Intermediate 11
##STR00073##
[0949] Synthesis of 8-Chloro-1,7-naphthyridine-3-carbonitrile
[0950] A screw-cap vial was charged with
3-chloro-1,7-naphthyridin-8(7H)-one (100 mg, 0.554 mmol), zinc
cyanide (52.7 .mu.l, 0.831 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (45.5 mg, 0.111
mmol), tris(dibenzylideneacetone)dipalladium(0) (40.6 mg, 0.044
mmol), DMF (2.74 mL) and water (28 .mu.L). The vial was purged with
argon, sealed, and stirred at 110.degree. C. for 1 hour. The
mixture was filtered through a pad of Celite, which was rinsed with
methanol and dimethylsulfoxide. The combined filtrates were
concentrated, and a few drops of water were added. The resulting
solids were collected by vacuum filtration, rinsed with water and
dried.
[0951] The solids were suspended in toluene (3.5 mL), and
phosphorus oxychloride (98 .mu.L, 1.052 mmol) and DIPEA (122 .mu.L,
0.701 mmol) were added. The reaction was stirred at 120.degree. C.
for 1.5 hours, cooled to RT, diluted with EtOAc, and washed with 2
M aqueous sodium carbonate. The organic portion was dried over
anhydrous sodium sulfate, filtered and concentrated. The crude
material was purified by silica gel chromatography, eluting with
5-50% EtOAc in heptanes, to provide the title compound (50 mg,
0.264 mmol) as a white solid. LC/MS (ESI.sup.+) m/z=190 (M+H).
Intermediate 12
##STR00074##
[0952] Synthesis of 3,8-Dichloro-5-fluoro-1,7-naphthyridine
Step 1:
3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
[0953] A pressure bottle was charged with
3-chloro-1,7-naphthyridin-8(7H)-one (15 g, 83 mmol), methanol (34.6
mL), ACN (173 mL) and
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (30.9 g, 87 mmol), and the mixture was
heated at 45.degree. C. for 15 hours. Water and ethyl acetate were
added, and the layers were separated. The aqueous portion was
extracted twice with ethyl acetate and once with DCM, and the
combined organic layers were dried with anhydrous sodium sulfate,
filtered and concentrated. The crude solid was triturated with a
minimum amount of ethyl acetate and filtered. The title
intermediate was isolated as an off-white solid (15.34 g, 80%) as a
3:1 mixture of diastereomers.
Step 2: 3,8-dichloro-5-fluoro-1,7-naphthyridine
[0954] A vial was charged with
3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
(7.5 g, 32.5 mmol), acetonitrile (130 mL) and phosphorus
oxychloride (9.09 mL, 98 mmol), and the mixture was stirred at
75.degree. C. for 15 hours. The mixture was concentrated, and the
crude material was purified by silica gel chromatography, eluting
with 0-50% ethyl acetate in heptanes, to provide the title compound
(5.57 g, 25 7 mmol, 79% yield) as a white solid. LC/MS (ESI.sup.+)
m/z=217 (M+H).
Intermediate 13
##STR00075##
[0955] Synthesis of
8-Chloro-5-fluoro-3-methoxy-1,7-naphthyridine
[0956] Using an analogous sequence of reactions to those described
for Intermediate 12, 3-chloro-1,7-naphthyridin-8(7H)-one was
converted to the title compound. LC/MS (ESI.sup.+) m/z=213
(M+H).
Intermediate 14
##STR00076##
[0957] Synthesis of 4,7-Dichloropyrido[3,2-d]pyrimidine
Step 1: 3-Amino-5-chloropicolinamide
[0958] To a suspension of 5-chloro-2-cyano-3-nitropyridine (1.274
mL, 10.9 mmol) in water (22 mL) was added 28% aqueous ammonium
hydroxide (3.94 mL, 28.3 mmol), and the reaction was stirred at RT
for 20 minutes. Sodium hydrosulfite (2.68 mL, 32.7 mmol) was added,
and the reaction mixture was stirred at RT for 70 minutes. The
yellow precipitate was collected by vacuum filtration to provide
the title compound (1.097 g, 6.39 mmol) as yellow solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.88 (br. s, 1H),
.delta. 7.73 (s, 1H), .delta. 7.39 (br. s, 1H), .delta. 7.23 (s,
1H), .delta. 7.06 (br. s, 2H). LC/MS (ESI.sup.+) m/z=172 (M+H).
Step 2: 7-Chloropyrido[3,2-d]pyrimidin-4(1H)-one
[0959] A suspension of 3-amino-5-chloropicolinamide (1.1 g, 6.41
mmol) in triethyl orthoformate (15.99 mL, 96 mmol) was stirred at
155.degree. C. for 22 hours. After cooling to RT, the yellow
precipitate was collected by vacuum filtration and washed with
hexanes to yield the title intermediate (1.03 g, 5.67 mmol) as a
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.20
(s, 1H) 8.27 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.25 Hz, 1H) 12.68 (br.
s., 1H). LC/MS (ESI.sup.+) m/z=182 (M+H).
Step 3: 4,7-Dichloropyrido[3,2-d]pyrimidine
[0960] To a mixture of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one
(250 mg, 1.377 mmol) in toluene (12 mL) were added DIPEA (0.73 mL,
4.20 mmol) and phosphorus oxychloride (0.391 mL, 4.27 mmol), and
the reaction was stirred at reflux for 1 hour. After cooling to RT,
the reaction mixture was concentrated to provide the title
compound. LC/MS (ESI.sup.+) m/z=200 (M+H).
Intermediate 15
##STR00077##
[0961] Synthesis of 4-Chloro-7-methoxypyrido[3,2-d]pyrimidine
Step 1: 7-Methoxypyrido[3,2-d]pyrimidin-4(1H)-one
[0962] A microwave vial was charged with
7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (110 mg, 0.606 mmol), a
0.5 M solution of sodium methoxide in methanol (3.65 mL, 1.817
mmol) and sodium methoxide (327 mg, 6.06 mmol). The vial was capped
and irradiated in a microwave reactor at 145.degree. C. for 30
minutes. The reaction was neutralized with saturated aqueous
ammonium chloride (3 mL), concentrated, and diluted with cold
water. The resulting precipitate was collected by vacuum filtration
and dried in vacuo to provide the title compound (107 mg, 0.604
mmol) as pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.95 (s, 3H) 7.49 (d, J=2.74 Hz, 1H) 8.11 (s, 1H) 8.47 (d,
J=2.74 Hz, 1H). LC/MS (ESI.sup.+) m/z=178 (M+H).
Step 2: 4-Chloro-7-methoxypyrido[3,2-d]pyrimidine
[0963] Using an analogous reaction to that described for
Intermediate 14, step 3, 7-methoxypyrido[3,2-d]pyrimidin-4(1H)-one
was converted to the title compound. LC/MS (ESI.sup.+) m/z=196
(M+H).
Intermediate 16
##STR00078##
[0964] Synthesis of 4-Chloro-5-fluoro-7-methoxyquinazoline
Step 1: 2-Amino-6-fluoro-4-methoxybenzonitrile
[0965] Ammonia gas was bubbled through a solution of
2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in
dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then
sealed and stirred at 90.degree. C. for 24 hours. The reaction
mixture was cooled to ambient temperature and concentrated in vacuo
to afford a tan residue. The residue was triturated with water,
collected be vacuum filtration, and dried in vacuo to afford the
title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS
(ESI.sup.+) m/z=167 (M+H).
Step 2: 5-Fluoro-7-methoxyquinazolin-4-ol
[0966] To a mixture of formic acid (11.43 mL, 298 mmol) and
sulfuric acid (0.866 mL, 16.25 mmol) was added
2-amino-6-fluoro-4-methoxybenzonitrile (0.9 g, 5.42 mmol) in
portions. The reaction mixture was stirred at 100.degree. C. for 1
hour, cooled to ambient temperature, and poured into 80 mL of an
ice-water mixture. The resulting precipitate was collected by
vacuum filtration and dried in vacuo to provide the title
intermediate (0.8 g, 4.12 mmol) as an off-white solid. LC/MS
(ESI.sup.+) m/z=195 (M+H).
Step 3: 4-Chloro-5-fluoro-7-methoxyquinazoline
[0967] To a suspension of 5-fluoro-7-methoxyquinazolin-4-ol (0.125
g, 0.644 mmol) in thionyl chloride (1.410 mL, 19.31 mmol) was added
N,N-dimethylformamide (0.028 mL, 0.361 mmol). The reaction was
stirred at 80.degree. C. for 6 hours and concentrated in vacuo. The
residue was suspended in saturated aqueous sodium bicarbonate and
extracted with dichloromethane. The organic layer was concentrated
in vacuo to generate the title compound (0.13 g, 0.611 mmol) as a
yellow solid. LC/MS (ESI.sup.+) m/z=213 (M+H).
Intermediate 17
##STR00079##
[0968] Synthesis of 3-Aminothieno[3,2-b]pyridine-6-carbonitrile
Step 1: Sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate
[0969] To a suspension of NaH (60% dispersion in mineral oil, 2.52
g, 63.0 mmol) in diethylether (75 mL) was added
3,3-dimethoxypropanenitrile (6.17 mL, 55.0 mmol) followed by methyl
formate (6.74 mL, 110 mmol). The solution was stirred for 3 days at
RT. The resulting solid was collected by vacuum filtration and
washed with ether to afford sodium
(E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (4.2 g, 25.4 mmol).
Step 2: 3-Aminothieno[3,2-b]pyridine-6-carbonitrile
[0970] To a solution of sodium
(E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (1012 mg, 6.13 mmol) in
methanol (12 mL) was added concentrated hydrochloric acid (503
.mu.L 6.13 mmol). The solution was stirred for 5 minutes, and then
a solution of thiophene-3,4-diamine (700 mg, 6.13 mmol) in methanol
(12 mL) was added. The solution was stirred at reflux for 3 hours,
and then a solution of concentrated HCl (1.0 mL) in methanol (2 mL)
was added. The reaction was stirred at reflux for an additional two
hours, quenched with TEA (3 mL), and concentrated. The crude
product was purified via silica gel chromatography, eluting with
0-100% ethyl acetate in heptanes, to provide the title compound
(250 mg, 1.427 mmol). MS m/z=176 (M+H).
Intermediate 18
##STR00080##
[0971] Synthesis of 3-Methoxy-1,7-naphthyridin-8-amine
Step 1: 3-Methoxy-N-(4-methoxybenzyl)-1,7-naphthyridin-8-amine
[0972] To a solution of 8-chloro-3-methoxy-1,7-naphthyridine (1 g,
5.14 mmol) in N,N-dimethylformamide (10.28 mL) was added potassium
carbonate (1.42 g, 10.28 mmol) followed by 4-methoxybenzylamine
(1.47 ml, 11.3 mmol). The reaction was stirred at 100.degree. C.
for 24 hours and then concentrated to generate a brown residue.
This was partitioned between ethyl acetate and water. The organic
layer was concentrated and purified by silica-gel chromatography,
eluting with 1-5% methanol in DCM, to provide the title compound
(1.37 g, 4.63 mmol) as a tan solid. LC/MS (ESI.sup.+) m/z=296
(M+H).
Step 2: 3-methoxy-1,7-naphthyridin-8-amine
[0973] To a solution of
N-(4-methoxybenzyl)-1,7-naphthyridin-8-amine (340 mg, 1.15 mmol) in
1,2-dichloroethane (5.80 mL) was added TFA (2.67 mL, 34.5 mmol).
The reaction was stirred at 75.degree. C. for 8 hours and then
concentrated. The residue was partitioned between DCM and aqueous
sodium bicarbonate. The organic layer was concentrated and purified
by silica-gel chromatography, eluting with 50-100% EtOAc in DCM, to
provide the title compound (171.7 mg, 0.98 mmol) as an off-white
solid. LC/MS (ESI.sup.+) m/z=176 (M+H).
Intermediate 19
##STR00081##
[0974] Synthesis of 5-(Difluoromethyl)picolinic acid
Step 1: 5-Formylpicolinonitrile
[0975] A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol)
and copper (I) cyanide (233 .mu.L, 7.58 mmol) in DMF (8.4 mL) was
stirred at 120.degree. C. for 1.5 hours, cooled to RT, and
partitioned between water and EtOAc. The solids were removed from
the aqueous layer by filtration, and the filtrate was extracted
with ethyl acetate. The combined organic layers were washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated. The crude product was purified by silica-gel
chromatography, eluting with a gradient of 40%-60% (40% ethyl
acetate in heptane) in heptane, to provide the title compound (236
mg, 1.786 mmol) as white solid. LC/MS (ESI.sup.+) m/z=133
(M+H).
Step 2: 5-(Difluoromethyl)picolinonitrile
[0976] To a solution of 5-formylpicolinonitrile (74 mg, 0.560 mmol)
in toluene (0.25 mL) was added bis(2-methoxyethyl)aminosulfur
trifluoride (0.258 mL, 1.400 mmol), and the reaction was stirred at
RT overnight. The reaction mixture was carefully quenched with
saturated aqueous sodium bicarbonate, diluted with water, and
extracted with DCM. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
crude material was purified by silica-gel chromatography, eluting
with a gradient of 40% to 60% (40% ethyl acetate/heptane) in
heptane, to provide the title compound (48 mg, 0.311 mmol) as white
solid. LC/MS (ESI.sup.+) m/z=155 (M+H).
Step 3: 5-(difluoromethyl)picolinic acid
[0977] A suspension of 5-(difluoromethyl)picolinonitrile (48 mg,
0.311 mmol) in 12 N aqueous hydrochloric acid (4.3 mL, 140 mmol)
was stirred at 110.degree. C. for 1.5 hours. After cooling to
ambient temperature, the reaction mixture was concentrated and
treated with DIPEA (2 mL). The mixture was concentrated and dried
in vacuo to provide the title compound in quantitative yield. LC/MS
(ESI.sup.+) m/z=174 (M+H).
Intermediate 20
##STR00082##
[0978] Synthesis of 2-Methoxyquinoxalin-5-amine
[0979] To a suspension of 5-aminoquinoxalin-2(1H)-one (440 mg, 2.73
mmol) in methanol (1 mL), DCM (8 mL) and acetonitrile (8 mL), at
0.degree. C., was added TEA (1.14 mL, 8.19 mmol), followed by
(trimethylsilyl)diazomethane (2 mL, 4.10 mmol; 2.0M in hexanes).
The reaction mixture was allowed to warm to RT and stirred for
additional 3 hours. The suspension was filtered, and the filtrate
was concentrated under reduced pressure. The crude product was
purified by silica gel chromatography, eluting with 10%-50% ethyl
acetate in hexane, to provide the title compound (167 mg, 0.953
mmol) as a light-yellow powder. LC/MS (ESI.sup.+) m/z=176
(M+H).
[0980] General amidation procedures: The following two (2) methods
were used to couple the amine core intermediates (see examples and
intermediates 1-15; note that the bromide need to be converted to
the corresponding amine to be used in the methods below).
Method A: HATU Procedure
[0981] To a solution of the aniline (1 equivalent) and the
carboxylic acid (1.1 equivalent) in DCM were added triethylamine
(1.5 eq) and
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate (HATU, 1.1 equivalent). The reaction
mixture was stirred at RT for 3 hours, diluted with DCM, and washed
with water and brine. The organic layer was concentrated.
[0982] The residue was redissolved in DCM, and TFA (10 equivalents)
was added. The reaction was stirred at RT for 1 hour, diluted with
DCM, and washed with saturated aqueous sodium bicarbonate and
brine, and concentrated. The crude product was purified by
silica-gel chromatography to provide the title compound.
Method B: DMTMM Procedure
[0983] To a solution of the aniline (1 equivalent) and the
carboxylic acid (1.1 equivalent) in 2:1 tetrahydrofuran/methanol
was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride (DMTMM, 1.5 equivalents). After about ten minutes, water
and saturated aqueous sodium bicarbonate were added, and the
mixture was extracted with DCM. The organic extract was washed with
brine and concentrated.
[0984] The residue was redissolved in DCM, and TFA (10 equivalents)
was added. The reaction was stirred at RT for 1 hour, diluted with
dichloromethane, and washed with saturated aqueous sodium
bicarbonate and brine, and concentrated. The crude product was
purified by silica-gel chromatography to provide the title
compound.
Examples 17-35
[0985] Using procedures similar to one of the general amidation
procedures described above, the appropriate aniline and carboxylic
acid were combined to provide the examples listed in Table 1:
TABLE-US-00001 TABLE 1 Example# Method Product Structure Analytical
Data 17 HATU Method N-(3-((3R)-5- amino-3,6,6- trimethyl-1,1-
dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5-
methoxy-2- pyrazine- carboxamide ##STR00083## LC/MS (ESI.sup.+) m/z
= 436 (M + H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.41 (s, 1 H) 8.88 (d, J = 1.27 Hz, 1 H) 8.40 (d, J = 1.37 Hz, 1
H) 7.75- 7.89 (m, 2 H) 7.13 (dd, J = 11.98, 8.85 Hz, 1 H) 6.00 (br.
s., 2 H) 4.01 (s, 3 H) 3.47-3.67 (m, 2 H) 1.61 (s, 3 H) 1.56 (s, 3
H) 1.46 (s, 3 H) 18 HATU Method N-(3-((3R)-5- amino-3,6,6-
trimethyl-1,1- dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)-5- fluoro-2- pyridine- carboxamide ##STR00084## LC/MS
(ESI.sup.+) m/z = 423 (M + H). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.53 (br. s., 1 H) 8.74 (d, J = 2.84 Hz, 1 H) 8.24
(dd, J = 8.95, 4.55 Hz, 1 H) 7.99 (td, J = 8.71, 2.84 Hz, 1 H)
7.80-7.91 (m, 2 H) 7.08-7.20 (m, 1 H) 6.02 (br. s., 2 H) 3.49-3.65
(m, 2 H) 1.63 (s, 3 H) 1.58 (s, 3 H) 1.49 (s, 3 H) 19 HATU Method
N-(3-((3R)-5- amino-3,6,6- trimethyl-1,1- dioxido-3,6-
dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5- chloro-2-
pyridine- carboxamide ##STR00085## LC/MS (ESI.sup.+) m/z = 439 (M +
H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.67 (s, 1 H)
8.85 (dd, J = 2.30, 0.73 Hz, 1 H) 8.12-8.30 (m, 2 H) 7.83- 8.01 (m,
2 H) 7.12- 7.28 (m, 1 H) 6.09 (br. s., 2 H) 3.45-3.86 (m, 2 H) 1.71
(s, 3 H) 1.66 (s, 3 H) 1.56 (s, 3 H) 20 DMTMM Method N-(3-((3R)-5-
amino-3,6,6- trimethyl-1,1- dioxido-3,6- dihydro-2H-1,4-
thiazin-3-yl)-4- fluorophenyl)-5- (difluoromethyl)- 2- pyridine-
carboxamide ##STR00086## LC/MS (ESI.sup.+) m/z = 455 (M + H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.48 (s, 3 H) 1.58
(s, 3 H) 1.63 (s, 3 H) 3.53- 3.64(m, 2 H) 6.02 (br. s., 2H)
7.13-7.29 (m, 2 H) 7.82-7.95 (m, 2 H) 8.28 (d, J = 1.37 Hz, 2 H)
8.94 (t, J = 1.22 Hz, 1 H) 10.68 (s, 1 H). 21 HATU Method
N-(3-((3R)-5- amino-3,6,6- trimethyl-1,1- dioxido-3,6-
dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5-
(trifluoromethyl)- 2- pyrazine- carboxamide ##STR00087## LC/MS
(ESI.sup.+) m/z = 479 (M + H). 22 HATU Method N-(3-((3R)-5-
amino-3,6,6- trimethyl-1,1- dioxido-3,6- dihydro-2H-1,4-
thiazin-3-yl)-4- fluorophenyl)-5- methoxy-2- pyridine- amide
##STR00088## _LC/MS (ESI.sup.+) m/z = 435 (M + H). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.34 (s, 1 H), 8.38 (d, J = 2.63 Hz, 1
H), 8.12 (d, J = 8.71 Hz, 1 H), 7.75-7.99 (m, 2 H), 7.60 (dd, J =
2.86, 8.71 Hz, 1 H), 7.13 (dd, J = 8.71, 11.80 Hz, 1 H), 6.03 (br.
s., 2 H), 3.93 (s, 3 H), 3.62 (d, J = 14.78 Hz, 1 H), 3.52 (d, J =
14.66 Hz, 1 H), 1.63 (s, 3 H), 1.57 (s, 3 H), 1.48 (s, 3 H). 23
HATU Method N-(3-((3R)-5- amino-3,6,6- trimethyl-1,1- dioxido-3,6-
dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5- cyano-2-
pyridine- carboxamide ##STR00089## _LC/MS (ESI.sup.+) m/z = 430 (M
+ H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.73 (s, 1 H),
9.08-9.30 (m, 1 H), 8.57 (dd, J = 1.95, 8.13 Hz, 1 H), 8.27 (d, J =
8.02 Hz, 1 H), 7.90 (d, J = 7.33 Hz, 1 H), 7.74- 7.87 (m, 1 H),
7.15 (dd, J = 8.88, 11.97 Hz, 1 H), 6.02 (br. s., 2 H), 3.63 (d, J
= 15.12 Hz, 1 H), 3.52 (d, J = 15.01 Hz, 1 H), 1.62 (s, 3 H), 1.57
(s, 3 H), 1.47 (s, 3 H). 24 HATU Method N-(3-((3R)-5- amino-3,6,6-
trimethyl-1,1- dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)-5- chloro-3-fluoro-2- pyridine- carboxamide
##STR00090## _LC/MS (ESI.sup.+) m/z = 457 (M + H). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.61 (s, 1 H), 8.64 (s, 1 H), 8.31 (dd,
J = 1.78, 10.14 Hz, 1 H), 7.66-7.90 (m, 2 H), 7.14 (dd, J = 8.82,
11.91 Hz, 1 H), 6.02 (br. s., 2 H), 3.63 (d, J = 14.66 Hz, 1 H),
3.52 (d, J = 15.12 Hz, 1 H), 1.62 (s, 3 H), 1.57 (s, 3 H), 1.46 (s,
3 H). 25 HATU Method N-(3-((3R)-5- amino-3,6,6- trimethyl-1,1-
dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5-
chloro-3-methyl- 2- pyridine- carboxamide ##STR00091## _LC/MS
(ESI.sup.+) m/z = 453 (M + H). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.48 (s, 1 H), 8.56 (d, J = 1.83 Hz, 1 H), 7.94-8.09 (m, 1
H), 7.78-7.92 (m, 1 H), 7.70 (d, J = 5.04 Hz, 1 H), 7.13 (dd, J =
9.11, 11.86 Hz, 1 H), 6.00 (br. s., 2H), 3.62 (d, J = 15.01 Hz, 1
H), 3.52 (d, J = 15.12 Hz, 1 H), 2.54 (s, 3 H), 1.62 (s, 3 H), 1.57
(s, 3H), 1.47 (s, 3 H). 26 HATU Method N-(3-((3R)-5- amino-3,6,6-
trimethyl-1,1- dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)-5- (2-butyn-1-yloxy)- 2- pyrazine- carboxamide
##STR00092## _LC/MS (ESI.sup.+) m/z = 474 (M + H). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.41 (s, 1 H), 8.88 (s, 1H), 8.44 (s, 1
H), 7.88 (dd, J = 2.46, 7.39 Hz, 1 H), 7.69-7.84 (m, 1 H), 7.13
(dd, J = 8.88, 11.86 Hz, 1 H), 6.01 (br. s., 2 H), 5.08 (d, J =
2.29 Hz, 2 H), 3.62 (d, J = 15.12 Hz, 1 H), 3.51 (d, J = 15.12 Hz,
1 H), 1.85 (t, J = 2.23 Hz, 3 H), 1.62 (s, 3 H), 1.57 (s, 3 H),
1.47 (s, 3 H). 27 HATU Method N-(3-((3R)-5- amino-3,6,6-
trimethyl-1,1- dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)-2- methyl-1,3- thiazole-4- carboxamide ##STR00093##
LC/MS (ESI.sup.+) m/z = 425 (M + H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.09 (s, 1 H), 8.25 (s, 1 H), 7.83 (d, J =
5.04 Hz, 1 H), 7.65-7.80 (m, 1 H), 7.11 (dd, J = 8.88, 11.86 Hz, 1
H), 6.00 (br. s., 2 H), 3.61 (d, J = 14.89 Hz, 1 H), 3.51 (d, J =
15.01 Hz, 1 H), 2.76 (s, 3 H), 1.62 (s, 3 H), 1.57 (s, 3H), 1.48
(s, 3 H) 28 HATU Method N-(3-((3R)-5- amino-3-methyl-
1,1-dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5-
methoxy-2- pyrazine- carboxamide ##STR00094## LC/MS (ESI.sup.+) m/z
= 408 (M + H). 29 HATU Method N-(3-((3R)-5- amino-3-methyl-
1,1-dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5-
chloro-2- pyridine- carboxamide ##STR00095## LC/MS (ESI.sup.+) m/z
= 411 (M + H). 30 HATU Method N-(3-((3R,6R)-5- amino-6-fluoro-
3,6-dimethyl-1,1- dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)-5- methoxy-2- pyrazine- carboxamide ##STR00096##
LC/MS (ESI.sup.+) m/z = 440 (M + H). 31 DMTMM Method
N-(3-(-5-amino-3- (fluoromethyl)- 6,6-dimethyl-1,1- dioxido-3,6-
dihydro-2H-1,4- thiazin-3-yl)-4- fluorophenyl)-5- methoxy-2-
pyrazine- carboxamide ##STR00097## LC/MS (ESI.sup.+) m/z = 454 (M +
H). 32 HATU Method N-(3-(-5-amino-3- (difluoromethyl)-
6,6-dimethyl-1,1- dioxido-3,6- dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)-5- methoxy-2- pyrazine- carboxamide ##STR00098##
LC/MS (ESI.sup.+) m/z = 472 (M + H). 33 DMTMM Method N-(3-((3S)-5-
amino-6,6- dimethyl-1,1- dioxido-3- (trifluoromethyl)-
3,6-dihydro-2H- 1,4-thiazin-3-yl)- 4-fluorophenyl)-5- methoxy-2-
pyrazine- carboxamide ##STR00099## LC/MS (ESI.sup.+) m/z = 490 (M +
H). 34 DMTMM Method N-(3-((3R)-5- amino-6,6- dimethyl-1,1-
dioxido-3- (trifluoromethyl)- 3,6-dihydro-2H- 1,4-thiazin-3-yl)-
4-fluorophenyl)-5- methoxy-2- pyrazine- carboxamide ##STR00100##
LC/MS (ESI.sup.+) m/z = 490 (M + H). 35 HATU Method N-(3-(-5-amino-
3,6,6-trimethyl- 1,1-dioxido-3,6- dihydro-2H-1,4-
thiazin-3-yl)-4,5- difluorophenyl)-5- chloro-2- pyridine-
carboxamide ##STR00101## LC/MS (ESI.sup.+) m/z = 457 (M + H).
Example 36
##STR00102##
[0986] Synthesis of
(S)--N-(3-(5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
[0987] The product of Example 32 was purified by chiral SFC, using
an AD-H column and eluting with 30% methanol/0.2% diethylamine in
CO.sub.2, to provide the title compound. LC/MS (ESI.sup.+) m/z=472
(M+H).
Example 37
##STR00103##
[0988] Synthesis of
(R)--N-(3-(5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydr-
o-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
[0989] The title compound is the other enantiomer recovered from
the chiral SFC purification of the product of Example 32, using an
AD-H column and eluting with 30% methanol/0.2% diethylamine in
CO.sub.2. LC/MS (ESI.sup.+) m/z=472 (M+H).
Example 38
##STR00104##
[0990] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloropicolinamide
[0991] The product of Example 35 was separated by chiral SFC, using
a ChiralPak IC column and eluting with 50% methanol/0.2%
diethylamine in CO.sub.2, to provide the title compound as an
off-white solid. LC/MS (ESI.sup.+) m/z=457 (M+H).
Example 39
##STR00105##
[0992] Synthesis of
(S)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4,5-difluorophenyl)-5-chloropicolinamide
[0993] The title compound is the other enantiomer recovered from
the chiral SFC purification of the product of Example 35, using a
ChiralPak column and eluting with 50% methanol/0.2% diethylamine in
CO.sub.2. LC/MS (ESI.sup.+) m/z=457 (M+H).
Example 40
##STR00106##
[0994] Synthesis of
(R)--N-(6-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide
[0995] A microwave vial was charged with
(R)-5-amino-3-(6-bromo-3-fluoropyridin-2-yl)-3,6,6-trimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide (38 mg, 0.104 mmol),
5-methoxypyrazine-2-carboxamide (23.97 mg, 0.156 mmol),
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (6.04 mg, 10.43
.mu.mol), tris(dibenzylideneacetone) dipalladium (0) (4.78 mg, 5.22
.mu.mol), cesium carbonate (0.365 mmol) and dioxane (1 mL). The
vial was purged with argon, sealed, and irradiated in a microwave
reactor at 110.degree. C. for 1 hour. After cooling to RT, the
reaction mixture was diluted with water and extracted with EtOAc.
The organic layer was concentrated, and the crude product was
purified by silica-gel chromatography, eluting with 2-8% MeOH in
ethyl acetate, to provide the title compound (18 mg, 0.041 mmol) as
an off-white solid. LC/MS (ESI.sup.+) m/z 437 (M+H). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm=9.97 (s, 1H), 9.02 (d, J=1.2
Hz, 1H), 8.35 (dd, J=2.9, 8.8 Hz, 1H), 8.22 (d, J=1.2 Hz, 1H), 7.48
(dd, J=8.9, 10.7 Hz, 1H), 4.15 (d, J=13.1 Hz, 1H), 4.08 (s, 3H),
3.37 (d, J=14.9 Hz, 1H), 1.84 (s, 3H), 1.71 (s, 3H), 1.67 (s,
3H).
Example 41
##STR00107##
[0996] Synthesis of
N-(4-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl-
)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide
[0997] In an analogous reaction to that described for Example 40,
5-amino-3-(2-bromo-5-fluoropyridin-4-yl)-3,6,6-trimethyl-3,6-dihydro-2H-1-
,4-thiazine 1,1-dioxide (0.070 g, 0.192 mmol) was converted to the
title compound (0.038 g) as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.09 (s, 1H), 8.95 (d, J=1.37 Hz, 1H),
8.44 (s, 1H), 8.38 (d, J=6.26 Hz, 1H), 8.28 (d, J=3.13 Hz, 1H),
6.23 (br. s., 2H), 4.02 (s, 3H), 3.68-3.79 (m, 1H), 3.58-3.67 (m,
1H), 1.61 (br. s., 6H), 1.45 (s, 3H). LC/MS (ESI.sup.+) m/z=437
(M+H).
Example 42
##STR00108##
[0998] Synthesis of
(R)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amin-
e
[0999] In an analogous reaction to that described for Example 1,
step 5, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)thio)propan-2-yl)carbamate
was converted to the title compound in 80% yield as an off-white
foam. LC/MS (ESI.sup.+) m/z=303, 305 (M+H; 2 bromine isotopes).
Example 43
##STR00109##
[1000] Synthesis of
(R)--N-(3-(5-amino-3-methyl-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophen-
yl)-5-methoxypyrazine-2-carboxamide
[1001] (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-yl)carb-
amate) was converted to the title compound as described in the HATU
procedure as a yellow oil. LC/MS (ESI.sup.+) m/z=376 (M+H). .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. ppm 8.93 (d, J=1.27 Hz, 1H)
8.31 (d, J=1.37 Hz, 1H) 7.88 (dd, J=7.38, 2.69 Hz, 1H) 7.77-7.81
(m, 1H) 7.17 (dd, J=12.08, 8.85 Hz, 1H) 4.09 (s, 3H) 3.32-3.38 (m,
4H) 1.83 (s, 3H).
Example 44
##STR00110##
[1002] Synthesis of
(2S,3R)-5-Amino-2-fluoro-3-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)-
amino)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
Step 1: tert-Butyl
((5R,6S)-6-fluoro-5-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)p-
henyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbama-
te
[1003] To a solution of tert-butyl
((5R)-5-(5-amino-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (75 mg, 0.180 mmol) and
8-chloro-3-methoxy-1,7-naphthyridine (38.5 mg, 0.198 mmol) in
2-propanol (4 mL) was added sulfuric acid (9.58 .mu.L, 0.180 mmol).
The reaction was stirred at 100.degree. C. for one hour, diluted
with water, and neutralized with saturated aqueous sodium
bicarbonate. The aqueous layer was extracted with ethyl acetate and
the combined organic layers were washed with brine and dried over
anhydrous sodium sulfate, filtered and concentrated.
Step 2:
(2S,3R)-5-Amino-2-fluoro-3-(2-fluoro-5-((3-methoxy-1,7-naphthyridi-
n-8-yl)amino)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1004] To a solution of tert-butyl
((5R,6S)-6-fluoro-5-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)p-
henyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbama-
te in DCM (10 mL) was added TFA (1.38 mL, 18.0 mmol). The reaction
was stirred at RT for 30 minutes, and then neutralized with
saturated aqueous sodium bicarbonate. The aqueous layer was
extracted with DCM, and the combined organic layers were
concentrated and purified via silica gel chromatography, eluting
with 20-100% EtOAC in heptanes, to afford the title compound (50
mg, 0.105 mmol). MS m/z=476 (M+H).
Examples 45-66
[1005] In a similar sequence of reactions to those described for
Example 44, the appropriate aniline and chloro-substituted
heterocycle were combined to provide the compounds listed in Table
2:
TABLE-US-00002 TABLE 2 Example# Product Structure Analytical Data
45 N-(3-((3R)-5-amino- 3,6,6-trimethyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-3- chloro-1,7-
naphthyridin-8-amine ##STR00111## LC/MS (ESI.sup.+) m/z = 462 (M +
H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.48 (s, 1 H)
8.90 (d, J = 2.35 Hz, 1 H) 8.51 (d, J = 2.45 Hz, 1 H) 8.08- 8.12
(m, 2 H) 7.96-8.02 (m, 1 H) 7.08-7.17 (m, 2 H) 6.03 (br. s, 2 H)
3.40- 3.73 (m, 2 H) 1.64 (s, 3 H) 1.57 (s, 3 H) 1.48 (s, 3 H) 46
N-(3-((3R)-5-amino- 3,6,6-trimethyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-3- methoxy-1,7-
naphthyridin-8-amine ##STR00112## LC/MS (ESI.sup.+) m/z = 458 (M +
H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.29 (s, 1 H)
8.63 (d, J = 2.84 Hz, 1 H) 8.14- 8.21 (m, 1 H) 8.04 (d, J = 5.67
Hz, 1 H) 7.92 (m, 1 H) 7.71 (d, J = 2.84 Hz, 1 H) 7.09-7.15 (m, 2
H) 6.07 (br. s., 2 H) 3.98 (s, 3 H) 3.45-3.74 (m, 2 H) 1.66 (s, 3
H) 1.59 (s, 3 H) 1.50 (s, 3 H) 47 N-(3-((3R)-5-amino-
3,6,6-trimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-
4-fluorophenyl)-2- methoxypyrido[3,4- b]pyrazin-5-amine
##STR00113## LC/MS (ESI.sup.+) m/z = 459 (M + H). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 9.35 (s, 1 H) 8.54 (s, 1 H) 8.21 (d,
J = 5.77 Hz, 1 H) 7.94-8.08 (m, 2 H) 7.01- 7.17 (m, 2 H) 6.02 (br.
s., 2 H) 4.06 (s, 3 H) 3.43-3.69 (m, 2 H) 1.64 (s, 3 H) 1.57 (s, 3
H) 1.48 (s, 3 H). 48 8-((3-((3R)-5-amino- 3,6,6-trimethyl-1,1-
dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)- 4- fluorophenyl)amino)-
1,7-naphthyridine-3- carbonitrile ##STR00114## LC/MS (ESI.sup.+)
m/z = 453 (M + H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
9.64 (s, 1 H) 9.23 (d, J = 1.96 Hz, 1 H) 8.99 (d, J = 1.96 Hz, 1 H)
8.22 (d, J = 5.67 Hz, 1 H) 8.01- 8.13 (m, 2 H) 7.23 (d, J = 5.77
Hz, 1 H) 7.11- 7.18 (m, 1 H) 6.06 (br. s., 2 H) 3.47-3.68 (m, 2 H)
1.66 (s, 3 H) 1.59 (s, 3 H) 1.50 (s, 3 H). 49 N-(3-((3R)-5-amino-
3,6,6-trimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-
4-fluorophenyl)-3- chloro-5-fluoro-1,7- naphthyridin-8-amine
##STR00115## .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 9.47 (s,
1 H), 9.00 (d, J = 4 Hz, 1 H), 8.58 (d, J = 4 Hz, 1 H), 8.15 (d, J
= 4 Hz, 1 H), 8.07-8.05 (m, 1 H), 8.02- 7.98 (m, 1 H), 7.12 (dd, J
= 8 Hz, 12 Hz, 1 H), 6.11 (br s, 2 H), 3.64 (d, J = 16 Hz, 1 H),
3.52 (d, J = 16 Hz, 1 H), 1.65 (s, 3 H), 1.58 (s, 3 H), 1.48 (s, 3
H). LC/MS (ESI.sup.+) m/z = 480 (M + H). 50 N-(3-((3R)-5-amino-
3,6,6-trimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-
4-fluorophenyl)-5- fluoro-3-methoxy- 1,7-naphthyridin-8- amine
##STR00116## .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 9.25 (s,
1 H), 8.70 (d, J = 4 Hz, 1 H), 8.08-8.05 (m, 2 H), 8.00- 7.98 (m, 1
H), 7.70 (d, J = 12 Hz, 1 H), 7.10 (dd, J = 4 Hz, 12 Hz, 1 H), 6.08
(br s, 2 H), 4.03 (s, 3 H), 3.64 (d, J = 16 Hz, 1 H), 3.52 (d, J =
16 Hz, 1 H), 1.65 (s, 3H), 1.58 (s, 3 H), 1.48 (s, 3 H). LC/MS
(ESI.sup.+) m/z = 476 (M + H). 51 N-(3-((3R)-5-amino-
3,6,6-trimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-
4-fluorophenyl)-7- methoxypyrido[3,2- d]pyrimidin-4-amine
##STR00117## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.48
(s, 3 H) 1.57 (s, 3 H) 1.64 (s, 3 H) 3.50-3.66 (m, 2 H) 3.99 (s, 3
H) 6.04 (br. s., 2 H) 7.15 (dd, J = 11.98, 8.85 Hz, 1 H) 7.60 (d, J
= 2.84 Hz, 1 H) 7.91-8.00 (m, 1 H) 8.08 (dd, J = 7.43, 2.64 Hz, 1
H) 8.63 (d, J = 2.8 Hz, 1 H) 8.59 (m, 1 H) 10.04 (s, 1 H). LC/MS
(ESI.sup.+) m/z = 459 (M + H). 52 N-(3-((3R)-5-amino-
3,6,6-trimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-
4-fluorophenyl)-7- chloropyrido[3,2- d]pyrimidin-4-amine
##STR00118## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.48
(s, 3 H) 1.57 (s, 3 H) 1.64 (s, 3 H) 3.50-3.66 (m, 2 H) 6.04 (br.
s., 2 H) 7.18 (dd, J = 11.93, 8.90 Hz, 1 H) 7.87-7.97 (m, 1 H) 8.12
(dd, J = 7.48, 2.59 Hz, 1 H) 8.40 (d, J = 2.25 Hz, 1 H) 8.65 (s, 1
H) 8.93 (d, J = 2.35 Hz, 1 H) 10.37 (s, 1 H). LC/MS (ESI.sup.+) m/z
= 463 (M + H). 53 N-(3-((3R)-5-amino- 3,6,6-trimethyl-1,1-
dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-5-
fluoro-7-methoxy-4- quinazolinamine ##STR00119## LC/MS (ESI.sup.+)
m/z = 476 (M + H). 54 N-(3-((3R)-5-amino- 3,6,6-trimcthyl-1,1-
dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-2-
methyl[1,3]thiazolo[4,5- c]pyridin-4-amine ##STR00120## LC/MS
(ESI.sup.+) m/z = 448 (M + H). .sup.1H NMR(400 MHz, DMSO-d.sub.6)
.delta. 9.00 (s, 1H), 7.86-8.09 (m, 3H), 7.42 (d, J = 5.58 Hz, 1H),
7.07 (dd, J = 8.90, 12.03 Hz, 1H), 5.99 (br. s., 2H), 3.62 (d, J =
15.16 Hz, 1H), 3.50 (d, J = 14.87 Hz, 1H), 2.87 (s, 3H), 1.66 (s,
3H), 1.58 (s, 3H), 1.50 (s, 3H). 55 N-(3-((3R)-5-amino-
3,6,6-trimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-
4-fluorophenyl)-2- (trifluoromethyl)pyrido [3,4-b]pyrazin-5- amine
##STR00121## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.49
(s, 3 H) 1.58 (s, 3 H) 1.66 (s, 3 H) 3.47-3.69 (m, 2 H) 6.04 (br.
s., 2 H) 7.15 (dd, J = 11.84, 9.10 Hz, 1 H) 7.36 (d, J = 5.97 Hz, 1
H) 7.98-8.19 (m, 2 H) 8.40 (d, J = 5.97 Hz, 1 H) 9.36 (s, 1 H) 9.96
(s, 1 H). LC/MS (ESI.sup.+) m/z = 497 (M + H). 56
N-(3-((3R)-5-amino- 3-methyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-3- methoxy-1,7-
naphthyridin-8-amine ##STR00122## LC/MS (ESI.sup.+) m/z = 430 (M +
H). 57 N-(3-((3R)-5-amino- 3-methyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-3- chloro-1,7-
naphthyridin-8-amine ##STR00123## LC/MS (ESI.sup.+) m/z = 434 (M +
H) 58 N-(3-((3R)-5-amino- 3-methyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-2- methyl[1,3]thiazolo[4,5-
c]pyridin-4-amine ##STR00124## LC/MS (ESI.sup.+) m/z = 420 (M + H)
59 N-(3-((3R,6R)-5- amino-6-fluoro-3,6- dimethyl-1,1-
dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-2-
methoxypyrido[3,4- b]pyrazin-5-amine ##STR00125## LC/MS (ESI.sup.+)
m/z = 463 (M + H) 60 8-((3-((3R,6R)-5- amino-6-fluoro-3,6-
dimethyl-1,1- dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)- 4-
fluorophenyl)amino)- 1,7-naphthyridine-3- carbonitrile ##STR00126##
LC/MS (ESI.sup.+) m/z = 457 (M + H) 61 N-(3-(5-amino-3-
(fluoromethyl)-6,6- dimethyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-3- methoxy-1,7-
naphthyridin-8-amine ##STR00127## LC/MS (ESI.sup.+) m/z = 476 (M +
H) 62 N-(3-(5-amino-3- (difluoromethyl)-6,6- dimethyl-1,1-
dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)- 4-fluorophenyl)-3-
methoxy-1,7- naphthyridin-8-amine ##STR00128## LC/MS (ESI.sup.+)
m/z = 494 (M + H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.37
(s, 1H), 8.70 (d, J = 2.74 Hz, 1H), 8.24-8.37 (m, 1H), 8.01-8.23
(m, 2H), 7.79 (d, J = 2.84 Hz, 1H), 7.14- 7.26 (m, 2H), 6.68 (br.
s., 2H), 6.04 (t, J = 56.0 Hz, 1H), 4.05 (s, 3H), 3.90 (d, J = 4.30
Hz, 2H), 1.70 (s, 3H), 1.54 (s, 3H) 63 N-(3-((3S)-5-amino-
6,6-dimethyl-1,1- dioxido-3- (trifluoromethyl)-3,6- dihydro-2H-1,4-
thiazin-3-yl)-4- fluorophenyl)-3- methoxy-1,7- naphthyridin-8-amine
##STR00129## .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.43
(s, 3 H) 1.66 (s, 3 H) 3.85- 4.08 (m, 5 H) 5.76 (s, 1 H) 6.81 (br.
s., 2 H) 7.10- 7.18 (m, 1 H) 7.72 (d, J = 2.78 Hz, 1 H) 8.06 (d, J
= 5.70 Hz, 1 H) 8.18 (dt, J = 8.77, 3.43 Hz, 1 H) 8.27 (dd, J =
7.45, 2.78 Hz, 1 H) 8.63 (d, J = 2.92 Hz, 1 H) 9.36 (s, 1 H). LC/MS
(ESI.sup.+) m/z = 512 (M + H). 64 N-(3-((3R)-5-amino-
6,6-dimethyl-1,1- dioxido-3- (trifluoromethyl)-3,6- dihydro-2H-1,4-
thiazin-3-yl)-4- fluorophenyl)-3- methoxy-1,7- naphthyridin-8-amine
##STR00130## .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.44
(s, 3 H) 1.66 (s, 3 H) 3.90- 4.08 (m, 5 H) 6.82 (br. s., 2 H)
7.11-7.19 (m, 2 H) 7.72 (d, J = 2.78 Hz, 1 H) 8.06 (d, J = 5.85 Hz,
1 H) 8.14-8.23 (m, 1 H) 8.27 (dd, J = 7.38, 2.85 Hz, 1 H) 8.63 (d,
J = 2.78 Hz, 1 H) 9.36 (s, 1 H). LC/MS (ESI.sup.+) m/z = 512 (M +
H) 65 N-(3-(5-amino-3,6,6- trimethyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 4,5-difluorophenyl)- 3-chloro-1,7-
naphthyridin-8-amine ##STR00131## LC/MS (ESI.sup.+) m/z = 480 (M +
H) 66 N-(5-((3R)-5-amino- 3,6,6-trimethyl-1,1- dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)- 6-fluoro-3-pyridinyl)- 3-methoxy-1,7-
naphthyridin-8-amine ##STR00132## .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.50 (s, 3 H) 1.63 (d, J = 16.82 Hz, 6 H)
3.54-3.71 (m, 2 H) 4.00 (s, 3 H) 6.13 (br. s., 2 H) 7.19 (d, J =
5.67 Hz, 1 H) 7.74 (d, J = 2.93 Hz, 1 H) 8.07 (d, J = 5.67 Hz, 1 H)
8.59-8.68 (m, 2 H) 8.83 (t, J = 2.25 Hz, 1 H) 9.70 (s, 1 H). LC/MS
(ESI.sup.+) m/z = 459 (M + H)
Example 67
##STR00133##
[1006] Synthesis of
(S)-5-Amino-3-(difluoromethyl)-3-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-
-8-yl)amino)phenyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1007] Example 62 was purified by chiral SFC, using an AD-H column
and eluting with 35% methanol/0.2% diethylamine in CO.sub.2, to
provide the title compound. LC/MS (ESI.sup.+) m/z=494 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H), 8.70 (d,
J=2.74 Hz, 1H), 8.24-8.37 (m, 1H), 8.01-8.23 (m, 2H), 7.79 (d,
J=2.84 Hz, 1H), 7.14-7.26 (m, 2H), 6.68 (br. s., 2H), 6.04 (t,
J=56.0 Hz, 1H), 4.05 (s, 3H), 3.90 (d, J=4.30 Hz, 2H), 1.70 (s,
3H), 1.54 (s, 3H).
Example 68
##STR00134##
[1008] Synthesis of
(R)-5-Amino-3-(difluoromethyl)-3-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-
-8-yl)amino)phenyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1009] The title compound is the other enantiomer recovered from
the chiral SFC purification of Example 62, using an AD-H column and
eluting with 35% methanol/0.2% diethylamine in CO.sub.2. LC/MS
(ESI.sup.+) m/z=494 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.37 (s, 1H), 8.70 (d, J=2.74 Hz, 1H), 8.24-8.37 (m, 1H),
8.01-8.23 (m, 2H), 7.79 (d, J=2.84 Hz, 1H), 7.14-7.26 (m, 2H), 6.68
(br. s., 2H), 6.04 (t, J=56.0 Hz, 1H), 4.05 (s, 3H), 3.90 (d,
J=4.30 Hz, 2H), 1.70 (s, 3H), 1.54 (s, 3H).
Example 69
##STR00135##
[1010] Synthesis of
(R)-5-Amino-3-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2,3-difluorophen-
yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1011] Example 65 was purified by chiral SFC, using a Chiralpak IC
column and eluting with 60% methanol/0.2% diethylamine in CO.sub.2,
to provide the title compound. LC/MS (ESI.sup.+) m/z=480 (M+H).
Example 70
##STR00136##
[1012] Synthesis of
(S)-5-Amino-3-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2,3-difluorophen-
yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1013] The title compound is the other enantiomer recovered from
the chiral SFC purification of Example 65, using a Chiralpak IC
column and eluting with 60% methanol/0.2% diethylamine in CO.sub.2.
LC/MS (ESI.sup.+) m/z=480 (M+H).
Example 71
##STR00137##
[1014] Synthesis of
(R)-5-Amino-3-(2,3-difluoro-5-((2-hydroxypyrido[3,4-b]pyrazin-5-yl)amino)-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1015] In an analogous reaction sequence described for Example 44,
tert-butyl
(5-(5-amino-2,3-difluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2-
H-1,4-thiazin-3-yl)carbamate and
5-chloro-2-methoxypyrido[3,4-b]pyrazine were combined to provide
the racemic product, which was purified by chiral SFC, using a
ChiralPak IC column and eluting with 50% methanol/0.2% diethylamine
in CO.sub.2, to provide the title compound. LC/MS (ESI.sup.+)
m/z=463 (M+H).
Example 72
##STR00138##
[1016] Synthesis of
(S)-5-Amino-3-(2,3-difluoro-5-((2-hydroxypyrido[3,4-b]pyrazin-5-yl)amino)-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1017] The title compound is the other enantiomer recovered from
the chiral SFC purification of Example 71, using a ChiralPak column
and eluting with 50% methanol/0.2% diethylamine in CO.sub.2. LC/MS
(ESI.sup.+) m/z=463 (M+H).
Example 73
##STR00139##
[1018] Synthesis of
(R)-3-((3-(5-Amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile
[1019] A microwave vial was charged with
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (125 mg, 0.344 mmol),
3-aminothieno[3,2-b]pyridine-6-carbonitrile (90 mg, 0.516 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (43.9 mg,
0.103 mmol), sodium tert-butoxide (93 mg, 0.964 mmol),
tris(dibenzylideneacetone)dipalladium(0) (31.5 mg, 0.034 mmol), and
toluene (1.72 mL). The vial was purged with argon, sealed, and
irradiated in a microwave reactor at 100.degree. C. for 1.5 hours.
The reaction was diluted with water and extracted with ethyl
acetate; the organic layer was concentrated. The crude product was
purified via silica gel chromatography, eluting with 20-100% ethyl
acetate in hexane, to the title compound (50 mg, 0.109 mmol, 32%
yield). LC/MS (ESI.sup.+) m/z=458 (M+H). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.07 (d, J=1.9 Hz, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.46
(s, 1H), 7.52 (dd, J=2.9, 7.2 Hz, 1H), 7.49 (s, 1H), 7.17-7.24 (m,
1H), 7.06 (dd, J=8.8, 11.9 Hz, 1H), 6.09 (br. s., 2H), 3.66 (d,
J=15.5 Hz, 1H), 3.51 (d, J=15.5 Hz, 1H), 1.63 (s, 3H), 1.58 (s,
3H), 1.47 (s, 3H).
Example 74
##STR00140##
[1020] Synthesis of
(3R,6R)-5-Amino-6-fluoro-3-(2-fluorophenyl-5-((3-methoxy-1,7-naphthyridin-
-8-yl)amino)phenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1021] In an analogous reaction to that described for Example 73,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (50 mg, 0.136 mmol) and
3-methoxy-1,7-naphthyridine-8-amine (29 mg, 0.163 mmol) were
converted to the title compound (7 mg, 0.015 mmol, 11% yield) as an
off-white solid. LC/MS (ESI.sup.+) m/z=462 (M+H).
Example 75
##STR00141##
[1022] Synthesis of
(R)-5-Amino-3-(2-fluoro-5-((2-methoxyquinoxalin-5-yl)amino)phenyl)-3,6,6--
trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1023] A sealable vial was charged with
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (34 mg, 0.094 mmol),
2-methoxyquinoxalin-5-amine (18.04 mg, 0.103 mmol) and
(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoe-
thyl)phenyl)]palladium(II) chloride (13.83 mg, 0.019 mmol). The
vial was purged with nitrogen, and tetrahydrofuran (0.1 mL) was
added, followed by lithium bis(trimethylsilyl)amide (234 .mu.L,
0.234 mmol; 1.0M solution in tetrahydrofuran). The reaction mixture
was stirred for 2 hours at 65.degree. C., cooled to ambient
temperature, and partitioned between 1 M aqueous hydrochloric acid
and ethyl acetate. The organic phase was separated and dried over
anhydrous magnesium sulfate, filtered, and concentrated. The crude
product was purified by reverse-phase preparative HPLC, eluting
with 10-100% (0.1% trifluoroacetic acid in acetonitrile) in (0.1%
trifluoroacetic acid in water). The product fractions were combined
and concentrated, and the residue was redissolved in
dichloromethane and washed with 2 M aqueous sodium carbonate. The
organic phase was dried over anhydrous magnesium sulfate, filtered,
and concentrated to provide the title compound as a greenish-yellow
solid. LC/MS (ESI.sup.+) m/z=458 (M+H). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.66 (s, 3H) 1.73 (s, 3H) 1.87 (s, 3H) 3.65
(d, J=4.30 Hz, 2H) 7.07 (dd, J=11.64, 8.71 Hz, 1H) 7.21 (dd,
J=15.06, 8.22 Hz, 2H) 7.25-7.30 (m, 4H) 7.40-7.52 (m, 2H) 7.80 (s,
1H) 8.31 (s, 1H).
Example 76
##STR00142##
[1024] Synthesis of
(R)-8-((3-(5-Amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile
[1025] A sealable vial was charged with
(R)-5-amino-3-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino)-2-fluor-
ophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
(150 mg, 0.313 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (25.7 mg, 0.063
mmol), tris(dibenzylideneacetone)dipalladium(0) (22.90 mg, 0.025
mmol), ZnCN.sub.2 (29.8 .mu.L, 0.469 mmol), N,N-dimethylformamide
(1.5 mL), and a drop of water. The vial was purged with argon and
the reaction was heated at 110.degree. C. for 1 hour. The reaction
was partitioned between water and dichloromethane, and the organic
portion was washed with brine, dried with anhydrous sodium sulfate,
filtered and concentrated. The crude product was purified by silica
gel chromatography, eluting with 5-75% (3:1 ethyl acetate/ethanol,
2% ammonium hydroxide) in heptanes, to provide the title compound
(80 mg, 0.170 mmol, 54.4% yield) as a yellow solid. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. (s, 1H), 9.33 (d, J=4 Hz, 1H),
9.14 (d, J=4 Hz, 1H), 8.24 (s, 1H), 8.12-8.10 (m, 1H), 8.00-7.98
(m, 1H), 7.13 (dd, J=8 Hz, 12 Hz, 1H), 6.05 (br s, 2H), 3.64 (d,
J=16 Hz, 1H), 3.51 (d, J=16 Hz, 1H), 1.65 (s, 3H), 1.58 (s, 3H),
1.48 (s, 3H). LC/MS (ESI.sup.+) m/z=471 (M+H).
Example 77
##STR00143##
[1026] Synthesis of
(R)-5-Amino-3-(5-((6-chloroisoxazolo[4,5-b]pyridin-3-yl)amino)-2-fluoroph-
enyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: 5-Chloro-3-fluoro-N-methoxy-N-methylpicolinamide
[1027] To a stirred mixture of 5-chloro-3-fluoropicolinic acid
(3.62 g, 20.62 mmol) in dichloromethane (50 mL) were added
1H-benzo[d][1,2,3]triazol-1-ol (0.42 g, 3.09 mmol),
N.sub.1-((ethylimino)methylene)-N.sub.3,N.sub.3-dimethylpropane-1,3-diami-
ne HCl (5.93 g, 30.9 mmol), N,O-dimethylhydroxylamine HCl (3.02 g,
30.9 mmol), and TEA (7.19 mL, 51.6 mmol). The reaction mixture was
stirred at RT for 2 hours, and then partitioned between ethyl
acetate and water. The aqueous layer was extracted with EtOAc, and
the combined organic layers were dried over anhydrous sodium
sulfate, filtered, and concentrated. The crude product was purified
by column chromatography, eluting with 0-100% EtOAc in heptane, to
provide the title intermediate (3.71 g) as a white solid.
Step 2: 5-Chloro-3-fluoropicolinaldehyde
[1028] To a solution of
5-chloro-3-fluoro-N-methoxy-N-methylpicolinamide (3.71 g, 16.97
mmol) in THF (50 mL) at -78.degree. C. was added al M solution of
lithium aluminum hydride in THF (7.81 mL, 7.81 mmol). After
stirring at -78.degree. C. for 30 minutes, the mixture was quenched
with water (35 mL) and brine (30 mL) and allowed to warm to ambient
temperature. The aqueous layer was extracted with ethyl acetate,
and the combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by column chromatography, eluting with 0-50%
ethyl acetate in heptane, to afford the title compound as a light
yellow oil.
Step 3: (E)-5-Chloro-3-fluoropicolinaldehyde oxime
[1029] To a solution of 5-chloro-3-fluoropicolinaldehyde (2.71 g,
17.0 mmol) and hydroxylamine (50 wt % in water, 1.40 g, 21.2 mmol)
in MeOH (30 mL) was added 5 N aqueous NaOH (5.10 mL, 25.5 mmol).
After 1.5 hours, the mixture was neutralized with concentrated HCl
and extracted with DCM. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated to
afford the title compound (2.61 g) as orange solid. The product was
used in next step without further purification.
Step 4: (Z)-5-Chloro-3-fluoro-N-hydroxypicolinimidoyl chloride
[1030] To a solution of (E)-5-chloro-3-fluoropicolinaldehyde oxime
(0.50 g, 2.86 mmol) in DMF (10 mL) was added N-chlorosuccinimide
(0.41 g, 3.08 mmol). The mixture was stirred at 50.degree. C. for
30 minutes, another portion of N-chlorosuccinimide (56 mg) was
added, and the reaction was stirred at 50.degree. C. for 30
minutes. The reaction mixture was poured into ice water and
extracted with EtOAc. The organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated to afford the title compound as a yellow oil.
Step 5:
N-(5-(5-Bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihy-
dro-2H-1,4-thiazin-3-yl)benzamide
[1031] To a solution of
(R,S)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1-
,4-thiazine 1,1-dioxide (2.42 g, 6.66 mmol) in DMF (40 mL) was
added TEA (1.39 mL, 9.99 mmol) and benzoic anhydride (1.66 g, 7.33
mmol). The reaction was stirred at ambient temperature for 1 hour,
diluted with saturated aqueous sodium carbonate, and extracted with
ethyl acetate. The organic layer was washed with water and brine,
dried over anhydrous sodium sulfate, and concentrated. The crude
product was purified by column chromatography, eluting with 0-50%
ethyl acetate in heptane, to provide the title compound (3.02 g) as
a yellow solid.
Step 6:
(R)--N-(5-(5-Amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)benzamide
[1032] A mixture of
N-(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H--
1,4-thiazin-3-yl)benzamide (3.00 g, 6.42 mmol), sodium azide (1.25
g, 19.26 mmol), (+)-sodium L-ascorbate (0.51 g, 2.57 mmol),
(1R,2R)--N.sub.1,N.sub.2-dimethylcyclohexane-1,2-diamine (1.01 mL,
6.42 mmol), and copper (I) iodide (0.49 g, 2.57 mmol) in ethanol
(34.5 mL) and water (15 mL) under a nitrogen atmosphere was stirred
at 70.degree. C. for 3 hours. The reaction was cooled to RT and
partitioned between ethyl acetate and water. The aqueous layer was
extracted with ethyl acetate, and the combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated. The crude product was resubjected to the reaction
conditions and stirred at 80.degree. C. for 5 hours. The reaction
was again cooled to RT and partitioned between ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate, and the
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by column chromatography, eluting with 0-60%
ethyl acetate in heptane, to afford the title compound (1.80 g) as
an off-white solid.
Step 7:
(Z)--N-(5-(5-(5-Chloro-3-fluoro-N'-hydroxypicolinimidamido)-2-fluo-
rophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)benz-
amide
[1033] A mixture of (Z)-5-chloro-3-fluoro-N-hydroxypicolinimidoyl
chloride (0.52 g, 2.47 mmol) and
N-(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H--
1,4-thiazin-3-yl)benzamide (0.83 g, 2.06 mmol) in THF (8 mL) was
stirred at reflux overnight, and then stirred at 75.degree. C. for
4 hours. The cooled reaction mixture was partitioned between ethyl
acetate and water. The aqueous phase was extracted with ethyl
acetate, and the combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, filtered and concentrated. The
crude product was purified by column chromatography, eluting with
20-100% ethyl acetate in heptane, to provide the title compound
(0.30 g) as an orange solid.
Step 8:
N-(5-(5-((6-Chloroisoxazolo[4,5-b]pyridin-3-yl)amino)-2-fluorophen-
yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)benzamide
[1034] To a solution of
(Z)--N-(5-(5-(5-chloro-3-fluoro-N'-hydroxypicolinimidamido)-2-fluoropheny-
l)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)benzamide
(0.60 g, 1.05 mmol) in DMF (25 mL) at 0.degree. C. under a nitrogen
atmosphere was added 60% NaH in mineral oil (0.15 g, 3.78 mmol).
The mixture was gradually warmed to ambient temperature and stirred
for 2 hours. The reaction was partitioned between water and EtOac,
and the aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with water and brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by column chromatography, eluting with 0-50%
ethyl acetate in heptane, to provide the title compound (0.43 g) as
an off-white solid.
Step 9:
(R)-5-Amino-3-(5-((6-chloroisoxazolo[4,5-b]pyridin-3-yl)amino)-2-f-
luorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1035] A sealed tube was charged with
N-(5-(5-((6-chloroisoxazolo[4,5-b]pyridin-3-yl)amino)-2-fluorophenyl)-2,2-
,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)benzamide
(0.43 g, 0.77 mmol), tetrahydrofuran (6 mL) and 2.0 M ammonia in
methanol (19.33 mL, 38.70 mmol). The tube was sealed and stirred at
60.degree. C. overnight. The reaction was concentrated in vacuo,
and the residue was triturated with DCM and then MeOH. The
resulting solid was purified by chiral SFC, using a ChiralCel OD-H
column and eluting with 55% (20 mM ammonia in MeOH) in CO.sub.2, to
provide the title compound as a white solid. .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.42 (br. s., 1H), 7.86 (br. s., 1H),
7.74-7.39 (m, 2H), 6.95 (br. s., 1H), 3.65 (br. s., 2H), 2.03-1.44
(m, 9H). LC/MS (ESI.sup.+) m/z=452 (M+H).
Example 78
##STR00144##
[1036] Synthesis of
(S)-5-Amino-3-(5-((6-chloroisoxazolo[4,5-b]pyridin-3-yl)amino)-2-fluoroph-
enyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1037] The title compound is the other enantiomer recovered from
the chiral SFC purification of Example 77, using a ChiralCel OD-H
column and eluting with 55% (20 mM ammonia in methanol) in
CO.sub.2. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.39 (br.
s., 1H), 7.81 (br. s., 1H), 7.69-7.39 (m, 2H), 6.93 (br. s., 1H),
3.65 (br. s., 2H), 1.89-1.52 (m, 9H). LC/MS (ESI.sup.+) m/z=452
(M+H).
Example 79
##STR00145##
[1038] Synthesis of
(R)-5-Amino-3-(2-fluoro-5-(naphthalen-1-ylthio)phenyl)-3,6,6-trimethyl-3,-
6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1039] To a solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (50 mg, 0.138 mmol) and
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.96 mg, 0.014
mmol) in dioxane (1 mL) were added 1-naphthalenethiol (0.021 mL,
0.151 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.30 mg,
6.88 .mu.mol), and DIPEA (0.048 mL, 0.275 mmol). The reaction was
flushed with argon, sealed, and stirred at 100.degree. C. for 6
hours. The reaction mixture was partitioned between water and
EtOAc; the organic layer was washed with water and brine and
concentrated. The crude product was purified by silica-gel
chromatography, eluting with 20-100% ethyl acetate in heptane, to
provide the title compound (47 mg, 0.106 mmol) as a off-white
powder. LC/MS (ESI.sup.+) m/z=443 (M+H).
Example 80
##STR00146##
[1040] Synthesis of
(R)-5-amino-3-(2-fluoro-5-(phenylethynyl)phenyl)-3,6,6-trimethyl-3,6-dihy-
dro-2H-1,4-thiazine 1,1-dioxide
[1041] To a solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.275 mmol) and ethynylbenzene
(0.060 mL, 0.551 mmol) in dioxane (1 mL) was added copper(I) iodide
(7.86 mg, 0.041 mmol), bis(triphenylphosphine)palladium(ii)
dichloride (19.32 mg, 0.028 mmol), and triethylamine (0.19 mL, 1.38
mmol). The vial was flushed with argon, sealed, and stirred at
100.degree. C. for 5 hours. The reaction was diluted with ethyl
acetate, washed with water and brine, dried over anhydrous sodium
sulfate, filtered, and concentrated. The crude product was purified
by reverse phase HPLC, eluting with a gradient of 15-90% (1% TFA in
ACN)/(1% trifluoroacetic acid in water). The product fractions were
combined and extracted with EtOAc. The organic layer was washed
with aqueous sodium carbonate and water, dried over anhydrous
sodium sulfate, filtered, and concentrated to provide the title
compound (44 mg, 0.114 mmol) as an off-white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.64 (s, 3H) 1.71 (s, 3H) 1.82
(s, 3H) 3.51-3.66 (m, 2H) 7.05 (dd, J=12.13, 8.41 Hz, 1H) 7.33-7.38
(m, 3H) 7.44 (ddd, J=8.41, 4.74, 2.20 Hz, 1H) 7.50-7.55 (m, 2H)
7.69 (dd, J=7.87, 2.20 Hz, 1H). LC/MS (ESI.sup.+) m/z=385
(M+H).
Example 81
##STR00147##
[1042] Synthesis of
3R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-th-
iazine 1,1-dioxide
Step 1: tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)sulfonyl)propan-2-yl)ca-
rbamate
[1043] In an analogous oxidation to that described for Example 1,
step 4, tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)thio)propan-2-yl)carbam-
ate was converted to the title compound (0.87 g, 1.94 mmol) as a
white foam. LC/MS (ESI.sup.+) m/z=471, 473 (M+Na; 2 bromine
isotopes).
Step 2:
(3R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2-
H-1,4-thiazine 1,1-dioxide
[1044] In an analogous reaction to that described for Example 5,
step 1, tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)sulfonyl)propan-2-yl)ca-
rbamate was converted to the title compound (120 mg, 0.344 mmol) as
an off-white foam. LC/MS (ESI.sup.+) m/z=349, 351 (M+H; 2 bromine
isotopes).
Example 82
##STR00148##
[1045] Synthesis of
N-(3-((3R)-5-Amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3--
yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
Step 1: tert-Butyl
((5R)-5-(5-amino-2-fluorophenyl)-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H--
1,4-thiazin-3-yl)carbamate
[1046] In an analogous sequence of reactions to those described for
Intermediate 2, steps 1-3,
(3R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-t-
hiazine 1,1-dioxide was converted to the title compound as a tan
solid. LC/MS (ESI.sup.+) m/z=522 (M+Na).
Step 2:
N-(3-((3R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thi-
azin-3-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
[1047] As described in the HATU procedure, tert-butyl
((5R)-5-(5-amino-2-fluorophenyl)-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H--
1,4-thiazin-3-yl)carbamate was converted to the title compound (20
mg, 0.047 mmol) as a tan solid. LC/MS (ESI.sup.+) m/z=422
(M+H).
Example 83
##STR00149##
[1048] Synthesis of
(R)-10-Amino-8-(5-bromo-2-fluorophenyl)-8-methyl-6-thia-9-azaspiro[4.5]de-
c-9-ene 6,6-dioxide
Step 1: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclopentyl)sulfonyl)propan-2-yl)c-
arbamate
[1049] To a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e (540 mg, 1.24 mmol) in DMF (4.1 mL) were added 1,4-dibromobutane
(0.16 mL, 1.37 mmol) and potassium carbonate (377 mg, 2.73 mmol).
The reaction was stirred at RT for 3 hours and then at 70.degree.
C. for 16 hours. The reaction mixture was cooled to RT and then
partitioned between ethyl acetate and water. The organic layer was
concentrated and purified by column chromatography, eluting with
0-1% methanol in DCM, to provide the title compound (375 mg, 0.766
mmol). LC/MS (ESI.sup.+) m/z=511, 513 (M+Na; 2 bromine
isotopes).
Step 2:
(R)-10-Amino-8-(5-bromo-2-fluorophenyl)-8-methyl-6-thia-9-azaspiro-
[4.5]dec-9-ene 6,6-dioxide
[1050] In an analogous reaction to that described for Example 1,
step 5, (R)-tert-butyl
(2-((5-bromo-2-fluorophenyl)-1-((1-cyanocyclopentyl)sulfonyl)propan-2-yl)-
carbamate was converted to the title compound (30 mg, 0.077 mmol)
as a tan solid. LC/MS (ESI.sup.+) m/z=389, 391 (M+H; 2 bromine
isotopes).
Example 84
##STR00150##
[1051] Synthesis of
(R)-10-Amino-8-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)phenyl-
)-8-methyl-6-thia-9-azaspiro[4.5]dec-9-ene 6,6-dioxide
[1052] In an analogous reaction to that described for Example 73,
(R)-10-amino-8-(5-bromo-2-fluorophenyl)-8-methyl-6-thia-9-azaspiro[4.5]de-
c-9-ene 6,6-dioxide (100 mg, 0.26 mmol) and
3-methoxy-1,7-naphthyridin-8-amine (58.5 mg, 0.33 mmol) were
converted to the title compound (35 mg, 0.072 mmol) as a tan solid.
LC/MS (ESI.sup.+) m/z=484 (M+H).
Example 85
##STR00151##
[1053] Synthesis of
(R)-8-Amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[2.5]oct-
-7-ene 4,4-dioxide
Step 1: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl)propan-2-yl)c-
arbamate
[1054] In an analogous reaction to that described in Example 83,
step 1, (R)-tert-butyl
(2-((5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbama-
te and 1,2 dibromoethane were combined to provide the title
intermediate (140 mg, 0.303 mmol) as a tan solid. LC/MS (ESI.sup.+)
m/z=483, 485 (M+Na; 2 bromine isotopes).
Step 2:
(R)-8-Amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[-
2.5]oct-7-ene 4,4-dioxide
[1055] In an analogous reaction to that described in Example 83,
step 2, (R)-tert-butyl
(2-((5-bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl)propan-2-yl)-
carbamate was converted to the title compound (35 mg, 0.097 mmol)
as an off-white solid. LC/MS (ESI.sup.+) m/z=361, 363 (M+H; 2
bromine isotopes).
Example 86
##STR00152##
[1056] Synthesis of
(R)-8-Amino-6-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)phenyl)-
-6-methyl-4-thia-7-azaspiro[2.5]oct-7-ene 4,4-dioxide
[1057] In an analogous reaction to that described for Example 73,
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[2.5]oct-
-7-ene 4,4-dioxide and 3-methoxy-1,7-naphthyridin-8-amine (58.5 mg,
0.33 mmol) were combined to provide the title compound (60 mg,
0.132 mmol) as a tan solid. LC/MS (ESI.sup.+) m/z=456 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.39 (s, 1H) 8.63
(d, J=2.84 Hz, 1H) 8.09-8.17 (m, 1H) 7.98-8.09 (m, 2H) 7.71 (d,
J=2.84 Hz, 1H) 7.09-7.18 (m, 2H) 5.88 (br. s., 2H) 3.98 (s, 3H)
3.60-3.77 (m, 2H) 1.85-1.94 (m, 1H) 1.78-1.83 (m, 1H) 1.73 (s, 3H)
1.52-1.60 (m, 1H) 1.48 (m, 1H).
Example 87
##STR00153##
[1058] Synthesis of
(R)-5-Amino-3-(2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazin-
e 1,1-dioxide
[1059] To a solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (0.6 g, 1.65 mmol) in ethanol (20 mL) was
added sodium bicarbonate (139 mg, 1.65 mmol) and 10 wt % palladium
on carbon (180 mg, 0.169 mmol). The flask was evacuated and
backfilled with hydrogen three times, and stirred at ambient
temperature under a hydrogen atmosphere for 1 hour. The reaction
mixture was filtered through Celite and concentrated to provide the
title compound (0.55 g, 1.934 mmol) as a light-yellow solid. LC/MS
(ESI.sup.+) m/z=285 (M+H).
Examples 88 and 89
##STR00154##
[1060] Synthesis of
(2R,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-2-(3-(trifluoromethyl)-
benzyl)-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide and
(2S,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-2-(3-(trifluoromethyl)-
benzyl)-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: (R)-tert-Butyl
(5-(2-fluorophenyl)-2,5,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazi-
n-3-yl)carbamate
[1061] To a suspension of
(R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazin-
e 1,1-dioxide (0.23 g, 0.809 mmol) in acetonitrile (5 mL) was added
di-tert-butyl dicarbonate (0.194 g, 0.890 mmol) and a solution of
sodium bicarbonate (0.102 g, 1.213 mmol) in water (1 mL). The
reaction was stirred at ambient temperature for 3 hours, and then
partitioned between water and ethyl acetate. The organic layer was
washed with brine and concentrated. The crude material was purified
by silica-gel chromatography, eluting with 0-100% ethyl acetate in
dichloromethane, to provide the title compound (0.20 g, 0.520 mmol,
64.3% yield) as a off-white solid. LC/MS (ESI.sup.+) m/z=385
(M+H).
Step 2: (R)-tert-Butyl
(5-(2-fluorophenyl)-2,5,5-trimethyl-1,1-dioxido-6-(3-(trifluoromethyl)ben-
zyl)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1062] To a solution of (R)-tert-butyl
(5-(2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazi-
n-3-yl)carbamate (100 mg, 0.260 mmol) in THF (2 mL) at -78.degree.
C. was added a 2.7 M solution of n-butyllithium in heptane (0.241
mL, 0.650 mmol). The reaction was stirred for 5 minutes at
-78.degree. C., and then at 0.degree. C. for 30 minutes. To the
reaction was added 3-(trifluoromethyl)benzyl bromide (0.079 mL,
0.520 mmol), and the reaction was warmed slowly to RT. The reaction
was neutralized with saturated aqueous ammonium chloride and
extracted with ethyl acetate. The organic layer was concentrated
and purified by silica-gel chromatography, eluting with 20-100%
ethyl acetate in heptane, to provide the title compound (45 mg,
0.083 mmol) as a colorless oil. LC/MS (ESI.sup.+) m/z=543 (M+H);
4:1 ratio of epimers.
Step 3:
(2R,3R)-5-Amino-3-(2-fluorophenyl)-3,6,6-trimethyl-2-(3-(trifluoro-
methyl)benzyl)-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide and
(2S,3R)-5-Amino-3-(2-fluorophenyl)-3,6,6-trimethyl-2-(3-(trifluoromethyl)-
benzyl)-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1063] To a solution of (R)-tert-butyl
(5-(2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-6-(3-(trifluoromethyl)ben-
zyl)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (45 mg, 0.083 mmol)
in dichloromethane (2 mL) was added TFA (0.128 mL, 1.66 mmol). The
reaction was stirred at RT for one hour, diluted with ethyl acetate
(10 mL), and neutralized with saturated aqueous sodium bicarbonate.
The organic layer was concentrated and purified by silica-gel
chromatography, eluting with 20-100% ethyl acetate in heptane. Two
isomers with the desired mass were isolated; the major isomer (21
mg, 0.047 mmol, 57.2%) was the (2R,3R) epimer, and the minor isomer
(6 mg, 0.014 mmol) was the (2S,3R) epimer. LC/MS (ESI.sup.+)
m/z=443 (M+H)
Example 90
##STR00155##
[1064] Synthesis of
(2S,3R)-5-Amino-2-fluoro-3-(2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2-
H-1,4-thiazine 1,1-dioxide
Step 1: (R)-tert-Butyl
(6-fluoro-5-(2-fluorophenyl)-2,5,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1-
,4-thiazin-3-yl)carbamate
[1065] To a solution of (R)-tert-butyl
(5-(2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazi-
n-3-yl)carbamate (100 mg, 0.260 mmol) in THF (2 mL) at -78.degree.
C. was added a 2.7 M solution of n-BuLi in heptane (0.289 mL, 0.780
mmol). The reaction was stirred for 5 minutes at -78.degree. C.,
and then at 0.degree. C. for 30 minutes. To the reaction was added
N-fluorobenzenesulfonimide (328 mg, 1.040 mmol), and the reaction
was warmed slowly to RT. After 30 minutes, the reaction was
neutralized with saturated aqueous ammonium chloride and extracted
with EtOAc. The organic layer was concentrated and purified by
silica-gel chromatography, eluting with 20-100% EtOAc in heptane,
to provide the titled intermediate (45 mg, 0.112 mmol) as a
light-yellow oil. LC/MS (ESI.sup.+) m/z=403 (M+H).
Step 2:
(2S,3R)-5-Amino-2-fluoro-3-(2-fluorophenyl)-3,6,6-trimethyl-3,6-di-
hydro-2H-1,4-thiazine 1,1-dioxide
[1066] To a solution of (R)-tert-butyl
(6-fluoro-5-(2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1-
,4-thiazin-3-yl)carbamate (45 mg, 0.112 mmol) in dichloromethane (2
mL) was added TFA (0.172 mL, 2.24 mmol). The reaction was stirred
at ambient temperature for 1 hour, diluted with ethyl acetate, and
neutralized with saturated aqueous sodium bicarbonate. The organic
layer was purified by silica-gel chromatography, eluting with 0-10%
methanol in dichloromethane, to provide the title compound (22 mg,
0.073 mmol) as an off-white solid. LC/MS (ESI.sup.+) m/z=303
(M+H).
Example 91
##STR00156##
[1067] Synthesis of
(2R,3R)-5-Amino-3-(2-fluorophenyl)-2,3,6,6-tetramethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide
[1068] To a solution of (R)-tert-butyl
(5-(2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazi-
n-3-yl)carbamate (120 mg, 0.312 mmol) in THF (2 mL) at -78.degree.
C. was added a 2.7 M solution of n-BuLi in heptane (0.347 mL, 0.936
mmol). The reaction was stirred for 5 minutes at -78.degree. C.,
and then at 0.degree. C. for 15 minutes. To the reaction was added
iodomethane (0.078 mL, 1.25 mmol), and the reaction was stirred at
0.degree. C. After 30 minutes, the reaction was neutralized with
saturated aqueous ammonium chloride and extracted with ethyl
acetate. The organic layer was purified by reverse-phase HPLC,
using a gradient of 30% to 70% (acetonitrile/0.1% TFA) in
(water/0.1% TFA). The product fractions were combined, neutralized
with saturated aqueous sodium bicarbonate, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated to provide
the title compound (20 mg, 0.067 mmol) as an off-white solid. LC/MS
(ESI.sup.+) m/z=299 (M+H).
Example 92
##STR00157##
[1069] Synthesis of
(R)-5-Amino-3-(3-bromo-2,6-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-
-1,4-thiazine 1,1-dioxide
[1070] Racemic
5-amino-3-(3-bromo-2,6-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide was purified by chiral SFC, using a ChiralPak
IC column and eluting with 25% (20 mM ammonia in methanol) in
CO.sub.2, to provide the title compound. LC/MS (ESI.sup.+) m/z=381,
383 (M+H; 2 bromine isotopes).
Example 93
##STR00158##
[1071] Synthesis of
(S)-5-Amino-3-(3-bromo-2,6-difluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-
-1,4-thiazine 1,1-dioxide
[1072] The title compound is the other enantiomer recovered from
the chiral SFC purification described in Example 92, using a
ChiralPak IC column and eluting with 25% (20 mM ammonia in
methanol) in CO.sub.2. LC/MS (ES.sup.+) m/z=381, 383 (M+H; 2
bromine isotopes).
Example 94
##STR00159##
[1073] Synthesis of
(R)-5-Amino-3-(5-amino-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide
[1074] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (180 mg, 0.45 mmol) in dichloromethane
(2.25 mL) was added TFA (0.69 mL, 9.01 mmol). The reaction was
stirred at RT for 1 hour. The reaction mixture was concentrated,
and the residue was partitioned between DCM and saturated aqueous
sodium bicarbonate. The organic layer was concentrated to provide
the title compound (65 mg, 0.22 mmol) as a tan solid. LC/MS
(ESI.sup.+) m/z=300 (M+H).
Example 95
##STR00160##
[1075] Synthesis of
(3R,6R)-5-Amino-3-(5-amino-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3,6-dihy-
dro-2H-1,4-thiazine 1,1-dioxide
[1076] In an analogous reaction to that described for Example 94,
tert-butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate was converted to the title
compound. LC/MS (ESI.sup.+) m/z=304 (M+H).
Example 96
##STR00161##
[1077] Synthesis of
(R)-4-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin--
3-yl)-4-fluorophenoxy)benzonitrile
[1078] To a solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) in toluene (0.50 mL) and
EtOAc (0.05 mL) was added 4-hydroxybenzonitrile (67 mg, 0.55 mmol),
copper(I) iodide (63 mg, 0.33 mmol), and cesium carbonate (179 mg,
0.55 mmol). The reaction mixture was stirred at 135.degree. C. for
17 hours. The reaction was diluted with DCM, washed with water and
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated. The crude mixture was purified by reverse-phase
silica-gel chromatography, eluting with a gradient of 0-100%
(ACN/1% ammonium hydroxide) in (water/1% ammonium hydroxide) to
provide the title compound (6 mg, 0.014 mmol) as a tan solid. LC/MS
(ESI.sup.+) m/z=402 (M+H).
Example 97
##STR00162##
[1079] Synthesis of
(R)-5-amino-3-(2-fluoro-5-(2-methoxy-4-methylphenoxy)phenyl)-3,6,6-trimet-
hyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1080] In an analogous reaction to that described for Example 96,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) was converted to the
title compound (0.012 g, 0.029 mmol) as a light yellow solid. LC/MS
(ESI.sup.+) m/z=421 (M+H).
Example 98
##STR00163##
[1081] Synthesis of
(R)-5-amino-3-(2-fluoro-5-(3-fluoro-5-(trifluoromethyl)phenoxy)phenyl)-3,-
6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1082] In an analogous reaction to that described for Example 96,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) was converted to the
title compound (0.018 g, 0.039 mmol) as a tan solid. LC/MS
(ESI.sup.+) m/z=463 (M+H).
Example 99
##STR00164##
[1083] Synthesis of
(R)-5-amino-3-(5-(3-ethylphenoxy)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dih-
ydro-2H-1,4-thiazine 1,1-dioxide
[1084] In an analogous reaction to that described for Example 96,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) was converted to the
title compound (0.022 g, 0.055 mmol) as a tan solid. LC/MS
(ESI.sup.+) m/z=405 (M+H).
Example 100
##STR00165##
[1085] Synthesis of
(R)-5-amino-3-(5-(4-chloro-3-ethylphenoxy)-2-fluorophenyl)-3,6,6-trimethy-
l-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1086] In an analogous reaction to that described for Example 96,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) was converted to the
title compound (0.015 g, 0.034 mmol) as a light yellow solid. LC/MS
(ESI.sup.+) m/z=439 (M+H).
Example 101
##STR00166##
[1087] Synthesis of
(R)-5-amino-3-(2-fluoro-5-(2-methoxy-5-methylphenoxy)phenyl)-3,6,6-trimet-
hyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1088] In an analogous reaction to that described for Example 96,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) was converted to the
title compound (0.010 g, 0.025 mmol) as a tan solid. LC/MS
(ESI.sup.+) m/z=421 (M+H).
Example 102
##STR00167##
[1089] Synthesis of
(R)-5-amino-3-(2-fluoro-5-(naphthalen-2-yloxy)phenyl)-3,6,6-trimethyl-3,6-
-dihydro-2H-1,4-thiazine 1,1-dioxide
[1090] In an analogous reaction to that described for Example 96,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (100 mg, 0.28 mmol) was converted to the
title compound (0.012 g, 0.027 mmol) as a light yellow solid. LC/MS
(ESI.sup.+) m/z=427 (M+H).
Example 103
##STR00168##
[1091] Synthesis of
(R)-5-amino-3-(2-fluoro-5-(pyridin-2-yloxy)phenyl)-3,6,6-trimethyl-3,6-di-
hydro-2H-1,4-thiazine 1,1-dioxide
Step 1:
(R)--N-(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)benzamide
[1092] To a solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (3.00 g, 8.26 mmol) in DMF (16.5 mL) was
added benzoic anhydride (2.24 g, 9.91 mmol), and TEA (2.30 mL, 16.5
mmol). The reaction mixture was stirred at RT for 17 hours, diluted
with ethyl acetate, and washed with water and brine. The organic
layer was dried over anhydrous sodium sulfate, filtered, and
concentrated. The crude product was purified by silica-gel
chromatography, eluting with 0-50% ethyl acetate in heptanes, to
provide the title intermediate (3.47 g, 7.42 mmol, 90% yield) as an
off-white solid. LC/MS (ESI.sup.+) m/z=467.0, 469.0 (M+H).
Step 2:
(R)--N-(5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)benza-
mide
[1093] To a solution of
(R)--N-(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydr-
o-2H-1,4-thiazin-3-yl)benzamide (3.77 g, 8.07 mmol) in degassed
1,4-dioxane (16.1 mL) were added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.07
g, 12.10 mmol) and potassium acetate (2.38 g, 24.20 mmol). The
flask was purged with nitrogen,
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (0.590 g, 0.807 mmol) was added, and the
flask was purged with nitrogen again, sealed, and heated to
100.degree. C. for 16 hours. The reaction mixture was cooled to
ambient temperature and diluted with ethyl acetate. The reaction
mixture was washed with water and brine, dried over anhydrous
sodium sulfate, filtered, and concentrated. The crude product was
purified by silica-gel chromatography, eluting with 0-50% ethyl
acetate in heptanes, to provide the title intermediate (3.54 g,
6.88 mmol, 85% yield) as a white solid. LC/MS (ESI.sup.+) m/z=515.2
(M+H).
Step 3:
(R)--N-(5-(2-fluoro-5-hydroxyphenyl)-2,2,5-trimethyl-1,1-dioxido-5-
,6-dihydro-2H-1,4-thiazin-3-yl)benzamide
[1094] To a solution of
(R)--N-(5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)benzamide
(3.7 g, 7.19 mmol) in dichloromethane (14.4 mL) was added 30%
aqueous hydrogen peroxide (0.882 mL, 8.63 mmol), and the reaction
was stirred at ambient temperature for four hours. The reaction was
diluted with DCM, washed with water and brine, dried over anhydrous
sodium sulfate, filtered, and concentrated. The crude product was
purified by silica-gel chromatography, eluting with 0-50% EtOAc in
heptanes to provide the title intermediate (2.64 g, 6.53 mmol) as a
white solid. LC/MS (ESI.sup.+) m/z=405.1 (M+H).
Step 4:
(R)-5-amino-3-(2-fluoro-5-hydroxyphenyl)-3,6,6-trimethyl-3,6-dihyd-
ro-2H-1,4-thiazine 1,1-dioxide
[1095] A solution of
(R)--N-(5-(2-fluoro-5-hydroxyphenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihy-
dro-2H-1,4-thiazin-3-yl)benzamide (1.9 g, 4.70 mmol) in ammonia (2
M in methanol) (23.5 mL, 47.0 mmol) was stirred at 55.degree. C.
for 17 hours. The reaction was cooled to ambient temperature and
concentrated. The crude product was purified by reverse phase
silica-gel chromatography, eluting with 0-100% (acetonitrile/1%
trifluoroacetic acid) in (water/1% trifluoroacetic acid) to provide
the title intermediate (1.1 g, 3.66 mmol) as an off-white solid.
LC/MS (ESI.sup.+) m/z=301.0 (M+H).
Step 5:
(R)-5-amino-3-(2-fluoro-5-(pyridin-2-yloxy)phenyl)-3,6,6-trimethyl-
-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1096] To a solution of
(R)-5-amino-3-(2-fluoro-5-hydroxyphenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1-
,4-thiazine 1,1-dioxide (65 mg, 0.216 mmol) in DMSO (0.43 mL) were
added 2-fluoropyridine (0.017 mL, 0.238 mmol) and cesium carbonate
(141 mg, 0.433 mmol), and the reaction mixture was stirred at
100.degree. C. for 16 hours. The reaction was cooled to ambient
temperature, diluted with ethyl acetate, and washed with water and
brine. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The crude product was purified by
silica-gel chromatography, eluting with 1.5-7% methanol in
dichloromethane to provide the title compound (23 mg, 0.061 mmol)
as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.42 (s, 3H) 1.55 (s, 3H) 1.61 (s, 3H) 3.47-3.72 (m, 2H) 6.08
(br. s., 2H) 6.96 (dt, J=8.34, 0.88 Hz, 1H) 7.01-7.06 (m, 1H) 7.11
(ddd, J=7.19, 4.94, 0.88 Hz, 1H) 7.16-7.23 (m, 2H) 7.83 (ddd,
J=8.34, 7.19, 2.05 Hz, 1H) 8.11-8.17 (m, 1H). LC/MS (ESI.sup.+)
m/z=378.1 (M+H).
[1097] The following compounds in Table 3 are examples of compounds
of Formulas I, II and III, and sub-formulas thereof, provided by
the present invention in Tables 1 and 2 hereinabove. The methods
used to prepare the exemplary compounds are included in Tables 1
and 2. Table I further provides the mass and biological data
(average nM IC.sub.50's for the enzyme and cell assays) for each
compound, where available.
TABLE-US-00003 TABLE 3 BACE1 HEK FRET cell assay assay CatD Example
IC.sub.50 IC.sub.50 IC50 No Compound Name (uM) (uM) (.mu.M) 28
N-(3-((3R)-5-amino-3-methyl-1,1- 0.0149 0.068 50.9
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 29
N-(3-((3R)-5-amino-3-methyl-1,1- 0.006 0.0108 118
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-2- pyridinecarboxamide 56
N-(3-((3R)-5-amino-3-methyl-1,1- 0.0627 0.0271 69.8
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-methoxy-1,7- naphthyridin-8-amine 43
N-(3-((3R)-5-amino-3-methyl-3,6- 0.0236 0.007 >400
dihydro-2H-1,4-thiazin-3-yl)-4- fluorophenyl)-5-methoxy-2-
pyrazinecarboxamide 57 N-(3-((3R)-5-amino-3-methyl-1,1- 0.0043
0.019 134 dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-chloro-1,7- naphthyridin-8-amine 58
N-(3-((3R)-5-amino-3-methyl-1,1- 0.19 0.292 304
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-2-
methyl[1,3]thiazolo[4,5-c]pyridin-4- amine 17
N-(3-((3R)-5-amino-3,6,6-trimethyl- .0021 0.0022 >400
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
methoxy-2-pyrazinecarboxamide 45
N-(3-((3R)-5-amino-3,6,6-trimethyl- .00059 0.0075 90.4
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
chloro-1,7-naphthyridin-8-amine 46
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0054 0.004 397
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
methoxy-1,7-naphthyridin-8-amine 18
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0019 0.0037 >400
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
fluoro-2-pyridinecarboxamide 19 N-(3-((3R)-5-amino-3,6,6-trimethyl-
.00085 0.0014 240 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5- chloro-2-pyridinecarboxamide 47
N-(3-((3R)-5-amino-3,6,6-trimethyl- .0029 0.0056 >400
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-2-
methoxypyrido[3,4-b]pyrazin-5- amine 48
8-((3-((3R)-5-amino-3,6,6-trimethyl- .00054 0.0019 66.7
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)amino)-
1,7-naphthyridine-3-carbonitrile 82 N-(3-((3R,6R)-5-amino-3,6-
0.0075 0.0125 >400 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide, N-(3-((3R,6S)-5-amino-3,6-
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide 34 N-(3-((3R)-5-amino-6,6-dimethyl-
0.883 >10.0 >400 1,1-dioxido-3-(trifluoromethyl)-3,6-
dihydro-2H-1,4-thiazin-3-yl)-4- fluorophenyl)-5-methoxy-2-
pyrazinecarboxamide 64 N-(3-((3R)-5-amino-6,6-dimethyl- 8.69
>10.0 >400 1,1-dioxido-3-(trifluoromethyl)-3,6-
dihydro-2H-1,4-thiazin-3-yl)-4- fluorophenyl)-3-methoxy-1,7-
naphthyridin-8-amine 32 N-(3-((3R)-5-amino-3- 0.0531 1.42 >400
(difluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide,
N-(3-((3S)-5- amino-3-(difluoromethyl)-6,6-
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide 62 N-(3-((3R)-5-amino-3- 0.241 1.82
>400 (difluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-methoxy-1,7- naphthyridin-8-amine,
N-(3-((3S)-5- amino-3-(difluoromethyl)-6,6-
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-methoxy-1,7-naphthyridin-8-
amine 84 N-(3-((8R)-10-amino-8-methyl-6,6- 0.0234 0.0575 283
dioxido-6-thia-9-azaspiro[4.5]dec-9-
en-8-yl)-4-fluorophenyl)-3-methoxy- 1,7-naphthyridin-8-amine 86
N-(3-((6R)-8-amino-6-methyl-4,4- 0.0136 0.0082 160
dioxido-4-thia-7-azaspiro[2.5]oct-7-
en-6-yl)-4-fluorophenyl)-3-methoxy- 1,7-naphthyridin-8-amine 74
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 0.0137 0.102 >400
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-methoxy-1,7-naphthyridin-8-
amine 78 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0138 0.0944 45.6
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-6-
chloroisoxazolo[4,5-b]pyridin-3- amine, N-(3-((3S)-5-amino-3,6,6-
trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
6-chloroisoxazolo[4,5-b]pyridin-3- amine, benzamide 49
N-(3-((3R)-5-amino-3,6,6-trimethyl- .00056 0.0151 27.1
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
chloro-5-fluoro-1,7-naphthyridin-8- amine 69
N-(3-((3R)-5-amino-3,6,6-trimethyl- .0014 0.0544 11.3
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-3-
chloro-1,7-naphthyridin-8-amine, N-
(3-((3S)-5-amino-3,6,6-trimethyl- 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-3-
chloro-1,7-naphthyridin-8-amine 35
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0027 0.0122 99.8
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-5- chloro-2-pyridinecarboxamide,
N-(3- ((3S)-5-amino-3,6,6-trimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4,5-difluorophenyl)-5-chloro-2- pyridinecarboxamide 36
N-(3-((3S)-5-amino-3- 0.0202 0.765 >400
(difluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 67
N-(3-((3S)-5-amino-3- 0.068 0.98 >400
(difluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-methoxy-1,7- naphthyridin-8-amine 76
8-((3-((3R)-5-amino-3,6,6-trimethyl- 0.002 0.0039 >44
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)amino)- 5-fluoro-1,7-naphthyridine-3-
carbonitrile 30 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 0.0031 0.0801
>400 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide,
N-(3-((3R,6S)-5-amino-6-fluoro-3,6-
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide 79 (5R)-5-(2-fluoro-5-(1- 2.5 4.94
33.7 naphthalenylsulfanyl)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 59
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 0.0033 0.178 388
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
2-methoxypyrido[3,4-b]pyrazin-5- amine 60
8-((3-((3R,6R)-5-amino-6-fluoro-3,6- <0.002 0.0808 99.9
dimethyl-1,1-dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-4-
fluorophenyl)amino)-1,7- naphthyridine-3-carbonitrile 20
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0027 0.0039 193
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
(difluoromethyl)-2- pyridinecarboxamide 50
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.002 0.0053 73.3
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
fluoro-3-methoxy-1,7-naphthyridin- 8-amine 51
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0027 0.003 81
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-7-
methoxypyrido[3,2-d]pyrimidin-4- amine 52
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.002 0.0023 36
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-7-
chloropyrido[3,2-d]pyrimidin-4- amine 53
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.739 0.399 320
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
fluoro-7-methoxy-4-quinazolinamine 21
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0074 0.011 >400
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
(trifluoromethyl)-2- pyrazinecarboxamide 73
3-((3-((3R)-5-amino-3,6,6-trimethyl- 0.002 0.0016 27.3
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)amino)thieno[3,2- b]pyridine-6-carbonitrile 66
N-(5-((3R)-5-amino-3,6,6-trimethyl- 0.0043 0.0067 101
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-
methoxy-1,7-naphthyridin-8-amine 75
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0114 0.212 47.6
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-2-
methoxy-5-quinoxalinamine 31 N-(3-((3R)-5-amino-3- 0.0038 0.0279
>400 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide,
N-(3-((3S)-5- amino-3-(fluoromethyl)-6,6-
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide 44
N-(3-((3R)-5-amino-2-fluoro-3,6,6- 0.0099 0.0604 357
trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-methoxy-1,7-naphthyridin-8-
amine 61 N-(3-((3R)-5-amino-3- 0.0065 0.0317 >400
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-methoxy-1,7- naphthyridin-8-amine,
N-(3-((3S)-5- amino-3-(fluoromethyl)-6,6-
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-methoxy-1,7-naphthyridin-8-
amine 54 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0172 0.137 >400
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-2-
methyl[1,3]thiazolo[4,5-c]pyridin-4-
amine 22 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0015 0.0031 >400
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
methoxy-2-pyridinecarboxamide 23
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0027 0.0027 617
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
cyano-2-pyridinecarboxamide 24 N-(3-((3R)-5-amino-3,6,6-trimethyl-
0.0006 0.0037 >400 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5- chloro-3-fluoro-2-
pyridinecarboxamide 25 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0003
0.0032 263 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5- chloro-3-methyl-2-
pyridinecarboxamide 26 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0004
5E-05 475 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5-(2- butyn-1-yloxy)-2-
pyrazinecarboxamide 27 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.051
0.0609 >400 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-2- methyl-1,3-thiazole-4-carboxamide
38 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.001 0.0065 72.8
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-5- chloro-2-pyridinecarboxamide
39 N-(3-((3S)-5-amino-3,6,6-trimethyl- 1.18 3.27 225
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-5- chloro-2-pyridinecarboxamide
69 N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0004 0.0231 8.56
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-3-
chloro-1,7-naphthyridin-8-amine 70
N-(3-((3S)-5-amino-3,6,6-trimethyl- 0.83 5.04 164
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4,5-difluorophenyl)-3-
chloro-1,7-naphthyridin-8-amine 41
N-(4-((3R)-5-amino-3,6,6-trimethyl- 0.252 0.935 333
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-
methoxy-2-pyrazinecarboxamide, N-(4-((3S)-5-amino-3,6,6-trimethyl-
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-
methoxy-2-pyrazinecarboxamide 40
N-(6-((3R)-5-amino-3,6,6-trimethyl- 8.2 6.98 >400
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-
methoxy-2-pyrazinecarboxamide 55
N-(3-((3R)-5-amino-3,6,6-trimethyl- 0.0052 0.0346 >133
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-2-
(trifluoromethyl)pyrido[3,4- b]pyrazin-5-amine 71
5-((3-((3R)-5-amino-3,6,6-trimethyl- 0.0037 0.0474 45.2
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4,5-
difluorophenyl)amino)pyrido[3,4- b]pyrazin-2(1H)-one 72
5-((3-((3S)-5-amino-3,6,6-trimethyl- 0.505 5.35 175
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4,5-
difluorophenyl)amino)pyrido[3,4- b]pyrazin-2(1H)-one 96
4-(3-((3R)-5-amino-3,6,6-trimethyl- 1.8 6.02 58.7
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenoxy)benzonitrile 97 (5R)-5-(2-fluoro-5-(2-methoxy-4- 11.7
6.86 182 methylphenoxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 98
(5R)-5-(2-fluoro-5-(3-fluoro-5- 0.135 5.04 56.3
(trifluoromethyl)phenoxy)phenyl)-
2,2,5-trimethyl-5,6-dihydro-2H-1,4- thiazin-3-amine 1,1-dioxide 99
(5R)-5-(5-(3-ethylphenoxy)-2- 1.43 6.68 86.8
fluorophenyl)-2,2,5-trimethyl-5,6- dihydro-2H-1,4-thiazin-3-amine
1,1- dioxide 100 (5R)-5-(5-(4-chloro-3- 1.55 >10.0 17.7
ethylphenoxy)-2-fluorophenyl)- 2,2,5-trimethyl-5,6-dihydro-2H-1,4-
thiazin-3-amine 1,1-dioxide 101 (5R)-5-(2-fluoro-5-(2-methoxy-5-
15.2 >10.0 194 methylphenoxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 102
(5R)-5-(2-fluoro-5-(2- 2.35 8.04 51.2
naphthalenyloxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 103
(5R)-5-(2-fluoro-5-(2- 0.119 0.213 246
pyridinyloxy)phenyl)-2,2,5-trimethyl-
5,6-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide
General Amidation Procedures to prepare compounds of Formulas I, II
and III, and sub-Formulas thereof (unprotected
amino-1,1-dioxido-2H-1,4-thiazin-3-yl cores)
Method C: DMTMM Procedure:
[1098] To a solution (0.14 M) of the aniline (1 equivalent; see
compounds 7, 8 10 in schemes 2, 3 and 4, respectively, see also the
examples herein) in MeOH was added the carboxylic acid (1
equivalent; R.sup.9--COOH) and
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium
chloride (1 equivalent). After stirring for 1 h at RT, the mixture
was diluted with EtOAc, and the organic layer was washed with
aqueous sodium bicarbonate, dried over MgSO.sub.4, and
concentrated. The crude material was purified by silica gel
chromatography to furnish the title compound.
Method D: T3P Procedure:
[1099] A suspension (0.1 M) of the carboxylic acid (1 equivalent;
R.sup.9--COOH), Hunig's base (1 equivalent), and the aniline (1
equivalent) in dichloromethane was cooled to 0.degree. C., and an
ethyl acetate solution of T3P (50% by weight, 1.40 equivalents) was
added. The reaction was allowed to warm naturally to room
temperature. After 6 h, the mixture was taken up in 5%
MeOH-dichloromethane, washed with aqueous sodium bicarbonate, and
the organic layer was dried over MgSO.sub.4, and concentrated. The
crude material was purified by silica gel chromatography to furnish
the title compound.
Method E: CuI Procedure:
[1100] A microwave vial was charged with the corresponding bromide
(1.0 equivalent), carboxamide (1.2 equivalents;
R.sup.9--CONH.sub.2), CuI (0.20 equivalents) and potassium
carbonate (3.0 equivalents). The vial was evacuated and backfilled
with nitrogen followed by the addition of dioxane (to give a
reaction concentration of 0.2M with respect to bromide) and
(1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine. The resulting
mixture was heated at 120.degree. C. for 17 h. The reaction was
brought to room temperature, diluted with EtOAc, filtered through
celite, concentrated and chromatographed on silica gel to provide
the title compound.
Method F: Pd Procedure:
[1101] A microwave vial was charged with the corresponding bromide
(1.0 equivalent), aniline (1.5 equivalent),
tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (0.10
equivalents),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.30
equivalents) and sodium t-butoxide (2.8 equivalents), purged with
nitrogen and toluene added (to give a reaction concentration of
0.2M with respect to bromide). The resulting mixture was sealed,
then heated at 100.degree. C. for 1 h, brought to room temperature,
diluted with water and extracted with EtOAc. The combined organics
were concentrated and chromatographed on silica gel to afford the
title compound.
Method G: Amination with CuI Procedure:
[1102] A microwave vial was charged with the corresponding bromide
(1.0 equivalent), 2,2,2-trifluoroacetamide (2.0 equivalents),
potassium carbonate (4.0 equivalents), N,N'-dimethyl
ethylenediamine (0.40 equivalents), copper(I) iodide (0.20
equivalents) and 4 A molecular sieves, then purged with nitrogen.
Dioxan was added to give a 0.9 M solution with respect to bromide,
mixture sealed, and heated at 120.degree. C. for 20 h. The reaction
was brought to room temperature, MeOH/water (1:1) was added and the
resulting mixture was heated at 80.degree. C. for 1 h. The mixture
was diluted with a 9:1 mixture saturated ammonium chloride/ammonium
hydroxide, extracted with DCM and chromatographed on silica gel to
afford the title compound.
Example 104
##STR00169##
[1103] Synthesis of
(R)-5-amino-3-(5-((7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4-yl)amin-
o)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1104] A reaction vial was charged with (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (33.9 mg, 0.085 mmol),
4-chloro-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidine (20 mg,
0.085 mmol) and 2-propanol (424 .mu.l, 0.085 mmol), followed by
p-toluenesulfonic acid monohydrate (32.3 mg, 0.170 mmol). The
resulting mixture was stirred at 80.degree. C. for 15 min. The
reaction mixture was diluted with saturated aqueous sodium
bicarbonate and extracted with EtOAc. The organic extract was
washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The crude material was absorbed onto a plug of silica
gel and eluted with a gradient of 20% to 35% to 50%
EtOAc/EtOH/Et.sub.3N (80/20/2) in (40% EtOAc in Heptane), to
provide
(R)-5-amino-3-(5-((7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4-yl)amin-
o)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (20 mg, 0.040 mmol, 47.3% yield) as off-white solid.
LC/MS (ESI.sup.+) m/z=499.2 (M+1).
Example 105
Amination Coupling Reaction
##STR00170##
[1105] Synthesis of
(R)-5-amino-3-(2-fluoro-5-((2-methylbenzo[d]thiazol-4-yl)amino)phenyl)-3,-
6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: Synthesis of (R)-tert-butyl
(5-(2-fluoro-5-((2-methylbenzo[d]thiazol-4-yl)amino)phenyl)-2,2,5-trimeth-
yl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1106] To a sealable tube was added
4-bromo-2-methylbenzo[d]thiazole (48.0 mg, 0.210 mmol),
(R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (70 mg, 0.175 mmol) and toluene (1.0 mL).
It was purged with Argon, then tris(dibenzylideneacetone)
dipalladium (0) (16.05 mg, 0.018 mmol), and tBuXphos (18.60 mg,
0.044 mmol) were added and the mixture was purged with Argon.
Sodium tert-butoxide (47.2 mg, 0.491 mmol) was added slowly to the
mixture. It was stirred at 100.degree. C. for 25 min. The reaction
mixture was diluted with sat'd NH.sub.4Cl and extracted with EtOAc.
The organic extract was washed with brine and dried over anhydrous
MgSO.sub.4. The solution was filtered and concentrated in vacuo to
give the crude material as a brown solid. The crude product was
used for next step directly. LC/MS (ESI.sup.+) m/z=547.2 (M+H).
Step 2: Synthesis of
(R)-5-amino-3-(2-fluoro-5-((2-methylbenzo[d]thiazol-4-yl)amino)phenyl)-3,-
6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1107] To a solution of (R)-tert-butyl
(5-(2-fluoro-5-((2-methylbenzo[d]thiazol-4-yl)amino)phenyl)-2,2,5-trimeth-
yl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (95 mg,
0.174 mmol) in DCM (1738 .mu.l) was added TFA (669 .mu.l, 8.69
mmol), and the solution was stirred at RT for 20 min. The reaction
mixture was concentrated, diluted with DCM and neutralized with
saturated aqueous NaHCO.sub.3. The organic extract was
concentrated, and purified by prep reverse phase HPLC using 0.1%
NH4OH in ACN and water as mobile phase to yield 32 mg of
(R)-5-amino-3-(2-fluoro-5-((2-methylbenzo[d]thiazol-4-yl)amino)phenyl)-3,-
6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (41.2% yield,
0.072 mmol). LC/MS (ESI.sup.+) m/z=447.0 (M+H).
General Cyanation Procedure
##STR00171##
[1108] Synthesis of
(R)-8-((3-(5-Amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile
[1109] A sealable vial was charged with
(R)-5-amino-3-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino)-2-fluor-
ophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
(150 mg, 0.313 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (25.7 mg, 0.063
mmol), tris(dibenzylideneacetone)dipalladium(0) (22.90 mg, 0.025
mmol), ZnCN.sub.2 (55 mg, 0.469 mmol), N,N-dimethylformamide (1.5
mL), and a drop of water. The vial was purged with argon and the
reaction was heated at 110.degree. C. for 1 hour. The reaction was
partitioned between water and dichloromethane, and the organic
portion was washed with brine, dried with anhydrous sodium sulfate,
filtered and concentrated. The crude product was purified by silica
gel chromatography, eluting with 5-75% (3:1 ethyl acetate/ethanol,
2% ammonium hydroxide) in heptanes, to provide the title compound
(80 mg, 0.170 mmol, 54.4% yield) as a yellow solid.
[1110] The following intermediates, within the examples, represent
various exemplary carboxylic acid, ester, carbamate or amine
intermediates as representative R.sup.9 groups for compounds of the
present invention.
Intermediate BY 001
##STR00172##
[1111] Synthesis of 5-((4-fluorobut-2-yn-1-yl)oxy)picolinic
acid
Step 1: methyl 5-((4-hydroxybut-2-yn-1-yl)oxy)picolinate
[1112] In a 500-mL flask, but-2-yne-1,4-diol (5.62 g, 65.3 mmol),
methyl 5-hydroxypicolinate (5.00 g, 32.7 mmol) and
triphenylphosphine (12.85 g, 49.0 mmol) were suspended in THF (100
mL). The suspension was cooled to 0.degree. C., and (E)-diisopropyl
diazene-1,2-dicarboxylate (9.52 mL, 49.0 mmol) was added over 1
minute. The reaction was stirred at 0.degree. C. for 2 h, then at
RT for 2 h. The reaction was filtered through Celite, rinsing with
DCM (500 mL). The filtrate was concentrated and the residue was
chromatographed on silica gel (600 mL), eluent 2% to 3% MeOH-DCM to
afford the title compound (3.43 g, 48%). MS: m/z=222 (M+H).
Step 2: methyl 5-((4-fluorobut-2-yn-1-yl)oxy)picolinate
[1113] In a 250-mL flask, methyl
5-((4-hydroxybut-2-yn-1-yl)oxy)picolinate (1.77 g, 8.00 mmol, 1
equiv) was suspended in DCM (50 mL). The suspension was cooled to
-78.degree. C., and Deoxo Fluor (2.21 mL, 12 mmol, 1.5 equiv) was
added dropwise. The mixture was allowed to warm naturally, to RT
overnight. The mixture was cooled to 0.degree. C., and quenched
with 50 mL of saturated aqueous NaHCO.sub.3. The mixture was
filtered through Celite, rinsing with 5% MeOH-DCM (100 mL). The
resulting filtrate's aqueous layer was separated and extracted with
5% MeOH-DCM (50 mL). The combined organics were dried over
MgSO.sub.4 and concentrated. The residue was chromatographed on
silica gel (80 mL) using 50% EtOAc-hexane to afford the title
compound (180 mg, 0.81 mmol, 10% yield). MS: m/z=224 (M+H).
Step 3: 5-((4-fluorobut-2-yn-1-yl)oxy)picolinic acid
[1114] Methyl 5-((4-fluorobut-2-yn-1-yl)oxy)picolinate (97 mg,
0.435 mmol, 1 equiv) was dissolved in a mixture of THF (1.5 mL) and
MeOH (1 mL). The solution was cooled to 0.degree. C., and aqueous
LiOH (1.0 M, 475 microliters, 0.475 mmol, 1.1 equiv) was added. The
reaction was warmed to RT and stirred for 5 h. The reaction was
neutralized with a dioxane solution of HCl (4.0 M, 0.119 mL, 0.475
mmol, 1.1 equiv). The mixture was concentrated, and azeotropically
dried by evaporation from toluene at reduced pressure, to give the
title compound (0.435 mmol, 91 mg).
Intermediate BY 002
##STR00173##
[1115] Synthesis of
6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid
Step 1: methyl 3-bromo-2-oxobutanoate
[1116] Methyl 2-oxobutanoate (6.73 g, 58.0 mmol) was dissolved in
DCM (60 mL). The solution was cooled to 0.degree. C., and bromine
(3.02 mL, 58.5 mmol) was added. The flask was stirred for 5 min at
0.degree. C., and the ice-water bath was removed. After 2 h, the
mixture was taken up in DCM (300 mL). The organic layer was
extracted with saturated aqueous NaHCO.sub.3 (60 mL), then with
half-saturated aqueous NaHCO.sub.3 (60 mL), dried over MgSO.sub.4
and concentrated to afford the title compound, which was used
without further purification (10.64 g, 54.6 mmol, 94%).
Step 2: methyl
6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylate
[1117] The methyl 3-bromo-2-oxobutanoate (1.502 g, 7.70 mmol) was
dissolved in DME (9 mL). The solution was cooled in an ice-water
bath. 5-Fluoropyridin-2-amine (0.785 g, 7.00 mmol) was added, and
the ice bath was removed. The mixture was stirred at RT for 2 days.
The thick suspension was filtered through a fine frit, rinsing the
solid with DME (15 mL). The recovered solid (1.535 g) was suspended
in MeOH (19 mL). The vessel was sealed and heated in an 80.degree.
C. oil bath. After 2.5 h, the reaction was cooled and concentrated.
The yellow solid was triturated with diethyl ether and dried under
vacuum to afford the title compound (777 mg, 48%).
Step 3: 6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylic
acid
[1118] Methyl 6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylate
(679 mg, 3.26 mmol) was suspended in MeOH (10 mL). Aqueous sodium
hydroxide (3.0 M, 1.63 mL, 4.89 mmol) was added. The vessel was
sealed and heated in a 60.degree. C. oil bath. After 3 h, the
mixture was concentrated. The residue was dissolved in a minimum
amount of water (10 mL). The mixture was neutralized with aqueous
HCl (5.0 M, 0.98 mL, 4.89 mmol). The solution was concentrated on
the rotovap. The solid residue was suspended in absolute ethanol
(20 mL). The suspension was filtered through a fine frit, and the
solid was collected, furnishing the title compound (984 mg).
Intermediate BY 003
##STR00174##
[1119] Synthesis of methyl
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylate
[1120] The title compound was prepared using the procedure for Step
2 of the preparation of Intermediate BY 002, except that
5-chloropyridin-2-amine was used instead of
5-fluoropyridin-2-amine.
Intermediate BY 004
##STR00175##
[1121] Synthesis of
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid
[1122] The title compound was prepared from Intermediate BY 003
using conditions described in Step 3 of the preparation of
Intermediate BY 002.
Intermediate BY 005
##STR00176##
[1123] Synthesis of
6-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid
Step 1: methyl
6-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylate
[1124] The title compound was prepared from Intermediate BY 003
using the general cyanation procedure as described herein.
Step 2: 6-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylic
acid
[1125] The title compound was prepared from methyl
6-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylate using the
procedure described in Step 3 of the synthesis of BY 002.
Intermediate BY 006
##STR00177##
[1126] Synthesis of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic
acid
[1127] The title compound was prepared using steps 2 and 3 of the
procedure used to prepare Intermediate BY 002, except that the
starting materials were 5-chloropyridin-2-amine and ethyl
3-bromo-2-oxopropanoate.
Intermediate BY 007
##STR00178##
[1128] Synthesis of
6-methoxy-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid
[1129] The title compound was prepared using steps 2 and 3 of the
procedure to prepare Intermediate BY 002, except that the starting
material was 5-methoxypyridin-2-amine.
Intermediate BY 008
##STR00179##
[1130] Synthesis of
6-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylic acid
[1131] The title compound was prepared using steps 1-3 of the
procedure to prepare Intermediate BY 002, except that methyl
2-oxopentanoate was used in step 1, and 5-chloropyridin-2-amine was
used in step 2.
Intermediate BY 009
##STR00180##
[1132] Synthesis of
6-chloro-3-isopropylimidazo[1,2-a]pyridine-2-carboxylic acid
[1133] The title compound was prepared using steps 1-3 of the
procedure to prepare Intermediate BY 002, except that methyl
4-methyl-2-oxopentanoate was used in step 1, and
5-chloropyridin-2-amine was used in step 2.
Intermediate X01
##STR00181##
[1134] Synthesis of 5-chloro-3-methoxypicolinic acid
[1135] 5-chloro-3-methoxypicolinonitrile (1 g, 5.45 mmol) was
dissolved in EtOH (20 mL) and treated with 5 M NaOH (5 mL). The
reaction mixture was heated at 100.degree. C. for 1 h. The reaction
mixture was cooled to RT and extracted with EtOAc. The aqueous
phase was neutralized with 1 M HCl. The aqueous phase was
back-extracted with EtOAc. The organic phase was separated and
dried over MgSO.sub.4. The solvent was removed under reduced
pressure to obtain the title compound as a yellow solid (115 mg).
M/S m/z=188.0 [M+H].sup.+. Calculated for C.sub.7H.sub.6ClNO.sub.3:
187.58
Intermediate X02
##STR00182##
[1136] Synthesis of 5-chloro-3-vinylpicolinic acid
[1137] A sealable vial was charged with
3-bromo-5-chloropicolinonitrile (700 mg, 3.22 mmol) and
dichlorobis(triphenyl-phosphine)palladium(II) (271 mg, 0.386 mmol).
The vial was evacuated and backfilled with nitrogen. 1,4-dioxane (5
mL) was added, followed by tri-n-butyl(vinyl)tin (1.225 mL, 3.86
mmol). The reaction mixture was heated to 100.degree. C. The
reaction mixture was diluted with water and EtOAc. The solvent was
removed under reduced pressure. The residue was dissolved in EtOH
(3 mL) and NaOH (1M, 6 mL). The cloudy solution was heated to
100.degree. C. for 15 min. The reaction mixture was cooled to RT,
the aqueous phase was separated and neutralized with 1 M HCl. The
aqueous phase was back-extracted with EtOAc. The organic phase was
separated and dried over MgSO.sub.4. The solvent was removed under
reduced pressure to obtain 5-chloro-3-vinylpicolinic acid (120 mg,
0.654 mmol, 20.30% yield) as a yellow solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 5.56 (d, J=11.11 Hz, 1H) 6.07 (d, J=17.54
Hz, 1H) 7.12 (dd, J=17.54, 11.11 Hz, 1H) 8.33 (d, J=2.19 Hz, 1H)
8.58 (d, J=2.19 Hz, 1H)
Intermediate X03
##STR00183##
[1138] Synthesis of 5-chloro-3-(prop-1-en-2-yl)picolinamide
[1139] A sealable vial was charged with
tetrakis(triphenylphosphine)palladium (133 mg, 0.115 mmol), sodium
carbonate (731 mg, 6.90 mmol) and 3-bromo-5-chloropicolinonitrile
(500 mg, 2.3 mmol).The vial was evacuated and backfilled with
Nitrogen. 1,4-Dioxane (5 mL) and water (1.5 mL) were added. The
reaction mixture was purged with Nitrogen for 2 min.
Isopropenylboronic acid pinacol ester (0.474 mL, 2.53 mmol) was
added and the reaction mixture was heated at 90.degree. C.
overnight. The reaction mixture was cooled to RT and partitioned
between water and EtOAc. The organic phase was dried over
MgSO.sub.4 and concentrated in vacuo. The residue was dissolved in
EtOH (5 mL) and NaOH (1M, 10 mL). The cloudy solution was heated at
100.degree. C. for 15 min. The reaction mixture was cooled to RT
and partitioned between water and EtOAc. The organic phase was
washed with 1 M HCl, dried over MgSO.sub.4 and concentrated under
reduced pressure. The crude material was absorbed onto a plug of
silica gel and purified by chromatography, eluting with a gradient
of 10% to 80% EtOAc in hexane, to provide the title compound (268
mg, 1.363 mmol, 59.3% yield) as a white solid. M/S m/z=197.0
[M+H].sup.+. Calculated for C.sub.9H.sub.9ClN.sub.2O: 196.63
R.sup.9--Intermediate 1:
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanamine
##STR00184##
[1140] Step 1:
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanol
[1141] To a solution of methyl
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.00 g, 4.45
mmol) in THF (10 mL) was added lithium borohydride, 2M solution in
THF (3.34 ml, 6.68 mmol) at rt. After the addition, the reaction
mixture was stirred at 60.degree. C. for 12 h. On cooling the
solution was acidified with 2N HCl solution, stirred for 1 h,
basified with saturated Na.sub.2CO.sub.3 solution and extracted
with DCM. The organic phase was concentrated and the solid obtained
was triturated with ether, filtered and dried to afford the title
compound (0.660 g, 3.36 mmol, 75% yield). LC/MS (ESI.sup.+)
m/z=197.0 (M+1).
Step 2:
6-chloro-2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine
[1142] A solution of
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.67 g, 3.41
mmol) in DCE (5 mL) was treated with thionyl chloride (0.497 ml,
6.81 mmol) and the resulting mixture stirred at 60.degree. C. for 1
h. The reaction was concentrated, diluted with DCM and washed with
0.5N NaOH solution. The organic was concentrated and residue
purified on silica gel eluting with 0-30% EtOAc in hexanes to
afford the title compound (0.763 g, 3.55 mmol, 104% yield). LC/MS
(ESI.sup.+) m/z=215.0 (M+1).
Step 3:
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanamine
[1143] A solution of
6-chloro-2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (0.763 g,
3.55 mmol) and sodium azide (0.461 g, 7.10 mmol) in DMF (5 mL) was
stirred at RT for 18 h. The reaction mixture was diluted with water
and extracted with EtOAc. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue obtained was added to a solution of triphenylphosphine
(1.303 g, 4.97 mmol) in THF (10 mL) and water (4 mL). The resulting
mixture was stirred overnight at RT and partitioned between EtOAc
and 3N aqueous HCl. The aqueous layer was separated and basified to
pH 10 with NH.sub.4OH solution and extracted with DCM. DCM was
dried and concentrated to afford the title compound (0.550 g, 2.81
mmol, 79% yield). The crude product was used without further
purification. LC/MS (ESI.sup.+) m/z=196.0 (M+1).
R.sup.9-Intermediate 2:
5-(cyclobutylmethoxy)-3-methylpicolinamide
##STR00185##
[1145] To a solution of 5-hydroxy-3-methylpyridine-2-carbonitrile
(0.841 mL, 7.90 mmol), cyclobutylmethanol (0.817 g, 9.48 mmol), and
triphenylphosphine (3.11 g, 11.85 mmol) in THF (10 mL) was added
diisopropyl azodicarboxylate (2.329 mL, 11.85 mmol) dropwise at rt.
After the addition, the reaction mixture was stirred at RT for 12
h, diluted with water and extracted with EtOAc. EtOAc was
concentrated and the residue purified on silica gel eluting with
0-50% ethyl acetate/hexanes to give
5-(cyclobutylmethoxy)-3-methylpicolinonitrile. To the
5-(cyclobutylmethoxy)-3-methylpicolinonitrile was added sodium
hydroxide 1N (39.5 mL, 39.5 mmol) in EtOH (15 mL). The reaction was
refluxed at 100.degree. C. for 18 h. The solid obtained after
cooling reaction mixture to RT was filtered, washed with water and
dried to afford the title compound (0.63 g, 2.86 mmol, 36.2%
yield). LC/MS (ESI.sup.+) m/z=221.0 (M+1). 119083-31-2.
R.sup.9-Intermediate 3: 5-(cyclobutylmethoxy)-3-methylpicolinic
acid
##STR00186##
[1147] To a solution of
5-(cyclobutylmethoxy)-3-methylpicolinonitrile was added sodium
hydroxide IN (39.5 mL, 39.5 mmol) in EtOH (15 mL). The reaction was
refluxed at 100.degree. C. for 18 h. The reaction mixture was
concentrated to half its volume and extracted with EtOAc. The
aqueous layer was acidified with 5N HCl to pH 4 and extracted with
EtOAc (2.times.). The organic layer was concentrated to afford the
title compound (0.7 g, 3.16 mmol, 40.0% yield). LC/MS (ESI.sup.+)
m/z=222.1 (M+1). 119083-31-3.
R.sup.9-Intermediate 4: 5-(2-fluoroethoxy)-3-methylpicolinamide
##STR00187##
[1149] In an analogous reaction to that described for
R.sup.9-Intermediate 2,5-(2-fluoroethoxy)-3-methylpicolinonitrile
(1.0 g, 5.55 mmol) was converted to the title compound (0.82 g,
4.14 mmol, 74.5% yield),). LC/MS (ESI.sup.+) m/z=199.0 (M+1).
R.sup.9-Intermediate 5: 5-(2-fluoroethoxy)-3-methylpicolinic
acid
##STR00188##
[1151] In an analogous reaction to that described for
R.sup.9-Intermediate 3,5-(2-fluoroethoxy)-3-methylpicolinonitrile
(1.0 g, 5.55 mmol) was converted to the title compound (0.103 g,
0.517 mmol, 9.32% yield). LC/MS (ESI.sup.+) m/z=200.0 (M+1).
Step 1 for R.sup.9-Intermediates 4 and 5:
5-(2-fluoroethoxy)-3-methylnicolinonitrile
##STR00189##
[1153] To a solution of 5-hydroxy-3-methylpyridine-2-carbonitrile
(0.794 mL, 7.46 mmol), 2-fluoroethanol (0.525 mL, 8.95 mmol), and
triphenylphosphine (2.93 g, 11.18 mmol) in THF (10 mL) was added
diisopropyl azodicarboxylate (2.198 mL, 11.18 mmol) dropwise
keeping temperature at RT. After the addition, the reaction mixture
was stirred at RT for 12 h, diluted with water and extracted with
EtOAc. EtOAc was concentrated and the residue purified on silica
gel eluting with 0-50% ethyl acetate/hexanes to give desired
product 5-(2-fluoroethoxy)-3-methylpicolinonitrile (1.2 g, 6.66
mmol, 89% yield)). LC/MS (ESI.sup.+) m/z=181.0 (M+1).
R.sup.9-Intermediate 6: 3-methyl-5-(oxetan-3-yloxy)picolinic
acid
##STR00190##
[1154] Step 1 for R.sup.9-Intermediate 6:
3-methyl-5-(oxetan-3-yloxy)picolinonitrile
[1155] To a stirred suspension of
5-hydroxy-3-methylpyridine-2-carbonitrile (0.397 mL, 3.73 mmol) and
sodium hydride, 60% dispersion in mineral oil (0.194 g, 4.85 mmol)
was added 3-oxetanyl tosylate (0.851 g, 3.73 mmol). The resulting
mixture was stirred at RT for 6 h, diluted with water, and
extracted with EtOAc. EtOAc was concentrated and the residue
purified on silica gel eluting with 0-50% ethyl acetate/hexanes to
afford the title compound (0.320 g, 1.682 mmol, 45.1% yield). LC/MS
(ESI.sup.+) m/z=191.0 (M+1).
Step 2: -methyl-5-(oxetan-3-yloxy)picolinic acid
[1156] In an analogous reaction to that described for
R.sup.9-Intermediate 3, -methyl-5-(oxetan-3-yloxy)picolinonitrile
(0.320 g, 1.682 mmol) was converted to the title compound (0.21 g,
1.004 mmol, 59.7% yield). LC/MS (ESI.sup.+) m/z=210.0 (M+1).
R.sup.9-Intermediate 7
##STR00191##
[1157] Synthesis of
4-chloro-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidine
Step 1: Synthesis of
7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one
[1158] A glass microwave reaction vessel was charged with
cyclopropylmethanol (3123 .mu.l, 38.6 mmol) followed by slow
addition of sodium hydride, 60% dispersion in mineral oil (416 mg,
17.35 mmol). The reaction mixture was stirred at RT for several
minutes. 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (350 mg, 1.928
mmol) was added, and the mixture was irradiated in a microwave
reactor at 140.degree. C. for 10 min. Then it was quenched with
saturated aqueous ammonium chloride and extracted with DCM. The
organic extract was washed with brine and dried over anhydrous
MgSO.sub.4. The solution was filtered and concentrated in vacuo to
give the crude material which was washed with Et.sub.2O and the
solid was collected by Buchner funnel to yield
7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one (50 mg,
0.230 mmol, 11.94% yield) as brown solid. LC/MS (ESI.sup.+)
m/z=218.1 (M+H).
Step 2: Synthesis of
4-chloro-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidine
[1159] To a mixture of
7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one (50 mg,
0.230 mmol) in Toluene (16440 were added diisopropylethylamine (122
.mu.l, 0.702 mmol) and phosphorus oxychloride (65.3 .mu.l, 0.714
mmol). The resulting reaction mixture was heated at 130.degree. C.
for 15 min. The reaction was concentrated, and the residue was
dissolved in DCM and neutralized with saturated aqueous sodium
bicarbonate. The aqueous layer was extracted with DCM. The combined
organic extract were washed with brine and dried over anhydrous
MgSO.sub.4, filtered and concentrated to give the crude material as
a dark brown solid. It was used for next step directly. LC/MS
(ESI.sup.+) m/z=236.1 (M+H).
R.sup.9-Intermediate 8
Synthesis of
2-((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)acetonitrile
Step 1: Synthesis of 5-chloropyrido[3,4-b]pyrazin-2-ol
[1160] A reaction vial was charged with
5-chloro-2-methoxypyrido[3,4-b]pyrazine (70 mg, 0.358 mmol) and
boron tribromide, 1.0 M in dichloromethane (1.074 mL, 1.074 mmol)
was added slowly. After stirring for 2.5h at RT, a further 0.3 mL
of boron tribromide, 1.0 M in dichloromethane was added and it was
stirred for another 2h. It was then concentrated and aqueous
NaHCO.sub.3 was added. The brown solid was collected by filtration,
washed with water and dried in-vacuuo to yield
5-chloropyrido[3,4-b]pyrazin-2-ol (56 mg, 0.308 mmol, 86% yield) as
brown solid. LC/MS (ESI.sup.+) m/z=182.1 (M+H).
Step 2: Synthesis of 2,5-dichloropyrido[3,4-b]pyrazine
[1161] A 100 mL flask was charged with
5-chloropyrido[3,4-b]pyrazin-2-ol (400 mg, 2.203 mmol) and
phosphorus oxychloride (8213 .mu.l, 88 mmol). The mixture was
stirred at 115.degree. C. for 0.5h. It was concentrated and diluted
with DCM. The black mixture was treated with sat. NaHCO.sub.3 until
slightly basic. The reaction mixture was extracted with DCM for
several times. The organic extract was dried over anhydrous
MgSO.sub.4, filtered through a silica plug and concentrated to give
the crude material as a orange solid. LC/MS (ESI.sup.+) m/z=200.1
(M+H).
Step 3: Synthesis of
2-((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)acetonitrile
[1162] To reaction vial were added formaldehyde cyanohydrin (244
.mu.l, 4.72 mmol) and sodium hydride, 60% dispersion in mineral oil
(12.6 mg, 0.315 mmol) slowly. The mixture was stirred at RT for 10
min. Then 2,5-dichloropyrido[3,4-b]pyrazine (35 mg, 0.157 mmol) was
added to the mixture. It was stirred at RT for 10 min. It was
quenched by addition of saturated aqueous NH.sub.4Cl, and extracted
with EtOAc. The organic extract was washed with Brine and dried
over anhydrous MgSO.sub.4, filtered and concentrated to give the
crude material as a orange solid. LC/MS (ESI.sup.+) m/z=221.1
(M+H).
[1163] By an analogous procedure, utilizing 2,2-difluoroethanol or
2,2,2-trifluoroethanol instead of formaldehyde cyanohydrin,
intermediates 5-chloro-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazine,
and 5-chloro-2-(2,2,2-trifluoroethoxy)pyrido[3,4-b]pyrazine were
obtained.
R.sup.9-Intermediate 9
Synthesis of 5-chloro-2-(2-fluoroethoxy)pyrido[3,4-b]pyrazine
[1164] To a reaction vial was added
5-chloropyrido[3,4-b]pyrazin-2-ol (30 mg, 0.165 mmol),
2-fluoroethyl 4-methylbenzenesulfonate (45.1 mg, 0.207 mmol) and
cesium carbonate (161 mg, 0.496 mmol) in DMF (1.0 mL). The solution
was stirred at 50.degree. C. for 1.25 h. Then the reaction was
heated at 60.degree. C. for 3 hr. The reaction mixture was diluted
with water and extracted with EtOAc. The organic extract was washed
with brine and dried over anhydrous MgSO.sub.4, filtered and
concentrated. The crude material was purified by silica-gel
chromatography, eluting with a gradient of 20% to 40% to 55% (40%
EtOAc in Heptane) in Heptane, to provide
5-chloro-2-(2-fluoroethoxy)pyrido[3,4-b]pyrazine (19 mg, 0.083
mmol, 50.5% yield) as white solid. LC/MS (ESI.sup.+) m/z=228.0
(M+H).
R.sup.9-Intermediate 10
Synthesis of 2-(but-2-yn-1-yloxy)-5-chloropyrido[3,4-b]pyrazine
[1165] A microwave reaction vessel was charged with
5-chloropyrido[3,4-b]pyrazin-2-ol (40 mg, 0.220 mmol) and
2-butyn-1-ol (0.046 mL, 0.661 mmol) in THF (0.8 mL) followed by
triphenylphosphine (173 mg, 0.661 mmol). The reaction mixture was
stirred for 10 min and diisopropyl azodicarboxylate (0.130 mL,
0.661 mmol) was then added slowly. The mixture was stirred at RT
for 10 min. It was quenched with water and extracted with EtOAc.
The organic extract was washed with brine and dried over anhydrous
MgSO.sub.4, filtered and concentrated. The crude material was
purified by silica gel chromatography to provide
2-(but-2-yn-1-yloxy)-5-chloropyrido[3,4-b]pyrazine (20 mg, 0.086
mmol, 38.9% yield) as light-yellow solid. LC/MS (ESI.sup.+)
m/z=234.0 (M+H).
Intermediate RR02
##STR00192##
[1166] Synthesis of 8-chloro-5-fluoro-1,7-naphthyridin-3-ol &
8-bromo-5-fluoro-1,7-naphthyridin-3-ol
[1167] To a solution of
8-chloro-5-fluoro-3-methoxy-1,7-naphthyridine (0.879 g, 4.13 mmol)
in 1,2-dichloroethane (40 mL) was added boron tribromide, 1.0M in
dichloromethane (30 ml, 30.0 mmol) via syringe. Upon completion of
addition, the reaction was heated at 70.degree. C. overnight. To
the reaction was added boron tribromide, 1.0M in dichloromethane
(10 mL). After 15 h the reaction was cooled to RT and the solvent
was removed in vacuo. The residue was stirred vigorously with DCM,
filtered, washed with water and solvent stripped at reduced
pressure to give 658 mg (80%) of a tan crystalline solid, comprised
of a mixture of 8-chloro-5-fluoro-1,7-naphthyridin-3-ol: MS
m/z=198.9, 200.0 (M+1) and 8-bromo-5-fluoro-1,7-naphthyridin-3-ol:
MS m/z=244.9 (M+1).
Intermediate RR03
##STR00193##
[1168] Synthesis of
8-chloro-3-(cyclopropylmethoxy)-5-fluoro-1,7-naphthyridine &
8-bromo-3-(cyclopropylmethoxy)-5-fluoro-1,7-naphthyridine
[1169] To a cooled (0.degree. C.) mixture of
8-bromo-5-fluoro-1,7-naphthyridin-3-ol &
8-chloro-5-fluoro-1,7-naphthyridin-3-ol (0.200 g, 0.453 mmol) and
triphenylphosphine (0.290 g, 1.106 mmol) in THF (5 mL) was added
cyclopropanemethanol (0.120 mL, 1.504 mmol) and diisopropyl
azodicarboxylate (0.220 mL, 1.120 mmol). The reaction was allowed
to warm to RT overnight. The reaction mixture was diluted with
EtOAc, evaporated onto silica gel and purified by flash
chromatography on silica gel eluting with EtOAc:hexanes
(0:1.fwdarw.1:2) to give 175 mg of a white crystalline solid
comprised of a mixture of
8-chloro-3-(cyclopropylmethoxy)-5-fluoro-1,7-naphthyridine. MS
m/z=258.9 (M+1). &
8-bromo-3-(cyclopropylmethoxy)-5-fluoro-1,7-naphthyridine. MS
m/z=298.9 (M+1).
Intermediate RR04
##STR00194##
[1170] Synthesis of
8-chloro-5-fluoro-3-(2,2,2-trifluoroethoxy)-1,7-naphthyridine &
8-bromo-5-fluoro-3-(2,2,2-trifluoroethoxy)-1,7-naphthyridine
[1171] To a mixture of 8-bromo-5-fluoro-1,7-naphthyridin-3-ol
compound with 8-chloro-5-fluoro-1,7-naphthyridin-3-ol (0.229 g,
0.519 mmol) and cesium carbonate (0.489 g, 1.501 mmol) in DMF (2
mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.200
mL, 1.387 mmol) via syringe at RT. After stiffing overnight the
mixture was diluted with EtOAc and washed with water (1.times.) and
brine (1.times.). The combined organic layers were dried over
MgSO.sub.4, were filtered and concentrated in vacuo to give 293 mg
(93%) of an off-white crystalline solid comprised of
8-chloro-5-fluoro-3-(2,2,2-trifluoroethoxy)-1,7-naphthyridine: MS
m/z=280.9, 283.0 (M+1) and
8-bromo-5-fluoro-3-(2,2,2-trifluoroethoxy)-1,7-naphthyridine: MS
m/z=324.8, 326.9 (M+1).
Intermediate RR05
##STR00195##
[1172] Synthesis of
8-chloro-3-(cyclobutylmethoxy)-5-fluoro-1,7-naphthyridine &
8-bromo-3-(cyclobutylmethoxy)-5-fluoro-1,7-naphthyridine
[1173] The titled compounds were prepared according to the
procedure for Intermediate RR03 using cyclobutanemethanol.
8-Chloro-3-(cyclobutylmethoxy)-5-fluoro-1,7-naphthyridine: MS
m/z=267.0 (M+1) and
8-bromo-3-(cyclobutylmethoxy)-5-fluoro-1,7-naphthyridine: MS
m/z=313.0 (M+1).
Intermediate RR06
##STR00196##
[1174] Synthesis of 8-chloro-5-fluoro-3-ethoxy-1,7-naphthyridine
& 8-bromo-5-fluoro-3-ethoxy-1,7-naphthyridine
[1175] The titled compounds were prepared according to the
procedure for Intermediate RR04 using ethyl methanesulfonate.
8-Chloro-5-fluoro-3-ethoxy-1,7-naphthyridine: MS m/z=227.0 (M+1)
and 8-bromo-5-fluoro-3-ethoxy-1,7-naphthyridine: MS m/z=271.0,
272.9 (M+1).
Intermediate RR07
##STR00197##
[1176] Synthesis of 8-chloro-5-fluoro-3-isobutoxy-1,7-naphthyridine
& 8-bromo-5-fluoro-3-isobutoxy-1,7-naphthyridine
[1177] The titled compounds were prepared according to the
procedure for Intermediate RR03 using isobutanol.
8-Chloro-5-fluoro-3-isobutoxy-1,7-naphthyridine: MS m/z=255.1
(M+1). 8-Bromo-5-fluoro-3-isobutoxy-1,7-naphthyridine: MS m/z=298.9
(M+1).
Intermediate RR08
##STR00198##
[1178] Synthesis of
8-chloro-3-(2,2-difluoroethoxy)-5-fluoro-1,7-naphthyridine &
8-bromo-3-(2,2-difluoroethoxy)-5-fluoro-1,7-naphthyridine
[1179] The titled compounds were prepared according to the
procedure for Intermediate RR04 using 2,2-difluoro ethyl
trifluoromethanesulfonate.
8-chloro-3-(2,2-difluoroethoxy)-5-fluoro-1,7-naphthyridine: MS
m/z=262.9, 265.0 (M+1) and
8-bromo-3-(2,2-difluoroethoxy)-5-fluoro-1,7-naphthyridine: MS
m/z=307.0, 308.9 (M+1).
Intermediate KR01
##STR00199##
[1180] Synthesis of
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-
-8-ene 5,5-dioxide
Step 1: 1-(methylsulfonyl)cyclobutanecarbonitrile
[1181] To a solution of 2-(methylsulfonyl)acetonitrile (1.00 g,
8.39 mmol) in acetonitrile (8.4 mL) was added potassium carbonate
(3.48 g, 25.2 mmol), followed by 1,3-dibromopropane (0.946 mL, 9.23
mmol). The reaction was stirred at 65.degree. C. for 18 hours. The
reaction mixture was cooled to ambient temperature and filtered.
The collected solids were rinsed with EtOAc. The filtrate was
collected, concentrated in vacuo, and purified by silica-gel
chromatography, eluting with 0-50% EtOAc in Heptanes, to provide
the title compound (0.80 g, 5.0 mmol, 60% yield) as a colorless
oil.
Step 2:
(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-s-
ulfinamide
[1182] In an analogous reaction to that described for Intermediate
1, step 2,1-(5-bromo-2-fluorophenyl)ethanone (50 g, 230 mmol) was
treated with (R)-2-methylpropane-2-sulfinamide (27.9 g, 230 mmol)
to give the title compound (54.13 g, 169 mmol, 73% yield). LC/MS
(ESI.sup.+) m/z=320 (M+H).
Step 3:
(R)--N--((R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclobutyl)sulf-
onyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[1183] In an analogous reaction to that described for Intermediate
1, step 3,
(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfi-
namide was converted to the title compound (8.96 g, 18.69 mmol, 60%
yield). LC/MS (ESI.sup.+) m/z=479 (M+H).
Step 4:
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-azaspiro[-
3.5]non-8-ene 5,5-dioxide
[1184] In an analogous sequence of reactions to those described for
Example 6, steps 2-3,
(R)--N--((R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclobutyl)sulfonyl)pr-
opan-2-yl)-2-methylpropane-2-sulfinamide was converted to the title
compound (2.09 g, 5.57 mmol, 67% yield). LC/MS (ESI.sup.+) m/z=375
(M+H).
Example 106
##STR00200##
[1185]
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-car-
boxamide
[1186] As described in the HATU coupling procedure, (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate and
4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid were
combined to provide the title compound (70 mg, 0.146 mmol, 69.7%
yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=478 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) d ppm 10.51 (s, 1H) 8.76 (br.
s, 1H) 7.65-8.09 (m, 3H) 7.13 (dd, J=12.08, 8.66 Hz, 1H) 6.02 (br.
s., 2H) 3.45-3.69 (m, 2H) 1.62 (s, 3H) 1.58 (s, 3H) 1.47 (s,
3H)
Example 107
##STR00201##
[1187] Synthesis of
(R)-5-amino-3-(5-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)methyl)am-
ino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
Step 1:
4-chloro-1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-3-carbo-
xamide
[1188] To a solution of
4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (0.38 g,
1.933 mmol) in DCM (12.89 ml) was added N-methylmorpholine (0.234
ml, 2.127 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.408 g, 2.127 mmol), and N,O-dimethylhydroxylamine
hydrochloride (0.207 g, 2.127 mmol). The reaction mixture was
stirred at ambient temperature overnight. The reaction was then
partitioned between ethyl acetate and water. The organic portion
was concentrated and the crude product was purified by silica-gel
chromatography, eluting with a gradient of 10-40% Ethyl
Acetate/Heptanes to give the title compound (270 mg, 1.127 mmol,
58.3% yield) as a white solid. LC/MS (ESI.sup.+) m/z=240 (M+H).
Step 2: 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde
[1189] To a solution of
4-chloro-1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide
(0.270 g, 1.127 mmol) in THF (5.6 mL) at 0.degree. C. was added
Lithium Aluminium Hydride (1M in THF, 0.563 ml, 0.563 mmol)
drop-wise. The reaction mixture was stirred for 45 minutes and then
quenched with aqueous NaHSO.sub.4 solution. The crude product was
extracted with EtOAc and concentrated in vacuo to give the title
compound (0.14 g, 0.775 mmol, 68.8% yield). LC/MS (ESI.sup.+)
m/z=181 (M+H).
Step 3:
(R)-5-amino-3-(5-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)me-
thyl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1190] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (90 mg, 0.225 mmol) in DCE (0.75 mL) was
added 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde (65.1
mg, 0.360 mmol) followed by acetic acid (64.5 .mu.l, 1.126 mmol).
The reaction was stirred for 5 minutes then sodium tri-acetoxy
borohydride (71.6 mg, 0.338 mmol) was added. The reaction mixture
was stirred for 2 hours. The reaction was then quenched with
aqueous sodium bicarbonate solution and extracted with
dichloromethane. The organic portion was concentrated, diluted in
dichloromethane and treated with TFA (521 .mu.l, 6.76 mmol). The
reaction mixture was stirred for 30 minutes and then partitioned
between aqueous sodium bicarbonate solution and dichloromethane.
The organic portion was concentrated and the crude product was
purified by silica-gel chromatography, eluting with a gradient of
10-50% (90/10/1 dichloromethane/methanol/ammonium hydroxide) in
dichloromethane to give the title compound (65 mg, 0.140 mmol,
62.2% yield) as a white solid. LC/MS (ESI.sup.+) m/z=464 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) d ppm 8.52 (s, 1H) 7.74 (t,
J=1.22 Hz, 1H,) 6.78-6.90 (m, 2H) 6.45-6.53 (m, 1H) 5.95 (br. s.,
1H) 5.93 (br. s., 2H) 4.19 (d, J=5.87 Hz, 2H) 3.36-3.59 (m, 2H)
1.57 (s, 3H) 1.55 (s, 3H) 1.44 (s, 3H)
Example 108
##STR00202##
[1191]
(R)-5-amino-3-(5-(((4-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3--
yl)methyl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazi-
ne 1,1-dioxide
Step 1: (R)-tert-butyl
(5-(5-(((4-chloro-1H-pyrazol-3-yl)methyl)amino)-2-fluorophenyl)-2,2,5-tri-
methyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1192] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (150 mg, 0.375 mmol) in DCE (12520 was
added acetic acid (107 .mu.l, 1.877 mmol) followed by
4-chloro-1H-pyrazole-3-carbaldehyde (58.8 mg, 0.451 mmol), The
reaction mixture was stirred for 5 minutes and then sodium
tri-acetoxy borohydride (119 mg, 0.563 mmol) was added. The
reaction mixture was stirred for 2 hours. The reaction was quenched
with aqueous sodium bicarbonate solution and extracted with DCM.
The organic portion was concentrated and the crude product was
purified by silica-gel chromatography, eluting with a gradient of
10-50% (90/10/1 DCM/MeOH/ammonium hydroxide) in dichloromethane to
give the title compound (120 mg, 0.233 mmol, 62.2% yield). LC/MS
(ESI.sup.+) m/z=514 (M+H).
Step 2:
(R)--S-amino-3-(S-(((4-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol--
3-1,1-dioxide
[1193] To a solution of (R)-tert-butyl
(5-(5-(((4-chloro-1H-pyrazol-3-yl)methyl)amino)-2-fluorophenyl)-2,2,5-tri-
methyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120
mg, 0.233 mmol) in DMF (0.78 mL) was added potassium carbonate (129
mg, 0.934 mmol) followed by 2,2,2-trifluoroethyl
trifluoromethanesulfonate (65.0 .mu.l, 0.280 mmol). The reaction
mixture was stirred at 60.degree. C. for 16 hours and then
partitioned between water and EtOAc. The organic portion was dried
over sodium sulfate and concentrated. The crude product was
purified by silica-gel chromatography, eluting with a gradient of
10-50% (90/10/1 dichloromethane/methanol/ammonium hydroxide) in DCM
to give the title compound (20 mg, 0.040 mmol) as a yellow solid.
LC/MS (ES.sup.+) m/z=496 (M+H).
Example 109
##STR00203##
[1194]
(R)-5-amino-3-(5-(((4-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5--
yl)methyl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazi-
ne 1,1-dioxide
[1195] To a solution of (R)-tert-butyl
(5-(5-(((4-chloro-1H-pyrazol-3-yl)methyl)amino)-2-fluorophenyl)-2,2,5-tri-
methyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120
mg, 0.233 mmol) in DMF (0.78 mL) was added potassium carbonate (129
mg, 0.934 mmol) followed by 2,2,2-trifluoroethyl
trifluoromethanesulfonate (65.0 .mu.l, 0.280 mmol). The reaction
mixture was stirred at 60.degree. C. for 16 hours and then
partitioned between water and ethyl acetate. The organic portion
was dried over sodium sulfate and concentrated. The crude product
was purified by silica-gel chromatography, eluting with a gradient
of 10-50% (90/10/1 dichloromethane/methanol/ammonium hydroxide) in
DCM to give the title compound (3 mg, 6.1 umol) as a yellow solid.
LC/MS (ESI.sup.+) m/z=496 (M+H).
Example 110
##STR00204##
[1196]
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)-5-methylpyrazine-2-carboxamide
[1197] As described in the HATU coupling procedure, (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (150 mg, 0.375 mmol) and
5-methylpyrazine-2-carboxylic acid (57.1 mg, 0.413 mmol) were
combined to provide the title compound (68 mg, 0.162 mmol, 36%
yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=420 (M+H).
Example 111
##STR00205##
[1198].RTM.-N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)-3,5-dimethylpyrazine-2-carboxamide
[1199] As described in the HATU coupling procedure,
.RTM.-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (150 mg, 0.375 mmol) and
3,5-dimethylpyrazine-2-carboxylic acid (62.8 mg, 0.413 mmol) were
combined to provide the title compound (80 mg, 0.185 mmol, 47%
yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=434 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) d ppm 10.55 (s, 1H) 8.50 (s,
1H) 7.80-7.86 (m, 1H) 7.74 (dd, J=7.53, 2.64 Hz, 1H) 7.15 (dd,
J=12.13, 8.90 Hz, 1H) 6.02 (br. S, 2H) 3.48-3.70 (m, 2H) 2.74 (s,
3H) 2.57 (s, 3H) 1.63 (s, 3H) 1.58 (s, 3H) 1.48 (s, 3H)
Example 112
##STR00206##
[1200] Synthesis of
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2-hydroxy-7-methyl-5-thia-8-azaspi-
ro[3.5]non-8-ene 5,5-dioxide
Step 1: (((1,3-dibromopropan-2-yl)oxy)methyl)benzene
[1201] To a suspension of -2-(benzyloxy)propane-1,3-diol (1 g, 5.49
mmol) in DCM (27.4 ml) at 0.degree. C., was added
triphenylphosphine (7.05 g, 26.9 mmol) and carbon tetrabromide
(8.74 g, 26.3 mmol). The reaction mixture was brought to ambient
temperature and stirred for 16 hours. The reaction mixture was
concentrated and the crude solid was rinsed with heptanes. The
filtrate was collected and concentrated in vacuo to provide the
title compound (0.85 g, 2.76 mmol) as a colorless oil.
Step 2: (R)-tert-butyl
(1-((3-(benzyloxy)-1-cyanocyclobutyl)sulfonyl)-2-(5-bromo-2-fluorophenyl)-
propan-2-yl)carbamate
[1202] In an analogous reaction to that described in example 83,
step 1, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e and (((1,3-dibromopropan-2-yl)oxy)methyl)benzene were combined to
provide the title compound (0.38 g, 0.65 mmol) as an off-white
solid. LC/MS (ESI.sup.+) m/z=603 (M+Na).
Step 3:
(R)-9-amino-2-(benzyloxy)-7-(5-bromo-2-fluorophenyl)-7-methyl-5-th-
ia-8-azaspiro[3.5]non-8-ene 5,5-dioxide
[1203] In an analogous reaction to that described in example 83,
step 2, (R)-tert-butyl
(1-((3-(benzyloxy)-1-cyanocyclobutyl)sulfonyl)-2-(5-bromo-2-fluorophenyl)-
propan-2-yl)carbamate was converted to the title compound (0.28 g,
0.58 mmol) as a tan solid. LC/MS (ESI.sup.+) m/z=481 (M+H).
Step 4:
R-9-amino-7-(5-bromo-2-fluorophenyl)-2-hydroxy-7-methyl-5-thia-8-a-
zaspiro[3.5]non-8-ene 5,5-dioxide
[1204] To a solution of
(R)-9-amino-2-(benzyloxy)-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-az-
aspiro[3.5]non-8-ene 5,5-dioxide (90 mg, 0.187 mmol) in DCM (0.75
mL) at -78.degree. C., was added boron trichloride (1M in DCM, 0.94
mL, 0.94 mmol). The reaction mixture was stirred for 3 hours and
then treated with 7N Ammonia in Methanol. The mixture was
concentrated and the crude product was purified by silica-gel
chromatography, eluting with 20-60% (90/10/1
dichloromethane/methanol/ammonium hydroxide) in dichloromethane, to
afford the title compound (70 mg, 0.179 mmol) as a white solid.
LC/MS (ESI.sup.+) m/z=391 (M+H).
Example 113
##STR00207##
[1205] Synthesis of
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-
-8-ene 5,5-dioxide
[1206] In an analogous sequence of reactions to those described for
example 83, steps 1-2, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e was converted to the title compound as a tan solid. LC/MS
(ESI.sup.+) m/z=375 (M+H).
Example 114
##STR00208##
[1207] Synthesis of (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate
[1208] In an analogous sequence of reactions to those described for
intermediate 2, steps 1-3,
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-
-8-ene 5,5-dioxide was converted to the title compound as an
off-white solid. LC/MS (ESI.sup.+) m/z=412 (M+H).
Example 115
##STR00209##
[1209]
(R)--N-(3-(9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-
-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide
[1210] As described in the HATU coupling procedure, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate (110 mg, 0.267 mmol)
5-chloro-2-pyridinecarboxylic acid (50.5 mg, 0.321 mmol) were
combined to provide the title compound (40 mg, 0.089 mmol, 33%
yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=451 (M+H).
Example 116
##STR00210##
[1211]
(R)-9-amino-7-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluoroph-
enyl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene 5,5-dioxide
[1212] In a similar sequence of reactions to those described for
Example 44, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate (350 mg, 0.851 mmol) and
3,8-dichloro-1,7-naphthyridine (152 mg, 0.766 mmol) were combined
to provide the title compound (260 mg, 0.549 mmol, 64.5% yield) as
a yellow solid. LC/MS (ESI.sup.+) m/z=474 (M+H).
Example 117
##STR00211##
[1213]
(R)-8-((3-(9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-
-en-7-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile
[1214] In an analogous reaction to that described for Example 76,
(R)-9-amino-7-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophenyl)--
7-methyl-5-thia-8-azaspiro[3.5]non-8-ene 5,5-dioxide (150 mg, 0.316
mmol) was converted to the title compound (35 mg, 0.075 mmol,
23.81% yield) as a yellow solid LC/MS (ESI.sup.+) m/z=465
(M+H).
Example 118
##STR00212##
[1215]
(2S,4s,7R)-9-amino-7-(5-bromo-2-fluorophenyl)-2-fluoro-7-methyl-5-t-
hia-8-azaspiro[3.5]non-8-ene 5,5-dioxide
Step 1: (R)-tert-butyl
(7-(5-bromo-2-fluorophenyl)-2-hydroxy-7-methyl-5,5-dioxido-5-thia-8-azasp-
iro[3.5]non-8-en-9-yl)carbamate
[1216] To a solution of
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2-hydroxy-7-methyl-5-thia-8-azaspi-
ro[3.5]non-8-ene 5,5-dioxide (0.070 g, 0.179 mmol) in Dioxane (0.9
mL) was added boc anhydride (0.063 g, 0.286 mmol) and a saturated
aqueous solution of sodium bicarbonate (0.9 mL). The resulting
mixture was stirred at ambient temperature for 16 hours and then
diluted with water and ethyl acetate. The organic layer was
collected, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The crude product was purified by silica-gel
chromatography, eluting with a gradient of 1-3% MeOH in DCM, to
provide the title compound (0.060 g, 0.122 mmol) as an off-white
solid. LC/MS (ESI.sup.+) m/z=491 (M+H).
Step 2:
(2S,4s,7R)-9-amino-7-(5-bromo-2-fluorophenyl)-2-fluoro-7-methyl-5--
thia-8-azaspiro[3.5]non-8-ene 5,5-dioxide
[1217] To a solution of (R)-tert-butyl
(7-(5-bromo-2-fluorophenyl)-2-hydroxy-7-methyl-5,5-dioxido-5-thia-8-azasp-
iro[3.5]non-8-en-9-yl)carbamate (0.150 g, 0.305 mmol) in DCM (2.04
mL) was added DAST (0.046 mL, 0.351 mmol). The resulting mixture
was stirred at 60.degree. C. for 15 minutes, cooled to RT and
poured onto a mixture of ice and aqueous sodium bicarbonate
solution. The mixture was then extracted with ethyl acetate. The
organic layer was concentrated and passed through a silica plug to
give the title compound (0.050 g, 0.127 mmol, 41.7% yield) as an
off-white solid. LC/MS (ESI.sup.+) m/z=393 (M+H).
Example 119
##STR00213##
[1218]
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2,2-difluoro-7-methyl-5-thia-
-8-azaspiro[3.5]non-8-ene 5,5-dioxide
Step 1: 2,2-difluoropropane-1,3-diol
[1219] To a solution of diethyl difluoromalonate (3.77 g, 19.22
mmol) in THF (19.22 ml) at 0.degree. C., was added Lithium
Aluminium Hydride (1M in THF, 30.8 ml, 30.8 mmol) drop-wise. The
reaction mixture was brought to ambient temperature and then
stirred for 16 hours. The reaction mixture was then slowly poured
onto an ice-cold suspension of 4 g of Na.sub.2SO.sub.4.10H.sub.2O
in 20 mL of THF. This was stirred for 1 h and the resulting slurry
was filtered, rinsed with 1:3 MeOH/EtOAc. The filtrate was
collected and concentrated to give the title compound (1.7 g, 15.17
mmol, 79% yield) as a white paste.
Step 2: 2,2-difluoropropane-1,3-diyl
bis(trifluoromethanesulfonate)
[1220] To a suspension of 2,2-difluoropropane-1,3-diol (0.69 g,
6.16 mmol) in Ether (41.0 ml) was added pyridine (2.191 ml, 27.1
mmol). The reaction mixture was cooled to -5.degree. C. and stirred
vigorously for 5 minutes. To this was added
trifluoromethanesulfonic anhydride (3.12 ml, 18.47 mmol). The
reaction mixture was stirred at -5.degree. C. for 30 minutes and
then at ambient temperature for 3 hours. The reaction mixture was
then filtered through a celite pad and the solids rinsed with
ether. The filtrate was concentrated and the residue dried in vacuo
to provide the title compound (1.65 g, 4.39 mmol, 71% yield) as a
brown oil.
Step 3: (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((1-cyano-3,3-difluorocyclobutyl)sulfonyl)p-
ropan-2-yl)carbamate
[1221] To a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e (1.57 g, 3.61 mmol) and 2,2-difluoropropane-1,3-diyl
bis(trifluoromethanesulfonate) (1.438 g, 3.82 mmol) in 1,4-dioxane
(36.1 ml) was added cesium carbonate (2.350 g, 7.21 mmol). The
reaction mixture was stirred at 55.degree. C. for 3 hours. The
reaction was partitioned between water and ethyl acetate. The
organic portion was concentrated and the crude product was purified
by silica-gel chromatography, eluting with a gradient of 0-1% MeOH
in DCM, to provide the title compound (1.2 g, 2.347 mmol, 65.1%
yield) as a white solid. LC/MS (ESI.sup.+) m/z=533 (M+Na).
Step 4:
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2,2-difluoro-7-methyl-5-thi-
a-8-azaspiro[3.5]non-8-ene 5,5-dioxide
[1222] A suspension of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((1-cyano-3,3-difluorocyclobutyl)sulfonyl)p-
ropan-2-yl)carbamate (1.19 g, 2.327 mmol) in HCl (4N in dioxane,
17.45 ml, 69.8 mmol) was heated at reflux for 15 hours. The
reaction mixture was then concentrated and partitioned between
aqueous sodium bicarbonate solution and DCM. The organic portion
was concentrated and passed through a silica gel plug to give the
title compound (957 mg, 2.327 mmol, quantitative yield) as a tan
solid. LC/MS (ESI.sup.+) m/z=411 (M+H).
Example 120
##STR00214##
[1223]
(R)--N-(3-(9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azasp-
iro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide
[1224] Using the standard CuI-driven amidation conditions
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2,2-difluoro-7-methyl-5-thia-8-aza-
spiro[3.5]non-8-ene 5,5-dioxide (0.105 g, 0.255 mmol) and
5-chloropicolinamide (0.060 g, 0.383 mmol) were combined to give
the title compound (20 mg, 0.041 mmol, 16.09% yield) as an
off-white solid. LC/MS (ESI.sup.+) m/z=487 (M+H). .sup.1H NMR (400
MHz, DMSO-d.sub.6) d ppm 10.74 (s, 1H) 8.84 (d, J=1.56 Hz, 1H)
8.13-8.35 (m, 2H) 7.93 (d, J=5.97 Hz, 2H) 7.12-7.35 (m, 1H) 6.31
(br. s., 2H) 3.58-3.89 (m, 2H) 3.06-3.34 (m, 4H) 1.72 (s, 3H)
Example 121
##STR00215##
[1225] Synthesis of
(R)--N-(3-(9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[1226] As described in the HATU coupling procedure, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate (100 mg, 0.243 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (49.4 mg, 0.243 mmol)
were combined to provide the title compound (20 mg, 0.040 mmol,
16.58% yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=497
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.49 (s, 1H) 8.43
(d, J=2.35 Hz, 1H) 7.80-7.86 (m, 1H) 7.74-7.78 (m, 1H) 7.72 (d,
J=2.15 Hz, 1H) 7.44 (t, J=1.00 Hz, 1H) 7.13 (dd, J=12.03, 8.80 Hz,
1H) 6.25 (br. s., 2H) 3.35-3.58 (m, 2H) 2.61-2.77 (m, 2H) 2.59 (s,
3H) 2.53-2.57 (m, 2H) 1.95-2.18 (m, 2H) 1.62 (s, 3H)
Example 122
##STR00216##
[1227] Synthesis of (R)-tert-butyl
(7-(5-(5-cyano-3-methylpicolinamido)-2-fluorophenyl)-7-methyl-5
5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate
[1228] As described in the HATU coupling procedure, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate (100 mg, 0.243 mmol) and
5-cyano-3-methylpicolinic acid (43.3 mg, 0.267 mmol) were combined
to provide the title compound (90 mg, 0.162 mmol, 66.7% yield) as
an off-white solid. LC/MS (ESI.sup.+) m/z=456 (M+H). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) ppm 10.68 (s, 1H) 8.98 (dd, J=1.96, 0.59
Hz, 1H) 8.40 (dd, J=1.96, 0.68 Hz, 1H) 7.79-7.86 (m, 1H) 7.71-7.76
(m, 1H) 7.10-7.20 (m, 1H) 6.26 (br. s., 2H) 3.36-3.62 (m, 2H)
2.56-2.82 (m, 4H) 2.55 (s, 3H) 1.95-2.20 (m, 2H) 1.62 (s, 3H)
Example 123
##STR00217##
[1229] Synthesis of
(R)--N-(3-(9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methylpicolinamide
[1230] As described in the HATU coupling procedure, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate (100 mg, 0.243 mmol) and
5-(difluoromethyl)-3-methylpicolinic acid (54.6 mg, 0.292 mmol)
were combined to provide the title compound (15 mg, 0.031 mmol,
12.85% yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=481
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.66 (br. s., 1H)
8.77 (s, 1H) 8.08-8.13 (m, 1H) 7.79-7.93 (m, 2H) 7.12-7.43 (m, 2H)
6.31 (br. s., 2H) 3.42-3.68 (m, 2H) 2.67-2.83 (m, 2H) 2.64 (s, 3H)
2.58-2.62 (m, 2H) 2.01-2.22 (m, 2H) 1.68 (s, 3H)
Example 125
##STR00218##
[1231]
N-(3-((2S,4s,7R)-9-amino-2-fluoro-7-methyl-5,5-dioxido-5-thia-8-aza-
spiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide
[1232] Using the standard CuI-driven amidation conditions
(2S,4s,7R)-9-amino-7-(5-bromo-2-fluorophenyl)-2-fluoro-7-methyl-5-thia-8--
azaspiro[3.5]non-8-ene 5,5-dioxide (0.016 g, 0.041 mmol) and
5-chloropicolinamide (9.56 mg, 0.061 mmol) were combined to give
the title compound (8 mg, 0.017 mmol, 41.9% yield) as an off-white
solid. LC/MS (ESI.sup.+) m/z=469 (M+H).
Example 124
##STR00219##
[1233] Synthesis of
(R)--N-(3-(9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.-
5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1234] Using the standard CuI-driven amidation conditions
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2,2-difluoro-7-methyl-5-thia-8-aza-
spiro[3.5]non-8-ene 5,5-dioxide (0.075 g, 0.182 mmol) and
5-chloro-3-methylpicolinamide (0.040 g, 0.237 mmol) were combined
to give the title compound (0.02 g, 0.040 mmol, 22% yield) as an
off-white solid. LC/MS (ESI.sup.+) m/z=501 (M+H). .sup.1H NMR (400
MHz, DMSO-d.sub.6) ppm 10.62 (s, 1H) 8.64 (d, J=1.86 Hz, 1H)
8.07-8.10 (m, 1H) 7.87-7.93 (m, 1H) 7.79 (dd, J=7.24, 2.64 Hz, 1H)
7.21 (dd, J=11.88, 8.95 Hz, 1H) 6.30 (br. s., 2H) 3.63-3.84 (m, 2H)
3.20-3.36 (m, 4H) 2.62 (s, 3H) 1.72 (s, 3H)
Example 126
##STR00220##
[1235] Synthesis of
(R)--N-(3-(9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.-
5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[1236] Using the standard CuI-driven amidation conditions
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-2,2-difluoro-7-methyl-5-thia-8-aza-
spiro[3.5]non-8-ene 5,5-dioxide (0.075 g, 0.182 mmol) and
5-(difluoromethoxy)-3-methylpicolinamide (0.048 g, 0.237 mmol) were
combined to give the title compound (0.01 g, 0.018 mmol, 10% yield)
as an off-white solid. LC/MS (ESI.sup.+) m/z=533 (M+H).
Example 127
##STR00221##
[1237] Synthesis of
(R)--N-(3-(9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7--
yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1238] Using the standard CuI-driven amidation conditions
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-
-8-ene 5,5-dioxide (152 mg, 0.405 mmol) and
5-chloro-3-methylpicolinamide (69.1 mg, 0.405 mmol) were combined
to give the title compound (38 mg, 0.068 mmol, 17% yield) as an
off-white solid. LC/MS (ESI.sup.+) m/z=465 (M+H).
Example 128
##STR00222##
[1239] Synthesis
(R)-9-amino-2,2-difluro-7-(2-fluoro-5-((2-methoxypyrido[3,4b]pyrazin-5-yl-
)amino)phenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene
5,5-dioxide
[1240] In a similar sequence of reactions to those described for
Example 44, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-az-
aspiro[3.5]non-8-en-9-yl)carbamate (100 mg, 0.223 mmol) and
5-chloro-2-methoxypyrido[3,4-b]pyrazine (39.3 mg, 0.201 mmol) were
combined to provide the title compound (20 mg, 0.039 mmol, 17.67%
yield) as a yellow solid. LC/MS (ESI.sup.+) m/z=507 (M+H).
Example 129
##STR00223##
[1241]
(R)-4-((3-(9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azasp-
iro[3.5
]non-8-en-7-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-car-
bonitrile
[1242] In a similar sequence of reactions to those described for
Example 44, (R)-tert-butyl
(7-(5-amino-2-fluorophenyl)-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-az-
aspiro[3.5]non-8-en-9-yl)carbamate (100 mg, 0.223 mmol) and
4-chloropyrido[3,2-d]pyrimidine-7-carbonitrile (46.9 mg, 0.246
mmol) were combined to provide the title compound (42 mg, 0.084
mmol, 37.5% yield) as a yellow solid. LC/MS (ESI.sup.+) m/z=502
(M+H).
Example 130
##STR00224##
[1243] tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate
Step 1: (R)-tert-butyl
(7-(5-bromo-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate
[1244] In an analogous reaction to that described for intermediate
2, step 1,
(R)-9-amino-7-(5-bromo-2-fluorophenyl)-7-methyl-5-thia-8-azaspiro[3.5]-
non-8-ene 5,5-dioxide was converted to the title compound (1.42 g,
2.99 mmol, 93% yield) as a tan solid. LC/MS (ESI.sup.+) m/z=475
(M+H).
Step 2: tert-butyl
((6S,7R)-7-(5-bromo-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate
[1245] In an analogous reaction to that described for example 4,
step 1, (R)-tert-butyl
(7-(5-bromo-2-fluorophenyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]no-
n-8-en-9-yl)carbamate (1.05 g, 2.209 mmol) was converted to the
title compound (690 mg, 1.399 mmol, 63.3% yield) as an off-white
solid. LC/MS (ESI.sup.+) m/z=493 (M+H).
Step 3: tert-butyl
((6S,7R)-7-(5-azido-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate
[1246] In an analogous reaction to that described for intermediate
2, step 2, tert-butyl
((6S,7R)-7-(5-bromo-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate was converted to the title
compound (628 mg, 1.378 mmol, quantitative yield) as a clear oil.
LC/MS (ESI.sup.+) m/z=478 (M+Na).
Step 4: tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate
[1247] In an analogous reaction to that described for intermediate
2, step 3, tert-butyl
((6S,7R)-7-(5-azido-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (628 mg, 1.378 mmol) was
converted to the title compound (420 mg, 0.978 mmol, 71% yield) as
a white foam LC/MS (ESI.sup.+) m/z=430 (M+H).
Example 131
##STR00225##
[1248]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide
[1249] As described in the HATU coupling procedure, tert-butyl
((6,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-
-azaspiro[3.5]non-8-en-9-yl)carbamate (0.15 g, 0.349 mmol) and
5-chloro-2-pyridinecarboxylic acid (0.066 g, 0.419 mmol) were
combined to provide the title compound (90 mg, 0.192 mmol, 55.0%
yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=469 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.64 (s, 1H) 8.78 (dd,
J=2.35, 0.68 Hz, 1H) 8.12-8.21 (m, 2H) 7.77-7.88 (m, 2H) 7.16 (dd,
J=11.93, 8.61 Hz, 1H) 6.56 (br. s., 2H) 5.90 (d, J=1.00 Hz, 1H)
2.59-2.86 (m, 4H) 1.93-2.27 (m, 2H) 1.60 (s, 3H)
Example 132
##STR00226##
[1250]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolina-
mide
[1251] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (88 mg, 0.205 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (41.6 mg, 0.205 mmol)
were combined to provide the title compound (45 mg, 0.087 mmol,
42.7% yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=515
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.56 (s, 1H) 8.47
(d, J=2.45 Hz, 1H) 7.87-7.93 (m, 1H) 7.76 (d, J=2.25 Hz, 1H)
7.67-7.70 (m, 1H) 7.48 (t, J=1.00 Hz, 1H) 7.20 (dd, J=11.98, 8.85
Hz, 1H) 6.63 (br. s., 2H) 5.95 (d, J=1.00 Hz, 1H) 2.65-2.86 (m, 4H)
2.62 (s, 3H) 1.97-2.35 (m, 2H) 1.66 (d, J=3.52 Hz, 3H)
Example 133
##STR00227##
[1252]
N-3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspir-
o[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1253] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (113 mg, 0.263 mmol) and
5-chloro-3-methylpyridine-2-carboxylic acid (32.5 .mu.l, 0.263
mmol) were combined to provide the title compound (55 mg, 0.114
mmol, 43.3% yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=483
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.53 (s, 1H) 8.56
(d, J=1.86 Hz, 1H) 8.01 (d, J=1.66 Hz, 1H) 7.80-7.88 (m, 1H) 7.62
(d, J=4.99 Hz, 1H) 7.16 (dd, J=11.84, 9.00 Hz, 1H) 6.58 (br. s.,
2H) 5.90 (d, J=1.00 Hz, 1H) 2.60-2.83 (m, 4H) 2.53 (s, 3H)
1.95-2.27 (m, 2H) 1.60 (d, J=3.23 Hz, 3H)
Example 134
##STR00228##
[1254]
8-((3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azasp-
iro[3.5]non-8-en-7-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitr-
ile
[1255] In an analogous reaction to that described for Example 76,
(6S,7R)-9-amino-7-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophen-
yl)-6-fluoro-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene 5,5-dioxide
(0.12 g, 0.244 mmol) was converted to the title compound (35 mg,
0.073 mmol, 29.7% yield) as a yellow solid LC/MS (ESI.sup.+)
m/z=483 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.70 (s, 1H)
9.23 (d, J=1.96 Hz, 1H) 8.99 (d, J=2.05 Hz, 1H) 8.24 (d, J=5.67 Hz,
1H) 8.09-8.13 (m, 1H) 8.00-8.06 (m, 1H) 7.24 (d, J=5.87 Hz, 1H)
7.15 (dd, J=11.79, 9.05 Hz, 1H) 6.62 (br. s, 2H) 5.91 (d, J=1.00
Hz, 1H) 2.55-2.82 (m, 4H) 1.92-2.26 (m, 2H) 1.64 (d, J=3.42 Hz,
3H)
Example 135
##STR00229##
[1256]
(6S,7R)-9-amino-6-fluoro-7-(2-fluoro-5-((2-methoxypyrido[3,4-b]pyra-
zin-5-yl)amino)phenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene
5,5-dioxide
[1257] In a similar sequence of reactions to those described for
Example 44, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (110 mg, 0.256 mmol) and
5-chloro-2-methoxypyrido[3,4-b]pyrazine (52.6 mg, 0.269 mmol) were
combined to provide the title compound (45 mg, 0.092 mmol, 36.0%
yield) as a yellow solid. LC/MS (ESI.sup.+) m/z=489 (M+H).
Example 136
##STR00230##
[1258]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methylpicolinam-
ide
[1259] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (120 mg, 0.279 mmol) and
5-(difluoromethyl)-3-methylpicolinic acid (62.7 mg, 0.335 mmol)
were combined to provide the title compound (67 mg, 0.134 mmol,
48.1% yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=499
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.63 (s, 1H) 8.71
(br. d, J=1.00 Hz, 1H) 8.01-8.08 (m, 1H) 7.82-7.90 (m, 1H) 7.63 (d,
J=4.50 Hz, 1H) 7.08-7.37 (m, 2H) 6.58 (br. s., 2H) 5.91 (d, J=1.00
Hz, 1H) 2.60-2.82 (m, 4H) 2.57 (s, 3H) 1.92-2.26 (m, 2H) 1.62 (d,
J=3.33 Hz, 3H)
Example 137
##STR00231##
[1260]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-methoxy-3-methylpicolinamide
[1261] As described in the HATU coupling procedure, with tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (120 mg, 0.279 mmol) and
5-methoxy-3-methylpicolinic acid (56 mg, 0.335 mmol) were combined
to provide the title compound (91 mg, 0.190 mmol, 68.1% yield) as
an off-white solid. LC/MS (ESI.sup.+) m/z=479 (M+H). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) ppm 10.36 (s, 1H) 8.22 (d, J=2.45 Hz, 1H)
7.82-7.88 (m, 1H) 7.58-7.64 (m, 1H) 7.40 (d, J=2.64 Hz, 1H) 7.13
(dd, J=11.93, 8.80 Hz, 1H) 6.57 (br. s, 2H) 5.90 (d, J=1.00 Hz, 1H)
3.91 (s, 3H) 2.62-2.82 (m, 4H) 2.61 (s, 3H) 1.95-2.26 (m, 2H) 1.60
(d, J=3.42 Hz, 3H)
Example 138
##STR00232##
[1262]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide
[1263] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (120 mg, 0.279 mmol) and
5-cyano-3-methylpicolinic acid (54.4 mg, 0.335 mmol) were combined
to provide the title compound (55 mg, 0.116 mmol, 41.6% yield) as
an off-white solid. LC/MS (ESI.sup.+) m/z=474 (M+H). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) ppm 10.71 (s, 1H) 8.96-8.99 (m, 1H) 8.38
8.42 (m, 1H) 7.82-7.88 (m, 1H) 7.58-7.62 (m, 1H) 7.18 (dd, J=11.98,
8.85 Hz, 1H) 6.59 (br. s., 2H) 5.91 (d, J=1.00 Hz, 1H) 2.55-2.83
(m, 4H) 2.53 (s, 3H) 1.95-2.27 (m, 2H) 1.61 (d, J=3.42 Hz, 3H)
Example 139
##STR00233##
[1264]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-3-methoxypicolinamide
[1265] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (120 mg, 0.279 mmol) and
5-chloro-3-methoxypicolinic acid (62.9 mg, 0.335 mmol) were
combined to provide the title compound (73 mg, 0.146 mmol, 52%
yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=499 (M+H).
Example 140
##STR00234##
[1266]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxa-
mide
[1267] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (127 mg, 0.296 mmol) and
5-(difluoromethyl)pyrazine-2-carboxylic acid (61.8 mg, 0.355 mmol)
were combined to provide the title compound (120 mg, 0.205 mmol,
69.3% yield) as an off-white solid. LC/MS (ESI.sup.+) m/z=486
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.91 (s, 1H)
9.37-9.39 (m, 1H) 9.08-9.10 (m, 1H) 7.81-7.89 (m, 2H) 7.11-7.42 (m,
2H) 6.59 (br. s., 2H) 5.92 (d, J=1.00 Hz, 1H) 2.58-2.82 (m, 4H)
1.94-2.27 (m, 2H) 1.62 (d, J=3.52 Hz, 3H)
Example 141
##STR00235##
[1268]
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspi-
ro[3.5]non-8-en-7-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyrid-
ine-2-carboxamide
[1269] As described in the HATU coupling procedure, tert-butyl
((6S,7R)-7-(5-amino-2-fluorophenyl)-6-fluoro-7-methyl-5,5-dioxido-5-thia--
8-azaspiro[3.5]non-8-en-9-yl)carbamate (77 mg, 0.179 mmol) and
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (45.3 mg,
0.215 mmol) were combined to provide the title compound (62 mg,
0.119 mmol, 66% yield) as an off-white solid. LC/MS (ESI.sup.+)
m/z=522 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.20 (s,
1H) 8.68-8.70 (m, 1H) 7.82-7.89 (m, 1 H) 7.75 (dd, J=7.34, 2.64 Hz,
1H) 7.70 (dd, J=9.63, 0.83 Hz, 1H) 7.43 (dd, J=9.63, 2.01 Hz, 1H)
7.14 (dd, J=11.98, 8.75 Hz, 1H) 6.58 (br. s, 2H) 5.91 (d, J=1.00
Hz, 1H) 2.81 (s, 3H) 2.58-2.77 (m, 4H) 1.96-2.28 (m, 2H) 1.62 (d,
J=3.91 Hz, 3H)
Example 142
##STR00236##
[1270] Synthesis of
(S)--N-(4-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide
[1271] Using procedure similar to the general CuI amidation
procedure, (S)-tert-butyl
(5-(2-bromo-5-fluoropyridin-4-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-
-2H-1,4-thiazin-3-yl)carbamate (0.09 g, 0.194 mmol),
5-methoxypyrazine-2-carboxamide (0.036 g, 0.233 mmol), copper(I)
iodide (2.0 mg, 9.69 .mu.mol), N,N'-dimethylethylenediamine (2.084
.mu.l, 0.019 mmol), and potassium carbonate (0.080 g, 0.581 mmol)
were combined to afford the title compound (0.016 g, 0.037 mmol,
18.91% yield). LC/MS (ESI.sup.+) m/z=437.1 (M+H); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm: 10.04 (s, 1H), 9.00 (d, J=0.78 Hz,
1H), 8.54 (d, J=6.26 Hz, 1H), 8.01-8.31 (m, 2H), 4.06 (s, 3H),
3.48-3.67 (m, 2H), 1.81 (s, 3H), 1.72 (s, 3H), 1.64 (s, 3H).
(NH.sub.2 very broad and not accounted for).
Example 143
##STR00237##
[1272] Synthesis of
(R)--N-(4-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide
[1273] A mixture of (R)-tert-butyl
(5-(2-bromo-5-fluoropyridin-4-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-
-2H-1,4-thiazin-3-yl)carbamate (0.09 g, 0.194 mmol),
5-methoxypyrazine-2-carboxamide (0.042 g, 0.271 mmol),
4,5-bis(diphenylphos-phino)-9,9-dimethyl-xanthene (0.011 g, 0.019
mmol), tris(dibenzylideneacetone) dipalladium (0) (0.018 g, 0.019
mmol), and cesium carbonate (0.189 g, 0.581 mmol) in Dioxane (1.5
mL) contained in a microwave vial was flushed with argon, capped,
and heated under microwave irradiation at 120.degree. C. for 1 hr.
The reaction mixture was cooled to RT, diluted with water and
extracted with EtOAc. The organic phase was concentrated and the
residue purified on silica gel eluting with 0-100% ethyl
acetate/hexanes to give the tile compound (0.035 g, 0.080 mmol,
41.4% yield). LC/MS (ESI.sup.+) m/z=437.1 (M+H); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm: 10.04 (s, 1H), 8.99 (d, J=1.37 Hz,
1H), 8.53 (d, J=6.26 Hz, 1H), 8.04-8.22 (m, 2H), 5.5-4.0 (brs. 2H),
4.06 (s, 3H), 3.46-3.69 (m, 2H), 1.80 (s, 3H), 1.72 (s, 3H), 1.64
(s, 3H).
Example 144
##STR00238##
[1274] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[1275] Using procedure similar to the general CuI amidation
procedure,
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (0.2 g, 0.551 mmol),
5-(difluoromethoxy)-3-methylpicolinamide (0.122 g, 0.606 mmol),
copper(I) iodide (0.005 g, 0.026 mmol),
N,N'-dimethylethylenediamine (5.92 .mu.l, 0.055 mmol), and
potassium carbonate (0.228 g, 1.652 mmol) were combined to afford
the title compound (0.182 g, 0.376 mmol, 68.2% yield). LC/MS
(ESI.sup.+) m/z=485.1 (M+H); .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm: 10.00 (s, 1H), 8.21 (d, J=1.37 Hz, 1H), 7.84-8.00 (m,
1H), 7.60 (dd, J=7.04, 2.54 Hz, 1H), 7.37 (d, J=2.15 Hz, 1H), 7.08
(dd, J=11.74, 8.80 Hz, 1H), 6.35-6.84 (m, 1H), 4.34-5.21 (m, 2H),
3.39-3.74 (m, 2H), 2.76 (s, 3H), 1.81 (s, 3H), 1.69 (s, 3H), 1.59
(s, 3H).
Example 145
##STR00239##
[1276] Synthesis of
(R)-5-amino-3-(2-(((6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methyl)am-
ino)-5-fluoropyridin-4-yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine-1,1-
-dioxide
[1277] A mixture of (R)-tert-butyl
(5-(2-bromo-5-fluoropyridin-4-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-
-2H-1,4-thiazin-3-yl)carbamate (0.152 g, 0.327 mmol),
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanamine (0.083 g,
0.426 mmol), Xantphos (0.019 g, 0.033 mmol), palladium (II) acetate
(7.35 mg, 0.033 mmol) and sodium t-butoxide (0.063 g, 0.655 mmol)
in 1,4-dioxane was microwaved at 100.degree. C. for 40 min, diluted
with water and extracted with EtOAc and DCM. The organics were
combined, concentrated and residue purified by silica gel
chromatography, eluting with 100% EtOAc to give (R)-tert-butyl
(5-(2-(((6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-5-fluo-
ropyridin-4-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-y-
l)carbamate. The (R)-tert-butyl
(5-(2-(((6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-5-fluo-
ropyridin-4-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-y-
l)carbamate was dissolved in Dioxane (3 mL) and hydrogen chloride,
4N in 1,4-dioxane (4.09 ml, 16.37 mmol) was added. The reaction
mixture was stirred at RT for 12h. The reaction mixture was
concentrated, diluted with water and extracted with DCM. The
aqueous phase was basified with 1N NaOH solution and extracted with
DCM. The DCM from the second extraction was dried and concentrated
to afford the title compound (0.08 g, 0.167 mmol, 51% yield). LC/MS
(ESI.sup.+) m/z=478.9 (M+); .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm: 7.78-7.98 (m, 2H), 7.48 (d, J=9.39 Hz, 1H), 7.12 (dd,
J=9.49, 1.86 Hz, 1H), 6.64 (d, J=5.28 Hz, 1H), 5.20 (br. s., 1H),
4.62 (d, J=5.09 Hz, 2H), 3.74-3.82 (m, 1H), 3.60-3.68 (m, 1H),
3.43-3.59 (m, 2H), 2.48 (s, 3H), 1.73 (s, 3H), 1.67 (s, 3H), 1.58
(br. s., 3H).
Example 146
##STR00240##
[1278] Synthesis of
(S)-9-amino-7-(2-bromo-5-fluoropyridin-4-yl)-7-methyl-5-thia-8-azaspiro[3-
.5]non-8-ene 5,5-dioxide
Step 1: 1-(2-bromo-5-fluoropyridin-4-yl)ethanol
[1279] To a solution of lithium diisopropylamide, 2.0M solution in
heptane/THF/ethylbenzene (42.0 mL, 84 mmol) in THF (50 mL), under
nitrogen atmosphere at -78.degree. C. was added a solution of
2-bromo-5-fluoropyridine (14.79 g, 84 mmol) in THF (50 mL) dropwise
over 15 min. The reaction mixture was stirred at -78.degree. C. for
2 h and acetaldehyde, anhydrous (5.19 mL, 92 mmol) was added
dropwise. The reaction mixture was allowed to warm to room
temperature over a period of 1 h and stirred at room temperature
for 2 h. The reaction mixture was quenched with dropwise addition
of H.sub.2O (450 mL) and the aqueous layer was extracted with ethyl
acetate (3.times.150 mL). The combined organic extract was dried
over sodium sulphate, filtered, and concentrated under reduced
pressure to afford a crude product which was purified by silica gel
column chromatography eluting with 0-40% EtOAc in hexane to afford
the title compound (13.64 g, 62.0 mmol, 73.8% yield). LC/MS
(ESI.sup.+) m/z=220.0 (M+).
Step 2:
(S)-9-amino-7-(2-bromo-5-fluoropyridin-4-yl)-7-methyl-5-thia-8-aza-
spiro[3.5]non-8-ene 5,5-dioxide
[1280] In an analogous sequence of reactions to those described for
Example 13, steps 2-5, 1-(2-bromo-5-fluoropyridin-4-yl)ethanol was
converted to the racemate
9-amino-7-(2-bromo-5-fluoropyridin-4-yl)-7-methyl-5-thia-8-azaspiro[3.5]n-
on-8-ene 5,5-dioxide. The racemate was purified by chiral SFC,
using a ChiralPak IC column and eluting with 25% (20 mM ammonia in
methanol) in CO.sub.2, to provide the title compound in 48%. LC/MS
(ESI.sup.+) m/z=377.9, 379.9 (M+H; 2 bromine isotopes). .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 8.17 (d, J=2.93 Hz, 1H), 7.59
(d, J=6.06 Hz, 1H), 5.07 (br. s., 2H), 3.42-3.52 (m, 1H), 3.29-3.40
(m, 1H), 2.95-3.09 (m, 1H), 2.83-2.94 (m, 1H), 2.43-2.63 (m, 2H),
2.19-2.37 (m, 2H), 1.66-1.75 (m, 3H).
Example 147
##STR00241##
[1281] Synthesis of
(R)-9-amino-7-(2-bromo-5-fluoropyridin-4-yl)-7-methyl-5-thia-8-azaspiro[3-
.5]non-8-ene 5,5-dioxide
[1282] The title compound is the other enantiomer recovered from
the chiral SFC purification described in Example 146 above, using a
ChiralPak IC column and eluting with 25% (20 mM ammonia in
methanol) in CO.sub.2 in 45.2% yield. LC/MS (ESI.sup.+) m/z=377.9,
379.9 (M+H; 2 bromine isotopes). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 8.17 (d, J=2.93 Hz, 1H), 7.59 (d, J=6.06
Hz, 1H), 5.07 (br. s., 2H), 3.42-3.52 (m, 1H), 3.29-3.40 (m, 1H),
2.95-3.09 (m, 1H), 2.83-2.94 (m, 1H), 2.43-2.63 (m, 2H), 2.19-2.37
(m, 2H), 1.66-1.75 (m, 3H).
Example 148
##STR00242##
[1283] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinam-
ide
[1284] Using procedure similar to the general CuI amidation
procedure,
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (0.100 g, 0.262 mmol),
5-(difluoromethoxy)-3-methylpicolinamide (63.6 mg, 0.315 mmol),
copper(I) iodide (0.005 g, 0.026 mmol),
N,N'-dimethylethylenediamine (40 mg, 0.454 mmol), and potassium
carbonate (0.109 g, 0.789 mmol) were combined to afford the title
compound (0.073 g, 0.145 mmol, 55.4% yield). LC/MS (ESI.sup.+)
m/z=503.9 (M+); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
10.00 (s, 1H), 8.21 (s, 1H), 7.89-8.04 (m, 1H), 7.63 (dd, J=7.04,
2.74 Hz, 1H), 7.36 (d, J=1.96 Hz, 1H), 7.09 (dd, J=11.83, 8.90 Hz,
1H), 6.37-6.84 (m, 1H), 5.00-4.4 (br s, 2H), 4.64-4.90 (m, 1H),
4.35-4.62 (m, 1H), 3.60-3.90 (m, 2H), 2.75 (s, 3H), 1.73 (s, 3H),
1.60 (s, 3H).
Example 149
##STR00243##
[1285] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-fluoroethoxy)-3-methylpicolinami-
de
[1286] Using procedure similar to the Amidation Method D,
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (0.053 g, 0.167 mmol) and
5-(2-fluoroethoxy)-3-methylpicolinic acid (0.040 g, 0.200 mmol) and
1-propanephosphonic acid cyclic anhydride (0.159 ml, 0.251 mmol)
were combined to afford the title compound (0.067 g, 0.134 mmol,
80% yield). LC/MS (ESI.sup.+) m/z=499.1 (M+); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm: 10.05 (s, 1H), 8.09 (d, J=2.54 Hz, 1H),
8.02 (ddd, J=8.80, 4.30, 2.93 Hz, 1H), 7.58 (dd, J=7.04, 2.74 Hz,
1H), 7.01-7.14 (m, 2H), 4.67-4.90 (m, 3H), 4.41-4.61 (m, 1H), 4.34
(dd, J=4.79, 3.23 Hz, 1H), 4.27 (dd, J=4.79, 3.23 Hz, 1H), 3.83 (s,
1H), 3.74 (s, 1H), 2.74 (s, 3H), 1.74 (s, 3H), 1.62 (s, 3H).
Example 150
##STR00244##
[1287] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methyl-5-(oxetan-3-yloxy)picolinami-
de
[1288] Using procedure similar to the Amidation Method D,
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (0.050 g, 0.158 mmol),
3-methyl-5-(oxetan-3-yloxy)picolinic acid (0.040 g, 0.189 mmol),
1-propanephosphonic acid cyclic anhydride (0.150 ml, 0.236 mmol)
were combined to afford the title compound (0.05 g, 0.098 mmol,
62.4% yield). LC/MS (ESI.sup.+) m/z=508.9 (M+); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm: 10.01 (s, 1H), 8.01 (ddd, J=8.90,
4.21, 2.74 Hz, 1H), 7.87 (d, J=2.74 Hz, 1H), 7.57 (dd, J=6.85, 2.74
Hz, 1H), 7.09 (dd, J=11.83, 8.90 Hz, 1H), 6.83 (d, J=2.35 Hz, 1H),
5.21-5.28 (m, 1H), 4.98 (td, J=6.65, 3.52 Hz, 2H), 4.67-4.87 (m,
3H), 4.39-4.62 (m, 1H), 3.64-3.86 (m, 2H), 2.71 (s, 3H), 1.74 (s,
3H), 1.61 (s, 3H).
Example 151
##STR00245##
[1289] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(cyclobutylmethoxy)-3-methylpicolin-
amide
[1290] Using procedure similar to the general CuI amidation
procedure,
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (0.200 mg, 0.525 mmol),
5-(cyclobutylmethoxy)-3-methylpicolinamide (127 mg, 0.577 mmol),
copper(I) iodide (19.9 mg, 0.105 mmol),
N,N'-dimethylethylenediamine (55 mg, 0.624 mmol), and potassium
carbonate (290.0 mg, 2.098 mmol) were combined to afford the title
compound (60.0 mg, 0.115 mmol, 21.97% yield). LC/MS (ESI.sup.+)
m/z=521.0 (M+1); .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
10.05 (s, 1H), 7.91-8.11 (m, 2H), 7.59 (dd, J=6.94, 2.64 Hz, 1H),
6.92-7.18 (m, 2H), 4.65-4.88 (m, 1H), 4.41-4.63 (m, 1H), 4.00 (d,
J=6.65 Hz, 2H), 3.65-3.85 (m, 2H), 2.76-2.86 (m, 1H), 2.74 (s, 3H),
2.10-2.26 (m, 2H), 1.83-2.03 (m, 4H), 1.73 (s, 3H), 1.62 (s,
3H).
Example 152
##STR00246##
[1291] Synthesis of
(R)-5-amino-3-(5-(((6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methyl)am-
ino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
Step 1: (6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanol
[1292] To a solution of methyl
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylate (0.503 g,
2.24 mmol) in THF (4.5 mL) at 0.degree. C. was added lithium
borohydride (2.0 M in THF, 1.20 mL, 2.40 mmol). The reaction
mixture was warmed to RT and stirred for 15 min, heated to
40.degree. C. for 4 h, then cooled to RT and quenched with
saturated NH.sub.4Cl. The reaction mixture was diluted with EtOAc
and saturated NH.sub.4Cl. The aqueous phase was extracted with
EtOAc (3.times.) and the combined organic extracts were washed with
brine (1.times.), dried over MgSO.sub.4, filtered, and
concentrated. Purification by flash column chromatography on silica
gel (10% to 100% EtOAc (10% MeOH) in hexanes) gave
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.245 g,
1.25 mmol, 56% yield) as a white solid.
Step 2: 6-chloro-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde
[1293] To a solution of
(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.242 g,
1.23 mmol) in DMSO (4 mL) at room temperature was added TEA (1.00
mL, 7.17 mmol) and sulfur trioxide pyridine complex (0.411 g, 2.58
mmol). The reaction mixture was stirred at RT for 15 min and then
diluted with EtOAc and water. The aqueous phase was extracted with
EtOAc (4.times.). The combined organic extracts were washed with
brine (1.times.), dried over MgSO.sub.4, filtered, and
concentrated. Purification by flash column chromatography on silica
gel (70% EtOAc in hexanes) gave
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (0.221 g,
1.14 mmol, 92% yield) as a white solid.
Step 3:
(R)-5-amino-3-(5-(((6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)me-
thyl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1294] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (0.102 g, 0.255 mmol) and
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (0.050 g,
0.26 mmol) in DCE (2 mL) at RT was added HOAc (0.015 mL, 0.26 mmol)
and sodium triacetoxyborohydride (0.074 g, 0.35 mmol). The reaction
mixture was stirred at RT for 25 min and TFA (2 mL) was added. The
reaction mixture was stirred at RT for 15 min and then
concentrated. The concentrate was diluted with EtOAc and water. The
aqueous phase was extracted with EtOAc (2.times.). The combined
organic extracts were washed with brine (1.times.), dried over
MgSO.sub.4, filtered, and concentrated. Purification by flash
column chromatography on silica gel (20% to 80% EtOAc (10% 2 M
NH.sub.3 in MeOH) in hexanes) gave
(R)-5-amino-3-(5-(((6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)methyl)am-
ino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (0.108 g, 0.226 mmol, 88% yield) as a white solid.
LC/MS (ESI.sup.+) m/z=478.0 (M+H).
Example 153
##STR00247##
[1295] Synthesis of
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-N-(4-chlorophenyl)-4-fluorobenzamide
Step 1: (R)-methyl
3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-
-fluorobenzoate
[1296] To a mixture of
9,9-dimethyl-4,5-bis(bis[3,5-dimethyl-4-methoxyphenyl]phosphino)xanthene
(0.104 g, 0.180 mmol), palladium (II) acetate (0.020 g, 0.089
mmol), and
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (0.899 g, 2.48 mmol) was added TEA (5.00 mL,
35.9 mmol) and MeOH (1.00 mL, 24.7 mmol). The nitrogen atmosphere
was replaced by carbon monoxide from a double balloon and the
reaction mixture was heated at 70.degree. C. for 24 h and then
cooled to RT. The reaction mixture was diluted with EtOAc and
saturated NaHCO.sub.3. The aqueous phase was extracted with EtOAc
(2.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated.
Purification by flash column chromatography on silica gel (70% to
100% EtOAc in hexanes) gave (R)-methyl
3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-
-fluorobenzoate (0.594 g, 1.74 mmol, 70% yield) as an off white
solid.
Step 2: (R)-methyl
3-(5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorobenzoate
[1297] To a mixture of (R)-methyl
3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-
-fluorobenzoate (0.079 g, 0.23 mmol) and di-tert-butyl dicarbonate
(0.076 g, 0.35 mmol) was added dioxane (2 mL) and saturated
NaHCO.sub.3 (0.250 mL). The reaction mixture was stirred at RT for
3 h, heated to 40.degree. C. for 3 h, cooled to room temperature,
and diluted with DCM. The organic phase was washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated to
give (R)-methyl 3-(5-((tert-butoxy
carbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3--
yl)-4-fluorobenzoate as a colorless oil that was used without
additional purification.
Step 3:
(R)-3-(5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido--
3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorobenzoic acid
[1298] To a solution of (R)-methyl
3-(5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorobenzoate (0.102 g, 0.231 mmol) in
MeOH (2 mL) at RT was added potassium hydroxide (0.025 g, 0.45
mmol). The reaction mixture was heated to 40.degree. C. for 15 h
and LiOH (10 mg) was added. The reaction mixture was heated at
60.degree. C. for 3 h, cooled to RT, and diluted with EtOAc and
brine. The pH was adjusted to pH 5 with 5 M HCl. The aqueous phase
was extracted with EtOAc (3.times.). The combined organic extracts
were washed with brine (1.times.), dried over MgSO.sub.4, filtered,
and concentrated. Purification by flash column chromatography on
silica gel (50% EtOAc (10% MeOH) in hexanes) gave
(R)-3-(5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dih-
ydro-2H-1,4-thiazin-3-yl)-4-fluorobenzoic acid (0.047 g, 0.11 mmol,
48% yield) as a white solid.
Step 4: (R)-tert-butyl
(5-(5-((4-chlorophenyl)carbamoyl)-2-fluorophenyl)-2,2,5-trimethyl-1,1-dio-
xido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1299] To a mixture of
(R)-3-(5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dih-
ydro-2H-1,4-thiazin-3-yl)-4-fluorobenzoic acid (0.047 g, 0.11 mmol)
and 4-chloroaniline (0.057 g, 0.45 mmol) was added DMF (1 mL), TEA
(0.025 mL, 0.18 mmol), and
1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide
hexafluorophosphate (0.048 g, 0.13 mmol). The reaction mixture was
stirred at RT for 18 h and then diluted with EtOAc and water. The
aqueous phase was extracted with EtOAc (1.times.). The combined
organic extracts were washed with brine (1.times.), dried over
MgSO.sub.4, filtered, and concentrated to give (R)-tert-butyl
(5-(5-((4-chlorophenyl)carbamoyl)-2-fluorophenyl)-2,2,5-trimethyl-1,1-dio-
xido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate as a white
solid.
Step 5:
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thia-
zin-3-yl)-N-(4-chlorophenyl)-4-fluorobenzamide
[1300] To a solution of (R)-tert-butyl
(5-(5-((4-chlorophenyl)carbamoyl)-2-fluorophenyl)-2,2,5-trimethyl-1,1-dio-
xido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.059 g, 0.11 mmol)
in DCM (2 mL) at room temperature was added trifluoroacetic acid
(2.0 mL, 0.11 mmol). The reaction mixture was stirred at RT for 15
min and then concentrated. The concentrate was diluted with EtOAc,
saturated NaHCO.sub.3, and water. The aqueous phase was extracted
with EtOAc (2.times.). The combined organic extracts were washed
with brine (1.times.), dried over MgSO.sub.4, filtered, and
concentrated. Purification by flash column chromatography on silica
gel (30% to 70% EtOAc (10% MeOH) in hexanes) followed by
reverse-phase HPLC (Shimadzu; Xbridge, 50 mm.times.150 mm, 10
.mu.m; eluted with 10% to 60% MeCN in water (0.1% TFA added to
mobile phase) at 40 mL/min) Relevant fractions were concentrated,
followed by neutralization of the TFA by partitioning between EtOAc
and NaHCO.sub.3 to give
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-N-(4-chlorophenyl)-4-fluorobenzamide (0.013 g, 0.030 mmol, 27%
yield) as a white solid. LC/MS (ESI.sup.+) m/z=438.0 (M+H).
Example 154
##STR00248##
[1301] Synthesis of
(R)-9-amino-7-(3-bromophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene
5,5-dioxide
Step 1:
(R,E)-N-(1-(3-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamid-
e
[1302] To a solution of 3'-bromoacetophenone (2.00 mL, 15.1 mmol)
in 2-methylTHF (30 mL) at room temperature was added
(R)-(+)-2-methyl-2-propanesulfinamide (3.47 g, 28.6 mmol) and
titanium (IV) ethoxide (8.00 mL, 38.2 mmol). The reaction mixture
was heated at 70.degree. C. for 15 h, cooled to room temperature
and poured into 100 mL of brine with stirring. The mixture was
filtered, and the aqueous phase of the filtrate was discarded. The
organic phase was dried over MgSO.sub.4, filtered, and
concentrated. Purification by flash column chromatography on silica
gel (5% to 30% EtOAc in hexanes) gave
(R,E)-N-(1-(3-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide
(4.07 g, 13.5 mmol, 89% yield) as a yellow oil.
Step 2:
(R)--N--((R)-2-(3-bromophenyl)-1-((1-cyanocyclobutyl)sulfonyl)prop-
an-2-yl)-2-methylpropane-2-sulfinamide
[1303] To a solution of 1-(methylsulfonyl)cyclobutanecarbonitrile
(1.04 g, 6.53 mmol) in THF (7 mL) at -78.degree. C. was added
n-butyllithium (1.6 M in hexane, 4.10 mL, 6.56 mmol). The solution
was stirred at -78.degree. C. for 15 min and a mixture of
(R,E)-N-(1-(3-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide
(1.32 g, 4.37 mmol) and trimethylaluminum (2 M in toluene, 2.20 mL,
4.40 mmol) (AlMe.sub.3 was added 10 min before addition to nitrile
solution at -78.degree. C.) in PhMe (13 mL) precooled to
-78.degree. C., was added dropwise via cannula. The reaction
mixture was stirred at -78.degree. C. for 45 min and, quenched with
saturated NH.sub.4Cl, warmed to room temperature and diluted with
saturated NH.sub.4Cl, water, and EtOAc. The aqueous phase was
discarded and the organic phase was washed with brine (1.times.),
dried over MgSO.sub.4, filtered, and concentrated. Purification by
flash column chromatography on silica gel (20% to 80% EtOAc in
hexanes) gave
(R)--N--((R)-2-(3-bromophenyl)-1-((1-cyanocyclobutyl)sulfonyl)propan-2-yl-
)-2-methylpropane-2-sulfinamide (1.29 g, 2.80 mmol, 64% yield) as a
white solid.
Step 3:
(R)-9-amino-7-(3-bromophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-
-ene 5,5-dioxide
[1304] To a solution of
(R)--N--((R)-2-(3-bromophenyl)-1-((1-cyanocyclobutyl)sulfonyl)propan-2-yl-
)-2-methylpropane-2-sulfinamide (1.29 g, 2.80 mmol) in dioxane (28
mL) at room temperature was added hydrogen chloride (4.0 M solution
in 1,4-dioxane, 3.50 mL, 14.00 mmol). The reaction mixture was
heated at 100.degree. C. for 15 h, cooled to room temperature, and
concentrated. The reaction mixture was diluted with EtOAc and
washed with 5 M NaOH (1.times.), brine (1.times.), dried over
MgSO.sub.4, filtered, and concentrated. Purification by flash
column chromatography on silica gel (1% to 10% MeOH in DCM) gave
(R)-9-amino-7-(3-bromophenyl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene
5,5-dioxide (0.634 g, 1.76 mmol, 64% yield) as a white solid. LC/MS
(ESI.sup.+) m/z=457.0, 359.0 (M+H).
Example 155
##STR00249##
[1305] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3,5-dimethoxypyrazine-2-carboxamide
Step 1: 3,5-dichloropyrazine-2-carboxylic acid
[1306] To a solution of LDA (2.0 M
heptane/tetrahydrofuran/ethylbenzene, 11.10 mL, 22.20 mmol) in THF
(75 mL) at -78.degree. C. was added a solution of
2,6-dichloropyrazine (1.44 g, 9.67 mmol) in THF (20 mL) at room
temperature over 20 min. The reaction mixture was stirred at
-78.degree. C. for 1.5 h and was then added via cannula to a 3-neck
flask containing dry ice at -78.degree. C. The reaction mixture was
warmed from -78.degree. C. to RT over 21 h and then quenched with 5
M HCl. The mixture was partitioned between brine and EtOAc. The
aqueous phase was acidified to pH 3.5 with 5 M HCl. The aqueous
phase was extracted with EtOAc (6.times.) and the combined organic
extracts were washed with brine (1.times.), dried over MgSO.sub.4,
filtered, and concentrated. Purification by flash column
chromatography on silica gel (5% to 10% MeOH in DCM) gave
3,5-dichloropyrazine-2-carboxylic acid (0.408 g, 2.11 mmol, 22%
yield) as a light brown solid.
Step 2: methyl 3,5-dichloropyrazine-2-carboxylate
[1307] To a solution of 3,5-dichloropyrazine-2-carboxylic acid
(0.304 g, 1.58 mmol) in MeOH (5 mL) and diethyl ether (5 mL) at RT
was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes,
4.00 mL, 8.00 mmol). The reaction mixture was stirred at RT for 30
min and then concentrated. Purification by flash column
chromatography on silica gel (5% to 20% EtOAc in hexanes) gave
methyl 3,5-dichloropyrazine-2-carboxylate (0.312 g, 1.51 mmol, 96%
yield) as a white solid.
Step 3: ethyl 3,5-dimethoxypyrazine-2-carboxylate
[1308] To a solution of methyl 3,5-dichloropyrazine-2-carboxylate
(0.312 g, 1.51 mmol) in THF (4.5 mL) at room temperature was added
sodium hydride (60% wt. dispersion, 0.199 g, 4.98 mmol) and
methanol (0.200 mL, 4.94 mmol). The reaction mixture was stirred at
room temperature for 30 min, diluted with EtOAc, and quenched with
saturated NH.sub.4Cl. The reaction mixture was partitioned between
brine and EtOAc. The aqueous phase was extracted with EtOAc
(3.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated.
Purification by flash column chromatography on silica gel (10% to
50% EtOAc in hexanes) gave ethyl
3,5-dimethoxypyrazine-2-carboxylate (0.314 g, 1.48 mmol, 98% yield)
as an off white solid.
Step 4: 3,5-dimethoxypyrazine-2-carboxylic acid
[1309] To a solution of ethyl 3,5-dimethoxypyrazine-2-carboxylate
(0.314 g, 1.48 mmol) in MeOH (5 mL) at RT was added potassium
hydroxide (0.135 g, 2.41 mmol). The reaction mixture was stirred at
RT for 17 h, quenched with 5 M HCl (0.48 mL), and diluted with
EtOAc. The solid was removed by filtration and the filtrate was
concentrated. Purification by flash column chromatography on silica
gel (10% MeOH in DCM) gave 3,5-dimethoxypyrazine-2-carboxylic acid
(0.261 g, 1.42 mmol, 96% yield) as a white solid.
Step 5:
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3,5-dimethoxypyrazine-2-carbox-
amide
[1310] In an analogous reaction to that described in Method C,
3,5-dimethoxypyrazine-2-carboxylic acid was coupled with
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide to generate the title compound
(85 mg, 0.18 mmol, 52% yield) as white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.55 (s br, 1H), 7.95 (m, 1H), 7.75 (s, 1H),
7.68 (dd, J=7.0, 2.7 Hz, 1H), 7.06 (dd, J=11.9, 8.8 Hz, 1H), 4.90
(s br, 2H), 4.75 (dd, J=47.6, 8.6 Hz, 1H), 4.50 (dd, J=47.1, 8.8
Hz, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 3.80 (d, J=15.2 Hz, 1H), 3.70
(d, J=15.4 Hz, 1H), 1.74 (s, 3H), 1.62 (s, 3H). LC/MS (ESI.sup.+)
m/z=484.0 (M+H).
Example 156
##STR00250##
[1311] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(cyclopropylmethoxy)pyrazine-2-carb-
oxamide
Step 1: methyl 5-(cyclopropylmethoxy)pyrazine-2-carboxylate and
cyclopropylmethyl 5-(cyclopropylmethoxy)pyrazine-2-carboxylate
[1312] To a suspension of sodium hydride (60% wt. dispersion, 0.562
g, 14.1 mmol) in THF (42 mL) at 0.degree. C. was added
(hydroxymethyl)cyclopropane (0.850 mL, 10.5 mmol). The solution was
stirred at 0.degree. C. for 30 min and then methyl
5-chloro-2-pyrazinecarboxylate (1.71 g, 9.91 mmol) was added as a
solid in one portion. The reaction mixture was stirred at 0.degree.
C. for 30 min and then quenched with saturated NH.sub.4Cl. The
reaction mixture was partitioned between water and EtOAc. The
aqueous phase was extracted with EtOAc (2.times.) and the combined
organic extracts were washed with brine (1.times.), dried over
MgSO.sub.4, filtered, and concentrated to give a 1:1 mixture of
methyl 5-(cyclopropylmethoxy)pyrazine-2-carboxylate and
cyclopropylmethyl 5-(cyclopropylmethoxy)pyrazine-2-carboxylate
which was used in the next step without further purification.
Step 2: 5-(cyclopropylmethoxy)pyrazine-2-carboxylic acid
[1313] To a solution of methyl
5-(cyclopropylmethoxy)pyrazine-2-carboxylate and cyclopropylmethyl
5-(cyclopropylmethoxy)pyrazine-2-carboxylate (prepared in the
previous step) in THF (15 mL) and water (15 mL). The reaction
mixture was stirred at room temperature for 30 min and acidified to
pH 5 with 1 M HCl. The reaction mixture was partitioned between
water and EtOAc. The aqueous phase was extracted with EtOAc
(2.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated.
Purification by flash column chromatography on silica gel (10% MeOH
in DCM) gave 5-(cyclopropylmethoxy)pyrazine-2-carboxylic acid
(0.489 g, 2.52 mmol, 25% yield) as an off white solid.
Step 3:
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-d-
ihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(cyclopropylmethoxy)pyrazine-
-2-carboxamide
[1314] In an analogous reaction to that described in Method C,
5-(cyclopropylmethoxy)pyrazine-2-carboxylic acid was coupled with
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide to generate the title compound
(84 mg, 0.17 mmol, 46% yield) as white solid. LC/MS (ESI.sup.+)
m/z=494.0 (M+H).
Example 157
##STR00251##
[1315] Synthesis of
(S)-8-((3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-ca-
rbonitrile
[1316] To a mixture of
8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (0.061 g, 0.29
mmol) and
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (0.075 g, 0.24 mmol) was added
a solution of sulfuric acid (0.013 mL, 0.47 mmol) in i-PrOH (1 mL).
The reaction mixture was heated at 85.degree. C. for 24 h and then
cooled to room temperature. The reaction mixture was partitioned
between saturated NaHCO.sub.3 and EtOAc. The aqueous phase was
discarded and the organic phase was washed with brine (1.times.),
dried over MgSO.sub.4, filtered, and concentrated. Purification by
flash column chromatography on silica gel (70% EtOAc in hexanes)
gave
(S)-8-((3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-ca-
rbonitrile (0.105 g, 0.215 mmol, 91% yield) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.96 (d, J=2.0 Hz, 1H),
8.81 (s br, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.21-8.16 (m, 1H), 8.09
(d, J=1.0 Hz, 1H), 7.73 (dd, J=6.9, 2.7 Hz, 1H), 7.11 (dd, J=11.8,
8.9 Hz, 1H), 4.81 (dd, J=47.3, 7.4 Hz, 1H), 4.80 (s br 2H), 4.52
(dd, J=46.8, 8.6 Hz, 1H), 3.84 (d, J=15.1 Hz, 1H), 3.75 (d, J=15.3
Hz, 1H), 1.77 (s, 3H), 1.65 (s, 3H). LC/MS (ESI.sup.+) m/z=489.0
(M+H).
Example 158
##STR00252##
[1317] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridi-
ne-2-carboxamide
[1318] In an analogous reaction to that described in Method C,
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid was
coupled with
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-
-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide to generate the title
compound (37 mg, 0.073 mmol, 21% yield) as white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.32 (s br, 1H), 8.02-7.97 (m, 1H),
7.96 (d, J=1.0 Hz, 1H), 7.67 (dd, J=7.0, 2.7 Hz, 1H), 7.48 (dd,
J=9.6, 0.8 Hz, 1H), 7.22 (dd, J=9.6, 2.0 Hz, 1H), 7.08 (dd, J=11.8,
8.9 Hz, 1H), 4.93 (s br, 2H), 4.76 (dd, J=47.7, 8.0 Hz, 1H), 4.58
(dd, J=47.1, 8.8 Hz, 1H), 3.81 (d, J=15.3 Hz, 1H), 3.70 (d, J=15.3
Hz, 1H), 2.81 (s, 3H), 1.74 (s, 3H), 1.63 (s, 3H). LC/MS
(ESI.sup.+) m/z=510.0 (M+H).
Example 159
##STR00253##
[1319] Synthesis of
(S)-5-amino-3-(2-fluoro-5-((5-fluoro-3-methoxy-1,7-naphthyridin-8-yl)amin-
o)phenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1320] To a mixture of
8-chloro-5-fluoro-3-methoxy-1,7-naphthyridine (0.102 g, 0.480 mmol)
and
(S)-5-amino-3-(5-amino-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (0.150 g, 0.473 mmol) was added
a solution of sulfuric acid (0.025 mL, 0.47 mmol) in i-PrOH (2.35
mL). The reaction mixture was heated at 80.degree. C. for 25 h and
then cooled to room temperature. The reaction mixture was diluted
with EtOAc (3 mL). The solid precipitate was collected by
filtration, washed with EtOAc (1.times.) and partitioned between
saturated NaHCO.sub.3 and EtOAc. The aqueous phase was discarded
and the organic phase was washed with brine (1.times.), dried over
MgSO.sub.4, filtered, concentrated, and dried under high vacuum to
give
(S)-5-amino-3-(2-fluoro-5-((5-fluoro-3-methoxy-1,7-naphthyridin-8-yl)amin-
o)phenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (0.184 g, 0.373 mmol, 79% yield) as a pale yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.71 (s br, 1H),
8.51 (d, J=2.7 Hz, 1H), 8.23-8.17 (m, 1H), 7.93 (d, J=1.6 Hz, 1H),
7.71 (dd, J=6.9, 2.7 Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.08 (dd,
J=11.9, 9.0 Hz, 1H), 4.81 (s br, 2H), 4.80 (dd, J=47.1, 8.4 Hz,
1H), 4.54 (dd, J=47.0, 8.7 Hz, 1H), 4.00 (s, 3H), 3.83 (d, J=15.5
Hz, 1H), 3.73 (d, J=15.3 Hz, 1H), 1.76 (s, 3H), 1.64 (s, 3H). LC/MS
(ESI.sup.+) m/z=494.0 (M+H).
Example 160
##STR00254##
[1321] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxamide
[1322] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (0.055 g, 0.138 mmol) in DCM (1 mL) was
added 4-nitrophenyl chloroformate (0.028 g, 0.138 mmol) as a solid.
1,2,3,6-Tetrahydropyridine (22 mg) was added to the reaction and
stirring was continued overnight. To the reaction was added
trifluoroacetic acid (0.200 mL, 2.60 mmol). The reaction was
evaporated to dryness and the residue was dissolved in MeCN and
purified by reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A
AXIA, 100.times.50 mm column) eluting with 0.1% TFA-H.sub.2O:0.1%
TFA CH.sub.3CN (9:1.fwdarw.1:9). The fractions containing the
desired product were combined and concentrated in vacuo. The
residue was dissolved in MeOH and loaded onto an Si-propylsulfonic
acid (Silicycle) cartridge eluting with MeOH then 2M NH.sub.3 in
MeOH to give 28 mg (50%) of a light-yellow crystalline solid. MS
m/z=409.0 (M+1).
Example 161
##STR00255##
[1323] Step 1:
(R)-5-amino-3-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)phenyl)-
-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1324] Following the general S.sub.NAr procedure using
8-chloro-3-methoxy-1,7-naphthyridine (2.44 g, 12.52 mmol),
(R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (5.00 g, 12.52 mmol), 50 mL iPrOH, and
sulfuric acid (0.67 mL, 12.52 mmol), the title compound was
isolated as a light yellow solid (4.38 g, 9.57 mmol, 76%
yield).
Step 2: (R)-5-amino-3-(2-fluoro-5-((3-hydroxy-1,7-naphthpyridin-8-1
amino)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1325] A pressure bottle was charged with
(R)-5-amino-3-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)phenyl)-
-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (4.38 g,
9.57 mmol) and DCM (19.15 ml) and was flushed with argon. BBr.sub.3
(1 M in DCM, 19.15 ml, 19.15 mmol) was added, the bottle was
sealed, and the reaction was heated at 50.degree. C. for 5 days.
The mixture was quenched slowly with saturated NaHCO.sub.3 until
basic. Water and EtOAc were added, and the solids were filtered and
washed with EtOAc. The aqueous portion was brought to neutral pH
with dilute HCl and was extracted with EtOAc/2% iPrOH. The layers
were separated and the combined organic portions were dried,
filtered and concentrated. The title compound was isolated as a
light yellow solid. (1.2 g, 2.71 mmol, 28.3% yield).
Step 3:
(R)-5-amino-3-(5-((3-(2,2-difluoroethoxy)-1,7-naphthyridin-8-yl)am-
ino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1326] A vial was charged with
(R)-5-amino-3-(2-fluoro-5-((3-hydroxy-1,7-naphthyridin-8-yl)amino)phenyl)-
-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (125 mg,
0.282 mmol), cesium carbonate (101 mg, 0.310 mmol) and DMSO (1127
.mu.l). 2-bromo-1,1-difluoroethane (23.57 .mu.l, 0.296 mmol) was
added, and the mixture was heated at 60.degree. C. for 6 h. Water
and EtOAc were added, and the layers were separated. The organic
portion was dried with Na.sub.2SO.sub.4, filtered and concentrated.
The crude material was purified by silica gel chromatography,
10-70% 75/25 EtOAc/EtOH/2% NH.sub.4OH in heptane to provide the
title compound (91 mg, 0.179 mmol, 63.6% yield) as a pale yellow
solid. MS m/z=508.2 (M+1).
Example 162
##STR00256##
[1327] Step 1: Methyl 5-bromo-3-(dibromomethyl)picolinate
[1328] A vial was charged with methyl 5-bromo-3-methylpicolinate
(2.03 g, 8.82 mmol), carbon tetrachloride (22.06 ml), benzoyl
peroxide (0.107 g, 0.441 mmol) and NBS (3.14 g, 17.65 mmol). The
mixture was heated at 80.degree. C. for 2 h. Another equivalent of
NBS and 50 mg benzoyl peroxide were added, and heating was
continued for 16 h. Upon cooling to RT the mixture was filtered
through Celite and washed with DCM. The filtrate was concentrated,
and the crude material was purified by silica gel, 10-50%
EtOAc/heptane to provide the title compound as a yellow oil (3.28
g, 8.46 mmol, 96% yield).
Step 2: 3-Bromopyrido[2,3-d]pyridazin-8(7H)-one
[1329] A pressure bottle was charged with methyl
5-bromo-3-(dibromomethyl)picolinate (3.28 g, 8.46 mmol), ethanol
(16.91 ml) and hydrazine hydrate (4.19 ml, 85 mmol). The bottle was
sealed, and the mixture was heated at 80.degree. C. for 1.5 h. The
mixture was heterogeneous upon cooling, so the solids were
filtered, washed with MeOH and dried. The filtrate was concentrated
and was triturated in MeOH. The solids were filtered, rinsed with
MeOH and dried to give a second crop of product. The title compound
(1.72 g, 7.61 mmol, 90% yield) was isolated as a yellow solid.
Step 3: 3-bromo-8-chloropyrido[2,3-d]pyridazine
[1330] A vial was charged with
3-bromopyrido[2,3-d]pyridazin-8(7H)-one (500 mg, 2.212 mmol) and
phosphorus oxychloride (4124 .mu.l, 44.2 mmol). The vial was capped
and the mixture was heated at 90.degree. C. for 2 h. The mixture
was concentrated and was used without further purification. MS
m/z=241 (M+MeOH adduct).
Step 4:
(R)-5-amino-3-(5-((3-bromopyrido[2,3-d]pyridazin-8-yl)amino)-2-flu-
orophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1331] Following the general S.sub.NAr procedure using
3-bromo-8-chloropyrido[2,3-d]pyridazine (500 mg, 2.05 mmol),
(R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (817 mg, 2.05 mmol), 5 mL iPrOH, and
sulfuric acid (0.11 mL, 2.05 mmol), the title compound was isolated
as a tan solid (500 mg, 0.985 mmol, 48.2% yield).
Step 5:
(R)-8-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)amino)pyrido[2,3-d]pyridazine-3-carbonitrile
[1332] Following the general cyanation procedure using
(R)-5-amino-3-(5-((3-bromopyrido[2,3-d]pyridazin-8-yl)amino)-2-fluorophen-
yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (125
mg, 0.25 mmol), ZnCN.sub.2 (44 mg, 0.37 mmol), S-Phos (20 mg, 0.049
mmol), Pd.sub.2 dba.sub.3 (18 mg, 0.020 mmol), and 0.985 mL DMF,
the title compound was isolated as a yellow solid (12 mg, 0.026
mmol, 10.74% yield).
Step 6: LS Method 3 (General S.sub.NAr with AcOH)
(3R,6R)-5-amino-6-fluoro-3-(2-fluoro-5-((2-(trifluoromethyl)pyrido[3,4-b]p-
yrazin-5-yl)amino)phenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1333] A vial was charged with
5-chloro-2-(trifluoromethyl)pyrido[3,4-b]pyrazine (48.6 mg, 0.208
mmol), tert-butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (84 mg, 0.208 mmol), and
acetic acid (833 .mu.l, 0.208 mmol). The mixture was stirred at
80.degree. C. for 30 min. The mixture was diluted with EtOAc and
washed twice with saturated NaHCO.sub.3. The organic portion was
dried with Na.sub.2SO.sub.4, filtered and concentrated. The crude
material was purified by silica gel chromatography, 0-50% 75/25/2
EtOAc/EtOH/2% NH.sub.4OH in heptane to provide the title compound
as an orange solid (50 mg, 0.100 mmol, 48.0% yield). MS m/z=501
(MH+)
Example 163
##STR00257##
[1334] Synthesis of
((R)-5-amino-3-(2-fluoro-5-(pyridin-2-ylthio)phenyl)-3,6,6-trimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide
[1335] A sealed tube containing
(R)-5-amino-3-(2-fluoro-5-mercaptophenyl)-3,6,6-trimethyl-3,6-dihydro-2H--
1,4-thiazine 1,1-dioxide (60 mg, 0.190 mmol), water (0.38 mL) and
2-fluoropyridine (0.016 mL, 0.190 mmol), was stirred at 100.degree.
C. for 17 hours. The reaction mixture was diluted with ethyl
acetate, washed once with water, once with sodium chloride, dried
with sodium sulfate, filtered through a fritted funnel and
concentrated. The residue was purified by silica gel
chromatography, eluent gradient 25-100% CH2Cl2:MeOH (90:10)/CH2Cl2,
to yield
(R)-5-amino-3-(2-fluoro-5-(pyridin-2-ylthio)phenyl)-3,6,6-trimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide (10 mg, 0.025 mmol) as a light
yellow solid. LC/MS (ESI.sup.+) m/z=394.1 (M+H).
Example 164
##STR00258##
[1336] Synthesis of
(2S,3R)-5-amino-3-(5-amino-2-fluorophenyl)-2-fluoro-3,6,6-trimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: tert-butyl
((5R,6S)-5-(5-bromo-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1337] To potassium t-butoxide (1M in THF) (3.02 ml, 3.02 mmol) in
THF (5 ml) at -78.degree. C. was added diisopropylamine (0.431 ml,
3.02 mmol) and the solution was stirred for 15 minutes.
Butyllithium (2.7 M in heptane) (0.957 ml, 2.70 mmol) was added and
the solution was stirred for 30 min, then (R)-tert-butyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (0.5 g, 1.079 mmol) in 5 ml THF was added
dropwise and the solution was stirred at -78.degree. C. for 45
minutes. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.953 g,
3.02 mmol) dissolved in 10 ml of THF was added. The solution was
stirred at -78.degree. C. for 15 minutes and allowed to slowly warm
to 0.degree. C. and quenched with saturated sodium carbonate. The
solution was extracted with ethyl acetate and the extracts were
concentrated. The product was purified by silica gel column
chromatography (loaded in 50/50 DCM/heptane) eluent 0-20% MTBE in
heptane to afford tert-butyl
((5R,6S)-5-(5-bromo-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (300 mg, 0.623 mmol,
57.8% yield). MS m/z=503.0 [M+Na]
Step 2: tert-butyl
((5R,6S)-5-(5-azido-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1338] A flask was charged with copper(I) iodide (0.158 g, 0.831
mmol), sodium azide (1.080 g, 16.62 mmol), (+)-sodium 1-ascorbate
(0.165 g, 0.831 mmol) and tert-butyl
((5R,6S)-5-(5-bromo-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1 g, 2.077 mmol).
Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.262 ml, 1.662 mmol),
ethanol (7 ml) and water (3 ml) were added, the flask was flushed
with nitrogen, capped, and heated at 50.degree. C. for 45 minutes.
The reaction mixture was diluted with water and ethyl acetate. The
organic layer was collected, dried over sodium sulfate and
concentrated to yield tert-butyl
((5R,6S)-5-(5-azido-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.921 g, 2.077 mmol) as
a yellow oil.
Step 3: tert-butyl
((5R,6S)-5-(5-amino-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1339] To a solution of tert-butyl
((5R,6S)-5-(5-azido-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.921 g, 2.077 mmol) in
THF (13.91 ml) and water (5 ml) was added trimethylphosphine (1M
solution in THF, 2.284 ml, 2.284 mmol), and the reaction was
stirred at room temperature for 15 minutes. The reaction was
partitioned between water and DCM. The organic layer was
concentrated, and the product was purified via silica gel column
chromatography (RediSep 40 g column) using 10-50% ethyl acetate in
heptane to afford tert-butyl
((5R,6S)-5-(5-amino-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (360 mg, 0.862 mmol,
41.5% yield). MS m/z=441 [M+Na].
Step 4:
(2S,3R)-5-amino-3-(5-amino-2-fluorophenyl)-2-fluoro-3,6,6-trimethy-
l-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1340] Tert-butyl
((5R,6S)-5-(5-amino-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (100 mg, 0.240 mmol) was
dissolved in 3 ml of DCM and 2 ml of TFA was added. The solution
was stirred for one hour at room temperature, then solvent stripped
at reduced pressure. The residue was taken up in DCM and was washed
with sodium bicarbonate and concentrated. The product was purified
via silica gel column chromatography (RediSep 40 g column) using 0
to 100% 90/10 ethyl acetate/MeOH in ethyl acetate to afford
(2S,3R)-5-amino-3-(5-amino-2-fluorophenyl)-2-fluoro-3,6,6-trimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide (60 mg, 79%). MS m/z=318.2
[M+H].
Intermediate 21
##STR00259##
[1341] Synthesis of 3-aminothieno[3,2-b]pyridine-6-carbonitrile
Step 1: Sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate
##STR00260##
[1343] To a suspension of sodium hydride (2.52 g, 63.0 mmol) in
ether (75 ml) was added 3,3-dimethoxypropanenitrile (6.17 ml, 55.0
mmol) followed by methyl formate (6.74 ml, 110 mmol). The solution
was allowed to stir for 3 days at room temperature. The solid was
filtered, washed with ether, and dried under vacuum to afford
sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (4.2 g, 25.4
mmol, 46.3% yield).
Step 2: 3-Aminothieno[3,2-b]pyridine-6-carbonitrile
[1344] Sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (1.7 g,
10.27 mmol) was dissolved in 20 ml of MeOH and concentrated
hydrochloric acid (844 .mu.l, 10.27 mmol) was added. The solution
was stirred for 5 minutes then thiophene-3,4-diamine (1173 mg,
10.27 mmol) in 20 ml MeOH was added. The solution was heated at
reflux for 2 hours. Additional concentrated HCl (3 ml) was added in
5 ml MeOH and the solution was refluxed for another hour. The rxn
was quenched with 10 ml of TEA and the solution was stirred for 15
minutes then concentrated. Ethyl acetate was added and the mixture
was sonicated and stirred. The solid triethylamine hydrochloride
was filtered off and washed with ethyl acetate. The filtrates were
concentrated. The product was purified via silica gel column
chromatography (RediSep 40 g column) using 0-100% ethyl acetate in
heptane to afford 3-aminothieno[3,2-b]pyridine-6-carbonitrile (400
mg, 2.283 mmol, 22.22% yield). MS m/z=176.0 [M+H].
Example 165
##STR00261##
[1345]
(R)-3-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile
[1346] A microwave vial was charged with
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (125 mg, 0.344 mmol),
3-aminothieno[3,2-b]pyridine-6-carbonitrile (125 mg), tert-butyl
XPhos (43.9 mg, 0.103 mmol), sodium tert-butoxide (93 mg, 0.964
mmol), Pd.sub.2 dba.sub.3 (31.5 mg, 0.034 mmol), and toluene (2
ml). The vessel was purged with argon and microwaved at 100.degree.
C. for 1.5 hours. The mixture was diluted with water and extracted
with ethyl acetate. The organic extracts were concentrated and the
residue was purified by silica gel column chromatography (RediSep
40 g column), eluent gradient 20-100% ethyl acetate in heptane to
afford
(R)-3-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile
(50 mg, 0.109 mmol, 31.8% yield). MS m/z=458.0 [M+H].
Example 166
##STR00262##
[1347]
(R)-3-((3-(5-(chloroamino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-amino)thieno[3,2-b]pyridine-6-carboni-
trile
[1348]
(R)-3-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile
(26 mg, 0.057 mmol) was dissolved in DMF (2 ml) and NCS (7.6 mg,
0.057 mmol) was added. The solution was stirred for 30 minutes,
quenched with saturated sodium bicarbonate, and extracted with
ethyl acetate. The organics were washed with water, dried with
sodium sulfate, filtered and concentrated to afford
(R)-3-((3-(5-(chloroamino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile
(20 mg, 0.041 mmol, 71.5% yield). MS m/z=492.0 [M+H].
Example 167
##STR00263##
[1349]
(R)-3-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)-amino)-2-chlorothieno[3,2-b]pyridine-6-carbon-
itrile
[1350]
(R)-3-((3-(5-(chloroamino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonit-
rile (15 mg, 0.030 mmol) was dissolved in acetic acid (2.5 ml) and
the solution was stirred at room temperature overnight. The
solution was then heated at 50.degree. C. for 24 hours. The
solution was concentrated, dissolved in DCM, washed with saturated
sodium bicarbonate, water, then dried with sodium sulfate,
filtered, and concentrated to afford
(R)-3-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)-2-chlorothieno[3,2-b]pyridine-6-carbonitrile
(14 mg). MS m/z=492 [M+H].
Example 168
##STR00264##
[1351]
(2S,3R)-5-amino-3-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluo-
rophenyl)-2-fluoro-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1352] Tert-butyl
((5R,6S)-5-(5-amino-2-fluorophenyl)-6-fluoro-2,2,5-trimethyl-1,1-dioxido--
5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (3.6 g, 8.62 mmol) and
TFA (10 ml, 130 mmol) were combined in 50 ml of DCM and stirred for
30 minutes. The solution was concentrated and dried under vacuum
for 30 minutes. 3,8-dichloro-1,7-naphthyridine (1.888 g, 9.49 mmol)
and IPA (60 ml) were added and the solution was heated at
80.degree. C. for 1.5 hours. The solution was quenched with 200 ml
of saturated sodium bicarbonate and 100 ml of water, extracted once
with 250 ml ethyl acetate, and the organic layer was separated and
concentrated. The product was purified via silica gel column
chromatography (RediSep 120 g column) using 20-100% ethyl
acetate/MeOH/NH4OH 90/10/1 in heptane to afford
(2S,3R)-5-amino-3-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophen-
yl)-2-fluoro-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (3.3 g, 6.88 mmol, 80% yield). MS m/z=480 [M+H].
Example 169
##STR00265##
[1353] Synthesis of
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-5-bromopyridin-2(1H)-one
[1354] A microwave vial was charged with
(R)-5-amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide (0.500 g, 1.373 mmol) (see example 14
for preparation), hydrogen chloride, 4.0M in dioxane (2.5 ml, 10.00
mmol) and water (1.0 mL). The vial was sealed and heated at
100.degree. C. for 22 hrs. The reaction mixture was concentrated
and the residue was neutralized with saturated NaHCO.sub.3 to pH
6-7, then extracted with EtOAc (2.times.). The organic layers were
combined, washed with brine, dried over Na.sub.2SO.sub.4 and
filtered. The filtrate was concentrated and purified by silica gel
chromatography, eluent gradient (0-10% MeOH/DCM) to afford the
title compound (338 mg) as yellow solid. LC/MS (ESI.sup.+) m/z=362,
364 (M+H; 2 bromine isotopes).
Example 170
##STR00266##
[1355] Synthesis of
(R)--N-(5-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-6-methoxypyridin-3-yl)-5-chloropicolinamide
Step 1:
(R)-5-amino-3-(5-bromo-2-methoxypyridin-3-yl)-3,6,6-trimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide
[1356]
(R)-5-amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-di-
hydro-2H-1,4-thiazine 1,1-dioxide (0.586 g, 0.280 mmol) (see
example 14 for preparation) was treated with sodium methylate (7.5
ml, 25% wt in MeOH). The mixture was heated at reflux for 45 min.
LCMS indicated conversion was completed. The reaction mixture was
allowed to cool to RT and quenched with water. The resulted
solution was concentrated under reduced pressure to remove MeOH.
The aqueous residue was extracted with EtOAc. The organic extracts
were washed with brine, dried over Na2SO4 and filtered. The
filtrate was concentrated and purified by silica gel column (0-5%
MeOH/DCM) to afford the title compound (518 mg) as light brown
foam. LC/MS (ESI.sup.+) m/z=376, 378 (M+H; 2 bromine isotopes).
Step 2:
R-N-(5-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thi-
azin-3-yl)-6-methoxypyridin-3-yl)-5-chloropicolinamide
[1357] A microwave vial was charged with
(R)-5-amino-3-(5-bromo-2-methoxypyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro-
-2H-1,4-thiazine 1,1-dioxide (0.200 g, 0.532 mmol),
5-chloropicolinamide (0.125 g, 0.797 mmol), copper(i) iodide (0.020
g, 0.106 mmol) and potassium carbonate, powder, particle size -325
mesh (0.220 g, 1.595 mmol). The vial was purged with N.sub.2
followed by the addition of 1,4-dioxane (2.0 mL) and
trans-n,n'-dimethyl-1,2-cyclohexanediamine (0.084 mL, 0.532 mmol).
The vial was sealed and heated at 120.degree. C. for 16 hrs. LCMS
indicated reaction went to completion. The reaction mixture was
allowed to cool to room temperature and then partitioned between
EtOAc and water. The aqueous layer was back extracted with EtOAc.
The organic layers were combined, washed with brine, dried over
Na2SO4 and filtered. The filtrate was concentrated and purified by
Shimadzu HPLC to afford the title compound (0.078 g, 0.173 mmol,
32.5% yield) as off-white solid (free base), LC/MS (ESI.sup.+)
m/z=452 (M+H).
Example 171
##STR00267##
[1358] Synthesis of
(R)--N-(5-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(difluoromethoxy)-3-methy-
lpicolinamide
Step 1: (R)-tert-butyl
(5-(5-bromo-2-oxo-1,2-dihydropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,-
6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1359] To a solution of
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-5-bromopyridin-2(1H)-one (0.623 g, 1.720 mmol) (see example 311
for preparation) in Dioxane (10.0 mL) was added di-tert-butyl
dicarbonate (0.563 g, 2.58 mmol) followed by Saturated sodium
bicarbonate (5.0 mL, 1.720 mmol). The mixture was stirred at room
temperature for 24 hrs. LCMS indicated full conversion to desired
product with MS+=462 plus trace of di-Boc product. The reaction
mixture was diluted with EtOAc and water. The separated organic
layer was washed with brine, dried over Na2 SO4 and filtered. The
filtrate was concentrated and dried in vacuo to afford the crude
title compound as yellow oil. It was carried on to next step
without purification. Assume theoretical yield. LC/MS (ESI.sup.+)
m/z=462, 464 (M+H; 2 bromine isotopes).
Step 2: (R)-tert-butyl
(5-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2,5-trimethyl-1,1-d-
ioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1360] To a solution of (R)-tert-butyl
(5-(5-bromo-2-oxo-1,2-dihydropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,-
6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.795 g, 1.719 mmol) in
MeCN (30 mL) was added potassium carbonate (0.356 g, 2.58 mmol)
followed by iodomethane (0.534 mL, 8.60 mmol). The mixture was
stirred at RT for 24 hrs. LCMS detected starting material and the
desired product with MS+=476. The reaction mixture was concentrated
to dryness and then diluted with EtOAc and water. The separated
organic layer was washed with brine, dried over Na2 SO4 and
filtered. The filtrate was concentrated and the resulted residue
was purified by silica gel chromatography (10-70% EtOAc/hexane) to
afford the title compound (0.31 g, 0.651 mmol, 37.8% yield) as
yellow solid. LC/MS (ESI.sup.+) m/z=476, 478 (M+H; 2 bromine
isotopes).
Step 3:
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thia-
zin-3-yl)-5-bromo-1-methylpyridin-2(1H)-one
[1361] To a solution of (R)-tert-butyl
(5-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2,5-trimethyl-1,1-d-
ioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.31 g, 0.651
mmol) in MeOH (2.0 mL) was added hydrogen chloride, 4m in
1,4-dioxane (2.0 ml, 8.00 mmol). The reaction was stirred at
ambient temperature for 24 hrs. LCMS indicated full conversion to
the desired product. The reaction mixture was concentrated to
dryness. The residue was neutralized with saturated NaHCO3 and then
extracted with EtOAc (2.times.). The organics were washed with
brine, dried over Na2SO4 and filtered. The filtrate was
concentrated and dried in vacuum to afford the crude title compound
(0.23 g, 0.611 mmol, 94% yield) as dark pink solid in about 80%
purity. It was carried on without further purification. LC/MS
(ESI.sup.+) m/z=376, 378 (M+H; 2 bromine isotopes).
Step 4:
(R)--N-(5-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(difluoromethoxy)--
3-methylpicolinamide
[1362] As described in the example 312, step 2,
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-5-bromo-1-methylpyridin-2(1H)-one (173 mg crude) was converted
to the title compound (37 mg) as a white solid. LC/MS (ESI.sup.+)
m/z=498 (M+H).
Example 172
##STR00268##
[1363] Synthesis of
(S)-9-amino-7-(5-bromo-2-fluorophenyl)-7-(fluoromethyl)-5-thia-8-azaspiro-
[3.5]non-8-ene 5,5-dioxide
Step 1: 1-(methylsulfonyl)cyclobutanecarbonitrile
[1364] A mixture of methanesulphonyl acetonitrile (15 g, 126 mmol),
1,3-dibromopropane (13.65 mL, 133 mmol) and potassium carbonate
(26.1 g, 189 mmol) in DMF (7.0 mL) was heated at 60.degree. C. for
6 hrs. The reaction was allowed to cool to RT and then diluted with
EtOAc and water. The separated aqueous layer was extracted with
EtOAc (2.times.). The organic extracts were combined, washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by silica gel column (0-40% EtOAc/hexane) to
afford 1-(methylsulfonyl)cyclobutanecarbonitrile (9.1 g, 57.2 mmol,
45.4% yield) as off-white solid.
Step 2: 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone
[1365] In an analogous reaction to that described for example 5,
step 1,1-bromo-4-fluorobenzene (22.0 mL, 200 mmol) was converted to
the title compound (11.5 g, 24% yield). LC/MS (ESI.sup.+) m/z=320
(M+H).
Step 3:
(R,Z)--N-(1-(5-Bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylp-
ropane-2-sulfinamide
[1366] In an analogous reaction to that described for example 5,
step 2, 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone (11.0 g, 46.8
mmol) was converted to the title compound (11.6 g, 34.3 mmol, 73.3%
yield) as yellow oil. LC/MS (ESI.sup.+) m/z=338, 340 (M+H; 2
bromine isotopes.
Step 4:
N-(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclobutyl)sulfonyl)-3-fl-
uoropropan-2-yl)-2-methylpropane-2-sulfinamide
[1367] In an analogous reaction to that described for example 5,
step 3,
(R,Z)--N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane--
2-sulfinamide (5.0 g, 14.78 mmol) was converted to the title
compound (3.81 g, 7.66 mmol, 51.8% yield) as yellow oil. LC/MS
(ESI.sup.+) m/z=497, 499 (M+H; 2 bromine isotopes).
Step 5:
9-amino-7-(5-bromo-2-fluorophenyl)-7-(fluoromethyl)-5-thia-8-azasp-
iro[3.5]non-8-ene 5,5-dioxide hydrochloride
[1368] A mixture of
N-(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclobutyl)sulfonyl)-3-fluoropro-
pan-2-yl)-2-methylpropane-2-sulfinamide (1.8 g, 3.62 mmol) and
hydrogen chloride, 4m in 1,4-dioxane (5.0 ml, 20.00 mmol) was
heated at 100.degree. C. for 3 days (over weekend). LCMS indicated
full conversion to the desired product. The reaction mixture was
concentrated and dried in vacuo to give a brown solid. The solid
was stirred in diethyl ether/hexane (1:1) for 15 min, and then
filtered. The filter cake was washed with ether and dried in vacuo
to afford the title compound as HCL salt. LC/MS (ESI.sup.+)
m/z=393, 395 (M+H; 2 bromine isotopes).
Step 6:
(S)-9-amino-7-(5-bromo-2-fluorophenyl)-7-(fluoromethyl)-5-thia-8-a-
zaspiro[3.5]non-8-ene 5,5-dioxide
[1369] Racemic
9-amino-7-(5-bromo-2-fluorophenyl)-7-(fluoromethyl)-5-thia-8-azaspiro[3.5-
]non-8-ene 5,5-dioxide was purified by chiral SFC, using a
ChiralPak IC column and eluting with 25% (20 mM ammonia in
methanol) in CO.sub.2, to provide the title compound. LC/MS
(ESI.sup.+) m/z=393, 395 (M+H; 2 bromine isotopes).
Example 173
##STR00269##
[1370] Synthesis of
(R)-3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-N-(4-cyano-2-hydroxyphenyl)-4-fluorobenzamide
Step 1: (R)-Methyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate
[1371] To a mixture of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-
-thiazine 1,1-dioxide (1.00 g, 2.75 mmol) in THF (15 mL) under
nitrogen was added triethylamine (0.77 mL, 5.51 mmol) and methyl
chloroformate (0.32 mL, 4.13 mmol). The mixture was stirred at room
temperature for 18 h. The mixture was diluted with saturated
Na.sub.2CO.sub.3 solution and extracted with EtOAc (2.times.). The
combined organic extracts were washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was
purified by flash column chromatography to afford (R)-methyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate as a white solid.
Step 2: (R)-Methyl
4-fluoro-3-(5-((methoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)benzoate
[1372] The title compound was prepared analogously by following the
procedure described in Step 1, PH-2.
Step 3:
(R)-4-Fluoro-3-(5-((methoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dio-
xido-3,6-dihydro-2H-1,4-thiazin-3-yl)benzoic acid
[1373] To a solution of (R)-methyl
4-fluoro-3-(5-((methoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,6-di-
hydro-2H-1,4-thiazin-3-yl)benzoate (0.2 g, 0.50 mmol) in THF (0.6
ml), MeOH (0.6 ml) and water (0.2 ml) was added lithium hydroxide
hydrate (0.57 ml, 0.57 mmol) and the resulting mixture was stirred
at room temperature for 20 h. Additional 1N LiOH (0.25 ml) was
added, and the reaction was stirred for another 2 h. The reaction
mixture was neutralized with 1N HCl and concentrated in vacuo to
afford
(R)-4-fluoro-3-(5-((methoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,-
6-dihydro-2H-1,4-thiazin-3-yl)benzoic acid as a white solid that
was used without additional purification.
Step 4:
(R)-3-(5-Amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thia-
zin-3-yl)-N-(4-cyano-2-hydroxyphenyl)-4-fluorobenzamide
[1374] A solution of
(R)-4-fluoro-3-(5-((methoxycarbonyl)amino)-3,6,6-trimethyl-1,1-dioxido-3,-
6-dihydro-2H-1,4-thiazin-3-yl)benzoic acid (0.193 g, 0.50 mmol) in
thionyl chloride (1.5 ml, 20.6 mmol) was stirred at 80.degree. C.
for 1 h. The cooled reaction was concentrated in vacuo, and the
resulting white solid (acid chloride) was taken up in dioxane (2
ml) and 4-amino-3-hydroxy-benzonitrile (0.1502 g, 1.120 mmol) was
added, followed by methanesulfonic acid (0.097 ml, 1.49 mmol); the
mixture was stirred at 100.degree. C. for 1 h. On cooling, the
reaction was diluted with CH.sub.2Cl.sub.2 and washed with
saturated NaHCO.sub.3 solution; the aqueous layer was
back-extracted with CH.sub.2Cl.sub.2 (1.times.). The combined
organic extracts were dried (MgSO.sub.4), filtered and concentrated
in vacuo. Flash column chromatography (eluent 0% to 5%
MeOH/CH.sub.2Cl.sub.2) afforded
(R)-3-(5-Amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-y-
l)-N-(4-cyano-2-hydroxyphenyl)-4-fluorobenzamide as a tan amorphous
solid. LC/MS (ESI.sup.+) m/z=445.0 (M+H).
Example 174
##STR00270##
[1375] Synthesis of
(3R,6R)-5-Amino-3-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophen-
yl)-6-fluoro-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1376] Using LS Method 3, tert-butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (100 mg, 0.25 mmol) and
3,8-dichloro-1,7-naphthyridine (78 mg, 0.25 mmol) were combined to
provide the title compound (49 mg, 42% yield) as a light-yellow
powder. LC/MS (ESI.sup.+) m/z=466 (M+H).
Example 175
##STR00271##
[1377] Synthesis of
(3R,6R)-5-Amino-3-((5-(7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluor-
ophenyl)-6-fluoro-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1378] Using LS Method 3, tert-butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (100 mg, 0.25 mmol) and
4,7-dichloropyrido[3,2-d]pyrimidine (50 mg, 0.25 mmol) were
combined to provide the title compound (125 mg, quantitative yield)
as an off-white powder. LC/MS (ESI.sup.+) m/z=467 (M+H).
Example 176 JS3
##STR00272##
[1379] Synthesis of
N-(3-(3R,6S)-5-Amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
Step 1:
(3R,6S)-5-Amino-3-(5-bromo-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1380] To a 0.degree. C. solution of
(R)-5-amino-3-(5-bromo-2-fluorophenyl)-3-methyl-3,6-dihydro-2H-1,4-thiazi-
ne 1,1-dioxide (0.78 g, 2 3 mmol) in N,N-dimethylformamide (15 mL)
was added N-fluorobenzenesulfonimide (0.73 g, 2.3 mmol) and cesium
carbonate (1.14 g, 3.5 mmol). The reaction was stirred at 0.degree.
C. for one hour, and then another portion of cesium carbonate (1.14
g, 3.5 mmol) was added to the reaction, followed by iodomethane
(0.145 mL, 2.3 mmol). The reaction was stirred for another 2 hours
at 0.degree. C. The reaction mixture was partitioned between water
and ethyl acetate; the organic layer was washed with water and
brine and concentrated. The two epimers were separated by chiral
SFC, using a ChiralCel OD-H column and eluting with 15% (0.1%
diethylamine in methanol) in CO.sub.2, to provide the title
compound (0.26 g, 30% yield) as a white solid. LC/MS (ESI.sup.+)
m/z=367, 369 (M+H; 2 bromine isotopes).
Step 2: tert-Butyl
((2S,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1381] In an analogous sequence to that described for Intermediate
2, steps 1-3,
(3R,6S)-5-amino-3-(5-bromo-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3,6-dihy-
dro-2H-1,4-thiazine 1,1-dioxide (0.26 g, 0.70 mmol) was converted
to the title compound (125 mg, 44% yield) as a white solid. LC/MS
(ESI.sup.+) m/z=404 (M+H).
Step 3:
N-(3-(3R,6S)-5-Amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-
-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
[1382] Using General Amidation Procedure A, tert-butyl
((2S,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (60 mg, 0.149 mmol) and
5-methoxypyrazine-2-carboxylic acid (24.07 mg, 0.156 mmol) were
combined to provide the title compound (49 mg, 0.112 mmol, 79%
yield) as a white powder. LC/MS (ESI.sup.+) m/z=440 (M+H).
Example 177
##STR00273##
[1383] Synthesis of
(3R,6R)-5-Amino-6-fluoro-3-(2-fluoro-5-((7-methoxypyrido[3,2-d]pyrimidin--
4-yl)amino)phenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1384] Using LS Method 3, tert-butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (100 mg, 0.25 mmol) and
4-chloro-7-methoxypyrido[3,2-d]pyrimidine (49 mg, 0.25 mmol) were
combined to provide the title compound (83 mg, 72.4% yield) as a
white powder. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.12 (s, 1H),
8.62 (d, J=2.8 Hz, 1H), 8.59 (s, 1H), 8.06-8.08 (m, 1H), 7.92-7.96
(m, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.16 (dd, J=8.8, 11.9 Hz, 1H),
6.62 (bs, 2H), 4.00 (s, 3H), 3.90 (d, J=15.3 Hz, 1H), 3.81 (d,
J=15.8 Hz, 1H), 1.88 (d, J=17.5 Hz, 6H), 1.67 (s, 3H). LC/MS
(ESI.sup.+) m/z=463 (M+H).
Example 178
##STR00274##
[1385] Synthesis of
(3R,6R)-5-Amino-3-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino)-2-f-
luorophenyl)-6-fluoro-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
Step 1:
(3R)-5-Amino-3-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino)-
-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1386] To a suspension of
(3R)-5-amino-3-(5-amino-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-t-
hiazine 1,1-dioxide (100 mg, 0.350 mmol) and
3,8-dichloro-5-fluoro-1,7-naphthyridine (84 mg, 0.386 mmol) in
2-propanol (1.7 mL) was added p-toluenesulfonic acid monohydrate
(147 mg, 0.771 mmol). The reaction was stirred at 90.degree. C. for
3 hours, and concentrated. The residue was partitioned between
dichloromethane and saturated aqueous sodium bicarbonate. The
organic layer was concentrated, adsorbed onto a silica-gel loading
column, and purified by column chromatography, eluting with 50-100%
ethyl acetate in heptane, to provide the title compound (136 mg,
83% yield) as a yellow oil. LC/MS (ESI.sup.+) m/z=466 (M+H).
Step 2:
(3R,6R)-5-Amino-3-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)ami-
no)-2-fluorophenyl)-6-fluoro-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1387] In an analogous reaction to that described for Example 3,
Route A, Step 2,
(3R)-5-amino-3-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino-
)-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (136 mg, 0.29 mmol) was converted to the title compound
(93 mg, 66% yield) as a yellow solid. LC/MS (ESI.sup.+) m/z=484
(M+H).
Example 179
##STR00275##
[1388] Synthesis of
8-((3-((3R,6R)-5-Amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1-
,4-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbon-
itrile
[1389] In an analogous sequence to that described for Example JS5,
Steps 1-2,
(3R)-5-amino-3-(5-amino-2-fluorophenyl)-3,6-dimethyl-3,6-dihydro-2H--
1,4-thiazine 1,1-dioxide (100 mg, 0.35 mmol) and
8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (80 mg, 0.39
mmol) were converted to the title compound (95 mg, 57% yield) as a
yellow powder. LC/MS (ESI.sup.+) m/z=475 (M+H).
Example 180
##STR00276##
[1390] Synthesis of
4-((3-((3R,6R)-5-Amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1-
,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitri-
le
[1391] Using LS Method 3, tert-butyl
((2R,5R)-5-(5-amino-2-fluorophenyl)-2-fluoro-2,5-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (100 mg, 0.25 mmol) and
4-chloropyrido[3,2-d]pyrimidine-7-carbonitrile (47 mg, 0.25 mmol)
were combined to provide the title compound (61 mg, 54% yield) as a
yellow powder. LC/MS (ESI.sup.+) m/z=475 (M+H).
Example 181
##STR00277##
[1392] Synthesis of
(8R)-10-Amino-8-(5-bromo-2-fluorophenyl)-8-methyl-2-oxa-6-thia-9-azaspiro-
[4.5]dec-9-ene 6,6-dioxide
[1393] A suspension of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e (1.0 g, 2.3 mmol) and cesium carbonate (0.75 g, 2.3 mmol) in
1,4-dioxane (25 mL) was stirred at 90.degree. C. for ten minutes,
cooled to ambient temperature, and added to a solution of
2-chloroethyl chloromethyl ether (0.23 mL, 2.3 mmol) in 1,4-dioxane
(25 mL). The reaction was stirred at ambient temperature for two
hours. Another portion of cesium carbonate (0.75 g, 2.3 mmol) was
added to the reaction, and the reaction was stirred overnight at
ambient temperature. After 16 hours, the reaction mixture was
partitioned between water and ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, filtered, and concentrated
to provide the crude intermediate.
[1394] The crude intermediate was dissolved in 4 M hydrochloric
acid in 1,4-dioxane (20 mL, 80 mmol), and the reaction was stirred
at ambient temperature. After 90 minutes, the reaction mixture was
concentrated, and the brown residue was dried under high vacuum. To
a suspension of the residue in toluene (20 mL) was added a 2-M
solution of trimethylaluminum in toluene (1.04 mL, 2.08 mmol), and
the reaction was stirred at 90.degree. C. After 1 hour, the
reaction was cooled to ambient temperature and partitioned between
ethyl acetate and 10% aqueous ETDA-ol. The organic layer was washed
with brine and concentrated. The crude product was purified by
reverse-phase silica-gel chromatography, eluting with 10-70% (0.1%
trifluoroacetic acid in acetonitrile) in (0.1% trifluoroacetic acid
in water). The product fractions were combined, neutralized with
saturated aqueous sodium bicarbonate, and extracted with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated to provide the title compound
(0.18 g, 13% yield) as a 1:1 mixture of diastereomers. LC/MS
(ESI.sup.+) m/z=391, 393 (M+H; 2 bromine isotopes).
Example 182
##STR00278##
[1395] Synthesis of
(8R)-10-Amino-8-(5-((3-chloro-1,7-naphthyridin-8-yl)amino-2-fluorophenyl)-
-8-methyl-2-oxa-6-thia-9-azaspiro[4.5]dec-9-ene 6,6-dioxide
Step 1:
(8R)-10-amino-8-(5-amino-2-fluorophenyl)-8-methyl-2-oxa-6-thia-9-a-
zaspiro[4.5]dec-9-ene 6,6-dioxide
[1396] In an analogous sequence to that described for Intermediate
2, steps 2-3,
(8R)-10-amino-8-(5-bromo-2-fluorophenyl)-8-methyl-2-oxa-6-thia-9-azaspiro-
[4.5]dec-9-ene 6,6-dioxide (140 mg, 0.358 mmol) was converted to
the title compound (88 mg, 75% yield) as an off-white solid. LC/MS
(ESI.sup.+) m/z=328 (M+H).
Step 2:
(8R)-10-amino-8-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluor-
ophenyl)-8-methyl-2-oxa-6-thia-9-azaspiro[4.5]dec-9-ene
6,6-dioxide
[1397] In an analogous reaction to that described for Example JS5,
Step 1,
(8R)-10-amino-8-(5-amino-2-fluorophenyl)-8-methyl-2-oxa-6-thia-9-azaspiro-
[4.5]dec-9-ene 6,6-dioxide (40 mg, 0.122 mmol) and
3,8-dichloro-1,7-naphthyridine (24.32 mg, 0.122 mmol) were
converted to the title compound (25 mg, 0.026 mmol, 20.88% yield)
as a 1:1 mixture of diastereomers. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.55 (s, 1H), 8.90 (d, J=2.4 Hz, 1H), 8.51
(d, J=2.4 Hz, 1H), 8.12-8.15 (m, 2H), 8.03-8.04 (m, 1H), 7.11-7.17
(m, 2H), 5.90 (bs, 2H), 4.22 (s, 2H), 4.02-4.11 (m, 1H), 3.56-3.86
(m, 3H), 2.34-2.55 (m, 2H), 1.68 (s, 3H). LC/MS (ESI.sup.+) m/z=490
(M+H).
Example 183
##STR00279##
[1398] Synthesis of
(1R,6R)-4-amino-6-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophen-
yl)-3,3-dimethyl-2-thia-5-azabicyclo[4.1.0]hept-4-ene
2,2-dioxide
Step 1:
(5)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide
[1399] To a solution of
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (3.22 g, 8.44 mmol) in ethanol
(15 mL) and ethyl acetate (5 mL) was added sodium bicarbonate (138
mg, 1.69 mmol) and 10 wt % palladium on carbon (0.90 g, 8.44 mmol).
The flask was evacuated and backfilled with hydrogen three times,
and stirred at room temperature under a hydrogen atmosphere for 2
hours. The reaction mixture was filtered through a Celite.RTM. pad,
and the filter cake was rinsed with ethyl acetate and ethanol. The
combined filtrates were concentrated in vacuo and the residue was
redissolved in ethyl acetate, washed with saturated aqueous sodium
bicarbonate, dried over sodium sulfate, filtered and evaporated to
provide the title compound (2.49 g, 8.23 mmol) as an off-white
solid. LC/MS (ESI.sup.+) m/z=303 (M+H).
Step 2:
(5)-5-amino-3-(2-fluoro-5-nitrophenyl)-3-(fluoromethyl)-6,6-dimeth-
yl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1400] To a solution of
(S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide (1.98 g, 6.55 mmol) in sulfuric acid
(8.73 mL, 0.16 mol) at 0.degree. C. was added potassium nitrate
(0.69 g, 6.88 mmol) portionwise. When the addition was completed,
the reaction mixture was allowed to warm to room temperature and
the mixture was stirred at room temperature for 30 min. The
reaction mixture was carefully poured into ice-water (100 mL) and
neutralized by the addition of aqueous ammonium hydroxide. The
mixture was diluted with water (10 mL) and extracted with ethyl
acetate (2.times.50 mL). The combined organic extracts were washed
with brine, dried over sodium sulfate, filtered, and concentrated
under vacuum to give the title compound (2.27 g, 6.64 mmol) as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.43 (dd,
J=3.03, 6.75 Hz, 1H), 8.25 (td, J=3.55, 8.95 Hz, 1H), 7.51 (dd,
J=9.00, 11.35 Hz, 1H), 6.58 (br. s., 2H), 4.59 (q, J=8.80 Hz, 1H),
4.48 (q, J=8.80 Hz, 1H), 3.68-3.87 (m, 2H), 1.61 (s, 3H), 1.47 (s,
3H). LC/MS (ESI.sup.+) m/z=348 (M+H).
Step 3: (S)-tert-butyl
(5-(2-fluoro-5-nitrophenyl)-5-(fluoromethyl)-2,2-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1401] To a solution of
(S)-5-amino-3-(2-fluoro-5-nitrophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (2.27 g, 6.54 mmol) in dioxane
(40 mL) was added saturated aqueous sodium bicarbonate (40 mL),
followed by di-tert-butyl dicarbonate (1.85 g, 8.50 mmol). The
reaction mixture was stirred at room temperature for 24 h. The
mixture was partitioned between water and ethyl acetate. The
organic layer was washed with water, brine, dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was absorbed onto a plug of silica gel and purified by
chromatography through a Redi-Sep pre-packed silica gel column (40
g), eluting with a gradient of 10% to 30% ethyl acetate in hexanes,
to provide the title compound (2.21 g, 4.96 mmol) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) 11.43 (br. s., 1H), 8.26-8.40 (m,
2H), 7.33 (dd, J=9.19, 10.76 Hz, 1H), 4.57-4.95 (m, 2H), 3.77-3.94
(m, 2H), 1.84 (s, 3H), 1.68 (s, 3H), 1.59 (s, 9H). LC/MS
(ESI.sup.+) m/z=470 (M+Na).
Step 4: tert-butyl
((1R,6R)-6-(2-fluoro-5-nitrophenyl)-3,3-dimethyl-2,2-dioxido-2-thia-5-aza-
bicyclo[4.1.0]hept-4-en-4-yl)carbamate
[1402] To a solution of (S)-tert-butyl
(5-(2-fluoro-5-nitrophenyl)-5-(fluoromethyl)-2,2-dimethyl-1,1-dioxido-5,6-
-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.79 g, 1.76 mmol) in THF
(10 mL) at -78.degree. C. under a nitrogen atmosphere was added
lithium bis(trimethylsilyl)amide (4.40 mL, 4.40 mmol; 1.0 M
solution in THF). The reaction mixture was stirred at -78.degree.
C. for 15 min and quenched by the addition of saturated aqueous
ammonium chloride (5 mL). The reaction mixture was warmed to room
temperature and partitioned between water and ethyl acetate. The
organic phase was separated, washed with water, brine, and dried
over anhydrous sodium sulfate, filtered, and concentrated. The
title compound was obtained (0.75 g, 1.75 mmol) as a tan solid and
used without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3) 11.19 (br. s., 1H), 8.21-8.38 (m, 2H), 7.36 (t, J=10.00
Hz, 1H), 3.59 (dd, J=6.36, 9.10 Hz, 1H), 2.31 (t, J=6.10 Hz, 1H),
2.23 (q, J=7.00 Hz, 1H), 1.67 (s, 6H), 1.53 (s, 9H). LC/MS
(ESI.sup.+) m/z=450 (M+Na).
Step 5: tert-butyl
((1R,6R)-6-(5-amino-2-fluorophenyl)-3,3-dimethyl-2,2-dioxido-2-thia-5-aza-
bicyclo[4.1.0]hept-4-en-4-yl)carbamate
[1403] To a solution of tert-butyl
((1R,6R)-6-(2-fluoro-5-nitrophenyl)-3,3-dimethyl-2,2-dioxido-2-thia-5-aza-
bicyclo[4.1.0]hept-4-en-4-yl)carbamate (0.73 g, 1.72 mmol) in
ethanol (21 mL) and ethyl acetate (7 mL) was added 10 wt %
palladium on carbon (183 mg, 1.72 mmol). The flask was evacuated
and backfilled with hydrogen three times, and stirred at room
temperature under a hydrogen atmosphere for 3.5 h. The reaction
mixture was filtered through a Celite.RTM. pad, and the filter cake
was rinsed with ethyl acetate and ethanol. The combined filtrates
were concentrated in vacuo to give the title compound (680 mg, 1.71
mmol) as an off-white solid. LC/MS (ESI.sup.+) m/z=398 (M+H).
Step 6:
(1R,6R)-4-amino-6-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-flu-
orophenyl)-3,3-dimethyl-2-thia-5-azabicyclo[4.1.0]hept-4-ene
2,2-dioxide
[1404] To a solution of tert-butyl
((1R,6R)-6-(5-amino-2-fluorophenyl)-3,3-dimethyl-2,2-dioxido-2-thia-5-aza-
bicyclo[4.1.0]hept-4-en-4-yl)carbamate (107 mg, 0.27 mmol) and
3,8-dichloro-1,7-naphthyridine (59 mg, 0.30 mmol) in 2-propanol (3
mL) was added 2 of drops of sulfuric acid. The reaction was stirred
at 90.degree. C. for one hour, and cooled to room temperature. The
mixture was neutralized with NaOH (1N, 5 mL) and extracted with DCM
(3.times.8 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was absorbed onto a plug of silica gel and purified by
chromatography through a Redi-Sep pre-packed silica gel column (12
g), eluting with a gradient of 1% to 4% MeOH (2M NH.sub.3) in DCM,
to provide the title compound (64 mg, 0.14 mmol) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) 8.92 (s, 1H), 8.70 (d, J=2.35 Hz,
1H), 8.10 (d, J=5.87 Hz, 1H), 7.98-8.07 (m, 2H), 7.86-7.96 (m, 1H),
7.07 (dd, J=8.80, 11.35 Hz, 1H), 6.94 (d, J=5.87 Hz, 1H), 3.41 (dd,
J=5.97, 9.10 Hz, 1H), 2.32 (dd, J=6.26, 9.19 Hz, 1H), 1.91 (dt,
J=1.56, 6.06 Hz, 1H), 1.66 (s, 3H), 1.65 (s, 3H). LC/MS (ESI.sup.+)
m/z=460 (M+H).
T Judd
Example 184
##STR00280##
[1405] Synthesis of
(R)-5-Amino-3-(5-bromo-2-fluoro-6-methylpyridin-3-yl)-3,6,6-trimethyl-3,6-
-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: 1-(5-bromo-2-fluoro-6-methylpyridin-3-yl)ethanol
[1406] N-Butyllithium, 2.5m solution in hexane (17.59 mL, 44.0
mmol) was added dropwise via syringe to a solution of DIPA (6.46
mL, 46.1 mmol) in THF (200 mL) at -78.degree. C. The solution was
warmed to 0.degree. C. for 15 minutes and then recooled to
-78.degree. C. Next, 3-bromo-6-fluoro-2-methylpyridine (5 mL, 41.9
mmol) was added dropwise via syringe and the resulting solution was
stirred 1 hour before acetaldehyde (2.82 mL, 50.3 mmol) was added
dropwise. The reaction was quenched with saturated aqueous ammonium
chloride at -78.degree. C. and diluted with water and EtOAc. The
layers were separated and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with water,
saturated aqueous sodium chloride, and dried over sodium sulfate.
The solution was filtered and concentrated in vacuo. The crude
material was purified by silica gel chromatography by eluting with
1:9 EtOAc/Hexanes to afford the title compound,
1-(5-bromo-2-fluoro-6-methylpyridin-3-yl)ethanol.
Step 2: 1-(5-bromo-2-fluoro-6-methylpyridin-3-yl)ethanone
[1407] Pyridinium dichromate (32.8 g, 87 mmol) was added in
portions to a solution of
1-(5-bromo-2-fluoro-6-methylpyridin-3-yl)ethanol (6.8 g, 29.1 mmol)
in DCM (60 ml) at 0.degree. C. The resulting mixture was stirred at
room temperature and 3 A sieves were added. After stirring
overnight, the reaction was filtered through a pad of magnesium
sulfate and celite, washed with DCM. The filtrate was concentrated
and then taken up in a 1:1 mixture of diethyl ether and hexanes and
filtered. The filtrate was concentrated and the crude material was
purified by silica gel chromatography by eluting with 1:20 EtOAc in
hexane, to provide
1-(5-bromo-2-fluoro-6-methylpyridin-3-yl)ethanone (4.9 g, 21.12
mmol, 72.7% yield) as a clear solid after drying under vacuum.
LC/MS (ESI.sup.+) m/z=232, 234 (M+H; 2 bromine isotopes).
Step 3:
(R)-5-Amino-3-(5-bromo-2-fluoro-6-methylpyridin-3-yl)-3,6,6-trimet-
hyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[1408] In an analogous sequence of reactions to those described for
Example 11, steps 3-6,
1-(5-bromo-2-fluoro-6-methylpyridin-3-yl)ethanone was converted to
the title compound in 42% yield. LC/MS (ESI.sup.+) m/z=378, 380
(M+H; 2 bromine isotopes).
Example 185--a, b, c & d
##STR00281## ##STR00282##
[1409] Step 1.
N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide
[1410] To a suspension of sodium hydride (1.86 g, 46.5 mmol) in THF
(80 ml) at 0.degree. C. was added (4-methoxyphenyl)methyl alcohol
(5.80 mL, 46.7 mmol) over 5 min. The reaction mixture was warmed to
RT for 1 h, then cooled to 0.degree. C. and a solution of
2-chloro-N-methoxy-N-methylacetamide (6.50 g, 47.3 mmol) in THF (20
mL) was added. The reaction mixture was warmed to room temperature
and stirred for 72 hr then quenched with NH.sub.4Cl and diluted
with EtOAc and water. The aqueous phase was extracted with EtOAc
(2.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated.
Purification by flash column chromatography on silica gel (120 g,
30% to 80% EtOAc in hexanes) gave
N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide (1.10 g, 4.60
mmol, 9.85% yield) as a yellow oil. ESI (M+Na) 262.1.
Step 2.
1-(5-bromo-2-fluorophenyl)-2-((4-methoxybenzyl)oxy)ethanone
[1411] To a solution of 4-bromo-1-fluoro-2-iodobenzene (1.85 g,
6.15 mmol) in THF (12 mL) at -78.degree. C. was added dropwise
butyllithium solution, 1.6m in hexane (3.85 ml, 6.16 mmol). The
solution was stirred at -78.degree. C. for 30 min and a solution of
N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide (1.10 g, 4.60
mmol) in THF (10 mL) at -78.degree. C. was added via cannula. The
reaction mixture was warmed from -78.degree. C. to -10.degree. C.
over 1.5 h and quenched with NH.sub.4Cl and diluted with EtOAc and
water. The aqueous phase was discarded and the organic phase was
washed with brine (1.times.), dried over MgSO.sub.4, filtered, and
concentrated. Purification by flash column chromatography on silica
gel (40 g, 5% to 10% EtOAc in hexanes) gave
1-(5-bromo-2-fluorophenyl)-2-((4-methoxybenzyl)oxy)ethanone (1.24
g, 3.51 mmol, 76% yield) as a white solid. ESI (M+Na) 377.7.
Step 3.
(Z)--N-(1-(5-bromo-2-fluorophenyl)-2-((4-methoxybenzyl)oxy)ethylid-
ene-2-methylpropane-2-sulfinamide
[1412] To a mixture of
1-(5-bromo-2-fluorophenyl)-2-((4-methoxybenzyl)oxy)ethanone (9.97
g, 28.2 mmol), titanium(IV) ethoxide (7.95 mL, 38.4 mmol) in DCM
(200 mL) at room temperature was added t-butylsulfinamide (8.55 g,
70.6 mmol). The mixture was heated to 40.degree. C. for 5 h. The
reaction was quenched with brine (200 mL) and EtOAc. The mixture
was filtered through celite and the cake was washed with EtOAc. The
two layers were separated. The aqueous layer was extracted with
EtOAc and the combined organic layers were washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was
purified by silica gel chromatography, eluent 0-70% EtOAc-hexanes
to give
(Z)--N-(1-(5-bromo-2-fluorophenyl)-2-((4-methoxybenzyl)oxy)ethyliden-
e)-2-methylpropane-2-sulfinamide (4.25 g, 33% yield) as yellow oil.
ESI (M+Na) 479.8.
Step 4.
N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-(-
(4-methoxybenzyl)oxy)propan-2-yl)-2-methylpropane-2-sulfinamide
[1413] N-butyllithium, 2.5m solution in hexane (2.1 mL, 5.2 mmol)
was added dropwise via syringe to a solution of
2-methyl-2-(methylsulfonyl)propanenitrile (0.766 g, 5.21 mmol) in
THF (10 mL) at -78.degree. C. After 25 minutes, a solution of
(Z)--N-(1-(5-bromo-2-fluorophenyl)-2-((4-methoxybenzyl)oxy)ethylidene)-2--
methylpropane-2-sulfinamide (1.32 g, 2.89 mmol) (azetroped with 5
mL of toluene before use) in THF (10 mL) cooled to 0.degree. C. and
pretreated with boron trifluoride diethyl etherate (0.357 ml, 2.89
mmol) at 0.degree. C. for 15 minutes, was added dropwise via
syringe. The reaction was stirred at -78.degree. C. for 2 h. The
reaction was quenched with saturated aqueous ammonium chloride at
-78.degree. C. and diluted with water and EtOAc. The layers were
separated and the aqueous layer was extracted with EtOAc
(3.times.). The combined organic extracts were washed with water,
saturated aqueous sodium chloride, and dried over sodium sulfate.
The crude material was purified by silica gel chromatography by
eluting with 0-50% EtOAc in hexane, to provide
N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-((4-meth-
oxybenzyl)oxy)propan-2-yl)-2-methylpropane-2-sulfinamide (1.24 g,
2.054 mmol, 71% yield) as a off-white solid. ESI (M+Na) 603.0.
Step 5
[1414] To a solution of
N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-((4-meth-
oxybenzyl)oxy)propan-2-yl)-2-methylpropane-2-sulfinamide (1.24 g,
2.054 mmol) in MeOH (17 mL) was added HCl (4M in 1,4-dioxane, 2.57
mL, 10.3 mmol) and stirred at RT for 50 min until SM was consumed.
The mixture was concentrated, diluted with DCM and neutralized with
10% Na.sub.2CO.sub.3 and 1 N NaOH. The organic phase was dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford a pale yellow
oil. The crude material was dissolved in DCE (17 mL) and
trimethylaluminum solution, 2.0 M in toluene (1.65 mL, 3.30 mmol)
was added dropwise. The resulting mixture was stirred at RT for 17
h. The mixture was cooled to 0.degree. C., diluted with saturated
aqueous sodium carbonate. The aqueous layer was extracted with
EtOAc (3.times.). The combined organic layers were washed with
brine, dried over sodium sulfate and concentrated to give a
light-yellow solid. A solution of the above crude material,
di-tert-butyl dicarbonate (1.80 g, 8.25 mmol), DIPEA (1.44 mL, 8.25
mmol), and DMAP (0.076 g, 0.62 mmol) in DCM (10 mL) was stirred at
30.degree. C. for 18 h. The crude product was concentrated to 5 mL
and chromatographed on silica gel, eluting with EtOAc/hexane
(0-20%) to give the product of step 5 (see scheme; 1.19 g, 1.7
mmol, 82% yield) as light-yellow oil. ESI (M+Na) 723.0.
Step 6
[1415] To a solution of compound from step 5 (680 mg, 0.97 mmol) in
THF (6.7 mL) at -78.degree. C. was added lithium
bis(trimethylsilyl)amide, 1.0M solution in THF (1.3 mL, 1.26 mmol)
dropwise. The mixture was stirred at -78.degree. C. for 1 h and
chloro(methoxy)methane (148 .mu.l, 1.94 mmol) in THF (0.2 mL) was
added dropwise. The resulting mixture was stirred at -78.degree. C.
for 2 h. The reaction was quenched with saturated aqueous ammonium
chloride at -78.degree. C. and diluted with water and EtOAc. The
layers were separated and the aqueous layer was extracted with
EtOAc (2.times.). The combined organic extracts were dried over
sodium sulfate. The crude material was dissolved in DCM and
purified by chromatography on silica gel, eluting with a gradient
of 0% to 20% EtOAc in hexane to give the product of step 6 (371 mg,
0.5 mmol, 51% yield) as white solid. ESI (M+Na) 765.0.
Step 7.
3-amino-4a-(5-bromo-2-fluorophenyl)-2,2-dimethyl-4a,5,7,7a-tetrahy-
dro-2H-furo[3,4-b][1,4]thiazine 1,1-dioxide
[1416] To a solution of compound from step 6 (74 mg, 0.100 mmol) in
DCM (1 mL) at -78.degree. C. was added boron tribromide, 1.0 M in
dichloromethane (1 mL, 1 mmol) dropwise. The reaction mixture was
stirred at -78.degree. C. for 1.5 h, then at 0.degree. C. for 4.5
h. The reaction was kept in refrigerator overnight. Additional
BBr.sub.3 (0.2 mL, 2 eq) was added and stirring was continued at
0.degree. C. for 1.5 h. The reaction was quenched by slow addition
of saturated NaHCO.sub.3 solution at 0.degree. C. The aqueous layer
was back extracted with DCM (2.times.) and the combined organics
dried (Na.sub.2SO.sub.4) and concentrated. The crude material was
purified by chromatography on silica gel, eluting with a gradient
of 0% to 50% EtOAc in hexane, to provide
3-amino-4a-(5-bromo-2-fluorophenyl)-2,2-dimethyl-4a,5,7,7a-tetrahydro-2H--
furo[3,4-b][1,4]thiazine 1,1-dioxide (27 mg, 0.069 mmol, 69% yield)
as white solid. ESI (M+1) 391.0.
[1417] Enantiomer separation was performed by Supercritical fluid
chromatography employing the following conditions: Stationary
phase: Chiralpak AD-H (Sum, 21 mm.times.25 cm, S/N=5271) with 20%
organic modifier: 80% carbon dioxide. Organic modifier: Methanol
with 20 mM ammonia. F=70 ml/min, T=40C, BPR=100 bar, P=179 bar, 272
nm
Step 8. 2941851#1,
(4aS,7aS)-3-amino-4a-(5-amino-2-fluorophenyl)-2,2-dimethyl-4a,5,7,7a-tetr-
ahydro-2H-furo[3,4-b][1,4]thiazine 1,1-dioxide
[1418] In an analogous sequence of reactions to those described for
Intermediate 2, steps 2-3,
(4aS,7aS)-3-amino-4a-(5-bromo-2-fluorophenyl)-2,2-dimethyl-4a,5,7,7a-tetr-
ahydro-2H-furo[3,4-b][1,4]thiazine 1,1-dioxide was converted to the
title compound in 61% overall yield. LC/MS (ESI.sup.+) m/z=328
(M+H).
2941850#1,
(4aR,7aR)-3-amino-4a-(5-amino-2-fluorophenyl)-2,2-dimethyl-4a,5-
,7,7a-tetrahydro-2H-furo[3,4-b][1,4]thiazine 1,1-dioxide
[1419] In an analogous sequence of reactions to those described for
Intermediate 2, steps 2-3,
(4aR,7aR)-3-amino-4a-(5-bromo-2-fluorophenyl)-2,2-dimethyl-4a,5,7,7a-tetr-
ahydro-2H-furo[3,4-b][1,4]thiazine 1,1-dioxide was converted to the
title compound in 86% overall yield. LC/MS (ESI.sup.+) m/z=328
(M+H).
Example 186
##STR00283## ##STR00284##
[1420] Synthesis of
(R)--N-(5-(8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-6-fluoropyridin-3-yl)-5-chloro-3-methylpicolinamide
Step 1. 1-(methylsulfonyl)cyclopropanecarbonitrile
[1421] To a solution of (methanesulphonyl) acetonitrile (10.0 g, 84
mmol, aldrich) in DMF (100 mL, aldrich) was added potassium
carbonate (15.20 mL, 252 mmol, aldrich) and 1,2-dichloroethane
(33.1 mL, 420 mmol). The resulting mixture was then heated at
85.degree. C. for overnight in a pressure tube. Then, the mixture
was cooled to RT and H.sub.2O (200 mL) was added. The mixture was
extracted with EtOAc (2.times.200 mL). The combined organic
extracts were dried over MgSO.sub.4 and concentrated. The residue
was dissolved in DCM (10 mL) and the mixture was then purified by
silica gel chromatography, eluent (0%-100% EtOAc/hexane) to give
6.68 g of the title compound as a light yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 3.18 (s, 3H), 1.84-1.91 (m, 2H),
1.70-1.77 (m, 2H).
Step 2. 1-(5-bromo-2-fluoropyridin-3-yl)ethanol
[1422] To a solution of 5-bromo-2-fluoropyridine (9.81 mL, 85 mmol)
in THF (150 mL) at -78.degree. C. under N.sub.2 was added LDA (2.0M
heptane/THF/ethylbenzene (51.1 mL, 102 mmol) dropwise. After
addition, the mixture was then stirred at -78.degree. C. for 30
min. Then, a solution of acetaldehyde, anhydrous (14.35 mL, 256
mmol) in THF (50 mL) was added drowpise. After addition, the
mixture was then allowed to warm to room temperature and stirred
for 2 h. The mixture was quenched with saturated ammonium chloride
(30 mL) at 0.degree. C. The organic layer (THF) was collected and
aqueous was extracted with EtOAc (1.times.100 mL). The combined
organic extracts were dried over MgSO.sub.4 and concentrated. The
residue was then dissolved in DCM (50 mL) and combined with another
batch (5.0 g scale of 5-bromo-2-fluoropyridine, processed under the
same conditions). The mixture was then purified by silica gel
chromatography, eluent 0%-80% EtOAc/hexanes, to give 19.19 g of the
title compound as a yellow oil. MS (ESI, positive ion) m/z: 219.9.
220.90 (M+H)
Step 3. 1-(5-bromo-2-fluoropyridin-3-yl)ethanone
[1423] To a solution of pyridinium dichromate (98 g, 262 mmol) in
DCM (200 mL) at 0.degree. C. was added a solution of
1-(5-bromo-2-fluoropyridin-3-yl)ethanol (19.19 g, 87 mmol) in DCM
(100 mL). After addition, the mixture was then stirred at RT 72 hr.
Pyridinium dichromate (15 g) was added and the mixture was stirred
at RT for an additional 12 h. Then, the mixture was filtered
through celite and the solid was washed with DCM (3.times.200 mL).
The combined filtrates were concentrated and the residue was
dissolved in DCM (10 mL). The mixture was then purified by silica
gel chromatography, eluent 0%-100% EtOAc/hexane, to give 11.0 g of
the title compound as a white solid. MS (ESI, positive ion) m/z:
218, 219.9 (M+H)
Step 4.
(R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropa-
ne-2-sulfinamide
[1424] To a solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanone
(10.93 g, 50.1 mmol) in THF (100 ml) was added
(R)-(+)-2-methyl-2-propanesulfinamide (12.15 g, 100 mmol) and
titanium (IV)-ethoxide (20.75 mL, 100 mmol). The resulting mixture
was then heated at reflux for 1 h. The mixture was cooled to RT and
brine (300 mL) was added. The mixture was stirred at RT for 15 min,
then filtered and the solid was washed with DCM (2.times.100 mL).
The organic layer was collected and the aqueous layer was dried
over MgSO.sub.4 and concentrated. The residue was then dissolved in
DCM (10 mL) and purified by silica gel chromatography, eluent
0%-100% EtOAc/hexane, to give 14.9 g of the title compound as a
yellow solid. MS (ESI, positive ion) m/z: 321, 323 (M+H).
Step 5.
N--((R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((1-cyanocyclopropyl)su-
lfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[1425] To a solution of 1-(methylsulfonyl)cyclopropanecarbonitrile
(6.63 g, 45.7 mmol) in THF (225 mL) under N.sub.2 at -78.degree. C.
was added butyllithium solution, 1.6m in hexane (28.5 mL, 45.7
mmol) dropwise. After addition, the mixture was stirred at this
temperature for 20 min. Then, a solution of
(R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-su-
lfinamide (9.0 g, 28.0 mmol) in toluene (90 mL) pre-treated with
trimethylaluminum solution, 2.0 m in toluene (14.01 mL, 28.0
mmol)-78.degree. C. was added to the mixture dropwise. After
addition, the mixture was stirred at -78.degree. C. for 45 min.
Then, the mixture was quenched with saturated ammonium chloride (30
mL) at -78.degree. C. and H.sub.2O (100 mL) was added. The mixture
was stirred at RT for 15 min. The organic layer was collected and
the aqueous layer was extracted with EtOAc (1.times.200 mL). The
combined organic extracts were dried over MgSO.sub.4 and
concentrated. The residue was then dissolved in MeOH and silica gel
was added. The mixture was concentrated and dried in vacuo. The
solid mixture was then purified by silica gel chromatography,
eluent 0%-100% EtOAc/DCM) to give 6.14 g of title compound as a
white solid. MS (ESI, positive ion) m/z: 466, 468 (M+H).
Step 6.
(R)-1-((2-amino-2-(5-bromo-2-fluoropyridin-3-yl)propyl)sulfonyl)cy-
clopropanecarbonitrile
[1426] To a solution of
N4R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((1-cyanocyclopropyl)sulfonyl)pro-
pan-2-yl)-2-methylpropane-2-sulfinamide (5.14 g, 11.02 mmol) in
MeOH (45 mL) and DCM (9.00 mL) was added hydrogen chloride, 4.0m
solution in 1,4-dioxane (8.27 mL, 33.1 mmol). After addition, the
mixture was the stirred at RT for 45 min. Then, the mixture was
concentrated and the crude was dissolved in DCM (100 mL), washed
with a solution of NaOH (10 N, 200 mL), dried over MgSO.sub.4,
concentrated, and dried in vacuo to give the desired product, which
was used in the next step without further purification. MS (ESI,
positive ion) m/z: 362.0, 364 (M+H).
Step 7.
(R)-8-amino-6-(5-bromo-2-fluoropyridin-3-yl)-6-methyl-4-thia-7-aza-
spiro[2.5]oct-7-ene 4,4-dioxide
[1427] To a solution of
(R)-1-((2-amino-2-(5-bromo-2-fluoropyridin-3yl)propyl)sulfonyl)cyclopropa-
necarbonitrile (3.99 g, 11.02 mmol, f) in 1,2-dichloroethane (50
mL) under N.sub.2 was added trimethylaluminum solution, 2.0M in
toluene (11.02 mL, 22.03 mmol) dropwise. After addition, the
mixture was then stirred at room temperature for 14 h. Then, the
mixture was quenched with 1N HCl solution (30 mL) at 0.degree. C.,
stirred at RT for 10 min, and concentrated to remove
1,2-dichloroethane. The aqueous was adjusted to pH>10 using NaOH
1.0 N, then, extracted with DCM (2.times.300 mL). The combined
organic extracts were dried over MgSO.sub.4 and concentrated in
vacuo. The crude product was crystallized using acetone/H.sub.2O to
give 3.3 g of the title compound as a white solid. MS (ESI,
positive ion) m/z: 362.0, 364 (M+H).
Step 8.
(R)--N-(5-(8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
7-en-6-yl)-6-fluoropyridin-3-yl)-5-chloro-3-methylpicolinamide
[1428] To a solution of
(R)-8-amino-6-(5-bromo-2-fluoropyridin-3-yl)-6-methyl-4-thia-7-azaspiro[2-
.5]oct-7-ene 4,4-dioxide (200 mg, 0.552 mmol) in 1,4-dioxane (1.3
mL) was added potassium carbonate (305 mg, 2.209 mmol), copper(I)
iodide (15.77 mg, 0.083 mmol), and
trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.013 mL, 0.083 mmol).
The resulting mixture was then stirred at RT for 15 min. Then,
5-chloro-3-methylpicolinamide (188 mg, 1.104 mmol) was added and
the mixture was then stirred at 105.degree. C. for 14 h. Copper(i)
iodide (15.77 mg, 0.083 mmol) and
trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.013 mL, 0.083 mmol)
were added and the mixture was then heated at 105.degree. C. for 14
h. The mixture was then cooled to RT, saturated NaHCO.sub.3 (5 mL)
was added and the mixture was extracted with DCM (2.times.20 mL).
The combined organic extracts were dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by silica gel
chromatography, eluent 0%-25% MeOH/DCM to give 145 mg of the title
compound as yellow solid. MS (ESI, positive ion) m/z: 452.1 (M+H).
.sup.1H NMR (DMSO-d6) d: 10.87 (s, 1H), 8.52-8.61 (m, 2H), 8.34
(dd, J=9.3, 2.6 Hz, 1H), 7.99-8.06 (m, 1H), 5.92 (s, 2H), 3.58-3.84
(m, 2H), 2.57 (s, 3H), 1.79 (dd, J=8.0, 4.7 Hz, 1H), 1.67 (s, 3H),
1.55-1.63 (m, 1H), 1.43-1.53 (m, 1H), 1.31-1.42 (m, 1H).
Example 187
##STR00285##
[1429] Step 1: Tert-butyl
((5R,6R)-6-allyl-5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5-
,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1430] To (R)-tert-butyl
(5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (3.03 g, 6.54 mmol) in THF (1.0 mL) at
-78.degree. C. was added lithium diisopropylamide, 2.0M solution in
THF/heptane/ethylbenzene (9.81 ml, 19.62 mmol) and the solution was
stirred for 15 minutes. allyl bromide (0.849 ml, 9.81 mmol) was
added and the mixture was stirred at -78.degree. C. to -60.degree.
C. for 2 h. The reaction was quenched with water at this
temperature and the mixture was extracted with DCM. The organic
extract was washed with satd NaCl (3.times.10 mL) and dried over
Na.sub.2SO.sub.4. The crude material was absorbed onto a plug of
silica gel and purified by silica gel chromatography, eluting with
a gradient of 5% to 40% EtOAc in hexane, to provide tert-butyl
((5R,6R)-6-allyl-5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5-
,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1.87 g, 3.71 mmol, 56.8%
yield) as white solid. .sup.1H NMR (400 MHz, CHLO.delta.OFORM-d)
.delta. 10.89 (s, 1H), 7.40-7.63 (m, 2H), 7.05 (dd, J=8.71, 12.23
Hz, 1H), 5.53 (dddd, J=5.77, 8.22, 10.03, 16.97 Hz, 1H), 4.80-5.04
(m, 2H), 3.85-4.09 (m, 1H), 2.87-3.10 (m, 1H), 2.22-2.32 (m, 1H),
1.97 (s, 3H), 1.87 (s, 3H), 1.76 (s, 3H), 1.47 (s, 9H).
Step 2: Tert-butyl
((5R,6R)-5-(5-bromo-2-fluorophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,-
1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[1431] A suspension of tert-butyl
((5R,6R)-6-allyl-5-(5-bromo-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5-
,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1.85 g, 3.67 mmol) and
sodium bicarbonate (0.617 g, 7.35 mmol) in DCM and MeOH was cooled
in ice-acetone bath. A mixture of O.sub.3 in oxygen gas was
introduced until the blue color persisted. The excess ozone was
removed by purging with oxygen gas for 5 minutes. Sodium
borohydride (0.209 g, 5.51 mmol) was added and the mixture was
stirred at 0.degree. C. After 30 minutes, the mixture was poured
into ice-cold 1 N HCl and extracted with DCM. The extracts were
washed with 1N HCl, brine, dried and concentrated to give crude
tert-butyl
((5R,6R)-5-(5-bromo-2-fluorophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,-
1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate as white
solid.
Step 3:
2-((2R,3R)-3-(5-bromo-2-fluorophenyl)-5-((tert-butoxycarbonyl)-ami-
no)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-2-yl)-ethyl
methanesulfonate
[1432] To a solution of crude tert-butyl
((5R,6R)-5-(5-bromo-2-fluorophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,-
1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1.862 g, 3.67
mmol) and triethylamine (1.531 ml, 11.01 mmol) in DCM at 0.degree.
C. was added methanesulfonyl chloride (0.454 ml, 5.87 mmol). The
mixture was allowed to warm to RT slowly with stirring for 16 h.
The reaction mixture was diluted with saturated aqueous NH.sub.4Cl
and extracted with EtOAc. The organic extract was washed with
saturated aqueous NaCl and concentrated in vacuo to give the crude
material. The crude material was purified by silica gel
chromatography, eluting with a gradient of 0% to 6% MeOH in DCM, to
provide
2-((2R,3R)-3-(5-bromo-2-fluorophenyl)-5-((tert-butoxycarbonyl)amino)-3,6,-
6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-2-yl)ethyl
methanesulfonate (1.90 g, 3.25 mmol, 88% yield) as off-white solid.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.93 (s, 1H), 7.56
(ddd, J=2.40, 4.28, 8.68 Hz, 1H), 7.50 (dd, J=2.35, 7.34 Hz, 1H),
7.10 (dd, J=8.71, 12.23 Hz, 1H), 4.48 (dt, J=3.86, 10.54 Hz, 1H),
4.30 (ddd, J=3.37, 5.70, 10.49 Hz, 1H), 4.21 (d, J=10.07 Hz, 1H),
2.88 (s, 3H), 2.46-2.63 (m, 1H), 1.92 (s, 3H), 1.90 (s, 3H),
1.79-1.87 (m, 1H), 1.76 (s, 3H), 1.47 (s, 9H).
Step 4: (R)-tert-butyl
(8-(5-bromo-2-fluorophenyl)-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro-
[2.5]oct-6-en-6-yl)carbamate
[1433] To a solution of
2-42R,3R)-3-(5-bromo-2-fluorophenyl)-5-((tert-butoxycarbonyl)amino)-3,6,6-
-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-2-yl)ethyl
methanesulfonate (1.04 g, 1.776 mmol) in THF was added potassium
t-butoxide (0.997 g, 8.88 mmol). The mixture was stirred at RT for
0.5 h. The reaction mixture was diluted with water, extracted with
ethyl acetate. The combined extracts were washed with brine, dried,
filtered and concentrated. The crude material was purified by
silica gel chromatography, eluting with a gradient of 10% to 50%
EtOAc in hexane, to provide the titled compound (R)-tert-butyl
(8-(5-bromo-2-fluorophenyl)-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro-
[2.5]oct-6-en-6-yl)carbamate (0.695 g, 1.420 mmol, 80% yield) as
white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 11.13 (s,
1H), 7.50 (ddd, J=2.45, 4.16, 8.66 Hz, 1H), 7.42 (dd, J=2.45, 7.14
Hz, 1H), 7.01 (dd, J=8.66, 11.88 Hz, 1H), 2.07 (s, 3H), 1.81 (s,
3H), 1.77 (s, 3H), 1.60-1.66 (m, 2H), 1.50 (s, 9H), 0.79-0.88 (m,
2H).
Example 188
##STR00286##
[1434] Synthesis of
(R)-5-amino-3-(5-((5-bromo-3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluoro-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1:
[1435] A suspension of 3-chloro-1,7-naphthyridin-8(7H)-one (1.6 g,
8.86 mmol) and N-bromosuccinimide (1.892 g, 10.63 mmol) in 8 mL of
DMF was stirred at rt. After 5 h, the reaction was treated with
water. The solid precipitate was filtered, washed with water and
ether, air-dried to give
5-bromo-3-chloro-1,7-naphthyridin-8(7H)-one (2.18 g, 8.40 mmol, 95%
yield) as an off-white solid.
Step 2:
[1436] A mixture of 5-bromo-3-chloro-1,7-naphthyridin-8(7H)-one
(1.82 g, 7.01 mmol) and phosphorus oxychloride (6.42 ml, 70.1 mmol)
was heated at 100 C. for 2 h. The POCl3 was evaporated under vacuum
to give crude 5-bromo-3,8-dichloro-1,7-naphthyridine (2.1 g, 7.56
mmol, 108% yield) as a tan solid which was used directly in the
next step.
Step 3:
[1437] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (505 mg, 1.264 mmol) and
5-bromo-3,8-dichloro-1,7-naphthyridine (492 mg, 1.770 mmol) in 4 mL
of isopropanol was added sulfuric acid, 95% (67.4 .mu.l, 1.264
mmol) and the reaction was sealed and stirred at 95 C. for 5 h. The
reaction was cooled and extracted with ethyl acetate, washed with
sat NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered and
evaporated to dryness. Chromatography on silica gel (DCM/ethyl
acetate=1:1 to 1:2 to ethyl acetate) gave
(R)-5-amino-3-(5-((5-bromo-3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluoro-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
(520 mg, 0.961 mmol, 76% yield) as a light yellow solid. LC/MS
(ESI.sup.+) m/z=541 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=11.29 (s, 1H), 10.12 (s, 1H), 9.65 (br. s., 1H), 9.26 (br.
s., 1H), 9.02 (d, J=2.2 Hz, 1H), 8.43 (d, J=2.3 Hz, 1H), 8.35 (s,
1H), 8.25 (dd, J=2.5, 7.6 Hz, 1H), 8.20-8.09 (m, 1H), 7.29 (dd,
J=8.9, 12.0 Hz, 1H), 4.36 (d, J=15.5 Hz, 1H), 4.12 (d, J=15.5 Hz,
1H), 1.95 (s, 3H), 1.84 (s, 3H), 1.72 (s, 3H)
Example 189
##STR00287##
[1438] Synthesis of
(R)-5-amino-3-(5-((3-chloro-5-((trimethylsilyl)ethynyl)-1,7-naphthyridin--
8-yl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1439] A mixture of
(R)-5-amino-3-(5-((5-bromo-3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluoro-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
(110 mg, 0.203 mmol), bis(triphenylphosphine)palladium(ii)
dichloride (14.28 mg, 0.020 mmol), copper(i) iodide (3.87 mg, 0.020
mmol) was evacuated and back filled with N.sub.2. To this was added
1 mL of dry dioxane, triethylamine (170 .mu.l, 1.220 mmol) and
(trimethylsilyl)-acetylene (43.1 .mu.l, 0.305 mmol). The reaction
was sealed and heated at 110 C. for 2 h. After cooling, the
solvents was evaporated under vacuum and the residue was submitted
to flash column (DCM/ethyl acetate=1:1 to 1:2 to ethyl acetate) to
give
(R)-5-amino-3-(5-((3-chloro-5-((trimethylsilyl)ethynyl)-1,7-naphthyridin--
8-yl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (80 mg, 0.143 mmol, 70.5% yield) as a light yellow
solid. LC/MS (ESI.sup.+) m/z=558 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d)=9.00 (s, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.2
Hz, 1H), 8.28 (s, 1H), 8.04-7.95 (m, 1H), 7.84 (d, J=4.9 Hz, 1H),
7.09 (dd, J=8.8, 11.7 Hz, 1H), 3.70-3.52 (m, 2H), 1.84 (s, 3H),
1.71 (s, 3H), 1.63 (s, 3H), 0.33 (s, 9H)
Example 190
##STR00288##
[1440] Synthesis of
(R)-5-amino-3-(5-((3-chloro-5-ethynyl-1,7-naphthyridin-8-yl)amino)-2-fluo-
rophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1441] To a solution of 70 mg
(R)-5-amino-3-(5-((3-chloro-5-((trimethylsilyl)ethynyl)-1,7-naphthyridin--
8-yl)amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (80 mg, 0.143 mmol) in 10 mL of MeOH was added
potassium carbonate (84 mg, 0.610 mmol) and the reaction was
stirred at rt for 2 h. The solvent was evaporated and the residue
was chromatographed on silica gel (DCM/ethyl acetate=1:1 to 1:2 to
ethyl acetate) to give
(R)-5-amino-3-(5-((3-chloro-5-ethynyl-1,7-naphthyridin-8-yl)amino)-2-fluo-
rophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
(60 mg, 0.123 mmol, 86% yield) as a light yellow solid. LC/MS
(ESI.sup.+) m/z=486 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d)=9.03
(s, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.33 (s,
1H), 8.10-7.97 (m, 1H), 7.83 (dd, J=2.8, 7.1 Hz, 1H), 7.10 (dd,
J=8.8, 11.7 Hz, 1H), 3.70-3.56 (m, 2H), 3.42 (s, 1H), 1.84 (s, 3H),
1.72 (s, 3H), 1.65 (s, 3H)
Example 191
##STR00289##
[1442] Synthesis of
(R)-5-amino-3-(5-((3-chloro-5-(hydroxymethyl)-1,7-naphthyridin-8-yl)-amin-
o)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
Step 1:
(R)-5-amino-3-(5-((3-chloro-5-vinyl-1,7-naphthyridin-8-yl)-amino)--
2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1443] A mixture of
(R)-5-amino-3-(5-((5-bromo-3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluoro-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
(150 mg, 0.277 mmol), tributyl(vinyl)tin (114 .mu.l, 0.361 mmol)
and 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloride
dichloromethane adduct (13.59 mg, 0.017 mmol) in 1 mL DMF was
flushed with N.sub.2 and was sealed and stirred at 110 C. for 1 h.
After cooling, the solvents were evaporated and the residue was
submitted to flash column (DCM to DCM/EtOAc=1:1 to 1:2) to give
crude
(R)-5-amino-3-(5-((3-chloro-5-vinyl-1,7-naphthyridin-8-yl)amino)-2-fluoro-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (95
mg, 0.195 mmol, 70.2% yield) as a yellow gum which was used
directly in the next step
Step 2:
(R)-8-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4--
thiazin-3-yl)-4-fluorophenyl)-amino)-3-chloro-1,7-naphthyridine-5-carbalde-
hyde
[1444] To a solution of crude
(R)-5-amino-3-(5-((3-chloro-5-vinyl-1,7-naphthyridin-8-yl)amino)-2-fluoro-
phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (90
mg, 0.184 mmol) in 3 mL of MeCN and 1.5 mL of water was added
4-methylmorpholine 4-oxide (64.8 mg, 0.553 mmol), osmium tetroxide
(1.407 mg, 5.53 .mu.mol), 0.2 mL of pH=7.2 phosphate buffer and
sodium periodate (197 mg, 0.922 mmol) and the reaction was stirred
at rt overnight. The reaction was diluted with water, extracted
with ethyl acetate, dried over Na.sub.2SO.sub.4, filtered and
evaporated to dryness. Silica gel chromatography (eluent hexanes
then hexanes/ethyl acetate=1:1 then 1:2 to ethyl acetate) gave
(R)-8-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)-3-chloro-1,7-naphthyridine-5-carbaldehyde
(50 mg, 0.102 mmol, 55.3% yield) as a yellow solid.
Step 3:
(R)-5-amino-3-(5-((3-chloro-5-(hydroxymethyl)-1,7-naphthyridin-8-y-
l)-amino)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1445] To a solution of
(R)-8-((3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)amino)-3-chloro-1,7-naphthyridine-5-carbaldehyde
(50 mg, 0.102 mmol) in 5 mL of MeOH was added sodium borohydride
(14 mg, 0.369 mmol) and the reaction was stirred at rt overnight.
The solvent was evaporated and the residue was submitted to silica
gel (ethyl acetate then ethyl acetate/MeOH=10:1) to give
(R)-5-amino-3-(5-((3-chloro-5-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino-
)-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide (11 mg, 0.022 mmol, 22% yield) as a light-yellow film.
LC/MS (ESI.sup.+) m/z=492 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=8.87 (s, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.35
(d, J=2.3 Hz, 1H), 8.05-7.95 (m, 2H), 7.83 (dd, J=2.4, 6.9 Hz, 1H),
7.09 (dd, J=8.8, 11.7 Hz, 1H), 4.82 (s, 2H), 3.64 (s, 2H), 1.86 (s,
3H), 1.72 (s, 3H), 1.64 (s, 3H)
Example 192
##STR00290##
[1446] Synthesis of
(R)-5-amino-3-(5-((3,5-dichloro-1,7-naphthyridin-8-yl)amino)-2-fluorophen-
yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: 3,5-dichloro-1,7-naphthyridin-8(7H)-one
[1447] A suspension of 3-chloro-1,7-naphthyridin-8(7H)-one (540 mg,
2.99 mmol) and N-chlorosuccinimide (479 mg, 3.59 mmol) in 10 mL of
MeCN was heated at 80 C. After 2 h, 100 mg more of
N-chlorosuccinimide was added. After 2 h, the reaction was cooled,
concentrated and was treated with water. The solid precipitate was
filtered, washed with water and ether, air-dried to give
3,5-dichloro-1,7-naphthyridin-8(7H)-one (630 mg, 2.93 mmol, 98%
yield) as an off-white solid.
Step 2: 3,5,8-trichloro-1,7-naphthyridine
[1448] A mixture of 3,5-dichloro-1,7-naphthyridin-8(7H)-one (430
mg, 2.000 mmol) and phosphorus oxychloride (2746 .mu.l, 30.0 mmol)
was heated at 100 C. for 2 h. The POCl3 was evaporated under vacuum
to give 3,5,8-trichloro-1,7-naphthyridine (510 mg, 2.184 mmol, 109%
yield) as a brown solid which was used directly in the next
step.
Step 3:
(R)-5-amino-3-(5-((3,5-dichloro-1,7-naphthyridin-8-yl)amino)-2-flu-
orophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine
1,1-dioxide
[1449] To a solution of (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (100 mg, 0.250 mmol) and
3,5,8-trichloro-1,7-naphthyridine (64.3 mg, 0.275 mmol) in 1.5 mL
of isopropanol was added sulfuric acid, 95% (13.34 .mu.l, 0.250
mmol) and the reaction was sealed and stirred at 85 C. overnight.
The reaction was cooled and extracted with ethyl acetate, washed
with sat NaHCO3, dried over Na2SO4, filtered and evaporated to
dryness. Flash column (DCM/ethyl acetate=1:1 to 1:2 to ethyl
acetate) gave
(R)-5-amino-3-(5-((3,5-dichloro-1,7-naphthyridin-8-yl)amino)-2-fluorophen-
yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (90 mg,
0.181 mmol, 72.4% yield) as a light yellow solid. LC/MS (ESI.sup.+)
m/z=496 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=8.85 (s,
4H), 8.67 (d, J=2.2 Hz, 4H), 8.32 (d, J=2.2 Hz, 1H), 8.11 (s, 1H),
8.05-7.98 (m, 1H), 7.79 (dd, J=2.7, 7.0 Hz, 1H), 7.09 (dd, J=8.9,
11.6 Hz, 1H), 3.71-3.55 (m, 2H), 1.84 (s, 3H), 1.71 (s, 3H), 1.64
(s, 3H).
Example 193
##STR00291##
[1450] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloropicolinamide
[1451] A mixture of
(S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6--
dihydro-2H-1,4-thiazine 1,1-dioxide (100 mg, 0.262 mmol),
5-chloropicolinamide (53.4 mg, 0.341 mmol), copper(I) iodide (9.99
mg, 0.052 mmol) and potassium carbonate (109 mg, 0.787 mmol)
contained in a microwave vial was evacuated and purged with N.sub.2
3 times. To this was added 1.5 mL of dry dioxane under N.sub.2,
followed by N,N'-dimethylcyclohexane-1,2-diamine (14.92 mg, 0.105
mmol) and the vial was sealed and heated in an oil bath at
125.degree. C. overnight (16 h). LCMS showed about 30% of desired
conversion. It was resealed and heated at 135 C. for 24 h. After
cooling, the reaction mixture was filtered through a silica gel pad
eluted with DCM/MeOH=10:1. After removal of the solvents under
vacuum, the residue was chromatographed on silica gel (DCM/ethyl
acetate=1:1 to ethyl acetate then ethyl acetate/MeOH=100:1 then
100:2 then 100:3) to give
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloropicolinamide (40 mg,
0.088 mmol, 33.4% yield) as an off-white solid. LC/MS (ESI.sup.+)
m/z=457 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=9.82
(br. s., 1H), 8.55 (br. s., 1H), 8.23 (d, J=8.2 Hz, 1H), 8.02-7.92
(m, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.72 (br. s., 1H), 7.11 (dd,
J=9.0, 11.7 Hz, 1H), 4.96-4.66 (m, 1H), 4.62-4.40 (m, 1H),
3.91-3.79 (m, 1H), 3.78-3.66 (m, 1H), 1.77 (br. s., 3H), 1.66 (br.
s., 3H)
Example 194
##STR00292##
[1452] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-(prop-1-en-2-yl)picolinamide
[1453] A sealable vial was charged with (R)-tert-butyl
(5-(5-(3-bromo-5-chloropicolinamido)-2-fluorophenyl)-2,2,5-trimethyl-1,1--
dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (100 mg, 0.162
mmol), tetrakis(triphenylphosphine)palladium (9.35 mg, 8.09
.mu.mol) and sodium carbonate (51.5 mg, 0.486 mmol). The vial was
evacuated and backfilled with nitrogen. 1,4-Dioxane (2 mL) and
water (0.6 mL) were added. The reaction mixture was purged with
Nitrogen then isopropenylboronic acid pinacol ester (0.030 g, 0.178
mmol) was added and the reaction mixture was heated to 80.degree.
C. 1 hr. The reaction temperature was increased to 90.degree. C.
for an additional hour. The reaction temperature was increased to
100.degree. C. for an additional hour. The reaction mixture was
cooled to rt and partitioned between water and EtOAc. The organic
extract was washed with saturated NaCl and dried over MgSO.sub.4.
The solution was concentrated under reduced pressure. The residue
was purified by reversed-phase HPLC (Gemini Axia 50.times.250 mm
C18, 10-100% CH.sub.3CN, 0.1% TFA/H.sub.2O, 0.1% TFA). The product
containing fractions were combined and neutralized with aq. sodium
carbonate solution. The product was extracted with DCM. The organic
phase was dried over MgSO.sub.4 and the solvent was removed under
reduced pressure to give the title compound as yellow solid (20 mg,
0.042 mmol, 25.8% yield).M/S m/z=479.0 [M+H].sup.+. Calculated for
C.sub.22H.sub.24ClFN.sub.4O.sub.3S: 478.97: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.45 (s, 3H) 1.57 (s, 3H) 1.61 (s, 3H)
2.08 (s, 3H) 3.44-3.57 (m, 1H) 3.57-3.72 (m, 1H) 5.06 (s, 1H) 5.20
(t, J=1.53 Hz, 1H) 6.02 (br. s., 2H) 7.11 (dd, J=12.13, 8.92 Hz,
1H) 7.58 (dd, J=7.45, 2.63 Hz, 1H) 7.76 (dd, J=8.84, 4.46 Hz, 1H)
7.98 (d, J=2.34 Hz, 1H) 8.62 (d, J=2.34 Hz, 1H) 10.54 (s, 1H)
Example 195
##STR00293##
[1454] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-vinylpicolinamide
[1455] A sealable vial was charged with (R)-tert-butyl
(5-(5-(3-bromo-5-chloropicolinamido)-2-fluorophenyl)-2,2,5-trimethyl-1,1--
dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (225 mg, 0.364
mmol) and dichlorobis(triphenyl-phosphine)palladium(II) (30.7 mg,
0.044 mmol). The vial was evacuated and backfilled with nitrogen.
1,4-Dioxane (3 mL) was added, followed by tri-n-butyl(vinyl)tin
(0.139 mL, 0.437 mmol). The reaction mixture was heated at
100.degree. C. for 40 min. The reaction mixture was cooled to RT
and partitioned between water and EtOAc. The organic phase was
separated, dried over MgSO.sub.4 and concentrated under reduced
pressure. The residue was dissolved in MeOH and washed with
hexanes. The MeOH containing fraction was concentrated under
reduced pressure and the residue was purified by reversed-phase
HPLC (Gemini Axia 50.times.250 mm C18, 10-100% CH.sub.3CN, 0.1%
TFA/H.sub.2O, 0.1% TFA). The product containing fractions were
combined and neutralized with aq. sodium carbonate solution. The
product was extracted with DCM. The organic phase was dried over
MgSO.sub.4 and the solvent was removed under reduced pressure to
give the title compound as a yellow solid (60 mg, 0.129 mmol, 35.4%
yield).M/S m/z=465.0 [M+H].sup.+. Calculated for
C.sub.21H.sub.22ClFN.sub.4O.sub.3S: 464.9: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.40-1.80 (m, 9H) 3.39-3.82 (m, 2H) 5.54
(d, J=11.55 Hz, 1H) 5.94-6.17 (m, 2H) 7.08-7.21 (m, 1H) 7.28 (dd,
J=17.61, 11.18 Hz, 1H) 7.61-7.92 (m, 2H) 8.38 (d, J=2.34 Hz, 1H)
8.64 (d, J=2.19 Hz, 1H) 10.61 (br. s., 1H)
Example 196
##STR00294##
[1456] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-ethylpicolinamide
[1457] A sealable vial was charged with
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-5-chloro-3-vinylpicolinamide (10 mg, 0.022
mmol) and EtOAc (1.5 mL). The solution was purged with nitrogen.
Palladium on activated carbon (10% wt., 12 mg, 10.75 .mu.mol) was
added. The reaction vessel was evacuated and backfilled with
hydrogen. The reaction mixture was stirred at RT for 1 h. The
reaction was repeated on a 30 mg scale and the crude reaction
mixtures were filtered through a pad of celite. The filtrate was
concentrated under reduced pressure, and the residue was purified
by reversed-phase HPLC (Gemini Axia 50.times.250 mm C18, 10-100%
CH.sub.3CN, 0.1% TFA/H.sub.2O, 0.1% TFA). The product containing
fractions were combined and neutralized with aq. sodium carbonate
solution. The product was extracted with EtOAc. The organic phase
was dried over MgSO.sub.4 and the solvent was removed under reduced
pressure to give the title compound as a light-yellow powder (23
mg). M/S m/z=467.0 [M+H].sup.+. Calculated for
C.sub.21H.sub.24ClFN.sub.4O.sub.3S: 466.96: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.20 (t, J=7.53 Hz, 4H) 1.46 (br. s., 3H)
1.57 (br. s., 3H) 1.62 (br. s., 3H) 2.90 (q, J=7.50 Hz, 2H)
3.46-3.58 (m, 1H) 3.63 (d, J=14.87 Hz, 1H) 6.03 (br. s., 2H)
7.00-7.25 (m, 1H) 7.66 (d, J=5.09 Hz, 1H) 7.83 (d, J=8.22 Hz, 1H)
8.02 (d, J=2.15 Hz, 1H) 8.57 (d, J=2.35 Hz, 1H) 10.54 (br. s.,
1H)
Example 197
##STR00295##
[1458] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethylpicolinamide
[1459] A sealable vial was charged with
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-vinylpicolinamide
(90 mg, 0.186 mmol) and EtOAc (5 mL). The solution was purged with
Nitrogen. Palladium on activated carbon (10% wt.; 60 mg) was added.
The reaction mixture was evacuated and backfilled with hydrogen.
The reaction mixture was stirred at rt for 1 h. The reaction
mixture was filtered through a pad of celite to obtain the title
product as a light brown solid (65 mg, 0.134 mmol, 72%). M/S
m/z=485.0 [M+H].sup.+. Calculated for
C.sub.21H.sub.23ClF.sub.2N.sub.4O.sub.3S: 484.9: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 1.21 (t, J=7.45 Hz, 3H) 1.49 (s, 3H)
1.60 (s, 3H) 2.91 (q, J=7.41 Hz, 2H) 3.52-3.66 (m, 1H) 3.67-3.83
(m, 1H) 4.34-4.51 (m, 1H) 4.53-4.76 (m, 1H) 6.32 (s, 2H) 7.17 (dd,
J=12.06, 8.99 Hz, 1H) 7.74 (dd, J=7.23, 2.70 Hz, 1H) 7.81-7.94 (m,
1H) 8.02 (d, J=2.34 Hz, 1H) 8.57 (d, J=2.34 Hz, 1H) 10.57 (s,
1H)
Example 198
##STR00296##
[1460] Synthesis of
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-isopropylpicolinamide
2,2,2-trifluoroacetate
[1461] A sealable vial was charged with
(S)--N-(3-(5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro--
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(prop-1-en-2-yl)picolinami-
de (85 mg, 0.171 mmol) and EtOH (12.5 mL). The solution was purged
with Nitrogen. Platinum on activated carbon (10 wt. %; 100 mg, 0.05
mmol) was added, followed by glacial acetic acid (0.1 mL). The
reaction mixture was evacuated, backfilled with hydrogen and
stirred for 1 h at RT. The reaction mixture was filtered through a
pad of celite to obtain the title product as a light-brown solid
(62 mg, 0.101 mmol, 59%).M/S m/z=499.1 [M+H].sup.+. Calculated for
C.sub.22H.sub.25ClF.sub.2N.sub.4O.sub.3S: 498.9: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 1.24 (d, J=8.04 Hz, 7H) 1.68 (s, 3H)
1.79 (s, 3H) 3.43-3.67 (m, 1H) 4.20 (br. s., 1H) 4.33 (br. s., 1H)
4.88 (br. s., 1H) 5.03 (br. s., 1H) 7.20-7.45 (m, 1H) 7.80 (d,
J=4.97 Hz, 1H) 7.96 (d, J=8.62 Hz, 1H) 8.13 (d, J=2.19 Hz, 1H) 8.57
(d, J=2.34 Hz, 1H) 8.98-9.54 (m, 1H) 9.60-10.07 (m, 1H) 10.75 (s,
1H) 10.95-11.34 (m, 1H)
Example 199
##STR00297##
[1462] Synthesis of
(R)--N-(3-(8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6--
yl)-4-fluorophenyl)-5-chloropicolinamide
Step 1: (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl)
propan-2-yl)carbamate
[1463] In an analogous reaction to that described for Example 83,
step 1, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-((cyanomethyl)sulfonyl)propan-2-yl)carbamat-
e (1 g, 2.297 mmol) was treated with 1,2-dibromoethane (0.277 mL,
3.22 mmol) to give the title compound (0.818 g, 1.773 mmol) as a
white solid. LC/MS (ESI.sup.+) m/z=483 (M+H).
Step 2:
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[-
2.5]oct-7-ene 4,4-dioxide
[1464] (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl)propan-2-yl)c-
arbamate (0.660 g, 1.431 mmol) was dissolved in 4N hydrochloric
acid in dioxane (7.15 mL, 28.6 mmol). The reaction mixture was
stirred at 18.degree. C. for 3 hours. The reaction mixture was
concentrated under vacuum then dried further under high vacuum to
yield a white solid. This was suspended in toluene (6.6 mL) then 2M
trimethylaluminum in toluene (0.858 mL, 1.717 mmol) was added. The
mixture was heated at 100.degree. C. for 2 hours. The reaction
mixture was cooled to 0.degree. C. and quenched with saturated
aqueous sodium carbonate. The mixture was diluted with
dichloromethane and the organic layer was washed with saturated aq.
sodium carbonate. The organic layer was concentrated under vacuum
to yield the title compound as a pale orange foam. The crude
material was purified by silica gel chromatography (0-100% 90:10:1
DCM/methanol/NH.sub.4OH) to afford the title compound as a white
foam. LC/MS (ESI.sup.+) m/z=361 (M+H).
Step 3: (R)-tert-butyl
(6-(5-bromo-2-fluorophenyl)-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oc-
t-7-en-8-yl)carbamate
[1465]
(R)-8-Amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[2-
.5]oct-7-ene 4,4-dioxide (0.100 g, 0.277 mmol) was dissolved in
dioxane (1.0 mL) then di-tert-butyl dicarbonate (0.091 g, 0.415
mmol) and saturated aq. sodium bicarbonate (0.5 mL, 0.277 mmol)
were added. The reaction mixture was stirred at 18.degree. C. for 5
hours. The reaction mixture was diluted with ethyl acetate then
washed with water and brine. The organic layer was concentrated
under vacuum, then purified by silica gel chromatography (eluting
with heptane/ethyl acetate, 0-70%) to afford the title compound
(0.119 g, 0.258 mmol) as a white foam/colorless oil. LC/MS
(ESI.sup.+) m/z=461.1 (M+H).
Step 4:
(R)--N-(3-(8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct--
7-en-6-yl)-4-fluorophenyl)-5-chloropicolinamide
[1466] In an analogous reaction to that described in Method C,
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[2.5]oct-
-7-ene 4,4-dioxide (0.050 g, 0.138 mmol) was treated with
5-chloropicolinamide (0.028 g, 0.180 mmol) to give the title
compound (0.033 g, 0.076 mmol) as a white solid; LC/MS (ESI.sup.+)
m/z=437.1 (M+H).
Intermediate 22
##STR00298##
[1467] Synthesis of Tert-butyl
((6R)-6-(5-amino-2-fluorophenyl)-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-a-
zaspiro[2.5]oct-7-en-8-yl)carbamate
Step 1: 1-(methylsulfonyl)cyclopropanecarbonitrile
[1468] (Methanesulfonyl) acetonitrile (10.00 g, 84 mmol) was
dissolved in DMF (24 mL) then cooled to 0.degree. C. Potassium
carbonate (24.36 g, 176 mmol) was added followed by dropwise
addition of 1,2-dibromoethane (7.16 mL, 83 mmol) via syringe. The
mixture was stirred at 0.degree. C. for 15 minutes then warmed to
18.degree. C. and stirred for 3 hours. The reaction mixture was
diluted with ethyl acetate then washed with water and brine. The
organic layer was dried over sodium sulfate and concentrated under
vacuum to yield the title compound (8.48 g, 58.4 mmol) as a brown
waxy solid.
Step 2:
N--((R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl-
)propan-2-yl)-2-methylpropane-2-sulfinamide
[1469] In an analogous reaction to that described for Intermediate
1, step 3,
(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfi-
namide (5.00 g, 15.61 mmol) (from KR01, step 2) was treated with
1-(methylsulfonyl)cyclopropane carbonitrile (4.31 g, 29.7 mmol) to
give the title compound (4.03 g, 8.66 mmol) as an off-white
foam/oil. LC/MS (ESI.sup.+) m/z=465.0 (M+H).
Step 3:
(R)-1-((2-amino-2-(5-bromo-2-fluorophenyl)propyl)sulfonyl)cyclopro-
pane carbonitrile hydrochloride
[1470]
N--((R)-2-(5-Bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl)-
propan-2-yl)-2-methylpropane-2-sulfinamide (4.03 g, 8.66 mmol) was
dissolved in DCM (17 mL) then cooled to 0.degree. C. and 4N HCl in
dioxane (12.99 mL, 52.0 mmol) was added. The reaction mixture was
warmed to 18.degree. C. and stirred for 4.5 hours. The reaction
mixture was concentrated under vacuum and the remaining solid was
further dried under high vacuum to give the title compound (3.61 g,
9.08 mmol) as a white solid. LC/MS (ESI.sup.+) m/z=361.0 (M+H).
Step 4:
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[-
2.5]oct-7-ene 4,4-dioxide
[1471]
(R)-1-((2-Amino-2-(5-bromo-2-fluorophenyl)propyl)sulfonyl)cycloprop-
anecarbonitrile hydrochloride (3.51 g, 8.83 mmol) was suspended in
toluene (35 mL) then added 2M trimethylaluminum in toluene (5.30
mL, 10.59 mmol) was added. The mixture was heated at 100.degree. C.
for 3 hours. The reaction mixture was cooled to 0.degree. C. and
quenched with saturated aqueous sodium carbonate (6.5 mL) and
diluted with ethyl acetate then washed with water and brine. The
organic layer was concentrated under vacuum then purified by silica
gel chromatography (eluting with 0-100% 90:10:1
DCM/methanol/NH.sub.4OH) to afford the title compound as a yellow
oil/foam. LC/MS (ESI.sup.+) m/z=361.0 (M+H).
Step 5: (R)-tert-butyl
(6-(5-bromo-2-fluorophenyl)-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oc-
t-7-en-8-yl)carbamate
[1472]
(R)-8-Amino-6-(5-bromo-2-fluorophenyl)-6-methyl-4-thia-7-azaspiro[2-
.5]oct-7-ene 4,4-dioxide (2.64 g, 7.31 mmol) was dissolved in
dioxane (26 mL) then di-tert-butyl dicarbonate (2.393 g, 10.96
mmol) and saturated aq. sodium bicarbonate (10.0 mL, 7.31 mmol)
were added. The reaction mixture was stirred at 18.degree. C. for 3
hours. The reaction mixture was diluted with ethyl acetate then
washed with water and brine. The organic layer was concentrated
under vacuum then purified by silica gel chromatography (eluting
with heptane/ethyl acetate, 0-70%) to afford the title compound
(2.96 g, 6.42 mmol) as a white solid. LC/MS (ESI.sup.+) m/z=461.0
(M+H).
Sep 6: tert-butyl
((6R)-6-(5-bromo-2-fluorophenyl)-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-a-
zaspiro[2.5]oct-7-en-8-yl)carbamate
[1473] A solution of 1M potassium tert-butoxide in THF (9.35 mL,
9.35 mmol) was diluted with THF (22 mL), cooled to -78.degree. C.
then diisopropylamine (1.332 mL, 9.35 mmol) was added dropwise via
syringe. The mixture was stirred at -78.degree. C. for 15 minutes.
2.82 M N-Butyllithium in heptane (3.08 mL, 8.68 mmol) was added
dropwise to this solution via syringe and the mixture was stirred
at -78.degree. C. for 45 minutes. A solution of (R)-tert-butyl
(6-(5-bromo-2-fluorophenyl)-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oc-
t-7-en-8-yl)carbamate (1.54 g, 3.34 mmol) in THF (3 mL) was added
dropwise via syringe and the mixture was stirred at -78.degree. C.
for 45 minutes. A solution of N-fluorobenzenesulfonimide (2.95 g,
9.35 mmol) in THF (9.5 mL) was added very quickly dropwise via
syringe. The mixture was stirred at -78.degree. C. for 2.5 hours.
The reaction was quenched with saturated aq. sodium bicarbonate
(.about.12 mL) at -78.degree. C. then warmed to room temperature.
The reaction mixture was diluted with ethyl acetate then washed
with water and brine. The organic layer was concentrated under
vacuum then purified by silica gel chromatography (eluting with
heptane/MTBE, 0-60%) to afford the title compound (0.805 g, 1.679
mmol) as a white foam/colorless oil in an 3:1 mixture of
diastereoisomers. LC/MS (ESI.sup.+) m/z=422.8 (M+H) as the
Boc-acid.
Step 7: tert-butyl
((6R)-6-(5-amino-2-fluorophenyl)-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-a-
zaspiro[2.5]oct-7-en-8-yl)carbamate
[1474] Tert-Butyl
((6R)-6-(5-bromo-2-fluorophenyl)-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-a-
zaspiro[2.5]oct-7-en-8-yl)carbamate (0.400 g, 0.834 mmol) was
dissolved in ethanol (2 mL) and water (0.800 mL) then (+)-sodium
1-ascorbate (0.066 g, 0.334 mmol), sodium azide (0.434 g, 6.68
mmol), copper(I) iodide (0.064 g, 0.334 mmol) and
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.105 mL, 0.668 mmol)
were added. The reaction mixture was heated at 50.degree. C. in a
Biotage microwave reactor for 40 minutes. The reaction mixture was
diluted with EtOAc then washed with water and brine. The organic
layer was concentrated under vacuum to afford 429 mg of a mixture
of azide and aniline as a light orange oil.
[1475] A mixture of tert-butyl
((6R)-6-(5-amino-2-fluorophenyl)-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-a-
zaspiro[2.5]oct-7-en-8-yl)carbamate and tert-butyl
((6R)-6-(5-azido-2-fluorophenyl)-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-a-
zaspiro[2.5]oct-7-en-8-yl)carbamate (0.368 g, 0.834 mmol) was
dissolved in THF (3.6 mL) and water (1.2 mL) then 1M
trimethylphosphine in THF (0.834 mL, 0.834 mmol) was added. The
mixture was stirred at 18.degree. C. for 1 hour. The reaction
mixture was diluted with ethyl acetate then washed with water and
brine. The organic layer was concentrated under vacuum to give 409
mg of crude material as an orange oil which was purified by silica
gel chromatography (eluting with heptane/ethyl acetate, 0-80%) to
afford the title compound (0.256 g, 0.616 mmol) as a white foam.
LC/MS (ESI.sup.+) m/z=416.1 (M+H).
Example 200
##STR00299##
[1476] Synthesis of
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-chloropicolinamide
[1477] Intermediate 22 (0.085 g, 0.205 mmol) and
5-chloro-2-pyridinecarboxylic acid (0.039 g, 0.246 mmol) were
dissolved in DMF (1 mL) then pyridine (0.050 mL, 0.614 mmol) was
added, followed by HATU (0.117 g, 0.307 mmol). The reaction mixture
was stirred at 18.degree. C. for 3 hours. The reaction mixture was
cooled to 0.degree. C. then diluted with water. A precipitate
formed which was collected on a glass frit, washing well with
additional water. The solid was dried under high vacuum. The crude
material (117 mg) was dissolved in dichloromethane (1.5 mL) then
TFA (0.400 mL) was added. The mixture was stirred for 1 hour at
18.degree. C. The reaction mixture was diluted with dichloromethane
then washed with sat. aq. sodium bicarbonate and brine. The organic
layer was concentrated under vacuum and was purified and
diastereoisomers separated by silica gel chromatography (eluting
with 25-100% 90:10:1 dichloromethane/methanol/NH.sub.4OH in 3:2
heptane/ethyl acetate) to afford the title compound (0.049 g, 0.108
mmol) as an off-white solid as the major diastereoisomer. LC/MS
(ESI.sup.+) m/z=455.0 (M+H).
Example 201
##STR00300##
[1478] Synthesis of
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-chloropicolinamide
[1479] Purification and separation of Intermediate 22 as previously
described afforded the title compound (0.011 g, 0.024 mmol) as a
white solid as the minor diastereoisomer. LC/MS (ESI.sup.+)
m/z=455.0 (M+H).
Example 202
##STR00301##
[1480] Synthesis of
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[1481] The title compound was prepared as described for Example DC2
using Intermediate DC1 (0.084 g, 0.202 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (0.049 g, 0.243 mmol).
The mixture of diastereoisomers was purified and separated by
silica gel chromatography (eluting with 15-100% 90:10:1
dichloromethane/methanol/NH.sub.4OH in 3:2 heptane/ethyl acetate)
to afford the title compound (0.061 g, 0.122 mmol) as an off-white
solid as the major diastereoisomer. LC/MS (ESI.sup.+) m/z=501.0
(M+H).
Example 203
##STR00302##
[1482] Synthesis of
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[1483] Purification and separation of Example 202 as previously
described afforded the title compound (0.016 g, 0.032 mmol) as a
pale yellow solid as the minor diastereoisomer. LC/MS (ESI.sup.+)
m/z=501.0 (M+H).
Example 204
##STR00303##
[1484] Synthesis of
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
Step 1:
(6R)-8-amino-6-(5-bromo-2-fluorophenyl)-5-fluoro-6-methyl-4-thia-7-
-azaspiro[2.5]oct-7-ene 4,4-dioxide
[1485] Example 199 (0.077 g, 0.161 mmol) was dissolved in DCM (1.0
mL) then trifluoroacetic acid (0.012 mL, 0.161 mmol) was added. The
reaction mixture was stirred at 18.degree. C. for 2 hours. Added
more trifluoroacetic acid (0.25 mL) and continued stirring at
18.degree. C. overnight. The reaction mixture was diluted with
dichloromethane then washed with sat. aq. sodium bicarbonate and
water. The organic layer was dried over sodium sulfate and
concentrated under vacuum to afford the title compound (0.062 g,
0.163 mmol) as a pale yellow solid. LC/MS (ESI.sup.+) m/z=378.9
(M+H).
Step 2:
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azasp-
iro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1486] The title compound was prepared as described in Method C
using
(6R)-8-amino-6-(5-bromo-2-fluorophenyl)-5-fluoro-6-methyl-4-thia-7-azaspi-
ro[2.5]oct-7-ene 4,4-dioxide (0.062 g, 0.163 mmol) and
5-chloro-3-methylpicolinamide (0.031 g, 0.180 mmol). The mixture of
diastereomers was separated by chiral SFC (OJ-H column (2.times.25
cm), eluent CO.sub.2, modified with 17% methanol w/0.2%
diethylamine as the eluent) to afford the title compound (0.0088 g,
0.019 mmol) as an off-white solid as the major diastereoisomer.
LC/MS (ESI.sup.+) m/z=469.0 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.59-1.81 (m, 3H) 1.84 (d, J=3.23 Hz, 3H)
1.90 (m, J=11.90, 4.10 Hz, 1H) 2.78 (s, 3H) 5.88 (dd, J=48.00, 4.00
Hz, 1H) 7.11 (dd, J=11.88, 8.85 Hz, 1H) 7.52 (dd, J=6.36, 2.05 Hz,
1H) 7.64 (d, J=1.76 Hz, 1H) 7.95 (ddd, J=8.88, 4.23, 2.54 Hz, 1H)
8.38 (d, J=2.15 Hz, 1H) 10.00 (br. s, 1H).
Example 205
##STR00304##
[1487] Synthesis of
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1488] Purification and separation of Example 204 as previously
described afforded the title compound (0.0055 g, 0.012 mmol) as an
off-white solid as the minor diastereoisomer. LC/MS (ESI.sup.+)
m/z=469.0 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.59-1.70 (m, 2H) 1.80-1.92 (m, 2H) 1.94 (s, 3H) 2.80 (s, 3H) 5.75
(d, J=44.00 Hz, 1H) 7.11 (dd, J=11.74, 8.90 Hz, 1H) 7.65 (dd,
J=2.15, 0.59 Hz, 1H) 7.72 (dd, J=6.94, 2.64 Hz, 1H) 7.98 (ddd,
J=8.80, 4.25, 2.79 Hz, 1H) 8.38 (d, J=2.15 Hz, 1H) 10.02 (br. s,
1H).
Example 206
##STR00305##
[1489] Synthesis of
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methylpicolinamide
[1490] The title compound was prepared as described for Example 199
using Intermediate 22 (0.080 g, 0.193 mmol) and
5-(difluoromethyl)-3-methylpicolinic acid (0.043 g, 0.231 mmol).
The mixture of diastereoisomers was purified and separated by
silica gel chromatography (eluting with 15-100% 90:10:1
dichloromethane/methanol/NH.sub.4OH in 3:2 heptane/ethyl acetate)
to afford the title compound (0.058 g, 0.120 mmol) as a white solid
and the major diastereoisomer. LC/MS (ESI.sup.+) m/z=485.0 (M+H).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.58-1.78 (m, 3H),
1.84 (dd, J=3.91, 0.98 Hz, 3H), 1.86-1.93 (m, 1H), 2.79-2.89 (m,
3H), 5.87 (dd, J=44.00, 4.00 Hz, 1H), 6.76 (t, J=56.00 Hz, 1H),
7.12 (dd, J=11.88, 8.85 Hz, 1H), 7.50-7.59 (m, 1H), 7.77 (s, 1H),
7.94 (ddd, J=8.83, 4.28, 2.84 Hz, 1H), 8.57 (s, 1H), 10.12 (s,
1H).
Example 207
##STR00306##
[1491] Synthesis of
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methylpicolinamide
[1492] Purification and separation of Example 206 as previously
described afforded the title compound (0.019 g, 0.039 mmol) as a
white solid as the minor diastereoisomer. LC/MS (ESI.sup.+)
m/z=485.0 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.63-1.71 (m, 1H) 1.73-1.82 (m, 1H) 1.82-1.95 (m, 2H) 1.96 (s, 3H)
2.86 (s, 3H) 5.74 (d, J=44.00 Hz, 1H) 6.76 (t, J=56.00 Hz, 1H) 7.13
(dd, J=11.74, 8.80 Hz, 1H) 7.72-7.83 (m, 2H) 8.00 (ddd, J=8.80,
4.30, 2.84 Hz, 1H) 8.58 (s, 1H) 10.17 (br. s, 1H).
Example 208
##STR00307##
[1493] Synthesis
(5R,6R)-8-amino-5-fluoro-6-(2-fluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5--
yl)amino)phenyl)-6-methyl-4-thia-7-azaspiro[2.5]oct-7-ene
4,4-dioxide
[1494] Intermediate 22 (0.050 g, 0.120 mmol) was suspended in
2,2,2-trifluoroethanol (1 mL) then Intermediate 10 (0.024 g, 0.120
mmol), p-toluenesulfonic acid monohydrate (0.023 g, 0.120 mmol) and
silver trifluoromethanesulfonate (0.031 g, 0.120 mmol)were added.
The reaction mixture was heated at 90.degree. C. for 2.5 hours. The
mixture was diluted with dichloromethane then washed with sat. aq.
sodium bicarbonate. The organic layer was concentrated under
vacuum, and was purified and separated by silica gel chromatography
(eluting with 15-100% 90:10:1 dichloromethane/methanol/NH.sub.4OH
in 3:2 heptane/ethyl acetate) to afford the title compound (0.0053
g, 0.011 mmol) as a yellow solid and the minor diastereoisomer.
LC/MS (ESI.sup.+) m/z=475.2
[1495] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.59-1.63
(m, 2H) 1.81-1.86 (m, 1H) 1.86-1.92 (m, 1H) 1.95 (s, 3H) 4.13 (s,
3H) 5.76 (d, J=48.00 Hz, 1H) 7.05 (d, J=5.87 Hz, 1H) 7.12 (dd,
J=11.74, 8.90 Hz, 1H) 7.81 (dd, J=6.85, 2.84 Hz, 1H) 8.16-8.26 (m,
2H) 8.29 (s, 1H) 8.61 (br. s, 1H).
Example 209
##STR00308##
[1496] Synthesis of
(5S,6R)-8-amino-5-fluoro-6-(2-fluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5--
yl)amino)phenyl)-6-methyl-4-thia-7-azaspiro[2.5]oct-7-ene
4,4-dioxide
[1497] Purification and separation of Example 208 as previously
described afforded impure material that was further purified by
preparative TLC (Whatman 20.times.20 cm plate; 1000 microns),
eluting with 1:1 90/10/1 dichloromethane/methanol/NH.sub.4OH:3:2
heptane/ethyl acetate. The title compound (0.0081 g, 0.017 mmol)
was isolated as a yellow solid as the major diastereoisomer. LC/MS
(ESI.sup.+) m/z=475.2 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.69-1.88 (m, 3H) 1.91 (d, J=3.23 Hz, 3H) 1.92-1.97 (m,
1H) 4.11 (s, 3H) 5.95 (dd, J=48.00, 4.00 Hz, 1H) 7.03 (d, J=5.97
Hz, 1H) 7.12 (dd, J=11.84, 8.90 Hz, 1H) 7.84-7.93 (m, 1H) 7.99-8.07
(m, 1H) 8.22 (d, J=5.97 Hz, 1H) 8.27 (s, 1H) 8.61 (br. s, 1H).
Example 210
##STR00309##
[1498] Synthesis of
N-(3-((5S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridine-2--
carboxamide
[1499] The title compound was prepared as described for Example 199
using Intermediate 22 (0.052 g, 0.125 mmol) and
6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (0.029 g,
0.138 mmol). The mixture of diastereoisomers was purified and
separated by silica gel chromatography (eluting with 15-100%
90:10:1 dichloromethane/methanol/NH.sub.4OH in 3:2 heptane/ethyl
acetate) to afford the title compound (0.024 g, 0.047 mmol) as a
white solid and the major diastereoisomer. LC/MS (ESI.sup.+)
m/z=508.0 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.61-1.76 (m, 3H) 1.78-1.93 (m, 4H) 2.82 (s, 3H) 5.86 (dd, J=44.00,
4.00 Hz, 1H) 7.10 (dd, J=11.88, 8.85 Hz, 1H) 7.22 (dd, J=9.63, 1.91
Hz, 1H) 7.43-7.50 (m, 1H) 7.61 (dd, J=7.04, 2.74 Hz, 1H) 7.88 (ddd,
J=8.85, 4.21, 2.79 Hz, 1H) 7.96 (dd, J=1.81, 0.73 Hz, 1H) 9.34 (br.
s, 1H).
Example 211
##STR00310##
[1500] Synthesis of
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5-
]oct-7-en-6-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridine-2--
carboxamide
[1501] Purification and separation of Example 210 as previously
described afforded impure material that was further purified by
reverse phase prep HPLC eluting with 0.1% NH.sub.4OH in ACN and
water. The title compound (0.00469 g, 9.23 umol) was isolated as a
white solid and the minor diastereoisomer. LC/MS (ESI.sup.+)
m/z=508.0 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
1.44-1.58 (m, 3H) 1.75 (s, 3H) 2.07-2.12 (m, 1H) 2.80 (s, 3H)
5.92-6.11 (m, 3H) 7.16 (dd, J=11.51, 8.90 Hz, 1H) 7.42 (dd, J=9.64,
1.84 Hz, 1H) 7.68 (d, J=9.67 Hz, 1H) 7.88-7.92 (m, 1H) 7.94-7.97
(m, 1H) 8.68 (br. s, 1H) 10.12 (s, 1H).
Example 212
##STR00311##
[1502] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-4-chlorobenzamide
[1503] To (R)-tert-butyl
(5-(5-amino-2-fluorophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,-
4-thiazin-3-yl)carbamate (0.1037 g, 0.260 mmol) in DCM at RT, were
added pyridine (63.5 ml, 779 mmol), and 4-pyrrolidinopyridine (3.85
mg, 0.026 mmol). 4-Chlorobenzoyl chloride (0.037 ml, 0.286 mmol)
was added and the mixture was allowed to stir for 1.5 h, then
volatiles stripped at reduced pressure. The residue was taken up in
DCM, trifluoroacetic acid (6.00 .mu.l, 0.078 mmol) was added, and
the mixture was stirred at RT for 1.5 h. The product was adsorbed
onto a plug of silica gel and chromatographed on silica gel,
eluting with a gradient of 0.5% to 10% MeOH in DCM, to provide
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-
-thiazin-3-yl)-4-fluorophenyl)-4-chlorobenzamide (0.0370 g, 0.084
mmol, 32.5% yield). LC/MS (ESI.sup.+) m/z=(M+H=437.9). .sup.1H NMR
(300 MHz, CHLOROFORM-d) .delta. ppm 1.62 (s, 3H) 1.71 (s, 3H) 1.80
(s, 3H) 3.62 (s, 2H) 7.09 (dd, J=11.69, 8.77 Hz, 1H) 7.40-7.49 (m,
2H) 7.62 (dd, J=7.16, 2.63 Hz, 1H) 7.69-7.75 (m, 1H) 7.75-7.82 (m,
2H) 7.90 (s, 1H)
Example 213
##STR00312##
[1504] Synthesis of
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-4-chloro-2-fluorobenzamide
[1505]
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-t-
hiazin-3-yl)-4-fluorophenyl)-4-chloro-2-fluorobenzamide was
synthesized using the same procedure as described for
(R)--N-(3-(5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-
-3-yl)-4-fluorophenyl)-4-chlorobenzamide utilizing
4-chloro-2-fluorobenzoyl chloride instead of 4-chlorobenzoyl
chloride.
Examples 214a and 214b
##STR00313##
[1506] Synthesis of
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspiro-
[2.5]oct-7-ene 4,4-dioxide (214a) and
(S)-8-amino-6-(5-bromo-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspiro-
[2.5]oct-7-ene 4,4-dioxide (214b)
Step 1: 1-(Methylsulfonyl)cyclopropanecarbonitrile
[1507] A mixture of 2-(methylsulfonyl)acetonitrile (1.3 g, 10.91
mmol), potassium carbonate (3.77 g, 27.3 mmol), and
1,2-dichloroethane (4.31 ml, 54.6 mmol) in DMF (20 mL) was heated
at 80.degree. C. for 24 h, the mixture was cooled, H.sub.2O added,
extracted with DCM (3.times.). The extracts dried over
Na.sub.2SO.sub.4, concentrated and purified by silica gel
chromatography (0-45% EtOAc/DCM) to give the light yellow product.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 3.13-3.23 (3H, m),
1.82-1.94 (2H, m), 1.66-1.78 (2H, m).
Step 2:
N-(2-(5-bromo-2-fluorophenyl)-1-((1-cyanocyclopropyl)sulfonyl)-3-f-
luoropropan-2-yl)-2-methylpropane-2-sulfinamide
[1508] To a stirred solution of
1-(methylsulfonyl)cyclopropanecarbonitrile (9.01 g, 62.1 mmol) in
THF (100 mL) at -78.degree. C. was added butyllithium 2.5 M (22.35
ml, 55.9 mmol) dropwise. After the addition, the mixture was
stirred for 2 h at -78C. In a separate flask, a mixture of
(Z)--N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-
-2-sulfinamide (10.50 g, 31.0 mmol) and borontrifluoride etherate
(4.41 g, 31.0 mmol) in THF (100 mL) was stirred at 0.degree. C. for
30 min, this mixture was then added to the previous mixture by
canula. After the addition, the reaction mixture was stirred at
-78.degree. C. in 2h, quenched with saturated NH.sub.4Cl, warmed to
RT, extracted with EtOAc (3.times.). The combined extracts were
dried over MgSO.sub.4, concentrated and purified by silica gel
chromatography (0-50% EtOAc/Hexane) to give the title compound
(6.74 g, 45%). LC/MS (ESI.sup.+) m/z: 483, 485 (M+H, 2 bromine
isotopes).
Step 3:
1-((2-amino-2-(5-bromo-2-fluorophenyl)-3-fluoropropyl)sulfonyl)
cyclopropanecarbonitrile
[1509] To a stirred solution of
N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-fluoropr-
opan-2-yl)-2-methylpropane-2-sulfinamide (5.09 g, 10.49 mmol) in
dioxane (30 mL) was added HCl (26.2 ml, 105 mmol). After the
addition, the mixture was stirred for 2 h, the mixture was
concentrated, added H.sub.2O, cooled in an ice bath, neutralized
with aqueous saturated NaHCO.sub.3, extracted with DCM (3.times.).
The extracts were dried over Na.sub.2SO.sub.4, concentrated and
purified by silica gel chromatography (30% EtOAc/Hexanes) to give
the title compound as a brown oil (3.25 g, 82%). LC/MS (ESI.sup.+)
m/z: 379, 381 (M+H, 2 bromine isotopes).
Step 4:
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-a-
zaspiro[2.5]oct-7-ene 4,4-dioxide (214-a) and
(S)-8-amino-6-(5-bromo-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspiro-
[2.5]oct-7-ene 4,4-dioxide (214-b)
[1510] To a stirred solution of
1-((2-amino-2-(5-bromo-2-fluorophenyl)-3-fluoropropyl)sulfonyl)cyclopropa-
necarbonitrile (1.8 g, 4.75 mmol) in toluene (10 mL) at 0.degree.
C. was added trimethylaluminum (2.85 ml, 5.70 mmol) dropwise. After
the addition, the mixture was gradually warmed to RT and stirred
for 16 h; the mixture was cooled in an ice bath, slowly quenched
with Rochelle's salt. The resulting mixture was stirred for 30
min., extracted with EtOAc, (3.times.), dried over MgSO.sub.4,
concentrated and purified by silica gel chromatography (0-50%
EtOAc/hexanes) to give the racemic mixture which was then separated
by chiral phase chromatography (ADH-20-MeOH(NH3) to give the
compound 1 (440 mg, 25%) and compound 2 (430 mg, 24%). LC/MS
(ESI.sup.+) m/z: 379, 381 (M+H, 2 bromine isotopes).
Peak#1 (compound 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.70
(1H, dd, J=7.0, 2.7 Hz), 7.47-7.60 (1H, m), 7.20 (1H, dd, J=11.9,
8.8 Hz), 6.24 (2H, br. s.), 4.61 (1H, d, J=2.9 Hz), 4.49 (1H, d,
J=2.5 Hz), 3.81 (1H, d, J=14.7 Hz), 3.71 (1H, d, J=14.7 Hz),
1.57-1.77 (2H, m), 1.34-1.56 (2H, m). Peak#2 (compound 2): .sup.1H
NMR (400 MHz, DMSO-d.sub.6) ppm 7.70 (1H, dd, J=7.0, 2.7 Hz), 7.55
(1H, ddd, J=8.6, 4.1, 2.7 Hz), 7.20 (1H, dd, J=11.9, 8.8 Hz), 6.24
(2H, br. s.), 4.61 (1H, d, J=2.9 Hz), 4.49 (1H, d, J=2.5 Hz), 3.81
(1H, d, J=14.7 Hz), 3.71 (1H, d, J=14.7 Hz), 1.57-1.79 (2H, m),
1.34-1.55 (2H, m).
Example 215
##STR00314##
[1511] Synthesis of
(R)--N-(3-(8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-
-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
Step 1:
(R)-8-amino-6-(5-azido-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-a-
zaspiro[2.5]oct-7-ene 4,4-dioxide
[1512] A mixture of
(R)-8-amino-6-(5-bromo-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspiro-
[2.5]oct-7-ene 4,4-dioxide (0.430 g, 1.134 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate
(0.045 g, 0.227 mmol), sodium azide (0.221 g, 3.40 mmol),
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.040 g, 0.283
mmol), copper(I) iodide (0.054 g, 0.283 mmol) in EtOH/H.sub.2O
(4:1, 2.5 mL) was heated at 90.degree. C. for 16 h; the reaction
mixture was cooled, added saturated NH.sub.4Cl, extracted with
EtOAc (3.times.). The extracts were dried over MgSO.sub.4,
concentrated to give the title product (389 mg, 101%) which was
used in the next step without further purification. LC/MS
(ESI.sup.+) m/z: 342 (M+H).
Step 2:
(R)-8-amino-6-(5-amino-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-a-
zaspiro[2.5]oct-7-ene 4,4-dioxide
[1513] To a stirred solution of
((R)-8-amino-6-(5-azido-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspir-
o[2.5]oct-7-ene 4,4-dioxide (0.389 g, 1.140 mmol) THF/H.sub.2O (4
mL, 3:1) was added trimethylphosphine (0.208 g, 1.368 mmol). After
the addition, the mixture was stirred for 1 h, added more H.sub.2O,
extracted with EtOAc (3.times.). The extracts were dried over
MgSO.sub.4, concentrated and purified by silica gel chromatography
(5% MeOH/DCM) to give the tan solid (150 mg, 42%). LC/MS
(ESI.sup.+) m/z: 316 (M+H).
Step 3:
(R)--N-(3-(8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[-
2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1514] To a stirred mixture of
(R)-8-amino-6-(5-amino-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspiro-
[2.5]oct-7-ene 4,4-dioxide (0.0625 g, 0.198 mmol) and
5-chloro-3-methylpicolinic acid (0.036 g, 0.208 mmol) in DCM (3 mL)
was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane
2,4,6-trioxide (0.378 g, 0.595 mmol). After the addition, the
mixture was stirred at RT for 16 h, saturated aqueous NaHCO.sub.3
was added, layers were separated, organic phase dried over
Na.sub.2SO.sub.4, concentrated and purified by silica gel
chromatography (30% EtOAc/DCM) to give the title compound as an off
white solid (51 mg, 55%). LC/MS (ESI.sup.+) m/z: 469 (M+H). .sup.1H
NMR (400 MHz, CHLOROFORM-d) ppm 10.01 (1H, s), 8.35-8.43 (1H, m),
7.96 (1H, ddd, J=8.8, 4.3, 2.8 Hz), 7.63-7.68 (2H, m), 7.09 (1H,
dd, J=11.7, 8.8 Hz), 4.82 (1H, dd, J=14.7, 8.8 Hz), 4.55 (1H, dd,
J=14.7, 8.8 Hz), 4.45 (2H, br. s.), 3.77 (2H, dd, J=14.5, 8.8 Hz),
2.79 (3H, s), 1.73-1.86 (2H, m), 1.56 (2H, m).
Example 216
##STR00315##
[1515] Synthesis of
(S)--N-(3-(8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-
-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[1516] The title compound (46 mg, 48%) was prepared by the method
of Example 215. LC/MS (ESI.sup.+) m/z: 469 (M+H). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 10.01 (1H, s), 8.35-8.43 (1H, m),
7.96 (1H, ddd, J=8.8, 4.3, 2.8 Hz), 7.63-7.68 (2H, m), 7.09 (1H,
dd, J=11.7, 8.8 Hz), 4.82 (1H, dd, J=14.7, 8.8 Hz), 4.55 (1H, dd,
J=14.7, 8.8 Hz), 4.45 (2H, br. s.), 3.77 (2H, dd J=14.5, 8.8 Hz),
2.79 (3H, s), 1.73-1.86 (2H, m), 1.56 (2H, m).
Example 217
##STR00316##
[1517] Synthesis of
(S)--N-(3-(8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-
-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl
picolinamide
[1518] The title compound (110 mg, 79%) was prepared by the method
of Example 215. LC/MS (ESI.sup.+) m/z: 501 (M+H). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 10.55 (1H, s), 8.42 (1H, d, J=2.5
Hz), 7.80-7.94 (2H, m), 7.71 (1H, d, J=2.3 Hz), 7-24-7.61 (1H, m),
7.17 (1H, dd, J=11.9, 8.6 Hz), 6.16 (2H, s), 4.59-4.75 (1H, m),
4.37-4.59 (1H, m), 3.84 (1H, d, J=14.3 Hz), 3.67 (1H, d, J=14.7
Hz), 2.58 (3H, s), 1.75-1.87 (1H, m), 1.51-1.63 (1H, m), 1.39-1.51
(1H, m), 1.26-1.39 (1H, m).
Example 218
##STR00317##
[1519] Synthesis of
(R)--N-(3-(8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-
-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl
picolinamide
[1520] The title compound (29 mg, 28%) was prepared by the method
of Example 217. LC/MS (ESI.sup.+) m/z: 501 (M+H). .sup.1H NMR (400
MHz, DMSO-d.sub.6) ppm 10.55 (1H, s), 8.42 (1H, d, J=2.5 Hz),
7.80-7.94 (2H, m), 7.71 (1H, d, J=2.3 Hz), 7-24-7.61 (1H, m), 7.17
(1H, dd, J=11.9, 8.6 Hz), 6.16 (2H, s), 4.59-4.75 (1H, m),
4.37-4.59 (1H, m), 3.84 (1H, d, J=14.3 Hz), 3.67 (1H, d, J=14.7
Hz), 2.58 (3H, s), 1.75-1.87 (1H, m), 1.51-1.63 (1H, m), 1.39-1.51
(1H, m), 1.26-1.39 (1H, m)
[1521] The following compounds in Table II are examples of
compounds of Formulas I, II and III, and sub-formulas thereof,
provided by the present invention hereinabove. The Mass
spectrometer data (mass found as measured by M+H.sup.+) and methods
used to prepare the exemplary compounds are also included in Table
II. Table II further provides the biological data (average nM
IC.sub.50's for the enzyme and cell assays) for each compound,
where available.
TABLE-US-00004 TABLE II BACE1 HEK FRET cell assay assay CatD
Example Mass Method IC.sub.50 IC.sub.50 IC50 No Compound Name Spec
Used (uM) (uM) (.mu.M) 146 (7S)-7-(2-bromo-5-fluoro-4- 377.9
Example >40.0 >15.6 >400.0 pyridinyl)-7-methyl-5-thia-8-
13, steps azaspiro[3.5]non-8-en-9-amine 5,5- 2-5 dioxide 147
(7R)-7-(2-bromo-5-fluoro-4- 377.9 Example 17 >15.6 43.5
pyridinyl)-7-methyl-5-thia-8- 13, steps
azaspiro[3.5]non-8-en-9-amine 5,5- 2-5 dioxide 219
N-(5-((3R)-5-amino-3,6,6-trimethyl- 476.9 as in 0.00144 0.0029 39.7
1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- 44
fluoro-3-methoxy-1,7-naphthyridin- 8-amine 220
N-(5-((3R)-5-amino-3,6,6-trimethyl- 480.9 as in <0.002 0.0033
15.2 1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3-pyridinyl)-3- 44
chloro-5-fluoro-1,7-naphthyridin-8- amine 221
8-((5-((3R)-5-amino-3,6,6-trimethyl- 471.9 as in 0.00194 0.0058
43.1 1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3- 44 pyridinyl)amino)-5-fluoro-1,7-
naphthyridine-3-carbonitrile 222
N-(5-((3R)-5-amino-3,6,6-trimethyl- 460 as in 0.00259 0.0036 280
1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3-pyridinyl)-2- 44
methoxypyrido[3,4-b]pyrazin-5- amine 223
N-(5-((3R)-5-amino-3,6,6-trimethyl- 462.9 as in 0.00082 0.0054 23.8
1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3-pyridinyl)-3- 44
chloro-1,7-naphthyridin-8-amine 224
N-(5-((3R)-5-amino-3,6,6-trimethyl- 497.9 as in 0.016 0.0399 457
1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3-pyridinyl)-2- 44
(trifluoromethyl)pyrido[3,4- b]pyrazin-5-amine 225
N-(5-((3R)-5-amino-3,6,6-trimethyl- 463.9 as in 0.00328 0.0122 33
1,1-dioxido-3,6-dihydro-2H-1,4- example
thiazin-3-yl)-6-fluoro-3-pyridinyl)-7- 44
chloropyrido[3,2-d]pyrimidin-4- amine 226
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 500 Example 0.00074 0.00574
>400 dimethyl-1,1-dioxido-3,6-dihydro- 44
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-(2-butyn-1-yloxy)-1,7-
naphthyridin-8-amine 227 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 515.2
EX 44 0.00659 >44.4 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
2-(trifluoromethyl)pyrido[3,4- b]pyrazin-5-amine 228
N-(3-((3R)-5-amino-2-fluoro-3,6,6- 481.1 EX 44 0.00328 58.9
trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
7-chloropyrido[3,2-d]pyrimidin-4- amine 229
4-((3-((3R)-5-amino-2-fluoro-3,6,6- 472.1 EX 44 0.00101 80.7
trimethyl-1,1-dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-4-
fluorophenyl)amino)pyrido[3,2- d]pyrimidine-7-carbonitrile 230
N-(5-((7R)-9-amino-7-methyl-5,5- 474.9 as in 0.00376 0.0188 23.2
dioxido-5-thia-8-azaspiro[3.5]non-8- example
en-7-yl)-6-fluoro-3-pyridinyl)-3- 44
chloro-1,7-naphthyridin-8-amine 231
N-(5-((7R)-9-amino-7-methyl-5,5- 471.9 as in 0.00641 0.0181 163
dioxido-5-thia-8-azaspiro[3.5]non-8- example
en-7-yl)-6-fluoro-3-pyridinyl)-2- 44 methoxypyrido[3,4-b]pyrazin-5-
amine 116 N-(3-((7R)-9-amino-7-methyl-5,5- 474 Ex 44 0.00115 0.0263
38.8 dioxido-5-thia-8-azaspiro[3.5]non-8-
en-7-yl)-4-fluorophenyl)-3-chloro- 1,7-naphthyridin-8-amine 128
N-(3-((7R)-9-amino-2,2-difluoro-7- 507 Ex 44 0.0259 0.199 330
methyl-5,5-dioxido-5-thia-8- azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 129
4-((3-((7R)-9-amino-2,2-difluoro-7- 502 Ex 44
methyl-5,5-dioxido-5-thia-8- azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)amino)pyrido[3,2- d]pyrimidine-7-carbonitrile 232
N-(3-((7R)-9-amino-6-fluoro-7- 489 Ex 44 0.0131 0.0784 303
methyl-5,5-dioxido-5-thia-8- azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 233
N-(3-((3S)-5-amino-3- 497.9 Example 0.00031 0.0845 143
(fluoromethyl)-6,6-dimethyl-1,1- 44 Step 1
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-chloro-5- fluoro-1,7-naphthyridin-8-amine
234 N-(3-((3S)-5-amino-3- 514.8 Example 0.00203 0.105 >14.8
(fluoromethyl)-6,6-dimethyl-1,1- 44 Step 1
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-2-
(trifluoromethyl)pyrido[3,4- b]pyrazin-5-amine 235
N-(3-((3S)-5-amino-3- 480.9 Example 0.00326 0.0308 68.2
(fluoromethyl)-6,6-dimethyl-1,1- 44 Step 1
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-7-
chloropyrido[3,2-d]pyrimidin-4- amine 236 4-((3-((3S)-5-amino-3-
472 Example 0.00073 0.0407 56.1 (fluoromethyl)-6,6-dimethyl-1,1- 44
Step 1 dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-
fluorophenyl)amino)pyrido[3,2- d]pyrimidine-7-carbonitrile 237
N-(3-((3S)-5-amino-3- 491 Example 0.00285 0.0409 661
(fluoromethyl)-6,6-dimethyl-1,1- 44 Step 1
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-2-
ethoxypyrido[3,4-b]pyrazin-5-amine 238 N-(3-((7S)-9-amino-7- 503
Example 0.00399 0.117 >400.0
(fluoromethyl)-5,5-dioxido-5-thia-8- 44 Step 1
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-2-ethoxypyrido[3,4-
b]pyrazin-5-amine 239 N-(3-((7S)-9-amino-7- 488 Example 0.00415
0.0237 390 (fluoromethyl)-5,5-dioxido-5-thia-8- 44 Step 1
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-3-methoxy-1,7-
naphthyridin-8-amine 240 N-(3-((7S)-9-amino-7- 493 Example 0.0017
0.0272 57.1 (fluoromethyl)-5,5-dioxido-5-thia-8- 44 Step 1
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-7-chloropyrido[3,2-
d]pyrimidin-4-amine 241 8-((3-((7S)-9-amino-7- 500.9 Example 0.0009
0.0479 >4.94 (fluoromethyl)-5,5-dioxido-5-thia-8- 44 Step 1
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)amino)-5-fluoro-1,7-
naphthyridine-3-carbonitrile 242 N-(3-((7S)-9-amino-7- 489 Example
0.00147 0.014 119 (fluoromethyl)-5,5-dioxido-5-thia-8- 44 Step 1
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-7-methoxypyrido[3,2-
d]pyrimidin-4-amine 243 N-(3-((7R)-9-amino-7- 492 Made by 0.00131
0.0779 363 (fluoromethyl)-5,5-dioxido-5-thia-8- method
azaspiro[3.5]non-8-en-7-yl)-4- of fluorophenyl)-3-chloro-1,7-
example naphthyridin-8-amine, N-(3-((7S)-9- 44 step1
amino-7-(fluoromethyl)-5,5-dioxido-
5-thia-8-azaspiro[3.5]non-8-en-7- yl)-4-fluorophenyl)-3-chloro-1,7-
naphthyridin-8-amine 244 N-(3-((7R)-9-amino-7- 492 Made by 3.53 528
(fluoromethyl)-5,5-dioxido-5-thia-8- method
azaspiro[3.5]non-8-en-7-yl)-4- of fluorophenyl)-3-chloro-1,7-
example naphthyridin-8-amine 44 step1 245 N-(3-((7S)-9-amino-7- 492
Made by 0.00056 0.0465 290 (fluoromethyl)-5,5-dioxido-5-thia-8-
method azaspiro[3.5]non-8-en-7-yl)-4- of
fluorophenyl)-3-chloro-1,7- example naphthyridin-8-amine 44 step1
246 N-(3-((7S)-9-amino-7- 489 Made by 0.00146 0.0216 811
(fluoromethyl)-5,5-dioxido-5-thia-8- method
azaspiro[3.5]non-8-en-7-yl)-4- of
fluorophenyl)-2-methoxypyrido[3,4- example b]pyrazin-5-amine 44
step1 247 N-(3-((4aR,7aR)-3-amino-2,2- 487 Example 0.704 2.8 477
dimethyl-1,1-dioxido-7,7a-dihydro- 44, step 1
2H-furo[3,4-b][1,4]thiazin-4a(5H)- yl)-4-fluorophenyl)-2-
methoxypyrido[3,4-b]pyrazin-5- amine 248
N-(3-((4aS,7aS)-3-amino-2,2- 487 Example 0.00304 0.0209 199
dimethyl-1,1-dioxido-7,7a-dihydro- 44, step 1
2H-furo[3,4-b][1,4]thiazin-4a(5H)- yl)-4-fluorophenyl)-2-
methoxypyrido[3,4-b]pyrazin-5- amine 249
5-((3-((4aS,7aS)-3-amino-2,2- 473 Example 0.00636 0.153 102
dimethyl-1,1-dioxido-7,7a-dihydro- 44, step 1
2H-furo[3,4-b][1,4]thiazin-4a(5H)-
yl)-4-fluorophenyl)amino)pyrido[3,4- b]pyrazin-2(1H)-one 250
N-(3-((8R)-6-amino-5,5,8-trimethyl- 485 Example 0.0212 0.059 113
4,4-dioxido-4-thia-7- 44 azaspiro[2.5]oct-6-en-8-yl)-4-
fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 117
8-((3-((7R)-9-amino-7-methyl-5,5- 465 Ex 76 0.00189 0.0051 28.3
dioxido-5-thia-8-azaspiro[3.5]non-8-
en-7-yl)-4-fluorophenyl)amino)-1,7- naphthyridine-3-carbonitrile
251 8-((3-((7R)-9-amino-6-fluoro-7- 483 Ex 76 0.00058 0.0135 42.8
methyl-5,5-dioxido-5-thia-8- azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)amino)-1,7- naphthyridine-3-carbonitrile 252
(5R)-5-(2-fluoro-5-((4- 437.1 79 1.21 1.9 35.9
methoxybenzyl)sulfanyl)phenyl)- 2,2,5-trimethyl-5,6-dihydro-2H-1,4-
thiazin-3-amine 1,1-dioxide 112 (2R,4r,7R)-9-amino-7-(5-bromo-2-
391 by 1.19 37.3 fluorophenyl)-7-methyl-5-thia-8- method
azaspiro[3.5]non-8-en-2-ol 5,5- of dioxide,
(2S,4s,7R)-9-amino-7-(5- example bromo-2-fluorophenyl)-7-methyl-5-
83 thia-8-azaspiro[3.5]non-8-en-2-ol 5,5-dioxide 113
(7R)-7-(5-bromo-2-fluorophenyl)-7- 375 by 4.05 30
methyl-5-thia-8-azaspiro[3.5]non-8- method en-9-amine 5,5-dioxide
of example 83 118 (2S,4s,7R)-7-(5-bromo-2- 393 by 4.09 >15.6
31.1 fluorophenyl)-2-fluoro-7-methyl-5- method
thia-8-azaspiro[3.5]non-8-en-9- of amine 5,5-dioxide example 83 119
(7R)-7-(5-bromo-2-fluorophenyl)- 411 by
2,2-difluoro-7-methyl-5-thia-8- method
azaspiro[3.5]non-8-en-9-amine 5,5- of dioxide example 83 253
(5R)-5-(2-fluoro-5-((2- 498 106 0.0276 1.03 1410
(trifluoromethyl)pyrido[3,4- b]pyrazin-5-yl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 254
N-(3-((3R)-5-amino-3,6,6-trimethyl- 496.1 106 0.0006 0.0006 354
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-(2-
butyn-1-yloxy)-1,7-naphthyridin-8- amine 255
(5R)-5-(2-fluoro-5-((4-(4- 522 106 0.663 3.99 50.5
(trifluoromethyl)phenyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 256
(5R)-5-(2-fluoro-5-((3-fluoro-5-(3- 477 106 0.65 1.82 195
methyl-5-isoxazolyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 257
(5R)-5-(5-((5-(2,2-dimethylpropyl)-2- 448 106 18.9 7.79 187
pyridinyl)oxy)-2-fluorophenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 258
(5R)-5-(5-((3-chloro-2- 412 106 0.0969 0.121 207
pyridinyl)oxy)-2-fluorophenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 259
(5R)-5-(2-fluoro-5-((4- 446 106 0.153 0.248 1050
(trifluoromethyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 260
N-(3-((3R)-5-amino-3,6,6-trimethyl- 498.2 106 0.0038 0.0075 250
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
(cyclopropylmethoxy)-1,7- naphthyridin-8-amine 261
(5R)-5-(2-fluoro-5-(2- 428.1 106 0.3 0.574 58.3
quinolinyloxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 262 (5R)-5-(5-((3,5-difluoro-4- 482 106 15.5
>15.6 68.1 (trifluoromethyl)-2-pyridinyl)oxy)-2-
fluorophenyl)-2,2,5-trimethyl-5,6- dihydro-2H-1,4-thiazin-3-amine
1,1- dioxide 263 (5R)-5-(2-fluoro-5-((3-methyl-2- 392 106 0.65
0.624 555 pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 264
(5R)-5-(2-fluoro-5-((4-methyl-2- 392 106 0.18 0.126 878
pyridinyl)oxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 265 (5R)-5-(2-fluoro-5-((5-methyl-2- 392 106
2.26 0.804 373 pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 266
(5R)-5-(2-fluoro-5-((6-methyl-2- 392 106 0.413 0.427 407
pyridinyl)oxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 267 (5R)-5-(5-((3-chloro-5- 480.1 106 0.603
0.874 221 (trifluoromethyl)-2-pyridinyl)oxy)-2-
fluorophenyl)-2,2,5-trimethyl-5,6- dihydro-2H-1,4-thiazin-3-amine
1,1- dioxide 268 6-(3-((3R)-5-amino-3,6,6-trimethyl- 409 106 0.318
0.305 920 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenoxy)-2,4- pyrimidinediamine 269
(5R)-5-(2-fluoro-5-((6- 446 106 0.248 0.574 132
(trifluoromethyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 270
(5R)-5-(2-fluoro-5-(2- 379 106 0.0935 0.0511 222
pyrazinyloxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 271 6-(3-((3R)-5-amino-3,6,6-trimethyl- 417 106
0.549 0.474 540 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenoxy)-5- methyl-3-pyridinecarbonitrile 272
6-(3-((3R)-5-amino-3,6,6-trimethyl- 417 106 2.69 2.02 217
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-2-
methyl-3-pyridinecarbonitrile 273 (5R)-5-(5-((3-amino-2- 393 106
1.5 1.01 >400.0 pyridinyl)oxy)-2-fluorophenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 274
(5R)-5-(2-fluoro-5-((3-fluoro-2- 396 106 0.0374 0.0348 153
pyridinyl)oxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 275 (5R)-5-(2-fluoro-5-((5-fluoro-2- 396 106
0.84 0.424 364 pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 276
(5R)-5-(5-((5-chloro-4-methyl-2- 426 106 2.71 2.63 421
pyridinyl)oxy)-2-fluorophenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 277
(5R)-5-(2-fluoro-5-((3-fluoro-5- 464 106 1.21 1.15 331
(trifluoromethyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 278
(5R)-5-(2-fluoro-5-((3- 446 106 0.341 0.359 147
(trifluoromethyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 279
(5R)-5-(2-fluoro-5-((5- 446 106 5.6 2.09 188 (trifluoromethyl)-2-
pyridinyl)oxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 280 2-(3-((3R)-5-amino-3,6,6-trimethyl- 403 106
0.039 0.0521 395 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenoxy)-4- pyridinecarbonitrile 281
(5R)-5-(5-((5-chloro-2,4'-bipyridin- 489 106 0.807 1.12 61.2
2'-yl)oxy)-2-fluorophenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 282
6-(3-((3R)-5-amino-3,6,6-trimethyl- 403 106 1.56 1.15 227
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-3-
pyridinecarbonitrile 283 6-(3-((3R)-5-amino-3,6,6-trimethyl- 403
106 0.0919 0.0828 12.9 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenoxy)-2- pyridinecarbonitrile 284
(5R)-5-(2-fluoro-5-((5-fluoro-6- 464 106 0.769 1.64 79.1
(trifluoromethyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 285
(5R)-5-(5-((4-bromo-2- 456, 106 0.0375 0.0918 374
pyridinyl)oxy)-2-fluorophenyl)-2,2,5- 458.1
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 286
(5R)-5-(2-fluoro-5-((4-(1-propyn-1- 416.1 106 0.228 0.787 119
yl)-2-pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 287
(5R)-5-(2-fluoro-5-((4-methoxy-2- 408.1 106 0.1 204
pyridinyl)oxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 288 (5R)-5-(2-fluoro-5-(2- 379.1 106 0.125 222
pyrimidinyloxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 289 (5R)-5-(2-fluoro-5-((4-phenyl-2- 454 106
0.0509 0.568 92.7 pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 290
(5R)-5-(5-(4,4'-bipyridin-2-yloxy)-2- 455 106 0.328 0.318 826
fluorophenyl)-2,2,5-trimethyl-5,6- dihydro-2H-1,4-thiazin-3-amine
1,1- dioxide 291 (5R)-5-(2-fluoro-5-(thieno[2,3- 434 106 0.517
0.914 242 c]pyridin-7-yloxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 292
4-(3-((3R)-5-amino-3,6,6-trimethyl- 477 106 2.01 2.23 219
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenoxy)thieno[3,2-c]pyridine- 7-carboxamide 293
2-(3-((3R)-5-amino-3,6,6-trimethyl- 479 106 0.836 0.68 50.9
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-4-
phenyl-3-pyridinecarbonitrile 294 (5R)-5-(2-fluoro-5-(1- 428 106
1.05 1.14 202 isoquinolinyloxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 295
2-(3-((3R)-5-amino-3,6,6-trimethyl- 431 106 2.64 2.48 1690
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-4,6-
dimethyl-3-pyridinecarbonitrile 296
2-(3-((3R)-5-amino-3,6,6-trimethyl- 417 106 0.263 0.515 232
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-6-
methyl-3-pyridinecarbonitrile 297 (5R)-5-(2-fluoro-5-((3-methoxy-2-
408 106 0.202 0.219 975 pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 298
(5R)-5-(2-fluoro-5-((6-methyl-4- 460 106 0.106 0.737 547
(trifluoromethyl)-2- pyridinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 299
(5R)-5-(5-((3,5-dichloro-2- 447 106 0.174 0.796 82.4
pyridinyl)oxy)-2-fluorophenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 300
6-(3-((3R)-5-amino-3,6,6-trimethyl 439 106 0.897 1.18 717
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-5-
fluoro-3-pyridinecarboxamide 301 (5R)-5-(5-(benzyloxy)-2- 391.2 106
1.06 184 fluorophenyl)-2,2,5-trimethyl-5,6-
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 302
(5R)-5-(2-fluoro-5-((2- 449 106 3.49 2.87 241
methyl[1,3]thiazolo[4,5-c]pyridin-4-
yl)oxy)phenyl)-2,2,5-trimethyl-5,6- dihydro-2H-1,4-thiazin-3-amine
1,1- dioxide 303 (5R)-5-(2-fluoro-5-((2- 460.2 106 1.22 2.54 1000
methoxypyrido[3,4-b]pyrazin-5- yl)oxy)phenyl)-2,2,5-trimethyl-5,6-
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 304
(5R)-5-(5-((3-chloro-1,7- 463 106 0.127 0.198 282
naphthyridin-8-yl)oxy)-2- fluorophenyl)-2,2,5-trimethyl-5,6-
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 305
(5R)-5-(2-fluoro-5-((3-methoxy-1,7- 459 106 2.07 680
naphthyridin-8-yl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 306
2-(3-((3R)-5-amino-3,6,6-trimethyl- 403.1 106 0.256 0.241 218
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-3-
pyridinecarbonitrile 307 2-(3-((3R)-5-amino-3,6,6-trimethyl- 437.1
106 0.168 0.258 298 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenoxy)-3- chloro-4-pyridinecarbonitrile 308
3-(3-((3R)-5-amino-3,6,6-trimethyl- 437 106 4.16 3.27 224
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-2-
chloro-4-pyridinecarbonitrile 309 (5R)-5-(2-fluoro-5-((4-methoxy-2-
409.1 106 0.101 0.0751 274 pyrimidinyl)oxy)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 310
2-(3-((3R)-5-amino-3,6,6-trimethyl- 417.2 106 1.34 0.931 444
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenoxy)-4-
methyl-3-pyridinecarbonitrile 311 (5R)-5-(2-fluoro-5-((3-methyl-4-
460.1 106 2.57 2.39 401 (trifluoromethyl)-2-
pyridinyl)oxy)phenyl)-2,2,5- trimethyl-5,6-dihydro-2H-1,4-thiazin-
3-amine 1,1-dioxide 312 2-(3-((3R)-5-amino-3,6,6-trimethyl- 471.1
106 2.89) 1.59 771 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenoxy)-4- (trifluoromethyl)-3-
pyridinecarbonitrile 313 N-(3-((3R)-5-amino-3,6,6-trimethyl- 456
Made by 0.00292 0.0063 887 1,1-dioxido-3,6-dihydro-2H-1,4- method
thiazin-3-yl)-4-fluorophenyl)-5- C of (difluoromethyl)-2- example
pyrazinecarboxamide 94 314 N-(3-((3R)-5-amino-3,6,6-trimethyl- 486
Amidation 0.00058 0.005 504 1,1-dioxido-3,6-dihydro-2H-1,4- method
A
thiazin-3-yl)-4-fluorophenyl)-5-(2,2- difluoroethoxy)-2-
pyrazinecarboxamide 315 N-(3-((3R)-5-amino-3,6,6-trimethyl- 455
Mthod A 0.0376 0.0253 253 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-2- quinolinecarboxamide 316
N-(3-((3R)-5-amino-3,6,6-trimethyl- 456 Mthod A 0.0412 0.018 36.6
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-2-
quinoxalinecarboxamide 317 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 478
Method A 0.00021 0.0036 >133.0 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(2-butyn-1-yloxy)-2-
pyrazinecarboxamide 318 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 439
Method A 0.0018 0.0688 >400.0 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyridinecarboxamide 319
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 459 Method A 0.00162 0.07
>400.0 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(difluoromethyl)-2-
pyridinecarboxamide 320 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 461
Method A 0.0008 0.0789 >400.0 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-chloro-3-fluoro-2-
pyridinecarboxamide 321 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 489
Method A 0.00072 0.0449 387 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-(difluoromethoxy)-3-methyl-2- pyridinecarboxamide 322
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 427 Method A 0.00195 0.134 1220
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-fluoro-2-pyridinecarboxamide 323
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 478 Method A 0.00386 0.288 931
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(trifluoromethyl)-2-
pyrazinecarboxamide 324 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 448
Method A 0.00102 0.0651 1370 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-cyano-3-methyl-2-
pyridinecarboxamide 325 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 508
Method A 0.00042 0.0445 1260 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(2,2,2-trifluoroethoxy)-2-
pyrazinecarboxamide 326 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 493
Method A 0.00277 0.0597 979 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
3-chloro-5-(difluoromethyl)-2- pyridinecarboxamide 327
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 468 Method A 0.00074 0.0204
>400.0 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-chloro-5-cyano-2-
pyridinecarboxamide 328 N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 487
Method A 0.00051 0.0928 598 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-chloro-3-(methoxymethyl)-2-
pyridinecarboxamide 329 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 475.1 A
0.00047 0.0058 >400.0 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-chloro-3-fluoro-2-
pyridinecarboxamide 330 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 503.1 A
0.00075 0.0041 136 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-(difluoromethoxy)-3-methyl-2- pyridinecarboxamide 331
N-(3-((3R)-5-amino-2-fluoro-3,6,6- 471 A .0003 0.0048 188
trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-chloro-3-methyl-2-
pyridinecarboxamide 332 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 492 A
0.00023 0.001 44.9 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(2-butyn-1-yloxy)-2-
pyrazinecarboxamide 333 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 522 A
0.0015 0.016 190 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(2,2,2-trifluoroethoxy)-2-
pyrazinecarboxamide 334 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 473 A
.0024 0.0055 307 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-(difluoromethyl)-2-
pyridinecarboxamide 335 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 501 A
0.00056 0.0068 311 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-chloro-3-(methoxymethyl)-2-
pyridinecarboxamide 336 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 487 A
0.0014 0.0053 533 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 3-chloro-5-methoxy-2-
pyridinecarboxamide 337 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 467
Method A 0.00313 0.0097 233 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- 5-methoxy-3-methyl-2-
pyridinecarboxamide 338 N-(3-((2S,4s,7R)-9-amino-2-fluoro- 499
Method A 0.00294 0.0108 59 7-methyl-5,5-dioxido-5-thia-8-
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethyl)-3-
methyl-2-pyridinecarboxamide 339 N-(3-((3R,6R)-5-amino-6-fluoro-
457 Method A 0.0181 0.196 109 2,3,6-trimethyl-1,1-dioxido-3,6-
dihydro-2H-1,4-thiazin-3-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 340 N-(3-((8R)-6-amino-5,5,8-trimethyl- 479
Method A 0.0051 0.0044 20 4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-6-en-8-yl)-4- fluorophenyl)-5-chloro-3-methyl-2-
pyridinecarboxamide 341 N-(3-((8R)-6-amino-5,5,8-trimethyl- 511.2
Method A 0.00599 0.0024 9.4 4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-6-en-8-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 143
N-(4-((3R)-5-amino-3,6,6-trimethyl- 437.1 AA 0.115 0.462 221
1,1-dioxido-3,6-dihydro-2H-1,4- Example 2
thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-
methoxy-2-pyrazinecarboxamide 145 (5R)-5-(2-(((6-chloro-3- 478.9 AA
0.44 0.412 102 methylimidazo[1,2-a]pyridin-2- Example 4
yl)methyl)amino)-5-fluoro-4- pyridinyl)-2,2,5-trimethyl-5,6-
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 194
N-(3-((3R)-5-amino-3,6,6-trimethyl- 419 AM 01 0.00518 0.00342 617
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
chloro-3-(1-methylethenyl)-2- pyridinecarboxamide 195
N-(3-((3R)-5-amino-3,6,6-trimethyl- 465 AM 02 0.00059 0.0039 108
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
chloro-3-ethenyl-2- pyridinecarboxamide 196
N-(3-((3R)-5-amino-3,6,6-trimethyl- 467 AM 03 0.00181 0.0054 200
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
chloro-3-ethyl-2- pyridinecarboxamide 197 N-(3-((3S)-5-amino-3- 485
AM 04 0.00146 0.208 416 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3- ethyl-2-pyridinecarboxamide 198
N-(3-((3S)-5-amino-3- 499.1 AM 05 0.00799 0.0914 850
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3-(1-
methylethyl)-2-pyridinecarboxamide 342
N-(3-((3R)-5-amino-3,6,6-trimethyl- 473 Method B 0.00061 0.0007 113
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
(trifluoromethyl)-2- pyridinecarboxamide 343
N-(3-((3R)-5-amino-3,6,6-trimethyl- 455 Method B 0.00511 0.0107 234
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
isoquinolinecarboxamide 344 N-(3-((3R)-5-amino-3,6,6-trimethyl- 472
Method B 0.00053 0.0004 388 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5- (difluoromethoxy)-2-
pyrazinecarboxamide 345 N-(3-((3R)-5-amino-3,6,6-trimethyl- 468
Method B 0.0313 0.0713 75.6 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-4- chloro-2-methoxybenzamide 346
N-(3-((3R)-5-amino-3,6,6-trimethyl- 503.9 B 0.00045 0.0014
>400.0 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5- (2,2,2-trifluoroethoxy)-2-
pyrazinecarboxamide 347 N-(5-((3R)-5-amino-3,6,6-trimethyl- 453.9 B
0.0011 0.0018 71 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- chloro-3-methyl-2-
pyridinecarboxamide 348 N-(5-((3R)-5-amino-3,6,6-trimethyl- 489.9 B
0.00589 0.00992 490 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-3- chloro-5-(difluoromethyl)-2-
pyridinecarboxamide 349 N-(5-((7R)-9-amino-7-methyl-5,5- 499.9 B
0.00078 0.0013 196 dioxido-5-thia-8-azaspiro[3.5]non-8-
en-7-yl)-6-fluoro-3-pyridinyl)-5-(2- butyn-1-yloxy)-3-methyl-2-
pyridinecarboxamide 350 N-(5-((7R)-9-amino-7-methyl-5,5- 529.9 B
0.00606 0.0345 >400.0 dioxido-5-thia-8-azaspiro[3.5]non-8-
en-7-yl)-6-fluoro-3-pyridinyl)-3-
methyl-5-(2,2,2-trifluoroethoxy)-2- pyridinecarboxamide 351
N-(3-((3R)-5-amino-3,6,6-trimethyl- 483 B 0.00052 0.0027 >14.8
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
chloro-3-(methoxymethyl)-2- pyridinecarboxamide 352
N-(3-((3R)-5-amino-3,6,6-trimethyl- 518.9 B 0.0008 0.0009 410
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
bromo-5-chloro-2- pyridinecarboxamide 353
N-(3-((3R)-5-amino-3,6,6-trimethyl- 452.0 Method B 0.00652 0.0166
708 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-4- chloro-2-methylbenzamide 354
N-(3-((3R)-5-amino-3,6,6-trimethyl- 452.0 Method B 0.0424 0.0187
1330 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-2- fluoro-4-methoxybenzamide 355
N-(3-((3R)-5-amino-3,6,6-trimethyl- 444 Method B 0.0003 0.0005 283
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-5-
cyano-3-methyl-2- pyridinecarboxamide 356
N-(3-((3R)-5-amino-3,6,6-trimethyl- 464.1 Method B 0.00035 0.0012
710 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-3- chloro-5-cyano-2-
pyridinecarboxamide 357 N-(3-((3R)-5-amino-3,6,6-trimethyl- 449.1
Method B 0.00283 0.0025 228 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-5- methoxy-3-methyl-2-
pyridinecarboxamide 358 N-(5-((7R)-9-amino-7-methyl-5,5- 497.9 B
0.00642 0.0095 139
dioxido-5-thia-8-azaspiro[3.5]non-8-
en-7-yl)-6-fluoro-3-pyridinyl)-5- (difluoromethoxy)-3-methyl-2-
pyridinecarboxamide 359 N-(5-((7R)-9-amino-7-methyl-5,5- 465.9 B
0.0022 .00521 105 dioxido-5-thia-8-azaspiro[3.5]non-8-
en-7-yl)-6-fluoro-3-pyridinyl)-5- chloro-3-methyl-2-
pyridinecarboxamide 360 N-(3-((3S)-5-amino-3- 451.1 Method B
0.00299 0.0245 636 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3,5-dimethyl-2- pyridinecarboxamide 361
N-(3-((3S)-5-amino-3- 473 Method B 0.0008 0.0193 437
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-
(difluoromethyl)-2- pyridinecarboxamide 362 N-(3-((3S)-5-amino-3-
489 Method B 0.0003 0.0035 303 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-
(difluoromethoxy)-2- pyridinecarboxamide 363 N-(3-((3S)-5-amino-3-
440.9 B 0.0017 0.0456 >400.0 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-fluoro-2- pyridinecarboxamide 364
N-(3-((3S)-5-amino-3- 504 Amidation 0.0005 0.0214 858
(fluoromethyl)-6,6-dimethyl-1,1- method B
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-(2,2-
difluoroethoxy)-2- pyrazinecarboxamide 365 N-(3-((3S)-5-amino-3-
486 Amidation 0.00097 0.0447 >400.0
(fluoromethyl)-6,6-dimethyl-1,1- method B
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-(2-
fluoroethoxy)-2- pyrazinecarboxamide 366 N-(3-((7S)-9-amino-7- 483
Amidation 0.00079 0.0141 241 (fluoromethyl)-5,5-dioxido-5-thia-8-
method B azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 367
N-(3-((7S)-9-amino-7- 522 Amidation 0.00507 0.0137 >400.0
(fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-6-chloro-3-
methylimidazo[1,2-a]pyridine-2- carboxamide 368
N-(3-((7S)-9-amino-7- 474 Amidation 0.00064 0.0046 222
(fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-cyano-3-methyl-2-
pyridinecarboxamide 369 N-(3-((7S)-9-amino-7- 499 Amidation 0.0014
.0123) 233 (fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethyl)-3-
methyl-2-pyridinecarboxamide 370 N-(3-((7S)-9-amino-7- 512.9
Amidation 0.00081 0.0273 >400.0
(fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-3-
(methoxymethyl)-2- pyridinecarboxamide 371 N-(3-((7S)-9-amino-7-
519 Amidation 0.00156 0.077 391
(fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-
(cyclopropylmethoxy)-3-methyl-2- pyridinecarboxamide 372
N-(3-((7S)-9-amino-7- 493.9 Amidation 0.00072 0.0071 367
(fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-3-chloro-5-cyano-2-
pyridinecarboxamide 373 N-(3-((7S)-9-amino-7- 479.1 Amidation
0.00245 0.0148 197 (fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-methoxy-3-methyl-
2-pyridinecarboxamide 374 N-(3-((7S)-9-amino-7- 547 Amidation
0.0011 0.0616 630 (fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-3-methyl-5-(2,2,2-
trifluoroethoxy)-2- pyridinecarboxamide 375 N-(3-((7S)-9-amino-7-
499 Amidation 0.0029 0.0298 781
(fluoromethyl)-5,5-dioxido-5-thia-8- method B
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-3-methoxy-2-
pyridinecarboxamide 376 N-(3-((3S)-5-amino-3- 474 Made 0.00223
0.0615 172 (fluoromethyl)-6,6-dimethyl-1,1- by method
dioxido-3,6-dihydro-2H-1,4-thiazin- C of 3-yl)-4-fluorophenyl)-5-
example 5 (difluoromethyl)-2- pyrazinecarboxamide 377
N-(3-((3S)-5-amino-3- 467 Made by 0.003 0.0098 335
(fluoromethyl)-6,6-dimethyl-1,1- method
dioxido-3,6-dihydro-2H-1,4-thiazin- C of
3-yl)-4-fluorophenyl)-5-methoxy-3- example 5
methyl-2-pyridinecarboxamide 378 N-(3-((3S)-5-amino-3- 459 (M + H)
C 0.0016 0.018 >400.0 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3,5-difluoro-2- pyridinecarboxamide 379
N-(3-((3S)-5-amino-3- 525 (M + H) C 0.00099 0.0115 775
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-chloro-5- (trifluoromethyl)-2-
pyridinecarboxamide 380 N-(3-((3S)-5-amino-3- 492 (M + H) C 0.0018
0.999 282 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3,5-dichloro-2- pyrazinecarboxamide 381
N-(3-((3S)-5-amino-3- 483 C 0.00086 0.0539 194
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3- ethenyl-2-pyridinecarboxamide 382
N-(3-((3S)-5-amino-3- 487 C 0.0018 0.0173 >400.0
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3- methoxy-2-pyridinecarboxamide 383
N-(3-((3S)-5-amino-3- 491 Method C 0.00262 0.02 217
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-
(trifluoromethyl)-2- pyridinecarboxamide 204
N-(3-((5S,6R)-8-amino-5-fluoro-6- 469 0.00087 0.0027 182
methyl-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 205
N-(3-((5R,6R)-8-amino-5-fluoro-6- 469 0.00044 0.0026 28
methyl-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 384
4-((5-((3R)-5-amino-3,6,6-trimethyl- 454.9 cyanation 0.00636 0.0239
47.3 1,1-dioxido-3,6-dihydro-2H-1,4- procedure
thiazin-3-yl)-6-fluoro-3- pyridinyl)amino)pyrido[3,2-
d]pyrimidine-7-carbonitrile 385
8-((5-((3R)-5-amino-3,6,6-trimethyl- 454 cyanation 0.00262 0.0037
67.6 1,1-dioxido-3,6-dihydro-2H-1,4- procedure
thiazin-3-yl)-6-fluoro-3- pyridinyl)amino)-1,7-naphthyridine-
3-carbonitrile 386 8-((5-((7R)-9-amino-7-methyl-5,5- 465.9
cyanation 0.00409 0.0141 54.7 dioxido-5-thia-8-azaspiro[3.5]non-8-
procedure en-7-yl)-6-fluoro-3-pyridinyl)amino)-
1,7-naphthyridine-3-carbonitrile 387 8-((3-((3S)-5-amino-3- 471.0
General 0.00044 0.0053 117 (fluoromethyl)-6,6-dimethyl-1,1-
cyanation dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)amino)-1,7- naphthyridine-3-carbonitrile 142
N-(4-((3S)-5-amino-3,6,6-trimethyl- 437.1 CuI 10 4.36 >400.0
1,1-dioxido-3,6-dihydro-2H-1,4- Amidation
thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-
methoxy-2-pyrazinecarboxamide 144
N-(3-((3R)-5-amino-3,6,6-trimethyl- 485.1 CuI 0.0006 0.0016 96.7
1,1-dioxido-3,6-dihydro-2H-1,4- Amidation
thiazin-3-yl)-4-fluorophenyl)-5- (difluoromethoxy)-3-methyl-2-
pyridinecarboxamide 120 N-(3-((7R)-9-amino-2,2-difluoro-7- 487 CuI
0.0013 0.0272 148 methyl-5,5-dioxido-5-thia-8- Amidation
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 125 N-(3-((2S,4s,7R)-9-amino-2-fluoro- 469 CuI
0.001 0.0107 42.8 7-methyl-5,5-dioxido-5-thia-8- Amidation
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 124 N-(3-((7R)-9-amino-2,2-difluoro-7- 501 CuI
<0.002 0.0246 96.3 methyl-5,5-dioxido-5-thia-8- Amidation
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-3-methyl-2-
pyridinecarboxamide 126 N-(3-((7R)-9-amino-2,2-difluoro-7- 533 CuI
0.00376 0.0177 45.6 methyl-5,5-dioxido-5-thia-8- Amidation
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 127 N-(3-((7R)-9-amino-7-methyl-5,5-
465 CuI 0.0016 0.0070 84.7 dioxido-5-thia-8-azaspiro[3.5]non-8-
Amidation en-7-yl)-4-fluorophenyl)-5-chloro-3-
methyl-2-pyridinecarboxamide 148 N-(3-((3S)-5-amino-3- 503.9 CuI
0.00163 0.0091 213 (fluoromethyl)-6,6-dimethyl-1,1- Amidation
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-
(difluoromethoxy)-3-methyl-2- pyridinecarboxamide 151
N-(3-((3S)-5-amino-3- 521 CuI 0.0017 0.1 232
(fluoromethyl)-6,6-dimethyl-1,1- Amidation
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-
(cyclobutylmethoxy)-3-methyl-2- pyridinecarboxamide 388
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 457.1 General 0.0004 0.0479 230
dimethyl-1,1-dioxido-3,6-dihydro- amidation
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- method D 5-chloro-3-methyl-2-
pyridinecarboxamide 389 N-(3-((3S)-5-amino-3- 509 Method 0.00026
0.0014 268 (fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-5-((4-fluoro-2- BY butyn-1-yl)oxy)-2- 001
pyridinecarboxamide 390 N-(3-((3S)-5-amino-3- 501 Method 0.00485
0.0236 379 (fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-6-cyano-3- BY methylimidazo[1,2-a]pyridine-2-
005 carboxamide 391 N-(3-((3S)-5-amino-3- 496 Method 0.00969 0.0361
303 (fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-6- BY chloroimidazo[1,2-a]pyridine-2- 006
carboxamide 392 N-(3-((3S)-5-amino-3- 506 Method 0.104 0.823 97.6
(fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-6-methoxy-3- BY
methylimidazo[1,2-a]pyridine-2- 007 carboxamide 393
N-(3-((3S)-5-amino-3- 494 Method 0.0117 0.0605 103
(fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-6-fluoro-3- BY
methylimidazo[1,2-a]pyridine-2- 002 carboxamide
394 N-(3-((3S)-5-amino-3- 524 Method 0.0083 0.0235 >14.8,
(fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-6-chloro-3- BY ethylimidazo[1,2-a]pyridine-2-
008 carboxamide 395 N-(3-((3S)-5-amino-3- 538 Method 0.0377 0.125
822 (fluoromethyl)-6,6-dimethyl-1,1- D from
dioxido-3,6-dihydro-2H-1,4-thiazin- intermediate
3-yl)-4-fluorophenyl)-6-chloro-3-(1- BY
methylethyl)imidazo[1,2-a]pyridine- 009 2-carboxamide 396
N-(3-((1R,6R)-4-amino-3,3- 451 Amidation 0.00239 0.862 187
dimethyl-2,2-dioxido-2-thia-5- method D
azabicyclo[4.1.0]hept-4-en-6-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 397
N-(5-((3R)-5-amino-3,6,6-trimethyl- 454.0 E 3.04 3.25 523
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-6-fluoro-2-methyl-3-
pyridinyl)-5-chloro-2- pyridinecarboxamide 398
N-(5-((3R)-5-amino-3,6,6-trimethyl- 439.9 E 0.002 0.0114 183
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- chloro-2-pyridinecarboxamide
399 N-(5-((3R)-5-amino-3,6,6-trimethyl- 423.9 E 0.0031 0.0393 419
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- fluoro-2-pyridinecarboxamide
400 N-(5-((3R)-5-amino-3,6,6-trimethyl- 485.9 E 0.0014 0.0089 156
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-
(difluoromethoxy)-3-methyl-2- pyridinecarboxamide 401
N-(5-((3R)-5-amino-3,6,6-trimethyl- 436 E 0.00398 0.0179 757
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-
methoxy-2-pyridinecarboxamide 402
N-(5-((3R)-5-amino-3,6,6-trimethyl- 504.9 E 0.0011 0.011 2780
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- (2,2,2-trifluoroethoxy)-2-
pyrazinecarboxamide 403 N-(5-((3R)-5-amino-3,6,6-trimethyl- 431 E
0.0019 0.0146 233 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- cyano-2-pyridinecarboxamide
404 N-(5-((3R)-5-amino-3,6,6-trimethyl- 455.9 E 0.011 0.0119 247
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-fluoro-3-pyridinyl)-5- (difluoromethyl)-2-
pyridinecarboxamide 405 N-(3-((3S)-5-amino-3- 521.9 E 0.0006 0.027
576 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-(2,2,2-
trifluoroethoxy)-2- pyrazinecarboxamide 406 N-(3-((3S)-5-amino-3-
448.1 E 0.00054 0.0143 >400.0 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-cyano-2- pyridinecarboxamide 407
N-(3-((3S)-5-amino-3- 497 E 0.00354 0.057 440
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3-(1- methylethenyl)-2-
pyridinecarboxamide 408 N-(3-((3S)-5-amino-3- 471 Method E 0.0004
0.0232 136 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3- methyl-2-pyridinecarboxamide 409
N-(3-((3S)-5-amino-3- 475 Method E 0.0006 0.0037 363
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3- fluoro-2-pyridinecarboxamide 410
N-(3-((7R)-9-amino-7- 515 Amidation 0.0023 0.0119 170
(fluoromethyl)-5,5-dioxido-5-thia-8- method E
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide, N- (3-((7S)-9-amino-7-(fluoromethyl)-
5,5-dioxido-5-thia-8- azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3- methyl-2-pyridinecarboxamide
411 N-(3-((7R)-9-amino-7- 515 Amidation 3.51 >15.6 514
(fluoromethyl)-5,5-dioxido-5-thia-8- mathod E
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 412 N-(3-((7S)-9-amino-7- 515
Amidation 0.00063 0.0082 78.9 (fluoromethyl)-5,5-dioxido-5-thia-8-
method E azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3- methyl-2-pyridinecarboxamide
413 N-(3-((4aR,7aR)-3-amino-2,2- 513 Method E 0.00265 0.0103 111
dimethyl-1,1-dioxido-7,7a-dihydro-
2H-furo[3,4-b][1,4]thiazin-4a(5H)- yl)-4-fluorophenyl)-5-
(difluoromethoxy)-3-methyl-2- pyridinecarboxamide, N-(3-
((4aS,7aS)-3-amino-2,2-dimethyl- 1,1-dioxido-7,7a-dihydro-2H-
furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3- methyl-2-pyridinecarboxamide
414 (5R)-5-(5-((2,2-difluoro-1,3- 456.9 F 3.2 2.53 33.9
benzodioxol-5-yl)amino)-2-fluoro-3- pyridinyl)-2,2,5-trimethyl-5,6-
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 415
(7R)-7-(5-amino-2-fluoro-3- 313 G 14.5 >15.6 104
pyridinyl)-7-methyl-5-thia-8- azaspiro[3.5]non-8-en-9-amine 5,5-
dioxide 106 N-(3-((3R)-5-amino-3,6,6-trimethyl- 478 Hatu 0.00174
112 1,1-dioxido-3,6-dihydro-2H-1,4- Method
thiazin-3-yl)-4-fluorophenyl)-4- chloro-1-(difluoromethyl)-1H-
pyrazole-3-carboxamide 110 N-(3-((3R)-5-amino-3,6,6-trimethyl- 420
Hatu 0.0202 0.0144 1840 1,1-dioxido-3,6-dihydro-2H-1,4- Method
thiazin-3-yl)-4-fluorophenyl)-5- methyl-2-pyrazinecarboxamide 111
N-(3-((3R)-5-amino-3,6,6-trimethyl- 434 Hatu 0.0182 0.0244
>400.0 1,1-dioxido-3,6-dihydro-2H-1,4- Method
thiazin-3-yl)-4-fluorophenyl)-3,5- dimethyl-2-pyrazinecarboxamide
416 N-(3-((7R)-9-amino-7-methyl-5,5- 451 Hatu 0.00236 0.0059 59.5
dioxido-5-thia-8-azaspiro[3.5]non-8- Method
en-7-yl)-4-fluorophenyl)-5-chloro-2- pyridinecarboxamide 121
N-(3-((7R)-9-amino-7-methyl-5,5- 497 Hatu 0.00311 0.0074 67.5
dioxido-5-thia-8-azaspiro[3.5]non-8- Method
en-7-yl)-4-fluorophenyl)-5- (difluoromethoxy)-3-methyl-2-
pyridinecarboxamide 122 N-(3-((7R)-9-amino-7-methyl-5,5- 456 Hatu
0.00076 0.00244 134 dioxido-5-thia-8-azaspiro[3.5]non-8- Method
en-7-yl)-4-fluorophenyl)-5-cyano-3- methyl-2-pyridinecarboxamide
123 N-(3-((7R)-9-amino-7-methyl-5,5- 481 Hatu 0.00457 0.0063 150
dioxido-5-thia-8-azaspiro[3.5]non-8- Method
en-7-yl)-4-fluorophenyl)-5- (difluoromethyl)-3-methyl-2-
pyridinecarboxamide 131 N-(3-((6S,7R)-9-amino-6-fluoro-7- 469 Hatu
0.0016 0.00901 162 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 132 N-(3-((7R)-9-amino-6-fluoro-7- 515 Hatu
0.00297 0.0058 61.8 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 127 N-(3-((7R)-9-amino-6-fluoro-7- 483
Hatu 0.001 0.0136 55.4 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-3-methyl-2-
pyridinecarboxamide 136 N-(3-((7R)-9-amino-6-fluoro-7- 499 Hatu
0.0021 0.0049 236 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethyl)-3-
methyl-2-pyridinecarboxamide 137 N-(3-((7R)-9-amino-6-fluoro-7- 479
Hatu 0.00363 0.0064 81.3 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-methoxy-3-methyl-
2-pyridinecarboxamide 122 N-(3-((7R)-9-amino-6-fluoro-7- 474 Hatu
0.00054 0.0019 194 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-cyano-3-methyl-2-
pyridinecarboxamide 139 N-(3-((7R)-9-amino-6-fluoro-7- 499 Hatu
0.0038 0.0118 408 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-chloro-3-methoxy-2-
pyridinecarboxamide 140 N-(3-((7R)-9-amino-6-fluoro-7- 486 Hatu
0.0088 0.0146 >400.0 methyl-5,5-dioxido-5-thia-8- Method
azaspiro[3.5]non-8-en-7-yl)-4- fluorophenyl)-5-(difluoromethyl)-2-
pyrazinecarboxamide 141 N-(3-((7R)-9-amino-6-fluoro-7- 522 Hatu
methyl-5,5-dioxido-5-thia-8- Method azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-6-chloro-3- methylimidazo[1,2-a]pyridine-2-
carboxamide 417 (7S)-7-(5-amino-2-fluorophenyl)-7- 330 intermeidate
2 2.1 3.65 69.7 (fluoromethyl)-5-thia-8- Step 2-3
azaspiro[3.5]non-8-en-9-amine 5,5- dioxide 167
3-((3-((3R)-5-amino-3,6,6-trimethyl- 492 JBH2 0.0139 1.44 11.8
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)amino)-
2-chlorothieno[3,2-b]pyridine-6- carbonitrile 164
(5R)-5-(5-amino-2-fluorophenyl)-6- 318.2 JBH1 3.72 3.03 190
fluoro-2,2,5-trimethyl-5,6-dihydro- 2H-1,4-thiazin-3-amine
1,1-dioxide 168 N-(3-((3R)-5-amino-2-fluoro-3,6,6- 480.2 JBH3
0.00092 0.0167 66.8 trimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
3-chloro-1,7-naphthyridin-8-amine 418
(7R)-7-(5-bromo-2-fluorophenyl)-7- 392.8 KR 001 >40.0 >15.6
>400.0 (fluoromethyl)-5-thia-8- azaspiro[3.5]non-8-en-9-amine
5,5- dioxide 107 (5R)-5-(5-(((4-chloro-1- 464 KR002 0.00227 81.1
(difluoromethyl)-1H-pyrazol-3- yl)methyl)amino)-2-fluorophenyl)-
2,2,5-trimethyl-5,6-dihydro-2H-1,4- thiazin-3-amine 1,1-dioxide 108
(5R)-5-(5-(((4-chloro-1-(2,2,2- 496 KR003 0.0452 0.161 49.8
trifluoroethyl)-1H-pyrazol-3- yl)methyl)amino)-2-fluorophenyl)-
2,2,5-trimethyl-5,6-dihydro-2H-1,4- thiazin-3-amine 1,1-dioxide 109
(5R)-5-(5-(((4-chloro-1-(2,2,2- 496 KR003 0.208 0.36 12.2
trifluoroethyl)-1H-pyrazol-5- yl)methyl)amino)-2-fluorophenyl)-
2,2,5-trimethyl-5,6-dihydro-2H-1,4- thiazin-3-amine 1,1-dioxide 173
3-((3R)-5-amino-3,6,6-trimethyl-1,1- 445 KS-1 2.29 >15.6 104
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-N-(4-cyano-2-hydroxyphenyl)- 4-fluorobenzamide 419
N-(3-((3R)-5-amino-3,6,6-trimethyl- 526.1 LS1 0.00451 0.026 631
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
(2,2,2-trifluoroethoxy)-1,7- naphthyridin-8-amine 161
N-(3-((3R)-5-amino-3,6,6-trimethyl- 508.2 LS1 0.0143 0.0178 447
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)-3-(2,2-
difluoroethoxy)-1,7-naphthyridin-8- amine 420
((8-((3-((3R)-5-amino-3,6,6- 483.2 161 0.00485 0.0054 1260
trimethyl-1,1-dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-4-
fluorophenyl)amino)-1,7-
naphthyridin-3-yl)oxy)acetonitrile 421
N-(3-((3R)-5-amino-3,6,6-trimethyl- 490.1 161 0.031 0.0115 1450
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-(2-
fluoroethoxy)-1,7-naphthyridin-8- amine 422
N-(3-((3R)-5-amino-3,6,6-trimethyl- 472.2 161 0.0184 0.029 958
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
ethoxy-1,7-naphthyridin-8-amine 162
8-((3-((3R)-5-amino-3,6,6-trimethyl- 454.1 LS2 0.0023 0.0015 418
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)amino)pyrido[2,3- d]pyridazine-3-carbonitrile 423
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 501 eg 162 0.0013 0.735
>133.0 dimethyl-1,1-dioxido-3,6-dihydro- step 6
2H-1,4-thiazin-3-yl)-4-fluorophenyl)- (General
2-(trifluoromethyl)pyrido[3,4- SnAr wth b]pyrazin-5-amine AcOH) 174
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 466.1 (M + H) eg 162 0.00033
0.119 101 dimethyl-1,1-dioxido-3,6-dihydro- step 6
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
3-chloro-1,7-naphthyridin-8-amine 175
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 467.0 (M + H) eg 162 0.00388
0.103 75.8 dimethyl-1,1-dioxido-3,6-dihydro- step 6
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
7-chloropyrido[3,2-d]pyrimidin-4- amine 177
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 463.1 (M + H) eg 162 0.00268
0.0782 175 dimethyl-1,1-dioxido-3,6-dihydro- step 6
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
7-methoxypyrido[3,2-d]pyrimidin-4- amine 180
4-((3-((3R,6R)-5-amino-6-fluoro-3,6- 458.1 (M + H) eg 162 0.0011
0.0894 65.5 dimethyl-1,1-dioxido-3,6-dihydro- step 6
2H-1,4-thiazin-3-yl)-4- fluorophenyl)amino)pyrido[3,2-
d]pyrimidine-7-carbonitrile 424 N-(5-((3R)-5-amino-3,6,6-trimethyl-
418.1 Made by 0.298 0.131 567 1,1-dioxido-3,6-dihydro-2H-1,4-
method thiazin-3-yl)-6-methoxy-3-pyridinyl)- of
2-pyridinecarboxamide example MX312 425
N-(5-((7R)-9-amino-7-methyl-5,5- 517.1 Made by
dioxido-5-thia-8-azaspiro[3.5]non-8- method
en-7-yl)-1-methyl-6-oxo-1,6- of dihydro-3-pyridinyl)-6-chloro-3-
example methylimidazo[1,2-a]pyridine-2- MX315 carboxamide 426
N-(3-((4aR,7aS)-3-amino-2,2- 467 Made by 0.0015 0.0136 170
dimethyl-1,1-dioxido-7,7a-dihydro- method E
2H-furo[3,4-b][1,4]thiazin-4a(5H)- of
yl)-4-fluorophenyl)-5-chloro-2- example pyridinecarboxamide, N-(3-
NC 1 ((4aS,7aR)-3-amino-2,2-dimethyl- 1,1-dioxido-7,7a-dihydro-2H-
furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 427 N-(3-((4aR,7aS)-3-amino-2,2- 481 Made by
0.001 0.033 220 dimethyl-1,1-dioxido-7,7a-dihydro- method E
2H-furo[3,4-b][1,4]thiazin-4a(5H)- of
yl)-4-fluorophenyl)-5-chloro-3- example
methyl-2-pyridinecarboxamide, N- NC 1 (3-((4aS,7aR)-3-amino-2,2-
dimethyl-1,1-dioxido-7,7a-dihydro-
2H-furo[3,4-b][1,4]thiazin-4a(5H)- yl)-4-fluorophenyl)-5-chloro-3-
methyl-2-pyridinecarboxamide 428 N-(3-((4aR,7aS)-3-amino-2,2- 477.8
Made by 0.00971 0.0373 309 dimethyl-1,1-dioxido-7,7a-dihydro-
method E 2H-furo[3,4-b][1,4]thiazin-4a(5H)- of
yl)-4-fluorophenyl)-5-methoxy-3- example
methyl-2-pyridinecarboxamide, N- NC 1 (3-((4aS,7aR)-3-amino-2,2-
dimethyl-1,1-dioxido-7,7a-dihydro-
2H-furo[3,4-b][1,4]thiazin-4a(5H)- yl)-4-fluorophenyl)-5-methoxy-3-
methyl-2-pyridinecarboxamide 185 (4aR,7aS)-4a-(5-bromo-2- 391 Made
in 30.2 >15.6 322 fluorophenyl)-2,2-dimethyl- step 7 of
4a,5,7,7a-tetrahydro-2H-furo[3,4- example b][1,4]thiazin-3-amine
1,1-dioxide, NC 1 (4aS,7aR)-4a-(5-bromo-2-
fluorophenyl)-2,2-dimethyl- 4a,5,7,7a-tetrahydro-2H-furo[3,4-
b][1,4]thiazin-3-amine 1,1-dioxide 429 N-(3-((4aR,7aS)-3-amino-2,2-
489.9 Made by 0.0046 0.157 131 dimethyl-1,1-dioxido-7,7a-dihydro-
method 2H-furo[3,4-b][1,4]thiazin-4a(5H)- Ex. 44
yl)-4-fluorophenyl)-3-chloro-1,7- step 1 of naphthyridin-8-amine,
N-(3- example ((4aS,7aR)-3-amino-2,2-dimethyl- NC 1
1,1-dioxido-7,7a-dihydro-2H- furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-
fluorophenyl)-3-chloro-1,7- naphthyridin-8-amine 185b
(4aS,7aS)-4a-(5-bromo-2- 390.8 Made in >40.0 >15.6 >400.0
fluorophenyl)-2,2-dimethyl- step 7 of
4a,5,7,7a-tetrahydro-2H-furo[3,4- example b][1,4]thiazin-3-amine
1,1-dioxide NC 1 after chiral separation, compound 1 185a
(4aR,7aR)-4a-(5-bromo-2- 390.8 Made in 4.83 >15.6 70.9
fluorophenyl)-2,2-dimethyl- step 7 of
4a,5,7,7a-tetrahydro-2H-furo[3,4- example b][1,4]thiazin-3-amine
1,1-dioxide NC 1 after chiral separation, compound 2 430
N-(3-((4aS,7aS)-3-amino-2,2- 477 Made by 0.0041 0.0117 144
dimethyl-1,1-dioxido-7,7a-dihydro- method E
2H-furo[3,4-b][1,4]thiazin-4a(5H)- of
yl)-4-fluorophenyl)-5-methoxy-3- example
methyl-2-pyridinecarboxamide NC 1, compound 2 183
N-(3-((1R,6R)-4-amino-3,3- 460 NT01 0.00305 4.74 87.9
dimethyl-2,2-dioxido-2-thia-5- azabicyclo[4.1.0]hept-4-en-6-yl)-4-
fluorophenyl)-3-chloro-1,7- naphthyridin-8-amine 152
(5R)-5-(5-(((6-chloro-3- 478 (M + H) PH-1 2.94 0.302 1460
methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)-2-fluorophenyl)-
2,2,5-trimethyl-5,6-dihydro-2H-1,4- thiazin-3-amine 1,1-dioxide 153
3-((3R)-5-amino-3,6,6-trimethyl-1,1- 438 (M + H) PH-2 4.68 3.21 237
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-N-(4-chlorophenyl)-4-
fluorobenzamide 154 (7R)-7-(3-bromophenyl)-7-methyl-5- 457/459 (M +
H) PH-3 6.06 2.39 31.2 thia-8-azaspiro[3.5]non-8-en-9- amine
5,5-dioxide 155 N-(3-((3S)-5-amino-3- 484 (M + H) PH-4 0.0043
0.0351 470 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3,5-dimethoxy- 2-pyrazinecarboxamide 156
N-(3-((3S)-5-amino-3- 494 (M + H) PH-5 0.0005 0.0049 835
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-
(cyclopropylmethoxy)-2- pyrazinecarboxamide 157
8-((3-((3S)-5-amino-3- 489 (M + H) PH-6 0.00056 0.0271 >14.8
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)amino)-5-
fluoro-1,7-naphthyridine-3- carbonitrile 158 N-(3-((3S)-5-amino-3-
510.0 (M + H) PH-7 0.00303 0.0106 4060
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-6-chloro-3- methylimidazo[1,2-a]pyridine-2-
carboxamide 159 N-(3-((3S)-5-amino-3- 494.0 (M + 1) PH-8 0.00055
0.0285 159 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-fluoro-3- methoxy-1,7-naphthyridin-8-amine
431 N-(3-((3S)-5-amino-3- 534 PH-8 0.0012 0.1 476
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-3-
(cyclopropylmethoxy)-5-fluoro-1,7- naphthyridin-8-amine 432
N-(3-((3S)-5-amino-3- 562 PH-8 0.00247 0.187 312
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-fluoro-3- (2,2,2-trifluoroethoxy)-1,7-
naphthyridin-8-amine 433 8-((3-((3S)-5-amino-3- 480 PH-8 0.0006
0.0314 111 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)amino)-5-
fluoro-1,7-naphthyridin-3-ol 434 N-(3-((3S)-5-amino-3- 548 PH-8
0.0015 0.341 32.3 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-3-
(cyclobutylmethoxy)-5-fluoro-1,7- naphthyridin-8-amine 435
N-(3-((3S)-5-amino-3- 508 PH-8 0.0016 0.049 >400.0
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-ethoxy-5- fluoro-1,7-naphthyridin-8-amine
436 N-(3-((3S)-5-amino-3- 536 PH-8 0.0043 0.626 61.6
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-fluoro-3-(2-
methylpropoxy)-1,7-naphthyridin-8- amine 437 N-(3-((3S)-5-amino-3-
544 PH-8 0.00223 0.0643 >1.65 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-3-(2,2-
difluoroethoxy)-5-fluoro-1,7- naphthyridin-8-amine 438
N-(3-((7S)-9-amino-7- 520 PH-8 0.00382 0.198 >1.65
(fluoromethyl)-5,5-dioxido-5-thia-8- azaspiro[3.5]non-8-en-7-yl)-4-
fluorophenyl)-3-ethoxy-5-fluoro-1,7- naphthyridin-8-amine 163
(5R)-5-(2-fluoro-5-(2- 394.1 PO-01 3.25 2.36 73.5
pyridinylsulfanyl)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 439
(5R)-5-(2-fluoro-5-((3-fluoro-2- 412 163 0.375 0.99 215
pyridinyl)sulfanyl)phenyl)-2,2,5-
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 440
2-((3-((3R)-5-amino-3,6,6-trimethyl- 419 PO-01 0.566 0.679 218
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-
fluorophenyl)sulfanyl)-4- pyridinecarbonitrile 441
N-(3-((3R)-5-amino-3,6,6-trimethyl- 491.2 Rena 0.00534 0.0138 407
1,1-dioxido-3,6-dihydro-2H-1,4- Method 1
thiazin-3-yl)-4-fluorophenyl)-2-(2-
fluoroethoxy)pyrido[3,4-b]pyrazin-5- amine 442
N-(3-((3R)-5-amino-3,6,6-trimethyl- 527 Rena 0.00322 0.0319 389
1,1-dioxido-3,6-dihydro-2H-1,4- Method 1
thiazin-3-yl)-4-fluorophenyl)-2- (2,2,2-trifluoroethoxy)pyrido[3,4-
b]pyrazin-5-amine 443 ((5-((3-((3R)-5-amino-3,6,6- 484 Rena 0.00287
0.004 346 trimethyl-1,1-dioxido-3,6-dihydro- Method 1
2H-1,4-thiazin-3-yl)-4- fluorophenyl)amino)pyrido[3,4-
b]pyrazin-2-yl)oxy)acetonitrile 444
N-(3-((3R)-5-amino-3,6,6-trimethyl- 509 Rena 0.00454 .0083) 242
1,1-dioxido-3,6-dihydro-2H-1,4- Method 1
thiazin-3-yl)-4-fluorophenyl)-2-(2,2-
difluoroethoxy)pyrido[3,4-b]pyrazin- 5-amine 445
N-(3-((3R)-5-amino-3,6,6-trimethyl- 497.2 Rena 0.00032 0.0002 178
1,1-dioxido-3,6-dihydro-2H-1,4- Method 1
thiazin-3-yl)-4-fluorophenyl)-2-(2-
butyn-1-yloxy)pyrido[3,4-b]pyrazin- 5-amine 104
N-(3-((3R)-5-amino-3,6,6-trimethyl- 499.2 Rena 0.00154 0.0052 358
1,1-dioxido-3,6-dihydro-2H-1,4- Method 1
thiazin-3-yl)-4-fluorophenyl)-7- (cyclopropylmethoxy)pyrido[3,2-
d]pyrimidin-4-amine 105 N-(3-((3R)-5-amino-3,6,6-trimethyl- 447
Rena 0.184 0.742 145 1,1-dioxido-3,6-dihydro-2H-1,4- Method 2
thiazin-3-yl)-4-fluorophenyl)-2- methyl-1,3-benzothiazol-4-amine
446 N-(3-((3R)-5-amino-3,6,6-trimethyl- 495 Rena 0.0022 0.263 13.9
1,1-dioxido-3,6-dihydro-2H-1,4- Method 2
thiazin-3-yl)-4-fluorophenyl)-3,6- dichloro-8-quinolinamine 447
N-(3-((3S)-5-amino-3- 477.0 Step 1 of 0.00088 0.0141 1120
(fluoromethyl)-6,6-dimethyl-1,1- general
dioxido-3,6-dihydro-2H-1,4-thiazin- SNAr 3-yl)-4-fluorophenyl)-2-
methoxypyrido[3,4-b]pyrazin-5- amine 448 N-(3-((3S)-5-amino-3-
480.0 Step 1 of 0.00037 0.0285 58.4
(fluoromethyl)-6,6-dimethyl-1,1- general
dioxido-3,6-dihydro-2H-1,4-thiazin- SNAr
3-yl)-4-fluorophenyl)-3-chloro-1,7- naphthyridin-8-amine 449
N-(3-((3S)-5-amino-3- 524.9 General 0.0302 0.159 375
(fluoromethyl)-6,6-dimethyl-1,1- Bicyclic
dioxido-3,6-dihydro-2H-1,4-thiazin- SNAR
3-yl)-4-fluorophenyl)-6-bromo-1- (Example phthalazinamine 44) 450
N-(3-((3S)-5-amino-3- 480.0 General 0.7
(fluoromethyl)-6,6-dimethyl-1,1- Bicyclic
dioxido-3,6-dihydro-2H-1,4-thiazin- SNAR
3-yl)-4-fluorophenyl)-6-chloro-1- (Example phthalazinamine 44) 149
N-(3-((3S)-5-amino-3- 499.1 T3P 0.00271 0.0651 855
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin- 3-yl)-4-fluorophenyl)-5-(2-
fluoroethoxy)-3-methyl-2- pyridinecarboxamide 150
N-(3-((3S)-5-amino-3- 508.9 T3P 0.0445 0.528 622
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-3-methyl-5-(3- oxetanyloxy)-2-
pyridinecarboxamide 184 (5R)-5-(5-bromo-2-fluoro-6-methyl- 377.9/
TJ14 8.11 3.99 127 3-pyridinyl)-2,2,5-trimethyl-5,6- 380.0
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 189
N-(3-((3R)-5-amino-3,6,6-trimethyl- 558 WQ2 0.0068 0.231 >4.94
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
chloro-5-((trimethylsilyl)ethynyl)-1,7- naphthyridin-8-amine 188
N-(3-((3R)-5-amino-3,6,6-trimethyl- 541 0.00083 0.0597 213
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-4-
bromo-6-chloro-1-isoquinolinamine 192
N-(3-((3R)-5-amino-3,6,6-trimethyl-methyl- 496 0.0007 0.0366 32.4
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3,5-
dichloro-1,7-naphthyridin-8-amine 190
N-(3-((3R)-5-amino-3,6,6-trimethyl- 486 0.0013 0.0448 63.9
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
chloro-5-ethynyl-1,7-naphthyridin-8- amine 191
(8-((3-((3R)-5-amino-3,6,6-trimethyl- 492 0.00447 0.0089 65
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-4-fluorophenyl)amino)- 3-chloro-1,7-naphthyridin-5-
yl)methanol 212 N-(3-((3R)-5-amino-3,6,6-trimethyl- 437.9 See
0.0102 0.0233 317 1,1-dioxido-3,6-dihydro-2H-1,4- Write up
thiazin-3-yl)-4-fluorophenyl)-4- chlorobenzamide 213
N-(3-((3R)-5-amino-3,6,6-trimethyl- 455.9 See 0.0123 0.029 442
1,1-dioxido-3,6-dihydro-2H-1,4- Write up
thiazin-3-yl)-4-fluorophenyl)-4- chloro-2-fluorobenzamide 160
N-(3-((3R)-5-amino-3,6,6-trimethyl- 409 see 0.575 0.681 >14.8
1,1-dioxido-3,6-dihydro-2H-1,4- experimental
thiazin-3-yl)-4-fluorophenyl)-3,6-
dihydro-1(2H)-pyridinecarboxamide 451
N-(3-((3R)-5-amino-3,6,6-trimethyl- 507/509 0.00068 0.0006 104
1,1-dioxido-3,6-dihydro-2H-1,4- thiazin-3-yl)-4-fluorophenyl)-3-
bromopyrido[2,3-d]pyridazin-8- amine 169
3-((3R)-5-amino-3,6,6-trimethyl-1,1- 361.9 MX311 21.1 >15.6
>400.0 dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-5-bromo-2(1H)-pyridinone 170
N-(5-((3R)-5-amino-3,6,6-trimethyl- 452 0.0225 0.0289 305
1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-6-methoxy-3-pyridinyl)-
5-chloro-2-pyridinecarboxamide 452
N-(5-((3R)-5-amino-3,6,6-trimethyl- 438 Amidation 0.00704 0.0159
1870 1,1-dioxido-3,6-dihydro-2H-1,4- method E
thiazin-3-yl)-6-oxo-1,6-dihydro-3- pyridinyl)-5-chloro-2-
pyridinecarboxamide 171 N-(5-((3R)-5-amino-3,6,6-trimethyl- 498.1
0.00927 0.0083 186 1,1-dioxido-3,6-dihydro-2H-1,4-
thiazin-3-yl)-1-methyl-6-oxo-1,6 dihydro-3-pyridinyl)-5-
(difluoromethoxy)-3-methyl-2- pyridinecarboxamide 176
N-(3-((3R,6S)-5-amino-6-fluoro-3,6- 440.1 (M + H) 0.0028 0.254 650
dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
5-methoxy-2-pyrazinecarboxamide 178
N-(3-((3R,6R)-5-amino-6-fluoro-3,6- 484.1 (M + H) 0.00038 0.379
32.1 dimethyl-1,1-dioxido-3,6-dihydro-
2H-1,4-thiazin-3-yl)-4-fluorophenyl)-
3-chloro-5-fluoro-1,7-naphthyridin- 8-amine 179
8-((3-((3R,6R)-5-amino-6-fluoro-3,6- 475.1 (M + H) 0.0008 0.157
>44.4 dimethyl-1,1-dioxido-3,6-dihydro- 2H-1,4-thiazin-3-yl)-4-
fluorophenyl)amino)-5-fluoro-1,7- naphthyridine-3-carbonitrile 453
(7R)-7-(5-bromo-2-fluorophenyl)-7-
methyl-5-thia-8-azaspiro[3.5]non-8- en-9-amine 5,5-dioxide,
(7S)-7-(5- bromo-2-fluorophenyl)-7-methyl-5-
thia-8-azaspiro[3.5]non-8-en-9- amine 5,5-dioxide 454
N-(5-((6R)-8-amino-6-methyl-4,4- 484 0.0031 0.0039 106
dioxido-4-thia-7-azaspiro[2.5]oct-7-
en-6-yl)-6-fluoro-3-pyridinyl)-5- (difluoromethoxy)-3-methyl-2-
pyridinecarboxamide 455 (6R)-6-(5-bromo-2-fluoro-3- 362/ 12.5
>15.6 100 pyridinyl)-6-methyl-4-thia-7- 364
azaspiro[2.5]oct-7-en-8-amine 4,4- dioxide 199
N-(3-((6R)-8-amino-6-methyl-4,4- 437.1 0.0019 0.0011 81
dioxido-4-thia-7-azaspiro[2.5]oct-7-
en-6-yl)-4-fluorophenyl)-5-chloro-2- pyridinecarboxamide 186
N-(5-((6R)-8-amino-6-methyl-4,4- 0.0024 0.0043 65.7
dioxido-4-thia-7-azaspiro[2.5]oct-7-
en-6-yl)-6-fluoro-3-pyridinyl)-5- chloro-3-methyl-2-
pyridinecarboxamide 181 (5R,8R)-8-(5-bromo-2- 391.0 (M + H) 16.3
>15.6 43.3 fluorophenyl)-8-methyl-2-oxa-6-thia-
9-azaspiro[4.5]dec-9-en-10-amine 6,6-dioxide, (5S,8R)-8-(5-bromo-2-
fluorophenyl)-8-methyl-2-oxa-6-thia-
9-azaspiro[4.5]dec-9-en-10-amine 6,6-dioxide 182
N-(3-((5R,8R)-10-amino-8-methyl- 490.1 (M + H) .0022 0.0306 63.6
6,6-dioxido-2-oxa-6-thia-9- azaspiro[4.5]dec-9-en-8-yl)-4-
fluorophenyl)-3-chloro-1,7- naphthyridin-8-amine, N-(3-
((5S,8R)-10-amino-8-methyl-6,6- dioxido-2-oxa-6-thia-9-
azaspiro[4.5]dec-9-en-8-yl)-4- fluorophenyl)-3-chloro-1,7-
naphthyridin-8-amine 200 N-(3-((5S,6R)-8-amino-5-fluoro-6- 455
0.0013 0.0039 55.6 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 201 N-(3-((5R,6R)-8-amino-5-fluoro-6- 455 DC1
0.00062 0.002 31.1 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-5-chloro-2-
pyridinecarboxamide 202 N-(3-((5S,6R)-8-amino-5-fluoro-6- 501 DC3
0.0015 0.0036 96.7 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 203 N-(3-((5R,6R)-8-amino-5-fluoro-6-
501 0.00048 0.0023 30.2 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 206 N-(3-((5S,6R)-8-amino-5-fluoro-6-
485 0.0019 0.0054 193 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-5-(difluoromethyl)-3-
methyl-2-pyridinecarboxamide 207 N-(3-((5R,6R)-8-amino-5-fluoro-6-
485 0.00092 0.0067 56.1 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-5-(difluoromethyl)-3-
methyl-2-pyridinecarboxamide 209 N-(3-((5S,6R)-8-amino-5-fluoro-6-
475.2 0.0085 0.0854 157 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-2-methoxypyrido[3,4-
b]pyrazin-5-amine 208 N-(3-((5R,6R)-8-amino-5-fluoro-6- 475.2
<0.002 0.0107 696 methyl-4,4-dioxido-4-thia-7-
azaspiro[2.5]oct-7-en-6-yl)-4- fluorophenyl)-2-methoxypyrido[3,4-
b]pyrazin-5-amine 210 N-(3-((5S,6R)-8-amino-5-fluoro-6- 508
methyl-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-6-chloro-3- methylimidazo[1,2-a]pyridine-2-
carboxamide 456 (5S)-5-(5-amino-2-fluorophenyl)-5- 318.1 2.53
>15.6 228 (fluoromethyl)-2,2-dimethyl-5,6-
dihydro-2H-1,4-thiazin-3-amine 1,1- dioxide 457
N-(3-((3S)-5-amino-3- 452.9 0.00065 0.0129 812
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-methoxy-2- pyridinecarboxamide 458
N-(3-((3S)-5-amino-3- 0.0009 0.0239 499
(fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-3- (methoxymethyl)-2-
pyridinecarboxamide 193 N-(3-((3S)-5-amino-3- 457 0.00076 0.0161
228 (fluoromethyl)-6,6-dimethyl-1,1-
dioxido-3,6-dihydro-2H-1,4-thiazin-
3-yl)-4-fluorophenyl)-5-chloro-2- pyridinecarboxamide 214a
(6R)-6-(5-bromo-2-fluorophenyl)-6- 316 >40.0 >15.6 >400.0
(fluoromethyl)-4-thia-7- azaspiro[2.5]oct-7-en-8-amine 4,4- dioxide
214b (6S)-6-(5-bromo-2-fluorophenyl)-6- 316 2.28 10.6 78.9
(fluoromethyl)-4-thia-7- azaspiro[2.5]oct-7-en-8-amine 4,4- dioxide
215 N-(3-((6R)-8-amino-6- 469 0.212 0.903 432
(fluoromethyl)-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 216
N-(3-((6S)-8-amino-6- 469 0.00054 0.0044 132
(fluoromethyl)-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide
217 N-(3-((6S)-8-amino-6- 501 0.0012 0.0061 46.8
(fluoromethyl)-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3- methyl-2-pyridinecarboxamide
218 N-(3-((6R)-8-amino-6- 501 0.15 0.83 637
(fluoromethyl)-4,4-dioxido-4-thia-7- azaspiro[2.5]oct-7-en-6-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3- methyl-2-pyridinecarboxamide
172 (7S)-7-(5-bromo-2-fluorophenyl)-7- 392.9 MX321 3.56 >15.6
45.4 (fluoromethyl)-5-thia-8- azaspiro[3.5]non-8-en-9-amine 5,5-
dioxide 459 (2R,5R)-5-(5-bromo-2- 381, 2.3 5.47 >400.0
fluorophenyl)-2-fluoro-2,5,6- 383
trimethyl-5,6-dihydro-2H-1,4-thiazin- 3-amine 1,1-dioxide 185c
(4aR,7aR)-4a-(5-amino-2- 328 >40.0 >15.6 >400.0
fluorophenyl)-2,2-dimethyl 4a,5,7,7a-tetrahydro-2H-furo[3,4-
b][1,4]thiazin-3-amine 1,1-dioxide 185d (4aS,7aS)-4a-(5-amino-2-
328 3.83 >15.6 152 fluorophenyl)-2,2-dimethyl
4a,5,7,7a-tetrahydro-2H-furo[3,4- b][1,4]thiazin-3-amine
1,1-dioxide 187 (8R)-8-(5-bromo-2-fluorophenyl)- 389, ZH001 30.7
>15.6 >400.0 5,5,8-trimethyl-4-thia-7- 391
azaspiro[2.5]oct-6-en-6-amine 4,4- dioxide
[1522] The present invention also provides methods for making
compounds of Formulas I-III, and sub-formulas therein. For example,
the compounds of the present invention and additional examples may
be made by the following methods, as similarly described in the
literature references mentioned below.
[1523] In one embodiment of the invention, there is provided a
method of making a compound of Formula II-A having a general
structure of
##STR00318##
the method comprising the step of reacting a compound 20
##STR00319##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, each
R.sup.2 and R.sup.3 of Formula II-A are as defined herein, with a
compound having the structure R.sup.9--COOH, wherein R.sup.9 is as
defined herein, to make a compound of Formula II-A.
[1524] In one embodiment of the invention, there is provided a
method of making a compound of Formula II-B having a general
structure of
##STR00320##
the method comprising the step of reacting a compound 20
##STR00321##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, each
R.sup.2 and R.sup.3 of Formula II-B are as defined herein, with a
compound having the structure
##STR00322##
wherein each W and each R.sup.10 are, independently, as defined
herein, in the presence of acid to make a compound of Formula
II-B.
[1525] In one embodiment of the invention, there is provided a
method of making a compound of Formula II-C
##STR00323##
the method comprising the step of reacting a compound 20
##STR00324##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, each
R.sup.2 and R.sup.3 of Formula II-C are as defined herein, with a
compound having the structure
##STR00325##
wherein V, each W and each R.sup.10 are, independently, as defined
herein, to make a compound of Formula II-C.
[1526] In another embodiment of the invention, there is provided a
method of making a compound of Formula III having a general formula
of
##STR00326##
the method comprising the step of reacting a compound 20
##STR00327##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, each
R.sup.2, R.sup.3 and R.sup.7 of Formula III are as defined herein,
with a compound having either structure of R.sup.7--COOH in the
presence of a base or R.sup.7 in the presence of an acid, wherein
R.sup.7 is as defined herein, to make a compound of Formula
III.
[1527] As can be appreciated by the skilled artisan, the above
synthetic schemes and representative examples are not intended to
comprise a comprehensive list of all means by which the compounds
described and claimed in this application may be synthesized.
Further methods will be evident to those of ordinary skill in the
art. Additionally, the various synthetic steps described above may
be performed in an alternate sequence or order to give the desired
compounds.
[1528] For example, in these procedures, the steps may be preceded,
or followed, by additional protection/deprotection steps as
necessary. Particularly, if one or more functional groups, for
example carboxy, hydroxy, amino, or mercapto groups, are or need to
be protected in preparing the compounds of the invention, because
they are not intended to take part in a specific reaction or
chemical transformation, various known conventional protecting
groups may be used. For example, protecting groups typically
utilized in the synthesis of natural and synthetic compounds,
including peptides, nucleic acids, derivatives thereof and sugars,
having multiple reactive centers, chiral centers and other sites
potentially susceptible to the reaction reagents and/or conditions,
may be used.
[1529] Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the inhibitor compounds described herein are known in the art and
include, for example, those such as described in R. Larock,
Comprehensive Organic Transformations, VCH Publishers (1989); T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3.sup.rd edition, John Wiley and Sons (1999); L. Fieser and M.
Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of
Heterocyclic Chemistry, 2.sup.nd edition (2001); M. Bodanszky, A.
Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag,
Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the
Alumino- and Borohydrides in Organic Synthesis, 2.sup.nd edition,
Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of
Reagents for Organic Synthesis, John Wiley and Sons (1995).
[1530] Salts, including pharmaceutically acceptable salts, of a
compound of the invention having a salt-forming group may be
prepared in a conventional manner or manner known to persons
skilled in the art. For example, acid addition salts of compounds
of the invention may be obtained by treatment with an acid or with
a suitable anion exchange reagent. A salt with two acid molecules
(for example a dihalogenide) may also be converted into a salt with
one acid molecule per compound (for example a monohalogenide); this
may be done by heating to a melt, or for example by heating as a
solid under a high vacuum at elevated temperature, for example from
50.degree. C. to 170.degree. C., one molecule of the acid being
expelled per molecule of the compound.
[1531] Acid salts can usually be converted to free-base compounds,
e.g. by treating the salt with suitable basic agents, for example
with alkali metal carbonates, alkali metal hydrogen carbonates, or
alkali metal hydroxides, typically potassium carbonate or sodium
hydroxide. Exemplary and suitable salts, and their preparation, are
described herein in the Definition section of the application.
[1532] All synthetic procedures described herein can be carried out
under known reaction conditions, advantageously under those
described herein, either in the absence or in the presence
(usually) of solvents or diluents. As appreciated by those of
ordinary skill in the art, the solvents should be inert with
respect to, and should be able to dissolve, the starting materials
and other reagents used. Solvents should be able to partially or
wholly solubilize the reactants in the absence or presence of
catalysts, condensing agents or neutralizing agents, for example
ion exchangers, typically cation exchangers for example in the
H.sup.+ form. The ability of the solvent to allow and/or influence
the progress or rate of the reaction is generally dependant on the
type and properties of the solvent(s), the reaction conditions
including temperature, pressure, atmospheric conditions such as in
an inert atmosphere under argon or nitrogen, and concentration, and
of the reactants themselves.
[1533] Suitable solvents for conducting reactions to synthesize
compounds of the invention include, without limitation, water;
esters, including lower alkyl-lower alkanoates, e.g., EtOAc; ethers
including aliphatic ethers, e.g., Et.sub.2O and ethylene glycol
dimethylether or cyclic ethers, e.g., THF; liquid aromatic
hydrocarbons, including benzene, toluene and xylene; alcohols,
including MeOH, EtOH, 1-propanol, IPOH, n- and t-butanol; nitriles
including CH.sub.3CN; halogenated hydrocarbons, including
CH.sub.2Cl.sub.2, CHCl.sub.3 and CCL; acid amides including DMF;
sulfoxides, including DMSO; bases, including heterocyclic nitrogen
bases, e.g. pyridine; carboxylic acids, including lower
alkanecarboxylic acids, e.g., AcOH; inorganic acids including HCl,
HBr, HF, H.sub.2SO.sub.4 and the like; carboxylic acid anhydrides,
including lower alkane acid anhydrides, e.g., acetic anhydride;
cyclic, linear, or branched hydrocarbons, including cyclohexane,
hexane, pentane, isopentane and the like, and mixtures of these
solvents, such as purely organic solvent combinations, or
water-containing solvent combinations e.g., aqueous solutions.
These solvents and solvent mixtures may also be used in
"working-up" the reaction as well as in processing the reaction
and/or isolating the reaction product(s), such as in
chromatography.
[1534] Purification methods are known in the art and include, for
example, crystallization, chromatography (liquid and gas phase, and
the like), extraction, distillation, trituration, reverse phase
HPLC and the like. Reactions conditions such as temperature,
duration, pressure, and atmosphere (inert gas, ambient) are known
in the art and may be adjusted as appropriate for the reaction.
[1535] The invention further encompasses "intermediate" compounds,
including structures produced from the synthetic procedures
described, whether isolated or generated in-situ and not isolated,
prior to obtaining the finally desired compound. Structures
resulting from carrying out steps from a transient starting
material, structures resulting from divergence from the described
method(s) at any stage, and structures forming starting materials
under the reaction conditions are all "intermediates" included in
the invention. Further, structures produced by using starting
materials in the form of a reactive derivative or salt, or produced
by a compound obtainable by means of the process according to the
invention and structures resulting from processing the compounds of
the invention in situ are also within the scope of the
invention.
[1536] The invention also provides new starting materials and/or
intermediates, as well as processes for the preparation thereof. In
select embodiments, such starting materials are used and reaction
conditions so selected as to obtain the desired compound(s).
Starting materials of the invention, are either known, commercially
available, or can be synthesized in analogy to or according to
methods that are known in the art. Many starting materials may be
prepared according to known processes and, in particular, can be
prepared using processes described in the examples. In synthesizing
starting materials, functional groups may be protected with
suitable protecting groups when necessary. Protecting groups, their
introduction and removal are described above.
[1537] Compounds of the present invention can possess, in general,
one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or non-racemic mixtures thereof. While shown without
respect to stereochemistry in Formulas I-III, the present invention
includes such optical isomers and diastereomers, as well as the
racemic and resolved, enantiomerically pure R and S stereoisomers,
as well as other mixtures of R and S stereoisomers and
pharmaceutically acceptable salts thereof.
[1538] The invention provides compounds of Formulas I, II and III,
and sub-Formulas thereof, and stereoisomers thereof. For example,
as shown in Formula III below, and for purposes of clarity, the
following isomers about the central quaternary carbon are deemed
equivalent and the same herein.
##STR00328##
[1539] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, e.g., by
formation of diastereoisomeric salts, by treatment with an
optically active acid or base. Examples of appropriate acids are
tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric,
and camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by reacting
compounds of the invention with an optically pure acid in an
activated form or an optically pure isocyanate. The synthesized
diastereoisomers can be separated by conventional means such as
chromatography, distillation, crystallization or sublimation, and
then hydrolyzed to deliver the enantiomerically pure compound. The
optically active compounds of the invention can likewise be
obtained by using optically active starting materials. These
isomers may be in the form of a free acid, a free base, an ester or
a salt. All such isomeric forms of such compounds are expressly
included in the present invention.
[1540] The compounds of the invention may also be represented in
multiple tautomeric forms. Tautomers often exist in equilibrium
with each other, and interconvert under environmental and
physiological conditions. The compounds of the invention may also
occur in cis- or trans- or E- or Z-double bond isomeric forms. The
invention expressly includes all tautomeric forms of the compounds
described herein.
[1541] All crystal forms of the compounds described herein are
expressly included in the present invention.
[1542] The present invention also includes isotopically-labeled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H (deuterium), .sup.3H (tritium), .sup.13C,
.sup.14C, .sup.15N, .sup.16O, .sup.17O, .sup.31P, .sup.32P,
.sup.35S, .sup.18F, and .sup.36Cl.
[1543] Compounds of the present invention that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically-labeled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Deuterated (.sup.2H), Tritiated (.sup.3H) and carbon-14, i.e.,
.sup.14C, isotopes are particularly preferred for their ease of
preparation and detection. Further, substitution with heavier
isotopes such as deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances.
Isotopically labeled compounds of this invention can generally be
prepared by substituting a readily available isotopically labeled
reagent for a non-isotopically labeled reagent.
Biological Evaluation
[1544] The compounds of the invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. The pharmacokinetic and pharmacodynamic properties of a
compound relate, directly and indirectly, to the ability of the
compound to be effective for its intended use.
[1545] Although the pharmacological properties of the compounds of
the invention (Formulas I-III) vary with structural change, in
general, activity possessed by compounds of Formulas I-III may be
demonstrated both in vitro as well as in vivo. The following
exemplified pharmacological assays have been carried out with the
compounds according to the invention, to assess and characterize
the compound's ability to modulate BACE activity and to regulate
the cleavage of amyloid beta precursor protein, thereby reducing or
inhibiting the production of amyloid beta.
In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy
Transfer) Assay (Enzyme Assay Data in the Example Tables I and
II)
[1546] The assay buffer used in this screen is 0.05 M acetate, pH
4.2, 10% DMSO final, 100 uM genapol (which is a nonionic detergent,
below its Critical Micelle Concentration). The Beta Secretase
enzyme (0.2 nM) is pre-incubated for one hour with inhibitors,
typically in about 1 uL of DMSO according to a serial dilution, are
added thereto. This assay is effectively started by the addition of
FRET substrate (50 nM) and the combination is incubated for one
hour. The FRET assay is terminated with by addition of Tris buffer,
which raises the pH to neutrality, and the fluorescence is
determined. The FRET substrate is a peptide with commercially
available fluorophore and quencher, on opposite sides of the BACE
cleavage site. Proteolytic cleavage of the FRET substrate releases
quenching of fluorescence (excitation 488 nm and emission 425
nm).
[1547] Where available, the in-vitro BACE FRET enzyme data for each
of the Examples is provided in Tables I and II.
In Vitro BACE Cell-Based Assay
[1548] The cell-based assay measures inhibition or reduction of
A.beta.40 in conditioned medium of test compound treated cells
expressing amyloid precursor protein.
[1549] Cells stably expressing Amyloid Precursor Protein (APP) were
plated at a density of 40K cells/well in 96 well plates (Costar).
The cells were cultivated for 24 hours at 37C. and 5% CO.sub.2 in
DMEM supplemented with 10% FBS. The test compounds were then added
to cells in 10-point dose response concentrations with the starting
concentration being either 100 .mu.M or 10 .mu.M. The compounds
were diluted from stock solutions in DMSO and the final DMSO
concentration of the test compounds on cells was 0.1%. After 24 h
of incubation with the test compounds the supernatant conditioned
media was collected and the A.beta. 40 levels were determined using
a sandwich ELISA. The IC.sub.50 of the compound was calculated from
the percent of control or percent inhibition of A.beta. 40 as a
function of the concentration of the test compound.
[1550] The sandwich ELISA to detect A.beta. 40 was performed in 96
well microtiter plates, which were pre-treated with goat
anti-rabbit IgG (Pierce). The capture and detecting antibody pair
that were used to detect A.beta. 40 from cell supernatants were
affinity purified pAb40 (Biosource) and biotinylated 6E10 (Signet
Labs Inc.), respectively. The optimal concentration for the pAb40
antibody was 3 .mu.g/ml in Superblock/TBS (Pierce) that was
supplemented with 0.05% Tween 20 (Sigma). Optimal concentration for
the detection antibody 6E10-biotinylated was 0.5 .mu.g/ml in
Superblock/TBS (Pierce) that had been supplemented with 2% normal
goat serum and 2% normal mouse serum.
[1551] Cellular supernatants were incubated with the capture
antibody for 3 h at 4.degree. C., followed by 3 wash steps in
TBS-tween (0.05%). The detecting antibody incubation was for 2 h at
4.degree. C., again followed by the wash steps as described
previously. The final readout of the ELISA is Time-Resolved
Fluorescence (counts per minute) using Delfia reagents
Streptavidin-Europium and Enhancement solutions (Perkin Elmer) and
the Victor 2 multilabel counter (Perkin Elmer).
[1552] Where available, the in-vitro BACE cell based data for each
of the Examples is provided in Tables I and II.
In Vitro Enzymatic Cathepsin D (Cat D) FRET (Fluorescence Resonance
Energy Transfer) Assay
[1553] Recombinant Cat D was expressed in CHO cells. The assay
buffer for CathepsinD is 0.05 M citrate pH 3.5, 10% DMSO final, 5
mM CHAPS. The Cat D enzyme (9 nM) is pre-incubated for one hour
with inhibitors, typically in about 1 uL of DMSO according to a
serial dilution, is added thereto. The assays are effectively
started by the addition of different FRET substrates (20 nM for Cat
D) and the combination is incubated for one hour. The FRET assay is
terminated with by addition of Tris buffer, which raises the pH to
neutrality, and the fluorescence is determined. The FRET substrate
is a peptide with commercially available fluorophore and quencher,
on opposite sides of the BACE cleavage site. The Cat D substrate
peptide sequence is based on sequence #1 of Table 1 from Gulnik et
al. FEB S Letters v413 p 379-384 1997. Proteolytic cleavage of the
FRET substrate releases quenching of fluorescence (Cat D excitation
500 nm and emission 580 nm).
[1554] Alternatively, a Cat D assay may also be run according to
the procedure described in the article, Characterization of new
fluorgenic substrates for the rapid and sensitive assay of
cathepsin E and cathepsin D, J. Biochem., 125:1137, 1999. In
addition, the cathepsin D and cathepsin E assays are described in
PCT publication WO2011069934. This WIPO publication describes BACE
inhibitor compounds having an amide linker connecting two aromatic
groups with extremely poor cathepsin D and/or cathepsin E
inhibitory activity (see Table 2).
[1555] Where available, the in-vitro Cat D FRET assay data for each
of the Examples, conducted by the first procedure, is provided. For
example, the compound of example 43 has a Cat D IC.sub.50 value of
>400 uM. As shown by the high micromolar Cat D data (very poorly
active or inactive against cat D), the compounds of the present
invention possess the unexpected property of little to no ability
to inhibit the activity of Cat D. It was surprisingly found that
incorporation of an amino- or amido-linker between the core of the
compounds and the R.sup.7 and R.sup.9 groups, respectively, has
conferred a significantly reduced, poor or no potency on the
protein Cat D. Thus, with this surprising selectivity profile, the
compounds of the present invention are believed to minimize, reduce
or completely eliminate any risk of retinal atrophy and abnormal
development of the eye and of the retinal pigmented epithelium as
it relates to the normal function and activity of Cat D.
In Vivo Inhibition of Beta-Secretase
[1556] Several animal models, including mouse, rat, dog, and
monkey, may be used to screen for inhibition of beta-secretase
activity in vivo following administration of a test compound
sample. Animals used in this invention can be wild type,
transgenic, or gene knockout animals. For example, the Tg2576 mouse
model, prepared and conducted as described in Hsiao et al., 1996,
Science 274, 99-102, and other non-transgenic or gene knockout
animals are useful to analyze in vivo inhibition of Amyloid beta
peptide (Abeta) production in the presence of inhibitory test
compounds. Generally, 2 to 18 month old Tg2576 mice, gene knockout
mice or non-transgenic animals are administered test compounds
formulated in vehicles, such as cyclodextran, phosphate buffers,
hydroxypropyl methylcellulose or other suitable vehicles. One to
twenty-four hours following the administration of compound, animals
are sacrificed, and brains as well as cerebrospinal fluid (CSF) and
plasma are removed for analysis of A-beta levels and drug or test
compound concentrations (Dovey et al., 2001, Journal of
Neurochemistry, 76, 173-181) Beginning at time 0, animals are
administered by oral gavage, or other means of delivery such as
intravenous injection, an inhibitory test compound of up to 100
mg/kg in a standard, conventional formulation, such as 2%
hydroxypropyl methylcellulose, 1% Tween80. A separate group of
animals receive 2% hydroxypropyl methylcellulose, 1% Tween80 alone,
containing no test compound, and serve as a vehicle-control group.
At the end of the test period, animals are sacrificed and brain
tissues, plasma or cerebrospinal fluid are collected. Brains are
either homogenized in 10 volumes (w/v) of 0.2% diethylamine (DEA)
in 50 mM NaCl (Best et al., 2005, Journal of Pharmacology and
Experimental Therapeutics, 313, 902-908), or in 10 volumes of 0.5%
TritonX-100 in Tris-buffered saline (pH at about 7.6). Homogenates
are centrifuged at 355,000g, 4.degree. C. for 30 minutes. CSF or
brain supernatants are then analyzed for the presence of A-beta
peptide by specific sandwich ELISA assays based on ECL
(Electrochemiluminescence) technology. For example, rat Abeta40 is
measured using biotinylated-4G8 (Signet) as a capture antibody and
Fab40 (an in-house antibody specific to the C-terminal of Abeta40)
as a detection antibody. For example, 4 hours after administration
of 30 mg/kg oral dose of the test compound in 2% hydroxypropyl
methylcellulose, 1% Tween80 (pH2.2) to 200 g male Sprague Dawley
rats, amyloid beta peptide levels are measured for reduction by X %
and Y % in cerebrospinal fluid and brain, respectively, when
compared to the levels measured in the vehicle-treated or control
mice.
Actual vehicles used: Oral: 2% HPMC, 1% Tween80, pH 2.2 [1557] IV:
5% EtOH, 45% Propylene glycol in 5% Dextrose
[1558] The compounds of the invention may be shown to reduce the
formation and/or deposition of amyloid beta peptide in the
cerebrospinal fluid (CSF) as well as in the brain of a mouse or rat
at either 3 mpk, 10 mpk or 30 mpk (mpk=mg compound per kg weight of
the animal) dosing concentrations after 4 hrs. The following
examples exhibited the following percent Abeta 40 reductions at 10
mpk (unless otherwise noted) in the CSF and brain of the rat,
respectively.
TABLE-US-00005 Ex. % reduction of rat % reduction of rat No. CSF
levels at 10pmk brain levels at 10mpk 17 84 71 45 63 34 46 76 64 18
73 57 19 83 74 47 82 66 48 79 59 76 60 46 30 56 37 219 42 9 222 65
49 228 67 58 229 61 43 233 25 0 235 38 14 236 35 1 317 23 0 321 44
37 324 44 29 329 27 20 330 78 72 331 67 59 332 24 11 346 69 48 359
55 24 377 68 53 387 43 27 144 79 72 120 39 18 148 68 57 388 33 7
398 63 39 400 58 25 401 69 48 402 43 10 408 62 37 412 52 33 131 10
-18 132 31 10 177 37 24 430 31 1 158 11 -5 159 45 31 447 62 42 171
1 3 457 67 50 458 35 8 193 57 30 216 57 14
Indications
[1559] According to the amyloid cascade hypothesis, cerebral
deposition of amyloid-beta peptide (A.beta.) is critical for
Alzheimer's disease (AD) pathogenesis. A.beta. generation is
initiated when .beta.-secretase (BACE1) cleaves the amyloid
precursor protein. De Meyer et al re-affirm the believed role which
the accumulation of beta-amyloid protein (A-beta) in cerebral
spinal fluid (CSF) in a subject plays in the progression of
symptoms, initially revealed as mild cognitive impairment, which
ultimately leads to AD. Arch Neurol. 67(8):949-956, 2010. Amyloid-b
(Ab) peptides generated from amyloid precursor protein (APP) by
proteolytic cleavage, such as by aspartyl protease enzymes
including beta-secreatase (BACE) and gamma-secretase, likely play a
causal role in AD pathogenesis (Tanzi and Bertram, Cell, (120):
545-555, 2005; Walsh and Selkoe, Neuron, (44): 181-193, 2004).
Although the precise mechanisms of Ab toxicity are unclear,
oligomeric forms of Ab may contribute to cognitive decline by
altering synaptic structure and function (Palop and Mucke, Nat.
Neuroscience, (13): 812-818, 2010; Selkoe, Behavioral Brain Res.,
(192): 106-113, 2008; Shankar et al., Nat. Medicine (14): 837-842,
2008). Transgenic mouse models that overexpress mutant APP and
produce high levels of Ab show amyloid plaque deposition, synaptic
deficits, learning and memory impairments, and other behavioral
abnormalities (Games et al., Nature, (373): 523-527, 1995; Gotz et
al., Molecular Psychiatry (9): 664-683, 2004; Hsia et al., Proc.
Natl. Academy of Science USA (96): 3228-3233, 1999; Hsiao et al.,
Science (274): 99-102, 1996, citing Harris et al, Neuron (68):
428-441, 2010).
[1560] For more than a decade, BACE1 has been a prime target for
designing drugs to prevent or treat AD. However, development of
such agents has turned out to be extremely challenging, with major
hurdles in cell penetration, oral bioavailability/metabolic
clearance, and brain access.
[1561] Bapineuzamab, a monoclonal amino-terminus specific
anti-amyloid antibody is presently in Phase III clinical trials for
the treatment of AD. Alzheimer's Research & Therapy, 1:2, 2009.
Each of the known genetic causes of AD is linked to A-beta.
Dementia, Down's Syndrome to APP over-production, are all believed
to be linked to the deposition of A-beta on the brain. With methods
for identifying brain amyloid deposition, positron emission
scanning (PET) and CSF measurements of Ab42, identification of AD
suffering individuals needing treatment is becoming easier amd more
common. It is firmly believed that by reducing the formation of
A-beta, one can begin to pre-treat AD. Vassar et al, Journal of
Neuroscience, 29 (41):12787 12794, 2009. One published pathway for
treatment of AD is inhibition of beta-secretase. Tirrell, Bloomberg
News, The Boston Globe, Jan. 7, 2010.
[1562] The US biotech company CoMentis is developing an orally
bioavailable small molecule CTS-21166, a highly potent, highly
selective and efficacious brain-penetrating beta-secretase
inhibitor. CoMentis successfully completed a Phase I study of
CTS-21166 in healthy volunteers in 2008. Results indicated that
CTS-21166 was safe, well-tolerated and pharmacodynamically active
at all dose levels. All clinical subjects administered CTS-21166
showed area-under-curve (AUC) reduction in plasma A-Beta40
reductions ranging from 40-75%. Because of the urgent need for AD
treatment, Phase II studies for CTS-2166 are planned, or ongoing,
for AD patients. In preclinical studies, CTS-21166 exhibits
excellent efficacy, selectivity, brain penetration and
pharmacologic activity.
[1563] Using a fragment-based chemistry strategy, Eli Lilly and
company generated LY2811376
[(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,-
3]thiazin-2-ylamine], an orally available non-peptidic BACE1
inhibitor that produces profound A.beta.-lowering effects in
animals. The biomarker changes obtained in preclinical animal
models translate into man at doses of LY2811376 that were safe and
well tolerated in healthy volunteers (US Ph I Clinical
trial--www.clinicaltrials.gov). Prominent and long-lasting A.beta.
reductions in lumbar CSF were measured after oral dosing of 30 or
90 mg of LY2811376. This represents the first translation of
BACE1-driven biomarker changes in CNS from preclinical animal
models to man. Because of toxicology findings identified in
longer-term preclinical studies, this compound is no longer
progressing in clinical development. However, BACE1 remains a
viable target because the adverse effects reported here were
recapitulated in LY2811376-treated BACE1 KO mice and thus are
unrelated to BACE1 inhibition. The magnitude and duration of
central A.beta. reduction obtainable with BACE1 inhibition
positions this protease as a tractable small-molecule target
through which to test the amyloid hypothesis in man. Neuroscience,
31(46):16507-16515, 2011
[1564] The compounds of the invention have been shown to modulate,
and specifically inhibit the activity of the beta-secretase enzyme,
thereby reducing the A-beta peptide fragments. Accordingly,
compounds of the invention are useful for, but not limited to, the
prevention or treatment of beta-secretase related diseases,
including Alzheimer's disease. The compounds of the invention have
the ability to modulate the activity of beta secretase enzyme,
thereby regulating the production of amyloid beta (Abeta peptide)
and reducing the formation and deposition of Abeta peptide in both
the cerebral spinal fluid as well as in the brain, resulting in a
decrease of amyloid plaque on the brain. In one embodiment of the
invention, there is provided a method of treating a disorder
related to a beta-secretase enzyme in a subject, the method
comprising administering to the subject an effective dosage amount
of a compound of Formulas I, II, III, and sub-formulae thereof. In
another embodiment, there is provided a method of reducing
production of amyloid beta, and of reducing plaque formation on the
brain. In another embodiment, there is provided a method for the
treatment, prevention or amelioration of a disease or disorder
characterized by the elevated beta-amyloid deposits or beta-amyloid
levels in a subject, the method comprising administering to the
subject a therapeutically effective amount of a compound according
to any of Formulas I-III. In yet another embodiment, the invention
provides a method of treating Alzheimer's disease, cognitive
impairment including mild, moderate and/or severe, Down's Syndrome,
cognitive decline, senile dementia, cerebral amyloid angiopathy or
a neurodegenerative disorder.
[1565] Accordingly, the compounds of the invention would be useful
in therapy as CNS agents in treating neurological disorders and
related conditions in subjects.
[1566] In one embodiment, the compounds of the invention are
provided for the manufacture of a medicament, or a pharmaceutical
composition, for the therapeutic and/or prophylactic treatment of
diseases and disorders characterized by elevated levels of
.beta.-amyloid and/or .beta.-amyloid oligomers and/or b-amyloid
plaques and further deposits, including Alzheimer's Disease. In
another embodiment, the invention provides compounds, in effective
dosage amounts, for the therapeutic and/or prophylactic treatment
of AD. Thus, the compounds of the invention may be used to treat
prodromol patients, i.e., subjects exhibiting the biomarkers and/or
hallmarks of developing AD.
[1567] Besides being useful for human treatment, the compounds of
the invention may be useful for veterinary treatment of companion
animals, exotic animals and farm animals, including mammals,
rodents, and the like. For example, animals including horses, dogs,
and cats may be treated with compounds provided herein.
Formulations and Method of Use
[1568] Treatment of diseases and disorders herein is intended to
also include therapeutic administration of a compound of the
invention, or a pharmaceutical salt thereof, or a pharmaceutical
composition of either to a subject (i.e., an animal, preferably a
mammal, most preferably a human) which may be in need of
preventative treatment, such as, for example, for pain,
inflammation and the like. Treatment also encompasses prophylactic
administration of a compound of the invention, or a pharmaceutical
salt thereof, or a pharmaceutical composition of either to a
subject (i.e., an animal, preferably a mammal, most preferably a
human). Generally, the subject is initially diagnosed by a licensed
physician and/or authorized medical practitioner, and a regimen for
prophylactic and/or therapeutic treatment via administration of the
compound(s) or compositions of the invention is suggested,
recommended or prescribed.
[1569] The amount of compound(s) which is/are administered and the
dosage regimen for treating neurological disorders and
beta-secretase mediated diseases with the compounds and/or
compositions of this invention depends on a variety of factors,
including the age, weight, sex and medical condition of the
subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about
0.01 to 500 mg/kg, advantageously between about 0.01 and about 50
mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even
more advantageously between about 0.1 and about 10 mg/kg body
weight may be appropriate, and should be useful for all methods of
use disclosed herein. The daily dose can be administered in one to
four doses per day.
[1570] While it may be possible to administer a compound of the
invention alone, in the methods described, the compound
administered normally will be present as an active ingredient in a
pharmaceutical composition. Thus, in another embodiment of the
invention, there is provided a pharmaceutical composition
comprising a compound of this invention in combination with a
pharmaceutically acceptable excipient, which includes diluents,
carriers, adjuvants and the like (collectively referred to herein
as "excipient" materials) as described herein, and, if desired,
other active ingredients. A pharmaceutical composition of the
invention may comprise an "effective amount" of a compound of the
invention or an "effective dosage amount" of a compound of the
invention. An "effective dosage amount" of a compound of the
invention includes an amount less than, equal to or greater than an
effective amount of the compound. For example, a pharmaceutical
composition in which two or more unit dosages, such as in tablets,
capsules and the like, are required to administer an effective
amount of the compound, or alternatively, a multi-dose
pharmaceutical composition, such as powders, liquids and the like,
in which an effective amount of the compound is administered by
administering a portion of the composition.
[1571] The compound(s) of the present invention may be administered
by any suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended. The compounds and compositions of the
present invention may, for example, be administered orally,
mucosally, topically, rectally, pulmonarily such as by inhalation
spray, or parentally including intravascularly, intravenously,
intraperitoneally, subcutaneously, intramuscularly intrasternally
and infusion techniques, in dosage unit formulations containing
conventional pharmaceutically acceptable carriers, adjuvants, and
vehicles.
[1572] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
For example, these may contain an amount of active ingredient from
about 1 to 2000 mg, advantageously from about 1 to 500 mg, and
typically from about 5 to 150 mg. A suitable daily dose for a human
or other mammal may vary widely depending on the condition of the
patient and other factors, but, once again, can be determined using
routine methods and practices.
[1573] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants or
other "excipients" appropriate to the indicated route of
administration. If orally administered on a per dose basis, the
compounds may be admixed with lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, to form the final formulation. For example, the active
compound(s) and excipient(s) may be tableted or encapsulated by
known and accepted methods for convenient administration. Examples
of suitable formulations include, without limitation, pills,
tablets, soft and hard-shell gel capsules, troches,
orally-dissolvable forms and delayed or controlled-release
formulations thereof. Particularly, capsule or tablet formulations
may contain one or more controlled-release agents, such as
hydroxypropylmethyl cellulose, as a dispersion with the active
compound(s).
[1574] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered
by injection as a composition with suitable carriers including
saline, dextrose, or water, or with cyclodextrin (ie. Captisol),
cosolvent solubilization (ie. propylene glycol) or micellar
solubilization (ie. Tween 80).
[1575] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[1576] The active ingredient may also be administered by injection
as a composition with suitable carriers including saline, dextrose,
or water. The daily parenteral dosage regimen will be from about
0.1 to about 30 mg/kg of total body weight, and preferably from
about 0.1 to about 10 mg/kg.
[1577] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[1578] The pharmaceutical compositions may be subjected to
conventional pharmaceutical operations such as sterilization and/or
may contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and
pills can additionally be prepared with enteric coatings. Such
compositions may also comprise adjuvants, such as wetting,
sweetening, flavoring, and perfuming agents. Accordingly, in yet
another embodiment of the present invention, there is provided a
method of manufacturing a medicament, the method comprising
combining an amount of a compound according to Formulas I-III with
a pharmaceutically acceptable carrier to manufacture the
medicament.
[1579] In yet another embodiment, the invention provides a method
of manufacturing a medicament for the treatment of Alzheimer's
disease, the method comprising combining an amount of a compound
according to Formulas I-III with a pharmaceutically acceptable
carrier to manufacture the medicament.
Combinations
[1580] While the compounds of the invention can be dosed or
administered as the sole active pharmaceutical agent, they can also
be used in combination with one or more compounds of the invention
or in conjunction with other agents. When administered as a
combination, the therapeutic agents can be formulated as separate
compositions that are administered simultaneously or sequentially
at different times, or the therapeutic agents can be given as a
single composition.
[1581] The phrase "co-therapy" (or "combination-therapy"), in
defining use of a compound of the present invention and another
pharmaceutical agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[1582] Specifically, the administration of compounds of the present
invention may be in conjunction with additional therapies known to
those skilled in the art in the prevention or treatment of
beta-secretase, gamma-secretase and/or other reagents known in
influence the formation and/or deposition of amyloid beta,
otherwise responsible for the formation of plaque on the brain.
[1583] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the accepted dosage
ranges. Compounds of Formulas I, II and III may also be
administered sequentially with other known medicinal agents. The
invention is not limited in the sequence of administration;
compounds of the invention may be administered either prior to,
simultaneous with or after administration of the known
anti-inflammatory agent.
[1584] The foregoing description is merely illustrative of the
invention and is not intended to limit the invention to the
disclosed compounds, compositions and methods. Variations and
changes, which are obvious to one skilled in the art, are intended
to be within the scope and nature of the invention, as defined in
the appended claims. From the foregoing description, one skilled in
the art can easily ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions. All patents and other
publications recited herein are hereby incorporated by reference in
their entireties.
* * * * *