U.S. patent application number 14/311728 was filed with the patent office on 2014-10-09 for biaryl pde4 inhibitors for treating inflammatory, cardiovascular and cns disorders.
The applicant listed for this patent is deCODE genetics ehf. Invention is credited to Alex Burgin, Mark E. Gurney, Timothy Hagen, Georgeta Hategan, Alexander Kiselyov, Adalie Motta, Vincent Sandanayaka, Gary Schiltz, Jasbir Singh.
Application Number | 20140301999 14/311728 |
Document ID | / |
Family ID | 40376234 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140301999 |
Kind Code |
A1 |
Singh; Jasbir ; et
al. |
October 9, 2014 |
BIARYL PDE4 INHIBITORS FOR TREATING INFLAMMATORY, CARDIOVASCULAR
AND CNS DISORDERS
Abstract
The present invention relates to a genus of biaryl compounds
containing at least one further ring. The compounds are PDE4
inhibitors useful for the treatment and prevention of stroke,
myocardial infarct and cardiovascular inflammatory diseases and
disorders. The compounds have general formula I: ##STR00001## A
particular embodiment is ##STR00002##
Inventors: |
Singh; Jasbir; (Naperville,
IL) ; Gurney; Mark E.; (Grand Rapids, MI) ;
Burgin; Alex; (Kingston, WA) ; Sandanayaka;
Vincent; (Northboro, MA) ; Kiselyov; Alexander;
(San Diego, CA) ; Motta; Adalie; (Naperville,
IL) ; Schiltz; Gary; (Naperville, IL) ;
Hategan; Georgeta; (Naperville, IL) ; Hagen;
Timothy; (Lisle, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
deCODE genetics ehf |
Reykjavik |
|
IS |
|
|
Family ID: |
40376234 |
Appl. No.: |
14/311728 |
Filed: |
June 23, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13430164 |
Mar 26, 2012 |
8791267 |
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14311728 |
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12275163 |
Nov 20, 2008 |
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13430164 |
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60989551 |
Nov 21, 2007 |
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Current U.S.
Class: |
424/94.1 ;
514/210.01; 514/210.18; 514/210.2; 514/237.2; 514/295; 514/297;
514/300; 514/319; 514/345; 514/352; 514/357; 514/370; 514/381;
514/458; 514/626; 514/648; 514/690; 544/124; 546/121; 546/303;
546/311; 548/193; 548/252; 548/950; 548/952; 548/953; 564/315 |
Current CPC
Class: |
C07D 213/74 20130101;
A61K 31/4427 20130101; C07D 213/84 20130101; A61P 29/00 20180101;
C07D 213/73 20130101; C07D 401/04 20130101; A61K 31/5377 20130101;
A61P 19/10 20180101; C07D 213/89 20130101; A61K 31/44 20130101;
A61P 25/28 20180101; A61K 31/4418 20130101; A61P 1/00 20180101;
C07D 213/76 20130101; A61P 9/10 20180101; C07D 213/79 20130101;
C07D 239/42 20130101; C07C 305/24 20130101; A61K 31/136 20130101;
C07D 205/04 20130101; A61P 19/08 20180101; C07D 403/04 20130101;
A61K 31/41 20130101; A61P 13/10 20180101; C07C 217/84 20130101;
C07B 2200/05 20130101; C07D 213/65 20130101; C07D 233/90 20130101;
C07C 65/40 20130101; C07D 471/04 20130101; A61P 25/14 20180101;
C07C 69/94 20130101; A61K 45/06 20130101; C07C 275/62 20130101;
C07D 275/06 20130101; C07D 473/40 20130101; C07C 275/32 20130101;
A61P 25/24 20180101; A61K 31/397 20130101; C07D 207/16 20130101;
C07D 285/12 20130101; C07D 213/40 20130101; A61P 43/00 20180101;
A61P 19/00 20180101; C07D 285/135 20130101; A61P 25/22 20180101;
A61P 11/06 20180101; C07D 213/38 20130101; A61P 35/00 20180101;
C07D 213/75 20130101; C07D 231/12 20130101; C07D 473/18 20130101;
C07C 307/10 20130101; C07D 213/64 20130101; C07D 401/06 20130101;
A61P 11/00 20180101; A61P 9/00 20180101; C07D 213/81 20130101; A61K
31/426 20130101; A61K 31/437 20130101; A61P 25/00 20180101; C07D
257/04 20130101; C07D 277/42 20130101 |
Class at
Publication: |
424/94.1 ;
546/303; 514/345; 514/690; 564/315; 514/648; 548/252; 514/381;
548/193; 514/370; 546/311; 514/352; 546/121; 514/300; 544/124;
514/237.2; 548/952; 514/210.01; 548/950; 514/210.2; 548/953;
514/210.18; 514/297; 514/295; 514/319; 514/357; 514/626;
514/458 |
International
Class: |
C07C 217/84 20060101
C07C217/84; A61K 31/4418 20060101 A61K031/4418; A61K 45/06 20060101
A61K045/06; A61K 31/136 20060101 A61K031/136; C07D 257/04 20060101
C07D257/04; A61K 31/41 20060101 A61K031/41; C07D 277/42 20060101
C07D277/42; A61K 31/426 20060101 A61K031/426; C07D 213/73 20060101
C07D213/73; A61K 31/44 20060101 A61K031/44; C07D 471/04 20060101
C07D471/04; A61K 31/437 20060101 A61K031/437; A61K 31/5377 20060101
A61K031/5377; C07D 205/04 20060101 C07D205/04; A61K 31/397 20060101
A61K031/397; C07D 401/04 20060101 C07D401/04; A61K 31/4427 20060101
A61K031/4427; C07D 213/65 20060101 C07D213/65 |
Claims
1. A compound of formula I ##STR00477## or salt thereof wherein
R.sup.1 is an optionally substituted heterocycle chosen from
pyrazole, pyrrole, indole, quinoline, isoquinoline,
tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole,
morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine,
thiene, furan, oxazole, oxazoline, oxazolidine, isoxazolidine,
isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine,
pyridazine, azepine, pyrazolidine, imidazole, imidazoline,
imidazolidine, purine, imidazolopyridine, pyrazine, thiazolidine,
isothiazole, 1,2-thiazine-1,1-dioxide,
2,6,7-trioxabicyclo[2.2.2]octane, quinuclidine, isothiazolidine,
benzimidazole, thiadiazole, benzopyran, benzothiazole,
benzotriazole, benzoxazole, benzoxadiazole, tetrahydrofuran,
tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine
sulfoxide, thiamorpholine sulfone, oxadiazole, triazole, tetrazole,
isoindole, pyrrolopyridine triazolopyridine and the dihydro and
tetrahydro congeners thereof; R.sup.2 is an optionally substituted
carbocycle or optionally substituted heterocycle of two or fewer
rings; R.sup.3 is chosen from --C(.dbd.O)NH.sub.2,
--(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-R.sup.30,
--(C.sub.2-C.sub.6)alkyl-R.sup.31, and saturated 4- or 5-membered
heterocycle optionally substituted with methyl; R.sup.30 is chosen
from --C(.dbd.O)NH.sub.2 and 4- or 5-membered heterocycle
optionally substituted with methyl; R.sup.31 is chosen from
(C.sub.1-C.sub.4)alkoxy, amino, hydroxy,
(C.sub.1-C.sub.6)alkylamino and di(C.sub.1-C.sub.6)alkylamino;
R.sup.4 is chosen from H and F; R.sup.6 is chosen from H,
(C.sub.1-C.sub.6)alkyl and halogen; X is N, N.fwdarw.O, or
C--R.sup.5; R.sup.5 is chosen from H, halogen, OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CF.sub.3, CN,
NH.sub.2, CH.sub.2OH, CH.sub.2NH.sub.2 and C.ident.CH; and M is
chosen from --C(R.sup.20)(R.sup.21)--, --O--, --NR.sup.22--,
--S(O).sub.n--, --C(.dbd.O)--,
--C(R.sup.20)(R.sup.21)C(R.sup.20)(R.sup.21)--,
--C(R.sup.20).dbd.C(R.sup.21)--, --C(R.sup.20)(R.sup.21)--O--,
--C(R.sup.20)(R.sup.21)--NR.sup.22--,
--C(R.sup.20)(R.sup.21)--S(O).sub.n--,
--C(R.sup.20)(R.sup.21)--C(.dbd.O)--, --O--C(R.sup.20)(R.sup.21)--,
--NR.sup.22--C(R.sup.20)(R.sup.21)--,
--S(O).sub.n--C(R.sup.20)(R.sup.21)--,
--C(.dbd.O)--C(R.sup.20)(R.sup.21)-- and ##STR00478## is a five or
six-membered ring optionally substituted with methyl; and n is
zero, one or two; and R.sup.20, R.sup.21 and R.sup.22 are selected
independently in each occurrence from H and (C.sub.1-C.sub.4)alkyl;
with the provisos that: (a) when R.sup.3 is methyl, M is CH.sub.2
and R.sup.2 is a five-membered ring heterocycle, then R.sup.1
cannot be pentamethyltetralin; (b) when R.sup.3 is methyl, M is
CH.sub.2 and R.sup.1 is a five-membered ring heterocycle, then
R.sup.2 cannot be pentamethyltetralin.
2. A compound or salt according to claim 1 wherein X is N or
N.fwdarw.O: ##STR00479##
3. A compound or salt according to claim 1 wherein X is CR.sup.5 of
formula: ##STR00480## wherein R.sup.2 is chosen from pyrazolyl and
substituted phenyl.
4. A compound or salt according to claim 1 wherein M is chosen from
--CH.sub.2--, --CH(OH)--, --C[(CH.sub.3)(OH)]--,
--C[(CH.sub.3)(NH.sub.2)]--, --C(.dbd.O)--, --O--, --NH--,
--N(CH.sub.3)--, --S(O).sub.n--, --CH.sub.2NH--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH--, --CH.sub.2S(O).sub.n--,
--CH.sub.2O-- and ##STR00481##
5-6. (canceled)
7. A compound or salt according to claim 1 wherein R.sup.1 is an
optionally substituted heterocycle chosen from pyrazole,
benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide,
pyrimidine, thiene, oxazolidine, isoxazole, azetidine, piperazine,
pyrrolidine, imidazole, imidazolidine, imidazolopyridine, pyrazine,
1,2-thiazine-1,1-dioxide, benzimidazole, thiadiazole,
benzotriazole, benzoxazole, oxadiazole, triazole, tetrazole,
isoindole, pyrrolopyridine, triazolopyridine and the dihydro and
tetrahydro congeners thereof.
8-9. (canceled)
10. A compound or salt according to claim 1 wherein said
substituted heterocycle is substituted with a substituent chosen
from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl,
carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy,
haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino,
alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido,
aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl,
aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino,
dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino,
heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl,
acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl,
heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid
amides, protected residues of aminoacids, protected residues of
amino acid amides, N-methylated amino acids and N-methylated amino
acid amides.
11. A compound or salt according to claim 1 wherein said
substituted heterocycle is substituted with a substituent chosen
from --CH.sub.3, --CH.sub.2CF.sub.3, --CF.sub.3, --CHO, --COOH,
--CN, halogen, --OH, --OEt, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NHEt, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt,
--NH(tBoc), --NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc), ##STR00482##
12. A compound or salt according to claim 1 wherein R.sup.2 is
chosen from optionally substituted phenyl, optionally substituted
monocyclic unsaturated heterocycle, unsubstituted bicyclic
unsaturated heterocycle and fluoro-substituted bicyclic unsaturated
heterocycle.
13. A compound or salt according to claim 8 wherein R.sup.2 is
chosen from optionally substituted phenyl, indole, benzodioxole,
benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole,
pyridine and pyridine N-oxide.
14. A compound or salt according to claim 13 wherein R.sup.2 is
chosen from meta-substituted phenyl, indole, benzodioxole,
2,2-difluorobenzodioxole, benzooxadiazole, benzimidazole,
5-(pyridin-4-yl)[1,2,4]oxadiazole,
5-(pyridin-4-yl)[1,3,4]oxadiazole, benzodioxan, 4-chloropyrazole,
4-(pyridin-4-yl)pyrazole, 6-chloropyridine,
3-(trifluoromethyl)pyrazole, and pyridine N-oxide.
15. A compound or salt according to claim 13 wherein R.sup.2 is
substituted phenyl: ##STR00483## wherein R.sup.7 is chosen from
hydrogen, halogen, nitro, cyano, halo(C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)oxaalkyl,
carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl
(--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; and R.sup.8 and R.sup.H are chosen
independently from H and F; wherein all of R.sup.7, R.sup.8, and
R.sup.13 may not be hydrogen.
16. A compound or salt according to claim 15, wherein R.sup.8 and
R.sup.13 are H and R.sup.7 is chosen from fluoro, chloro, bromo,
nitro, cyano, acetyl, trifluoromethyl, methoxy, trifluoromethoxy,
oxadiazolyl, tetrazolyl, methylthio, methanesulfinyl,
methanesulfonyl, methansulfonamido, amino, methoxymethyl,
hydroxyethyl, and morpholinyl.
17. A compound or salt according to claim 1 wherein R.sup.1 is
chosen from optionally substituted five membered heteroaryl,
optionally substituted six-membered heteroaryl, optionally
substituted 4-7 membered non-aryl heterocycle, and optionally
substituted fused bicycle.
18. A compound or salt according to claim 17, wherein R.sup.1 is
chosen from optionally substituted five membered heteroaryls
selected from thiazoles, thiadiazoles, pyrazoles, oxadiazole,
isoxazoles, triazoles, imidazoles, thiophenes, tetrazoles and
oxazoles; optionally substituted six membered hereroaryls selected
from pyridines, pyrimidines, pyridazinones, pyrimidinone,
pyridinone, pyrazines and diazines; optionally substituted 5- and
6-membered non-aryl heterocyclics selected from
tetrahydrothiophenes, piperazine, oxazolidinones, imidazolidinones,
morpholines, piperidines, pyrrolidinones, pyrrolidinediones,
pyrrolidines, piperidinones, piperidinediones and
trioxa-bicyclo[2.2.2]octanes; and optionally substituted fused
bicycles selected from benzoxazolones, indoles, isoindolinediones,
2H-pyrrolopyridinediones, purines, indolinediones,
triazolopyridinones, benzimidazoles, benzoxadiazoles, quinolines
and quinolones; wherein the substituents are chosen independently
from hydrogen, halogen, halo(C.sub.1-C.sub.6)alkyl, hydroxyl,
(C.sub.1-C.sub.6)alkoxy, carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
aminocarbonyl (--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl,
cyano, carbonyl (oxo), acyl, hydroxy(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, nitro, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
mercapto, (C.sub.1-C.sub.6)alkylthio, sulfoxide, sulfone,
sulfonate, sulfonimide, acylamino, amidino, phenyl, benzyl,
heteroaryl, phenoxy, benzyloxy, heteroaryloxy,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl, formylamino(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkylamino,
--(CH.sub.2).sub.p--NR.sup.12CO--(CH.sub.2).sub.q--NR.sup.9R.sup.10,
--NHSO.sub.2R.sup.11,
--OCH.sub.2CH.sub.2NR.sup.9R.sup.10--NHSO.sub.2NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10, --(CH.sub.2).sub.p--NHCOR.sup.9,
OCONR.sup.9R.sup.10 and NR.sup.12COOR.sup.11; R.sup.3 is chosen
from --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3, --CHF.sub.2 and
--CH.sub.2F; R.sup.5 is chosen from H, --F, --OH, --CH.sub.3,
--OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and --C.ident.CH; R.sup.2
is (a) phenyl and R.sup.7 is chosen from H, halogen, nitro, acetyl,
hydroxyethyl, --NH.sub.2, --SCH.sub.3, methoxycarbonyl,
--SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --CN,
--CF.sub.3, --CH.sub.2OCH.sub.3; or (b) benzoxadiazole,
benzodioxole, 2,2-difluorobenzodioxole, benzoxadiazole,
benzodioxan, benzimidazole, oxadiazole, pyrazole, pyridine and
pyridine N-oxide; R.sup.9 is chosen from H, (C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarboxy(C.sub.1-C.sub.6)alkyl; R.sup.10 is
H, (C.sub.1-C.sub.6)alkyl, or taken together, or R.sup.9 and
R.sup.10 together form a heterocycle optionally substituted with
(C.sub.1-C.sub.6)alkyl; p is 0 or 1, q is 0, 1 or 2, R.sup.11 is
linear (C.sub.1-C.sub.6)alkyl, R.sup.12 is H or
(C.sub.1-C.sub.6)alkyl; or two adjacent substituents together form
an optionally substituted fused heterocyclic ring; with the
provisos that (i) when R.sup.5 is H, R.sup.3 is --CH.sub.3 and
R.sup.1 is substituted or unsubstituted pyrazole, then R.sup.2 is
m-nitrophenyl or optionally substituted heterocycle; (ii) when
R.sup.5 is H, R.sup.3 is --CH.sub.3, and R.sup.2 is
meta-(trifluoromethyl)phenyl, then R.sup.1 is not ##STR00484##
(iii) when R.sup.5 is H, R.sup.3 is --CH.sub.3, and R.sup.2 is
m-nitrophenyl then R.sup.1 is not ##STR00485## and (iv) when
R.sup.5 is H, R.sup.3 is --CH.sub.3, and R.sup.2 is m-methoxyphenyl
or m-acetylphenyl, then R.sup.1 is not ##STR00486##
19. A compound or salt according to claim 1 of formula ##STR00487##
wherein R.sup.1a is phenyl, five-membered heteroaryl, six-membered
heteroaryl, 4-7 membered non-aryl heterocycle or fused bicycle;
R.sup.14 is chosen from H, --CH.sub.2NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NHEt, --CH.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2NHC(.dbd.O)CH.sub.3, --NHCH.sub.3,
--NHEt, --NH(tBoc), --CHO, --NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl,
--NHSO.sub.2NH.sub.2, --NHEt, --N(CH.sub.3).sub.2, --NH.sub.2,
--COOH, --C(.dbd.O)NH.sub.2, --CH.sub.2C(.dbd.O)NH.sub.2,
--CH.sub.2COOH, --CH.sub.2COOEt, --CN, --OCH.sub.3,
--OC(.dbd.O)NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2, halogen,
--CH.sub.2NHC(.dbd.O)OEt, --NHSO.sub.2CH.sub.3,
--N(SO.sub.2CH.sub.3).sub.2, --NHC(.dbd.O)OCH.sub.3, --OH,
--CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --SO.sub.2NH.sub.2,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --COOCH.sub.3, --COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt, --NH(Et)C(.dbd.O)OEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH, --CH.sub.2NHSO.sub.2CH.sub.3,
--OEt, --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
3'-nitro-6-methoxybiphenyl-3-ylmethyl,
tetrahydroimidazol-2-on-1-yl,
3-methyltetrahydroimidazol-2-one-1-yl, pyrazol-1-yl, ##STR00488##
R.sup.15 is chosen from H, NO.sub.2, OH, NH.sub.2, and
--NHSO.sub.2NH.sub.2; or R.sup.15 together with R.sup.14 forms
methylene dioxy; wherein both of R.sup.14 and R.sup.15 may not be
hydrogen; R.sup.27 is chosen from hydrogen, halogen, nitro, cyano,
halo(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; R.sup.28 is chosen from H and F, or
R.sup.27 together with R.sup.28 forms a five-membered ring wherein
both of R.sup.27 and R.sup.28 may not be hydrogen.
20. A compound or salt according to claim 19 wherein R.sup.27 and
R.sup.28 represent a fused heterocycle at 3- and 4-positions so
that the residue formed from R.sup.27 and R.sup.28 together with
the phenyl to which they are attached is chosen from:
##STR00489##
21. A compound or salt according to claim 19 wherein R.sup.27 is
chosen from halogen, nitro, acetyl, hydroxyethyl, amino,
methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl,
trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken
together R.sup.7 and R.sup.8 are methylenedioxy or
difluoromethylenedioxy.
22. A compound or salt according to claim 21 wherein R.sup.1a is
chosen from a triazole, a pyridine or pyridine-N-oxide, a pyrazole,
a tetrahydrothiophene, an imidazole, a pyrimidine, a thiadiazole,
and an imidazopyridine.
23. A compound or salt according to claim 1 wherein R.sup.5 is
fluoro, H, CN or OH.
24. A compound or salt according to claim 1 wherein R.sup.3 is
methyl or fluoromethyl.
25. A compound or salt according to claim 1 of formula:
##STR00490## wherein R.sup.3 is methyl or fluorinated methyl; Y is
N; R.sup.27a is chosen from halogen, cyano, acetyl, methylthio,
nitro and trifluoromethyl; and R.sup.16 is chosen from
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19 and ##STR00491## wherein
##STR00492## is a 4-7 membered ring heterocycle attached through
its nitrogen; R.sup.17, and R.sup.18 are independently chosen from
H, (C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkyl; R.sup.19
is chosen from H, (C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, --[(C.sub.1-C.sub.6)alkyl]COOH, and
--[(C.sub.1-C.sub.6)alkyl]COO(C.sub.1-C.sub.6)alkyl; and R.sup.20
is chosen from a carboxylic acid, a carboxamide, a carboxylic
ester, a primary, secondary or tertiary alcohol and a primary,
secondary or tertiary amine.
26. A compound or salt according to claim 25 wherein X is CH, CF or
N--O; M is --CH.sub.2-- or --S--; R.sup.27a is chosen from chloro,
cyano, acetyl and methylthio; and R.sup.16 is chosen from
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19, ##STR00493##
27. A compound or salt according to claim 26 wherein Y is CH; M is
--CH.sub.2--; R.sup.27a is chloro; and R.sup.16 is
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19.
28. A compound or salt according to claim 27 wherein R.sup.16 is
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19 and R.sup.17, R.sup.18 and
R.sup.10 are all hydrogen.
29. (canceled)
30. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound or pharmaceutically acceptable
salt according to claim 1 and optionally a second agent chosen from
cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and
antioxidants.
31. (canceled)
32. A pharmaceutical composition according to claim 30 wherein said
second agent is chosen from tacrine, huperzine, donepezil,
lanicemine, remacemide, neramexane, memantine, vitamin E and
coenzyme Q10.
33. A method for the treatment or prophylaxis of a disease or
condition mediated by phosphodiesterase-4 comprising administering
to a mammal a therapeutically effective amount of a compound
according to claim 1, wherein said disease or condition is chosen
from stroke, myocardial infarct, cardiovascular inflammatory
conditions, cancer, asthma, or COPD.
34-36. (canceled)
37. A method for improving cognitive function, or for treating
schizophrenia or Huntington's disease, depression or anxiety,
bladder inflammation, bladder overactivity, pain arising from
bladder inflammation, or bone loss, comprising administering to a
mammal a therapeutically effective amount of a compound according
to claim 1.
38-43. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
application 60/989,551, filed Nov. 21, 2007, the entire disclosure
of which is incorporated herein by reference. The application is
related to, but does not claim priority from, four other US
non-provisional applications filed of even date herewith and having
Jasbir Singh as a common inventor. The applications are titled
"BIARYL PDE4 INHIBITORS FOR TREATING PULMONARY AND CARDIOVASCULAR
DISORDERS", "SUBSTITUTED BENZOAZOLE PDE4 INHIBITORS FOR TREATING
INFLAMMATORY, CARDIOVASCULAR AND CNS DISORDERS", "SUBSTITUTED
BENZOAZOLE PDE4 INHIBITORS FOR TREATING PULMONARY AND
CARDIOVASCULAR DISORDERS" and "4- (OR 5-) SUBSTITUTED CATECHOL
DERIVATIVES". Their disclosures are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a chemical genus of biaryl
inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment
and prevention of stroke, myocardial infarct, cardiovascular
inflammatory diseases and central nervous system disorders.
BACKGROUND OF THE INVENTION
[0003] PDE4 is the major cAMP-metabolizing enzyme found in
inflammatory and immune cells. PDE4 inhibitors have proven
potential as anti-inflammatory drugs, especially in inflammatory
pulmonary diseases such as asthma, COPD and rhinitis. They suppress
the release of cytokines and other inflammatory signals and inhibit
the production of reactive oxygen species. A large number of PDE4
inhibitors have been developed for a variety of clinical
indications (Torphy and Page. 2000. TIPS 21, 157-159; Burnouf and
Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005.
Lancet 365, 167-175). To quote from a recent article in the British
Journal of Pharmacology, "PDE4 inhibitors have been in development
as a novel anti-inflammatory therapy since the 1980s with asthma
and chronic obstructive pulmonary disease (COPD) being primary
indications. Despite initial optimism, none have yet reached the
market. In most cases, the development of PDE4 inhibitors of
various structural classes, including cilomilast, filaminast,
lirimilast, piclamilast, tofimilast . . . has been discontinued due
to lack of efficacy. A primary problem is the low therapeutic ratio
of these compounds, which severely limits the dose that can be
given. Indeed, for many of these compounds it is likely that the
maximum tolerated dose is either sub-therapeutic or at the very
bottom of the efficacy dose-response curve. Therefore, the
challenge is to overcome this limitation." [Giembycz, Brit. J.
Pharmacol. 155, 288-290 (2008)]. Many of the PDE4 inhibitors of the
prior art have not reached the market because of the adverse side
effect of emesis (Giembycz 2005. Curr. Opin. Pharm. 5, 238-244).
Analysis of all known PDE4 inhibitors suggests that they are
competitive with cAMP and bind within the active site (Houslay et
al. 2005. DDT 10, 1503-1519); this may explain their narrow
therapeutic ratio. The compounds of the present invention are
non-competitive inhibitors of cAMP while being gene-specific
inhibitors (PDE4D), and, based on the target rationale and in vitro
potency, a person of skill in the art would expect the compounds to
be useful as anti-inflammatory agents for the treatment,
amelioration or prevention of inflammatory diseases and of
complications arising therefrom and useful as CNS agents for
amelioration of the cognitive decline in Alzheimer's disease,
Parkinson's disease, the treatment of schizophrenia and depression,
and neuroprotective in Huntington's disease.
SUMMARY OF THE INVENTION
[0004] The present invention relates to compounds exhibiting PDE4
enzyme inhibition, having the general formula I
##STR00003##
[0005] In these compounds,
R.sup.1 is an optionally substituted carbocycle or optionally
substituted heterocycle of three or fewer rings; R.sup.2 is an
optionally substituted carbocycle or optionally substituted
heterocycle of two or fewer rings; R.sup.3 is chosen from H,
--C(.dbd.O)NH.sub.2, --(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-R.sup.30,
--(C.sub.2-C.sub.6)alkyl-R.sup.31, and saturated 4- or 5-membered
heterocycle optionally substituted with methyl; R.sup.30 is chosen
from --C(.dbd.O)NH.sub.2 and 4- or 5-membered heterocycle
optionally substituted with methyl; R.sup.31 is chosen from
(C.sub.1-C.sub.4)alkoxy, amino, hydroxy,
(C.sub.1-C.sub.6)alkylamino and di(C.sub.1-C.sub.6)alkylamino;
R.sup.4 is chosen from H and F; R.sup.6 is chosen from H,
(C.sub.1-C.sub.6)alkyl and halogen;
X is N, N.fwdarw.O, or C--R.sup.5;
[0006] R.sup.5 is chosen from H, halogen, OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CF.sub.3, CN,
NH.sub.2, CH.sub.2OH, CH.sub.2NH.sub.2 and C.ident.CH; and M is
chosen from direct bond, --C(R.sup.20)(R.sup.21)--, --O--,
--NR.sup.22--, --S(O).sub.n--, --C(.dbd.O)--,
--C(R.sup.20)(R.sup.21)C(R.sup.20)(R.sup.21)--,
--C(R.sup.20).dbd.C(R.sup.21)--, --C(R.sup.20)(R.sup.21)--O--,
--C(R.sup.20)(R.sup.21)--NR.sup.22--,
--C(R.sup.20)(R.sup.21)--S(O).sub.n--,
--C(R.sup.20)(R.sup.21)--C(.dbd.O)--, --O--C(R.sup.20)(R.sup.21)--,
--NR.sup.22--C(R.sup.20)(R.sup.21)--,
--S(O).sub.n--C(R.sup.20)(R.sup.21)--,
--C(.dbd.O)--C(R.sup.20)(R.sup.21)-- and
##STR00004##
is a five or six-membered ring optionally substituted with methyl;
n is zero, one or two; and R.sup.20, R.sup.21 and R.sup.22 are
selected independently in each occurrence from H and
(C.sub.1-C.sub.4)alkyl.
[0007] The present invention also relates to two subgenera of
compounds of formula I. The first, in which X is N or N.fwdarw.O,
is represented by the formulae:
##STR00005##
[0008] The second, in which X is CR.sup.5 is represented by the
formula:
##STR00006##
[0009] The present invention also relates to pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of at least one compound of the
general formula I described above. When the compound is present as
a salt, the salt should be a pharmaceutically acceptable salt.
[0010] In a third aspect, the invention relates to methods for the
treatment or prophylaxis of a disease or condition mediated by
phosphodiesterase-4. The methods comprise administering to a mammal
a therapeutically effective amount of a compound having the general
formula I. The disease or condition may be related to allergic,
acute or chronic inflammation. The disease may be, for example,
atherosclerosis, thrombosis, stroke, acute coronary syndrome,
stable angina, peripheral vascular disease, critical leg ischemia,
intermittent claudication, abdominal aortic aneurysm or myocardial
infarction.
[0011] Selective PDE4 inhibitors of the invention are expected to
be useful in improving cognition and thus useful for treating
learning disorders, memory loss and other cognitive dysfunctions.
Selective PDE4 inhibitors of the invention are also useful for
treating asthma and Chronic Obstructive Pulmonary Disease (COPD).
Compounds of the invention, which inhibit tumor growth and
metastases, also find utility in the treatment and prevention of
cancer, including esophageal cancer, brain cancer, pancreatic
cancer, and colon cancer.
[0012] These and other embodiments of the present invention will
become apparent in conjunction with the description and claims that
follow.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Throughout this specification the substituents are defined
when introduced and retain their definitions.
[0014] Unless otherwise specified, alkyl is intended to include
linear, branched, or cyclic hydrocarbon structures and combinations
thereof. A combination would be, for example, cyclopropylmethyl.
Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms.
Examples of lower alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, s- and t-butyl and the like. Preferred alkyl
groups are those of C.sub.20 or below; C.sub.1 to C.sub.8 are more
preferred. Cycloalkyl is a subset of alkyl and includes cyclic
hydrocarbon groups of from 3 to 8 carbon atoms. Examples of
cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl
and the like.
[0015] C.sub.1 to C.sub.20 hydrocarbon includes alkyl, cycloalkyl,
polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof.
Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and
naphthylethyl. Hydrocarbon refers to any substituent comprised of
hydrogen and carbon as the only elemental constituents.
[0016] Unless otherwise specified, the term "carbocycle" is
intended to include ring systems in which the ring atoms are all
carbon but of any oxidation state. Thus (C.sub.3-C.sub.10)
carbocycle refers to both non-aromatic and aromatic systems,
including such systems as cyclopropane, benzene, cyclopentene and
cyclohexene; (C.sub.8-C.sub.12) carbopolycycle refers to such
systems as norbornane, decalin, indane and naphthalene. Carbocycle,
if not otherwise limited, refers to monocycles, bicycles and
polycycles.
[0017] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon
atoms of a straight, branched or cyclic configuration and
combinations thereof attached to the parent structure through an
oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to
groups containing one to four carbons. For the purpose of this
application, alkoxy and lower alkoxy include methylenedioxy and
ethylenedioxy. Alkoxyalkyl refers to ether groups of from 3 to 8
atoms of a straight, branched, cyclic configuration and
combinations thereof attached to the parent structure through an
alkyl. Examples include methoxymethyl, methoxyethyl, ethoxypropyl,
and the like. Alkoxyaryl refers to alkoxy substituents attached to
an aryl, wherein the aryl is attached to the parent structure.
Arylalkoxy refers to aryl substituents attached to an oxygen,
wherein the oxygen is attached to the parent structure. Substituted
arylalkoxy refers to a substituted aryl substituent attached to an
oxygen, wherein the oxygen is attached to the parent structure.
[0018] Oxaalkyl refers to alkyl residues in which one or more
carbons (and their associated hydrogens) have been replaced by
oxygen. Examples include methoxypropoxy; 3,6,9-trioxadecyl;
2,6,7-trioxabicyclo[2.2.2]octane and the like. The term oxaalkyl is
intended as it is understood in the art [see Naming and Indexing of
Chemical Substances for Chemical Abstracts, published by the
American Chemical Society, 196, but without the restriction of
127(a)], i.e. it refers to compounds in which the oxygen is bonded
via a single bond to its adjacent atoms (forming ether bonds); it
does not refer to doubly bonded oxygen, as would be found in
carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl
residues in which one or more carbons has been replaced by sulfur
or nitrogen, respectively. Examples include ethylaminoethyl and
methylthiopropyl.
[0019] Unless otherwise specified, acyl refers to formyl and to
groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight,
branched, cyclic configuration, saturated, unsaturated and aromatic
and combinations thereof, attached to the parent structure through
a carbonyl functionality. One or more carbons in the acyl residue
may be replaced by nitrogen, oxygen or sulfur as long as the point
of attachment to the parent remains at the carbonyl. Examples
include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,
benzyloxycarbonyl and the like. Lower-acyl refers to groups
containing one to four carbons. The double bonded oxygen, when
referred to as a substituent itself is called "oxo".
[0020] Aryl and heteroaryl mean (i) a phenyl group (or benzene) or
a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4
heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or
10-membered aromatic or heteroaromatic ring system containing 0-4
heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or
14-membered aromatic or heteroaromatic ring system containing 0-5
heteroatoms selected from O, N, or S. Aryl, as understood herein,
includes residues in which one or more rings are aromatic, but not
all need be. Thus aromatic 6- to 14-membered carbocyclic rings
include, e.g., benzene, naphthalene, indane, tetralin, and fluorene
and the 5- to 10-membered aromatic heterocyclic rings include,
e.g., imidazole, pyridine, indole, thiophene, benzopyranone,
thiazole, furan, benzimidazole, quinoline, isoquino line,
quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
[0021] Arylalkyl refers to a substituent in which an aryl residue
is attached to the parent structure through alkyl. Examples are
benzyl, phenethyl and the like. Heteroarylalkyl refers to a
substituent in which a heteroaryl residue is attached to the parent
structure through alkyl. In one embodiment, the alkyl group of an
arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6
carbons. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl
and the like.
[0022] Heterocycle means a cycloalkyl or aryl carbocycle residue in
which from one to three carbons is replaced by a heteroatom
selected from the group consisting of N, O and S. The nitrogen and
sulfur heteroatoms may optionally be oxidized, and the nitrogen
heteroatom may optionally be quaternized. Unless otherwise
specified, a heterocycle may be non-aromatic or aromatic. It is to
be noted that heteroaryl is a subset of heterocycle in which the
heterocycle is aromatic. Examples of heterocyclic residues that
fall within the scope of the invention include pyrazole, pyrrole,
indole, quinoline, isoquino line, tetrahydroisoquino line, benzo
furan, benzodioxan, benzodioxole (commonly referred to as
methylenedioxyphenyl, when occurring as a substituent), morpholine,
thiazole, pyridine (including 2-oxopyridine), pyridine N-oxide,
pyrimidine, thiophene (i.e. thiene), furan, oxazole, oxazoline,
oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine,
piperazine, piperidine, pyrrolidine, pyridazine, azepine,
pyrazolidine, imidazole, imidazo line, imidazolidine,
imidazolopyridine, pyrazine, thiazolidine, isothiazole,
1,2-thiazine-1,1-dioxide, quinuclidine, isothiazolidine,
benzimidazole, thiadiazole, benzopyran, benzothiazole,
benzotriazole, benzoxazole, tetrahydrofuran, tetrahydropyran,
benzothiene, thiamorpholine, thiamorpholine sulfoxide,
thiamorpholine sulfone, oxadiazole, triazole, tetrazole, isatin
(dioxoindole), phthalimide (dioxoisoindole), pyrrolopyridine,
triazolopyridine and the dihydro and tetrahydro congeners of the
fully unsaturated ring systems among the foregoing.
[0023] An oxygen heterocycle is a heterocycle containing at least
one oxygen in the ring; it may contain additional oxygens, as well
as other heteroatoms. Oxygen heterocycles found in the examples of
the invention include tetrahydrofuran, benzodioxole, morpholine,
isoxazole and 2,6,7-trioxabicyclo[2.2.2]octane. A sulphur
heterocycle is a heterocycle containing at least one sulphur in the
ring; it may contain additional sulphurs, as well as other
heteroatoms. A nitrogen heterocycle is a heterocycle containing at
least one nitrogen in the ring; it may contain additional
nitrogens, as well as other heteroatoms.
[0024] As used herein, the term "optionally substituted" may be
used interchangeably with "unsubstituted or substituted". The term
"substituted" refers to the replacement of one or more hydrogen
atoms in a specified group with a specified radical. For example,
substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to
alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H
atoms in each residue are replaced with halogen, haloalkyl, alkyl,
acyl, alkoxyalkyl, hydroxyalkyl, carbonyl (i.e. oxo), phenyl,
heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl,
carboxy, alkoxycarbonyl [--C(.dbd.O)O-alkyl], alkoxycarbonylamino
[--NHC(.dbd.O)O-alkyl], alkoxycarbonylaminoalkyl
[-alkyl-NHC(.dbd.O)O-alkyl], carboxyalkylcarbonylamino
[--NHC(.dbd.O)-alkyl-COOH], carboxamido [--C(.dbd.O)NH.sub.2],
aminocarbonyloxy [--OC(.dbd.O)NH.sub.2], alkylaminocarbonyl
[--C(.dbd.O)NH-alkyl], dialkylaminocarbonyl
[--C(.dbd.O)N(alkyl).sub.2], aminocarbonylalkyl
[-alkyl-C(.dbd.O)NH.sub.2], cyano, acetoxy, nitro, amino,
alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl,
alkylaminoalkyl (including cycloalkylaminoalkyl),
dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino,
heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl,
acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl,
heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, and benzyloxy. Although oxo is included among the
substituents referred to in "optionally substituted", it will be
appreciated by persons of skill in the art that, because oxo is a
divalent radical, there are circumstances in which it will not be
appropriate as a substituent (e.g. on phenyl). Additional
substituents that are considered within the scope of the term,
particularly for R.sup.1, are the are the residues of amino acids,
amino acid amides, protected residues of aminoacids and their
amides, and N-methylated (mono- or di-, as appropriate) amino acids
and amino acid amides.
[0025] For the purpose of R.sup.1, the substituents alkyl, acyl,
alkoxyalkyl, hydroxyloweralkyl, phenyl, heteroaryl,
benzenesulfonyl, loweralkoxy, haloalkoxy, oxaalkyl, alkoxycarbonyl,
alkoxycarbonylamino, carboxamido, alkylaminocarbonyl, amino,
alkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl,
heterocyclylalkoxy, alkylthio, sulfonylamino, alkylsulfinyl,
alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino,
aryl, benzyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy,
phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, oxaalkyl,
amino sulfonyl, amidino, guanidino, ureido, benzyloxyphenyl, and
benzyloxy may be further substituted with one or two substituents
from the list of substituents above. Substituents that are
considered within the scope of the term, particularly for R.sup.1,
are the are the residues of amino acids, amino acid amides and
protected residues of amino acids and their amides, as well as the
following specific residues: --CH.sub.3, --CH.sub.2CF.sub.3,
--CF.sub.3, --CHO, --COOH, --CN, halogen, --OH, --OEt,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2OC(.dbd.O)NHEt, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt,
--NH(tBoc), --NHCH.sub.2COOH ("residue of glycine"),
--N(CH.sub.3)CH.sub.2COOH ("residue of N-methylglycine"),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
##STR00007##
The term "a residue of an amino acid, amino acid amide", etc.
refers to an amino acid etc. minus the functional groups that are
considered part of the bond to the parent structure. For example,
in the molecule P-143 illustrated below:
##STR00008##
after one subtracts the hydrogen that connects (BOC)glycinamide to
the phenyl ring, the structure of A that remains is:
##STR00009##
This is not sensu stricto a protected amino acid amide, since it
lacks the hydrogen on the C-terminal amide. This and similar
structures that lack atoms at the points of attachment (e.g. the OH
of COOH or the H of NH.sub.2) are referred to herein as "residues"
of their respective parents.
[0026] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy,
respectively, substituted with one or more halogen atoms. The terms
"alkylcarbonyl" and "alkoxycarbonyl" mean --C(.dbd.O)alkyl or
--C(O)alkoxy, respectively.
[0027] The term "halogen" means fluorine, chlorine, bromine or
iodine. In one embodiment, halogen may be fluorine or chlorine.
[0028] Substituents R.sup.n are generally defined when introduced
and retain that definition throughout the specification and in all
independent claims.
[0029] In the characterization of some of the substituents, it is
recited that certain substituents may combine to form rings. Unless
stated otherwise, it is intended that such rings may exhibit
various degrees of unsaturation (from fully saturated to fully
unsaturated), may include heteroatoms and may be substituted with
lower alkyl or alkoxy.
[0030] It will be recognized that the compounds of this invention
can exist in radiolabeled form, i.e., the compounds may contain one
or more atoms containing an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and
chlorine include .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.35S, .sup.18F, and .sup.36Cl, respectively. Compounds that
contain those radioisotopes and/or other radioisotopes of other
atoms are within the scope of this invention. Tritiated, i.e.
.sup.3H, and carbon-14, i.e., .sup.14C, radioisotopes are
particularly preferred for their ease in preparation and
detectability. Compounds that contain isotopes .sup.11C, .sup.13N,
.sup.15O and .sup.18F are well suited for positron emission
tomography. Radiolabeled compounds of formula I of this invention
and prodrugs thereof can generally be prepared by methods well
known to those skilled in the art. Conveniently, such radio labeled
compounds can be prepared by carrying out the procedures disclosed
in the Examples and Schemes by substituting a readily available
radiolabeled reagent for a non-radio labeled reagent.
[0031] As used herein (particularly in the claims), and as would be
understood by the person of skill in the art, the recitation of "a
compound" is intended to include salts, solvates, co-crystals and
inclusion complexes of that compound as well as any stereoisomeric
form, or a mixture of any such forms of that compound in any ratio.
Thus, in accordance with some embodiments of the invention, a
compound as described herein, including in the contexts of
pharmaceutical compositions, methods of treatment, and compounds
per se, is provided as the salt form. Thus, for example, the
recitation "a compound of formula I" as depicted above, in which
R.sup.1 is imidazolyl, would include imidazolium salts. In a
particular embodiment, the term "compound of formula I" refers to
the compound or a pharmaceutically acceptable salt thereof.
[0032] The compounds described herein may contain asymmetric
centers and may thus give rise to enantiomers, diastereomers, and
other stereoisomeric forms. Each chiral center may be defined, in
terms of absolute stereochemistry, as (R)- or (S)-. The present
invention is meant to include all such possible isomers, in any
ratio from racemic to optically pure forms. Optically active (R)-
and (S)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques. The prefix
"rac" refers to a racemate. When the compounds described herein
contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended that the
compounds include both E and Z geometric isomers. The
representation of the configuration of any carbon-carbon double
bond appearing herein is selected for convenience only, and unless
explicitly stated, is not intended to designate a particular
configuration. Thus a carbon-carbon double bond depicted
arbitrarily as E may be Z, E, or a mixture of the two in any
proportion. Likewise, all tautomeric forms are also intended to be
included.
[0033] The term "solvate" refers to a compound of Formula I in the
solid state, wherein molecules of a suitable solvent are
incorporated in the crystal lattice. A suitable solvent for
therapeutic administration is physiologically tolerable at the
dosage administered. Examples of suitable solvents for therapeutic
administration are ethanol and water. When water is the solvent,
the solvate is referred to as a hydrate. In general, solvates are
formed by dissolving the compound in the appropriate solvent and
isolating the solvate by cooling or using an antisolvent. The
solvate is typically dried or azeotroped under ambient conditions.
Inclusion complexes are described in Remington: The Science and
Practice of Pharmacy 19.sup.th Ed. (1995) volume 1, page 176-177,
which is incorporated herein by reference. The most commonly
employed inclusion complexes are those with cyclodextrins, and all
cyclodextrin complexes, natural and synthetic, are specifically
encompassed within the claims.
[0034] The term "pharmaceutically acceptable salt" refers to salts
prepared from pharmaceutically acceptable non-toxic acids or bases
including inorganic acids and bases and organic acids and bases.
When the compounds of the present invention are basic, salts may be
prepared from pharmaceutically acceptable non-toxic acids including
inorganic and organic acids. Suitable pharmaceutically acceptable
anions for the compounds of the present invention include acetate,
benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate,
carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate,
gluconate, glutamate, glycolate, bromide, chloride, isethionate,
lactate, maleate, malate, mandelate, methanesulfonate, mucate,
nitrate, pamoate, pantothenate, phosphate, succinate, sulfate,
tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate,
adipate, alginate, aminosalicylate, anhydromethylenecitrate,
ascorbate, aspartate, calcium edetate, camphorate, camsylate,
caprate, caproate, caprylate, cinnamate, cyclamate,
dichloroacetate, edetate (EDTA), edisylate, embonate, estolate,
esylate, fluoride, formate, gentisate, gluceptate, glucuronate,
glycerophosphate, glycolate, glycollylarsanilate, hexylresorcinate,
hippurate, hydroxynaphthoate, iodide, lactobionate, malonate,
mesylate, napadisylate, napsylate, nicotinate, oleate, orotate,
oxalate, oxoglutarate, palmitate, pectinate, pectinate polymer,
phenylethylbarbiturate, picrate, pidolate, propionate, rhodanide,
salicylate, sebacate, stearate, tannate, theoclate, tosylate and
the like. The desired salt may be obtained by ion exchange of
whatever counter ion is obtained in the synthesis of the quat.
These methods are well known to persons of skill. Although
pharmaceutically acceptable counter ions will be preferred for
preparing pharmaceutical formulations, other anions are quite
acceptable as synthetic intermediates. When the compounds contain
an acidic side chain, suitable pharmaceutically acceptable base
addition salts for the compounds of the present invention include
metallic salts made from aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc or organic salts made from lysine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine.
[0035] The graphic representations of racemic, ambiscalemic and
scalemic or enantiomerically pure compounds used herein are taken
from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges
are used to denote the absolute configuration of a chiral element;
wavy lines and single thin lines indicate disavowal of any
stereochemical implication which the bond it represents could
generate; solid and broken bold lines are geometric descriptors
indicating the relative configuration shown but denoting racemic
character; and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute
configuration.
[0036] Terminology related to "protecting", "deprotecting" and
"protected" functionalities occurs throughout this application.
Such terminology is well understood by persons of skill in the art
and is used in the context of processes that involve sequential
treatment with a series of reagents. In that context, a protecting
group refers to a group, which is used to mask a functionality
during a process step in which it would otherwise react, but in
which reaction is undesirable. The protecting group prevents
reaction at that step, but may be subsequently removed to expose
the original functionality. The removal or "deprotection" occurs
after the completion of the reaction or reactions in which the
functionality would interfere. Thus, when a sequence of reagents is
specified, as it is in the processes of the invention, the person
of ordinary skill can readily envision those groups that would be
suitable as "protecting groups". Suitable groups for that purpose
are discussed in standard textbooks in the field of chemistry, such
as Protective Groups in Organic Synthesis by T. W. Greene [John
Wiley & Sons, New York, 1991], which is incorporated herein by
reference.
[0037] A comprehensive list of abbreviations utilized by organic
chemists appears in the first issue of each volume of the Journal
of Organic Chemistry. The list, which is typically presented in a
table entitled "Standard List of Abbreviations", is incorporated
herein by reference.
[0038] In general, the compounds of the present invention may be
prepared by the methods illustrated in the general reaction schemes
as, for example, described below, or by modifications thereof,
using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants that are in themselves known, but
are not mentioned here. The starting materials, are either
commercially available, synthesized as described in the examples or
may be obtained by the methods well known to persons of skill in
the art.
[0039] PDE4 inhibitors have been shown to be effective therapeutic
agents in clinical studies. For example, administration of
cilomilast and roflumilast (PDE4 inhibitors) to patients suffering
from asthma and COPD showed initially excellent results, although
the effect of cilomilast disappeared on long-term trial [Lipworth,
Lancet 365, 167-175 (2005)]. Genetic studies have clearly
demonstrated an association between PDE4D and ischemic stroke
(Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). L-454,560, a
selective PDE4 inhibitor has been shown to improve learning in a
rat model in vivo [Huang et al. Biochemical Pharmacology 73,
1971-1981 (2007)]. This suggests that selective PDE4 inhibitors
will be useful in treating learning disorders, memory loss (e.g.
Alzheimer's disease) and other cognitive dysfunctions. Rolipram,
another selective PDE4 inhibitor, has been shown to enhance
cognition in multiple rodent models [Blokland et al., Current
Pharmaceutical Design 12, 2511-2523 (2006)] as well as in primates
[Rutten et al., 2008, Psychopharmacology 196, 643-648 (2008)].
Rolipram also improves the outcome in two separate studies in mice
in vivo in models accepted by persons of skill in the art as
predictive of utility in schizophrenia [Kanes et al., Neuroscience
144, 239-246 (2007); Davis and Gould, Behav. Neurosci. 119, 595-602
(2005)]. Rolipram has also been shown to exhibit a neuroprotective
effect in a rat model of Huntington's disease [DeMarch et al.
Neurobiol. Dis. 25, 266-273 (2007)]. This suggests that PDE4
modulators will be useful for treating many CNS disorders.
Selective PDE4 inhibitors (e.g. rolipram) are also useful for
treating bone loss [Yao et al., J. Musculoskelet. Neuronal
Interact. 7, 119-130 (2007)].
[0040] Additionally, a PDE4 inhibitor, YM976, was shown to
ameliorate the effects of experimentally-induced interstitial
cystitis in rats, resulting in a decrease in the frequency of
urination and an increase in the volume of urine at each time of
urination [Kitta et al., BJU Int. 102, 1472-1476 (2008)]. Another
PDE4 inhibitor, IC485, was shown to be equally efficacious as
tolteradine tartrate, a marketed drug for treating overactive
bladder, in a rodent model of obstructive bladder [Kaiho et al. BJU
Int. 101, 615-20 (2008)]. These findings suggest that PDE4
inhibitors will be useful in treating symptoms of bladder
overactivity, inflammation and pain.
[0041] In addition to the foregoing studies demonstrating utility
in in vivo models, a number of authors have suggested connections
between PDE4 inhibition and putative utilities as antidepressants
[Houslay et al., Drug Discov Today 10, 1503-1519 (2005); Polesskaya
et al., Biol. Psychiatr. 61, 56-64 (2007); anon. Current Opin.
Invetig. Drugs 5, 34-39 (2004)] and as anxiolytics [Zhang et al.,
Neuropsychopharmacology Aug. 15, 2007 Epub; Chemy et al., Biochim.
Biophys. Acta 1518, 27-35 (2001)]. Rolipram has been shown in human
clinical trials to ameliorate depression [Hebenstreit et al.,
Pharmacopsychiat. 22, 156-160 (1989)]. Other possible utilities may
include Pick's disease and epilepsy.
[0042] Furthermore, the compounds, compositions and methods of the
present invention may be useful in treating cancer.
Phosphodiesterase activity has been shown to be associated with
hematological malignancies [Lerner et al., Biochem. J. 393, 21-41
(2006); Ogawa et al., Blood 99, 3390-3397 (2002)]. The compounds
may also be administered to overcome cognitive impairment induced
by one or more of the following agents, alcohol, amphetamine,
antipsychotic medication, anti-retroviral therapy, MDMA
(3,4-methylenedioxy-N-methylamphetamine, cannabis, cocaine, delta-9
tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other
opiates, ketamine and metamphetamine.
[0043] Furthermore, the compounds, compositions and methods of the
present invention, particularly when radio labeled as described
above or labeled by methods well-known in the art with florescent
and spin labels, may be employed as imaging agents and in other
ways for diagnosis and/or treatment. Moreover, immobilization of
compounds of the invention on solid support could be of utility for
affinity purification and modification of compounds of the
invention with chemically active groups may be used for protein
labeling.
[0044] For many of the utilities outlined above, it may be
advantageous to administer compounds of the general formula I
together with cholinesterase inhibitors (e.g. tacrine, huperzine,
donepezil); NMDA antagonists (e.g. lanicemine, remacemide,
neramexane, memantine); calpain inhibitors (e.g. CEP-3122);
antioxidants (e.g. vitamin E, coenzyme Q10) and agents that have
shown clinical efficacy but whose mechanism is unclear (e.g.
dimebon). Compounds of formula I may also be administered together
with one or more of the following agents to improve cognition:
amisulpride, atomoxetine, bromocryptine, buspirone, caffeine,
chlorpromazine, clonidine, clozapine, diazepam, flumazenil,
fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan,
modafinil, olanzapine, paroxetine, pergolide, phenserine,
quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.
[0045] The terms "methods of treating or preventing" mean
amelioration, prevention or relief from the symptoms and/or effects
associated with disorders. The term "preventing" as used herein
refers to administering a medicament beforehand to forestall or
obtund an acute episode. The person of ordinary skill in the
medical art (to which the present method claims are directed)
recognizes that the term "prevent" is not an absolute term. In the
medical art it is understood to refer to the prophylactic
administration of a drug to substantially diminish the likelihood
or seriousness of a condition, and this is the sense intended in
applicants' claims. As used herein, reference to "treatment" of a
patient is intended to include prophylaxis.
[0046] The term "mammal" is used in its dictionary sense. Humans
are included in the group of mammals, and humans would be the
preferred subjects of the methods.
[0047] The cognitive impairment to be treated may arise from one or
more of the following disorders, which may not in themselves be
necessarily associated with PDE4 abnormality: acute pain,
AD/HD--Attention deficit hyperactivity disorder, AIDS dementia
complex, alcoholism, amphetamine addiction,
amygdalo-hippocampectomy, anorexia nervosa, anterior parietal
damage, antisocial behavior, antisocial personality disorder,
anxiety, autism, basal ganglia lesions, bipolar disorder,
borderline personality disorder, camptocormia, capgras syndrome,
carcinoid syndrome, carotid endarterectomy surgery, chronic drug
misuse, chronic fatigue syndrome, chronic occupational solvent
encephalopathy, chronic pain, brain ischemia, coronary artery
bypass surgery, critical illness requiring intensive care, dementia
Alzheimer-type (DAT), dementia Lewy Body type, dementia of frontal
type, dementia caused by ischemia, dental pain, developmental
dyslexia, diabetes, dorsolateral frontal cortical compression,
Down's Syndrome, drug abuse, dysexecutive syndrome, fibromyalgia,
frontal lobe damage, frontal lobe excision, frontal variant
frontotemporal dementia, gluten ataxia, hallucinosis, head injury,
hearing loss, heart disease, heart failure, heavy social drinking,
hepatic encephalopathy, heroin addiction, herpes encephalitis,
hippocampal atrophy, HIV/AIDS, Huntington's disease, hydrocephalus,
hypercortisolemia, hyperostosis frontalis interna, hypertension,
idiopathic pain, insomnia, Korsakoff syndrome, late paraphrenia,
lead exposure, left ventricular systolic dysfunction, orbitofrontal
cortex lesion, liver failure, long term health effects of diving,
Machado-Joseph disease, mad hatter's disease, manic depression,
melancholia, mercury poisoning, mild cognitive impairment (MCI),
mild cognitive impairment (MCI) of aging, motor neuron disease,
multiple sclerosis, multiple system atrophy, narcolepsy, neuronal
migration disorders, normal pressure hydrocephalus, obsessive
compulsive disorder, organophosphate pesticide exposure, panic
disorder, paraphrenia, Parkinson's disease, periventricular brain
insult, personality disorder, gasoline sniffing, phenylketonuria,
post-concussion syndrome, premature birth needing intensive care,
premenstrual dysphoric disorder, progressive supranuclear palsy,
psychopathy, psychosis, questionable dementia, renal cancer,
Roifman syndrome, schizoaffective disorder, schizophrenia, seasonal
affective disorder, self harm, semantic dementia, specific language
impairment, social withdrawal in schizophrenia, solvent
encephalopathy, spina bifida, Steele-Richardson-Olzsewski syndrome,
stiff person syndrome, striatocapsular infarct, subarachnoid
hemorrhage, substance abuse, tardive dyskinesia, temporal lobe
excision, temporal lobe lesion, tinnitus, Tourette's syndrome,
transient cerebral ischemia, traumatic brain injury,
trichotillomania, tuberous sclerosis, and white matter lesions.
[0048] While it may be possible for compounds of formula Ito be
administered as the raw chemical, it will often be preferable to
present them as part of a pharmaceutical composition. In accordance
with an embodiment of the present invention there is provided a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt thereof, together with one or more
pharmaceutically carriers thereof and optionally one or more other
therapeutic ingredients. The carrier(s) must be "acceptable" in the
sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
Furthermore, when reference is made in an independent claim to a
compound or a pharmaceutically acceptable salt thereof, it will be
understood that claims which depend from that independent claim
which refer to such a compound also include pharmaceutically
acceptable salts of the compound, even if explicit reference is not
made to the salts in the dependent claim.
[0049] The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous
and intraarticular), rectal and topical (including dermal, buccal,
sublingual and intraocular) administration. The most suitable route
may depend upon the condition and disorder of the recipient. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into
association a compound of formula I or a pharmaceutically
acceptable salt or solvate thereof ("active ingredient") with the
carrier, which constitutes one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both and then, if
necessary, shaping the product into the desired formulation.
[0050] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary or paste.
[0051] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, lubricating, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine a mixture of the powdered compound moistened
with an inert liquid diluent. The tablets may optionally be coated
or scored and may be formulated so as to provide sustained, delayed
or controlled release of the active ingredient therein. The
pharmaceutical compositions may include a "pharmaceutically
acceptable inert carrier", and this expression is intended to
include one or more inert excipients, which include starches,
polyols, granulating agents, microcrystalline cellulose, diluents,
lubricants, binders, disintegrating agents, and the like. If
desired, tablet dosages of the disclosed compositions may be coated
by standard aqueous or nonaqueous techniques, "Pharmaceutically
acceptable carrier" also encompasses controlled release means.
[0052] Pharmaceutical compositions may also optionally include
other therapeutic ingredients, anti-caking agents, preservatives,
sweetening agents, colorants, flavors, desiccants, plasticizers,
dyes, and the like. Any such optional ingredient must be compatible
with the compound of formula Ito insure the stability of the
formulation. The composition may contain other additives as needed,
including for example lactose, glucose, fructose, galactose,
trehalose, sucrose, maltose, raffinose, maltitol, melezitose,
stachyose, lactitol, palatinite, starch, xylitol, mannitol,
myoinositol, and the like, and hydrates thereof, and amino acids,
for example alanine, glycine and betaine, and peptides and
proteins, for example albumen.
[0053] Examples of excipients for use as the pharmaceutically
acceptable carriers and the pharmaceutically acceptable inert
carriers and the aforementioned additional ingredients include, but
are not limited to binders, fillers, disintegrants, lubricants,
anti-microbial agents, and coating agents.
[0054] The dose range for adult humans is generally from 0.005 mg
to 10 g/day orally. Tablets or other forms of presentation provided
in discrete units may conveniently contain an amount of compound of
formula I which is effective at such dosage or as a multiple of the
same, for instance, units containing 5 mg to 500 mg, usually around
10 mg to 200 mg. The precise amount of compound administered to a
patient will be the responsibility of the attendant physician.
However, the dose employed will depend on a number of factors,
including the age and sex of the patient, the precise disorder
being treated, and its severity.
[0055] A dosage unit (e.g. an oral dosage unit) can include from,
for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to
500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25
mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,
75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg,
300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described
herein.
[0056] For additional information about pharmaceutical compositions
and their formulation, see, for example, Remington: The Science and
Practice of Pharmacy, 20.sup.th Edition, 2000. The agents can be
administered, e.g., by intravenous injection, intramuscular
injection, subcutaneous injection, intraperitoneal injection,
topical, sublingual, intraarticular (in the joints), intradermal,
buccal, ophthalmic (including intraocular), intranasaly (including
using a cannula), or by other routes. The agents can be
administered orally, e.g., as a tablet or cachet containing a
predetermined amount of the active ingredient, gel, pellet, paste,
syrup, bolus, electuary, slurry, capsule, powder, granules, as a
solution or a suspension in an aqueous liquid or a non-aqueous
liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid
emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a
liposomal formulation (see, e.g., EP 736299, WO 99/59550 and WO
97/13500), via formulations described in WO 03/094886 or in some
other form. The agents can also be administered transdermally (i.e.
via reservoir-type or matrix-type patches, microneedles, thermal
poration, hypodermic needles, iontophoresis, electroporation,
ultrasound or other forms of sonophoresis, jet injection, or a
combination of any of the preceding methods (Prausnitz et al. 2004,
Nature Reviews Drug Discovery 3:115)). The agents can be
administered locally, for example, at the site of injury to an
injured blood vessel. The agents can be coated on a stent. The
agents can be administered using high-velocity transdermal particle
injection techniques using the hydrogel particle formulation
described in U.S. 20020061336. Additional particle formulations are
described in WO 00/45792, WO 00/53160, and WO 02/19989. An example
of a transdermal formulation containing plaster and the absorption
promoter dimethylisosorbide can be found in WO 89/04179. WO
96/11705 provides formulations suitable for transdermal
administration. The agents can be administered in the form a
suppository or by other vaginal or rectal means. The agents can be
administered in a transmembrane formulation as described in WO
90/07923. The agents can be administered non-invasively via the
dehydrated particles described in U.S. Pat. No. 6,485,706. The
agent can be administered in an enteric-coated drug formulation as
described in WO 02/49621. The agents can be administered
intranasaly using the formulation described in U.S. Pat. No.
5,179,079. Formulations suitable for parenteral injection are
described in WO 00/62759. The agents can be administered using the
casein formulation described in U.S. 20030206939 and WO 00/06108.
The agents can be administered using the particulate formulations
described in U.S. 20020034536.
[0057] The agents, alone or in combination with other suitable
components, can be administered by pulmonary route utilizing
several techniques including but not limited to intratracheal
instillation (delivery of solution into the lungs by syringe),
intratracheal delivery of liposomes, insufflation (administration
of powder formulation by syringe or any other similar device into
the lungs) and aerosol inhalation. Aerosols (e.g., jet or
ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder
inhalers (DPIs)) can also be used in intranasal applications.
Aerosol formulations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous medium and can be placed
into pressurized acceptable propellants, such as hydrofluoroalkanes
(HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof),
dichlorodifluoromethane (or other chlorofluorocarbon propellants
such as a mixture of Propellants 11, 12, and/or 114), propane,
nitrogen, and the like. Pulmonary formulations may include
permeation enhancers such as fatty acids, and saccharides,
chelating agents, enzyme inhibitors (e.g., protease inhibitors),
adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat),
preservatives (e.g., benzalkonium chloride or chlorobutanol), and
ethanol (normally up to 5% but possibly up to 20%, by weight).
Ethanol is commonly included in aerosol compositions as it can
improve the function of the metering valve and in some cases also
improve the stability of the dispersion. Pulmonary formulations may
also include surfactants which include but are not limited to bile
salts and those described in U.S. Pat. No. 6,524,557 and references
therein. The surfactants described in U.S. Pat. No. 6,524,557,
e.g., a C.sub.8-C.sub.16 fatty acid salt, a bile salt, a
phospholipid, or alkyl saccharide are advantageous in that some of
them also reportedly enhance absorption of the compound in the
formulation. Also suitable in the invention are dry powder
formulations comprising a therapeutically effective amount of
active compound blended with an appropriate carrier and adapted for
use in connection with a dry-Powder inhaler. Absorption enhancers
which can be added to dry powder formulations of the present
invention include those described in U.S. Pat. No. 6,632,456. WO
02/080884 describes new methods for the surface modification of
powders. Aerosol formulations may include U.S. Pat. No. 5,230,884,
U.S. Pat. No. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437,
U.S. 20030165436, and WO 96/40089 (which includes vegetable oil).
Sustained release formulations suitable for inhalation are
described in U.S. 20010036481A1, 20030232019A1, and U.S.
20040018243A1 as well as in WO 01/13891, WO 02/067902, WO
03/072080, and WO 03/079885. Pulmonary formulations containing
microparticles are described in WO 03/015750, U.S. 20030008013, and
WO 00/00176. Pulmonary formulations containing stable glassy state
powder are described in U.S. 20020141945 and U.S. Pat. No.
6,309,671. Other aerosol formulations are described in EP 1338272A1
WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, WO
91/04011, and U.S. Pat. No. 6,294,153 and U.S. Pat. No. 6,290,987
describes a liposomal based formulation that can be administered
via aerosol or other means. Powder formulations for inhalation are
described in U.S. 20030053960 and WO 01/60341. The agents can be
administered intranasally as described in U.S. 20010038824.
[0058] Solutions of medicament in buffered saline and similar
vehicles are commonly employed to generate an aerosol in a
nebulizer. Simple nebulizers operate on Bernoulli's principle and
employ a stream of air or oxygen to generate the spray particles.
More complex nebulizers employ ultrasound to create the spray
particles. Both types are well known in the art and are described
in standard textbooks of pharmacy such as Sprowls' American
Pharmacy and Remington's The Science and Practice of Pharmacy.
Other devices for generating aerosols employ compressed gases,
usually hydro fluorocarbons and chlorofluorocarbons, which are
mixed with the medicament and any necessary excipients in a
pressurized container, these devices are likewise described in
standard textbooks such as Sprowls and Remington.
[0059] The agent can be incorporated into a liposome to improve
half-life. The agent can also be conjugated to polyethylene glycol
(PEG) chains. Methods for pegylation and additional formulations
containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified
liposomes) can be found in Harris and Chess, Nature Reviews Drug
Discovery 2:214-221 and the references therein. The agent can be
administered via a nanocochleate or cochleate delivery vehicle
(BioDelivery Sciences International). The agents can be delivered
transmucosally (i.e. across a mucosal surface such as the vagina,
eye or nose) using formulations such as that described in U.S. Pat.
No. 5,204,108. The agents can be formulated in microcapsules as
described in WO 88/01165. The agent can be administered
intra-orally using the formulations described in U.S. 20020055496,
WO 00/47203, and U.S. Pat. No. 6,495,120. The agent can be
delivered using nanoemulsion formulations described in WO
01/91728A2.
[0060] In general, compounds of formula I may be prepared by the
methods illustrated in the general reaction schemes as, for
example, described below, or by modifications thereof, using
readily available starting materials, reagents and conventional
synthesis procedures. In these reactions, it is also possible to
make use of variants that are in themselves known, but are not
mentioned here.
[0061] The present invention relates to compounds exhibiting PDE4
enzyme inhibition, having the general formula I
##STR00010##
[0062] In one embodiment, X is CR.sup.5, R.sup.2 is pyrazolyl or
substituted phenyl and R.sup.3 is other than H. In another
embodiment, M is chosen from direct bond, --CH.sub.2--, --CH(OH)--,
--C[(CH.sub.3)(OH)]--, --C[(CH.sub.3)(NH.sub.2)]--, --C(.dbd.O)--,
--O--, --NH--, --N(CH.sub.3)--, --S(O).sub.n--, --CH.sub.2NH--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH--, --CH.sub.2S(O).sub.n--,
--CH.sub.2O-- and
##STR00011##
[0063] There are two subgenera of compounds of formula I. The
first, in which X is N or N.fwdarw.O, is represented by the
formulae:
##STR00012##
[0064] The second, in which X is CR.sup.5 is represented by the
formula:
##STR00013##
[0065] In one embodiment, R.sup.1 is a substituted phenyl. In
another embodiment, R.sup.1 is phenyl and R.sup.2 is pyrazolyl or
substituted phenyl. In another embodiment, R.sup.1 is substituted
phenyl and R.sup.2 is pyrazolyl or substituted phenyl.
[0066] In another embodiment, R.sup.1 is an unsubstituted
heterocycle. In another embodiment, R.sup.1 is a substituted
heterocycle. In both heterocycle embodiments, the heterocycle may
be chosen from pyrazole, pyrrole, indole, quinoline, isoquinoline,
tetrahydroisoquinoline, benzo furan, benzodioxan, benzodioxole,
morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine,
thiene, furan, oxazole, oxazoline, oxazolidine, isoxazolidine,
isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine,
pyridazine, azepine, pyrazolidine, imidazole, imidazoline,
imidazolidine, purine, imidazolopyridine, pyrazine, thiazolidine,
isothiazole, 1,2-thiazine-1,1-dioxide,
2,6,7-trioxabicyclo[2.2.2]octane, quinuclidine, isothiazolidine,
benzimidazole, thiadiazole, benzopyran, benzothiazole,
benzotriazole, benzoxazole, benzoxadiazole, tetrahydrofuran,
tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine
sulfoxide, thiamorpholine sulfone, oxadiazole, triazole, tetrazole,
isoindole, pyrrolopyridine, triazolopyridine and the dihydro and
tetrahydro congeners thereof, whether specifically named or not.
For example, a dihydro congener of indole would be indoline or
dihydroindole; a tetrahydro congener of pyridine would be
piperidine. In a further embodiment, R.sup.1 is an optionally
substituted heterocycle chosen from pyrazole, benzodioxole,
morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine,
thiene, oxazolidine, isoxazole, azetidine, piperazine, pyrrolidine,
imidazole, imidazolidine, imidazolopyridine, pyrazine,
1,2-thiazine-1,1-dioxide, benzimidazole, thiadiazole,
benzotriazole, benzoxazole, oxadiazole, triazole, tetrazole,
isoindole, pyrrolopyridine, triazolopyridine and their dihydro and
tetrahydro congeners.
[0067] In an embodiment, the substituted phenyl or substituted
heterocycle is substituted with a substituent chosen from halogen,
haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl,
phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy,
oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,
alkoxycarbonylamino, carboxyalkyl, alkoxycarbonylaminoalkyl,
carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy,
alkylaminocarbonyl, dialkylaminocarbonyl, amino carbonylalkyl,
cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl,
(alkyl)(aryl)aminoalkyl, alkylamino alkyl, dialkylaminoalkyl,
dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy,
mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino,
alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl,
arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl,
acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl,
heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid
amides, protected residues of aminoacids, protected residues of
amino acid amides, N-methylated amino acids and N-methylated amino
acid amides. Exemplary amino acids are glycine, alanine and
proline.
[0068] In another embodiment, the substituted phenyl or substituted
heterocycle is substituted with a substituent chosen from
--CH.sub.3, --CH.sub.2CF.sub.3, --CF.sub.3, --CHO, --COOH, --CN,
halogen, --OH, --OEt, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NHEt, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt,
--NH(tBoc), --NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
##STR00014##
One embodiment of compounds of the first genus are those in which
R.sup.3 is methyl or fluoromethyl; R.sup.6 is H; and M is
--CH.sub.2-- or --CH.sub.2O--.
[0069] In an embodiment, R.sup.2 is chosen from optionally
substituted phenyl, optionally substituted monocyclic unsaturated
heterocycle, unsubstituted bicyclic unsaturated heterocycle and
fluoro-substituted bicyclic unsaturated heterocycle. In a further
embodiment, R.sup.2 is chosen from optionally substituted phenyl,
indole, benzodioxole, benzoxadiazole, benzodioxan, benzimidazole,
oxadiazole, pyrazole, pyridine and pyridine N-oxide. In a further
embodiment, R.sup.2 is chosen from meta-substituted phenyl, indole,
benzodioxole, 2,2-difluorobenzodioxole, benzooxadiazole,
benzimidazole, 5-(pyridin-4-yl)[1,2,4]oxadiazole,
5-(pyridin-4-yl)[1,3,4]oxadiazole, benzodioxan, 4-chloropyrazole,
4-(pyridin-4-yl)pyrazole, 6-chloropyridine,
3-(trifluoromethyl)pyrazole, and pyridine N-oxide.
[0070] In another embodiment, R.sup.2 is substituted phenyl:
##STR00015##
wherein R.sup.7 is chosen from hydrogen, halogen, nitro, cyano,
halo(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylamino carbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; and R.sup.8 and R.sup.13 are chosen
independently from H and F. In a further embodiment, R.sup.8 and
R.sup.13 are H and R.sup.7 is chosen from hydrogen, fluoro, chloro,
bromo, nitro, cyano, acetyl, trifluoromethyl, methoxy,
trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio,
methanesulfinyl, methanesulfonyl, methansulfonamido, amino,
methoxymethyl, hydroxyethyl, and morpholinyl.
[0071] In another embodiment, R.sup.1 is chosen from optionally
substituted phenyl, optionally substituted five membered
heteroaryl, optionally substituted six-membered heteroaryl,
optionally substituted 4-7 membered non-aryl heterocycle, and
optionally substituted fused bicycle.
[0072] For example, R.sup.1 may be chosen from optionally
substituted phenyls; optionally substituted five membered
heteroaryls selected from thiazoles, thiadiazoles, pyrazoles,
oxadiazole, isoxazoles, triazoles, imidazoles, thiophenes,
tetrazoles and oxazoles; optionally substituted six membered
hereroaryls selected from pyridines, pyrimidines, pyridazinones,
pyrimidinone, pyridinone, pyrazines and diazines; optionally
substituted 5- and 6-membered non-aryl heterocyclics selected from
tetrahydrothiophenes, piperazine, oxazolidinones, imidazolidinones,
morpholines, piperidines, pyrrolidinones, pyrrolidinediones,
pyrrolidines, piperidinones, piperidinediones and
trioxa-bicyclo[2.2.2]octanes; and optionally substituted fused
bicycles selected from benzoxazolones, indoles, isoindolinediones,
2H-pyrrolopyridinediones, purines, indolinediones,
triazolopyridinones, benzimidazoles, benzoxadiazoles, quinolines
and quinolones; wherein the substituents are chosen independently
from hydrogen, halogen, halo(C.sub.1-C.sub.6)alkyl, hydroxyl,
(C.sub.1-C.sub.6)alkoxy, carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
aminocarbonyl (--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl,
cyano, carbonyl (oxo), acyl, hydroxy(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, nitro, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
mercapto, (C.sub.1-C.sub.6)alkylthio, sulfoxide, sulfone,
sulfonate, sulfonimide, acylamino, amidino, phenyl, benzyl,
heteroaryl, phenoxy, benzyloxy, heteroaryloxy,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl, formylamino(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkylamino,
--(CH.sub.2).sub.p--NR.sup.12CO--(CH.sub.2).sub.q--NR.sup.9R.sup.10,
--NHSO.sub.2R.sup.11,
--OCH.sub.2CH.sub.2NR.sup.9R.sup.10--NHSO.sub.2NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10, --(CH.sub.2).sub.p--NHCOR.sup.9,
OCONR.sup.9R.sup.10 and NR.sup.12COOR.sup.11;
R.sup.3 is chosen from --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3,
--CHF.sub.2 and --CH.sub.2F; R.sup.5 is chosen from H, --F, --OH,
--CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and
--C.ident.CH;
R.sup.2 is
[0073] (a) phenyl and R.sup.7 is chosen from H, halogen, nitro,
acetyl, hydroxyethyl, --NH.sub.2, --SCH.sub.3, methoxycarbonyl,
--SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --CN,
--CF.sub.3, --CH.sub.2OCH.sub.3; or
[0074] (b) benzoxadiazole, benzodioxole, 2,2-difluorobenzodioxole,
benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole,
pyridine and pyridine N-oxide;
R.sup.9 is chosen from H, (C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarboxy(C.sub.1-C.sub.6)alkyl; R.sup.10 is
H, (C.sub.1-C.sub.6)alkyl, or taken together, or R.sup.9 and
R.sup.10 together form a heterocycle optionally substituted with
(C.sub.1-C.sub.6)alkyl; p is 0 or 1, q is 0, 1 or 2, R.sup.11 is
linear (C.sub.1-C.sub.6)alkyl, R.sup.12 is H or
(C.sub.1-C.sub.6)alkyl; or two adjacent substituents together form
an optionally substituted fused heterocyclic ring. When R.sup.5 is
H, R.sup.3 is --CH.sub.3 and R.sup.1 is substituted or
unsubstituted pyrazole, compounds that have been tested and found
active are those in which R.sup.8 is --NO.sub.2 or R.sup.8
represents two adjacent substituents that form an optionally
substituted, fused heterocycle. When R.sup.5 is H, R.sup.3 is
--CH.sub.3, R.sup.2 is --CF.sub.3, and R.sup.1 is
##STR00016##
the compound does not appear to be active in initial screening.
When R.sup.5 is H, R.sup.3 is --CH.sub.3, R.sup.2 is --NO.sub.2,
and R.sup.1 is
##STR00017##
the compound does not appear to be active in initial screening.
And, when R.sup.5 is H, R.sup.3 is --CH.sub.3, R.sup.2 is
--OCH.sub.3 or --COCH.sub.3, and R.sup.1 is
##STR00018##
the compound does not appear to be active in initial screening.
[0075] One embodiment of compounds of the second genus has the
formula
##STR00019##
wherein [0076] R.sup.1a is phenyl, five-membered heteroaryl,
six-membered heteroaryl, 4-7 membered non-aryl heterocycle or fused
bicycle; [0077] R.sup.14 is chosen from H,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NHEt, --CH.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2NHC(.dbd.O)CH.sub.3, --NHCH.sub.3, --NHEt, --NH(tBoc),
--CHO, --NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2,
--NHEt, --N(CH.sub.3).sub.2, --NH.sub.2, --COOH,
--C(.dbd.O)NH.sub.2, --CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH,
--CH.sub.2COOEt, --CN, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--NH(CH.sub.3)C(.dbd.O)NH.sub.2, halogen, --CH.sub.2NHC(.dbd.O)OEt,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --OH,
--CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --SO.sub.2NH.sub.2,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --COOCH.sub.3, --COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt, --NH(Et)C(.dbd.O)OEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH, --CH.sub.2NHSO.sub.2CH.sub.3,
--OEt, --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
3'-nitro-6-methoxybiphenyl-3-ylmethyl,
tetrahydroimidazol-2-on-1-yl,
3-methyltetrahydroimidazol-2-one-1-yl, pyrazol-1-yl,
[0077] ##STR00020## [0078] R.sup.15 is chosen from H, NO.sub.2, OH,
NH.sub.2, and --NHSO.sub.2NH.sub.2; or [0079] R.sup.15 together
with R.sup.14 forms methylene dioxy; [0080] R.sup.27 is chosen from
hydrogen, halogen, nitro, cyano, halo(C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)oxaalkyl,
carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl
(--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; [0081] R.sup.28 is chosen from H and
F, or [0082] R.sup.27 together with R.sup.28 forms a five-membered
ring.
[0083] In further embodiments R.sup.27 and R.sup.28 represent a
fused heterocycle at 3- and 4-positions so that the residue formed
from R.sup.27 and R.sup.28 together with the phenyl to which they
are attached is chosen from:
##STR00021##
[0084] In other embodiments, R.sup.27 is chosen from halogen,
nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl,
methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and
1,3,4-thiadiazol-2-yl, or taken together R.sup.7 and R.sup.8 are
methylenedioxy or difluoromethylenedioxy. In the foregoing
embodiments, R.sup.1a may be chosen from a benzene ring, a
triazole, a pyridine or pyridine-N-oxide, a pyrazole, a
tetrahydrothiophene, an imidazole, a pyrimidine, a thiadiazole, and
an imidazopyridine.
[0085] In an embodiment of the invention, R.sup.5 is fluoro, H, CN
or OH. In other embodiments, R.sup.3 is methyl or fluoromethyl.
[0086] Another embodiment of compounds of the invention have the
formula
##STR00022##
[0087] In these compounds R.sup.3 is methyl or fluorinated methyl;
Y is CH or N; R.sup.27a is chosen from halogen, cyano, acetyl,
methylthio, nitro and trifluoromethyl; and R.sup.16 is chosen from
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19 and
##STR00023##
wherein
##STR00024##
is a 4-7 membered ring heterocycle attached through its nitrogen;
R.sup.17, and R.sup.18 are independently chosen from H,
(C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkyl; R.sup.19 is
chosen from H, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
--[(C.sub.1-C.sub.6)alkyl]COOH, and
--[(C.sub.1-C.sub.6)alkyl]COO(C.sub.1-C.sub.6)alkyl; and R.sup.20
is chosen from a carboxylic acid, a carboxamide, a carboxylic
ester, a primary, secondary or tertiary alcohol and a primary,
secondary or tertiary amine. Examples of a carboxylic acid, a
carboxamide, a carboxylic ester, a primary, secondary or tertiary
alcohol and a primary, secondary or tertiary amine include --COOH,
--CONH.sub.2, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --COOCH.sub.3,
--CH.sub.2OH, --CH(CH.sub.3)OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2NH.sub.2, --CH(CH.sub.3)NH.sub.2 and
--C(CH.sub.3).sub.2NH.sub.2. In a further embodiment, X is CH, CF
or N.fwdarw.O; M is --CH.sub.2-- or --S--; R.sup.27a is chosen from
chloro, cyano, acetyl and methylthio; and R.sup.16 is chosen from
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19,
##STR00025##
In a further embodiment, Y is CH; M is --CH.sub.2--; R.sup.27a is
chloro; and R.sup.16 is --NR.sup.17C(.dbd.O)NR.sup.18R.sup.19. In
yet a further embodiment, R.sup.16 is
--NR.sup.17C(.dbd.O)NR.sup.18R.sup.19 and R.sup.17, R.sup.18 and
R.sup.19 are all hydrogen.
[0088] Examples of the foregoing substituents on phenyl,
five-membered heteroaryl, six-membered heteroaryl, 4-7 membered
non-aryl heterocycle or fused bicycles (R.sup.1a) may be described
by the formula VI:
##STR00026##
in which [0089] R.sup.14 is chosen from H,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NHEt, --CH.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2NHC(.dbd.O)CH.sub.3, --NHCH.sub.3, --NHEt, --NH(tBoc),
--CHO, --NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2,
--NHEt, --N(CH.sub.3).sub.2, --NH.sub.2, --COOH,
--C(.dbd.O)NH.sub.2, --CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH,
--CH.sub.2COOEt, --CN, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--NH(CH.sub.3)C(.dbd.O)NH.sub.2, halogen, --CH.sub.2NHC(.dbd.O)OEt,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --OH,
--CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --SO.sub.2NH.sub.2,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --COOCH.sub.3, --COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt, --NH(Et)C(.dbd.O)OEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH, --CH.sub.2NHSO.sub.2CH.sub.3,
--OEt, --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
3'-nitro-6-methoxybiphenyl-3-ylmethyl,
tetrahydroimidazol-2-on-1-yl,
3-methyltetrahydroimidazol-2-one-1-yl, pyrazol-1-yl,
[0089] ##STR00027## [0090] R.sup.15 is chosen from H, NO.sub.2, OH,
NH.sub.2, and --NHSO.sub.2NH.sub.2; Or [0091] R.sup.15 together
with R.sup.14 forms methylene dioxy.
[0092] In certain embodiments, R.sup.3 is chosen from --CH.sub.3,
--CH.sub.2CH.sub.3, --CF.sub.3, --CHF.sub.2 and --CH.sub.2F. In
certain embodiments, R.sup.5 is chosen from H, --F, --OH,
--CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and
--C.ident.CH. In certain embodiments, R.sup.7, is chosen from H,
halogen, nitro, acetyl, hydroxyethyl, --NH.sub.2, --SCH.sub.3,
methoxycarbonyl, --SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3,
--OCF.sub.3, --CN, --CF.sub.3, --CH.sub.2OCH.sub.3 and oxadiazole,
and a fused heterocycle at 3- and 4-positions.
[0093] In certain embodiments of the compounds I, R.sup.5 may be
fluoro, H, CN or OH. In certain embodiments of the compounds I,
R.sup.3 may be methyl or fluoromethyl. (Fluoromethyl is intended to
include CHF.sub.2, CH.sub.2F and CF.sub.3.)
[0094] All of the compounds, except for those identified in
paragraph [0071], falling within the foregoing parent genus I and
its subgenera are useful as PDE4 inhibitors, but not all the
compounds are novel. In particular, certain known species fall
within the genus I, although no utility in inhibiting PDE4 has been
suggested for these species. It may be found upon examination that
compounds that have been excluded from the claims are patentable to
the inventors in this application; it may also be found that
additional species and genera not presently excluded are not
patentable to the inventors in this application. In either case,
the exclusion of species and genera in applicants' claims are to be
considered artifacts of patent prosecution and not reflective of
the inventors' concept or description of their invention. The
invention, in a composition aspect, is all active compounds of
formula I except those that are in the public's possession. In
particular, a search of the literature indicates that certain
compounds in which X is N, R.sup.3 is methyl, M is CH.sub.2,
R.sup.2 is a five-membered ring heterocycle, and R.sup.1 is a
substituted tetralin are known. Similarly certain compounds in
which X is N, R.sup.3 is methyl, M is CH.sub.2, R.sup.1 is a
five-membered ring heterocycle, and R.sup.2 is a substituted
tetralin are known.
[0095] In general, the compounds of the present invention may be
prepared by the methods illustrated in the general reaction schemes
as, for example, described below, or by modifications thereof,
using readily available starting materials, reagents and
conventional synthesis procedures.
[0096] Generally compounds of the Formula I, where R.sup.2 is a
substituted aryl/heteroaryl and the two biaryl groups are linked by
a C--C bond, may be prepared from appropriately functionalized
alkoxy-aryl ether derivatives containing desirable functionalities
W, where W may for example be CH, N, COH, CF, etc (Route A, Scheme
A1). The biaryl portion can be constructed first, typically via
Suzuki or Stille coupling (G1->G2). In such case either
Y=halogen or OSO2R(OTf, ONf) and the other reagent would be
R2-B(OR)2 or R2-SnR3' or vise versa, where R2-halogen is coupled
with G1 containing boronate/boronic acid or trialkyltin as Y. When
A is a carbon derived substituent, e.g. CH3, CH2OH, CO2R'', CN etc.
these groups are converted to provide intermediate G3 where D is
either a halogen or OTf, ONf, or OCOOR' (carbonate) such that
substituent (R1) is introduced by employing a transition-metal
catalyzed coupling reactions such as Suzuki, Stille or Negishi
reaction. An alternative route to compounds of type G4 involves
essentially reversing the order of incorporation of R1 and R2
fragments. The route B, as highlighted in Scheme A1, allows
formation of G6, where the R2 fragment is introduced at later stage
in the sequence, analogous to chemistries employed for G1-G2, for
examples Suzuki, Stille coupling.
##STR00028##
[0097] One may attach R1, which may be aryl, heterocyclic, acyclic,
aliphatic, or any other desirable variety of functionality, to the
central aromatic ring (Ar) by a wide rage of tether groups M. The
central aromatic ring (Ar) may be a biaryl ring system with a R2
group already attached, or the R2 group may be attached subsequent
to that of R1. The linker group M may be a linear chain of one or
more atoms consisting of C, N, O, or S. The linker group M may also
consist of functionalities including, but not limited to amide,
sulfonamide, sulfone, or ketone. It is evident to one skilled in
the art that many of these exemplified functional groups may be
attached in more than one way, for example, Ar--CH2-O--R1 or
Ar--O--CH2-R1. Considering those compounds with M groups such as S
or O, the heteroatom may originally be in the Ar or the R1 group.
Some examples of how the two groups can then be joined are
nucleophilic aromatic substitution, metal-promoted coupling, and
nucleophilic displacement (Scheme A2). Chemical reactivity of the
Ar and R1 groups should of course be considered when determining
which partner contains the linker heteroatom, and which shall serve
as the reaction partner. For example, it is well understood that in
aromatic ring systems an electron-withdrawing group para- or ortho-
to a leaving group (e.g. halogen) allows susceptibility of the
aromatic halogen for nucleophilic displacement. Thus, Ar1 group
containing NO2, CO2R, ketone, CN etc. would allow formation of
aryl-M-aryl(heteroaryl) intermediates. The linker group M may also
be subject to further elaboration. For example, sulfides may be
oxidized to sulfoxides and sulfones and amines may be subjected to
alkylation or reductive amination. Well known synthetic
transformations can be used to create tether groups M such as ether
amide, sulfonamide, and the like. The functional group location in
the precursor Ar and R1 groups can be used to dictate the nature
and type of the linkage (e.g. alternative ethers), as mentioned
above.
##STR00029##
[0098] The key fragments Ar and R1 could also be joined using non
transition-metal catalyzed C--C bond forming coupling reactions.
When A=H, Fridele-Crafts acylation or alkylation can be employed to
combine the Ar and R1 groups. Given the chemical reactivity of the
aromatic para-methoxy group in the Ar ring, Friedel-Crafts
acylation would typically involve a suitably elaborated R1-COCl
(acid chloride) group to form compound G10. In this case J=CO,
which can be reduced to the secondary alcohol (typically with
hydride-based reducing agents). If a R'MgX or other such
organometallic agent is used, the J=CO group can be transformed
into the tertiary alcohol with simultaneous addition of an R'
group. In another variation, the J=CO group can be converted into
the imine or oxime using standard procedures and addition of an
R'MgX-type reagent results in the tertiary amine derivative. If
desired, the J=CO group can be reduced, using a number of well
established methods, to the CH2 group (M). In another variation,
when A=H, an aldehyde group can be introduced using either
Vilsmeier reaction or using Lewis acid (TiC14, BF3.OEt2 etc.)
mediated reaction with dichloromethylmethyl. The aldehyde
functionality can subsequently be transformed into a suitable
transition-metal catalyzed coupling reaction partner. Alternatively
the aldehye could be used for Wittig reaction forming olefin or
CH2CH2 linkage to incorporate R1. In yet another variation,
substituent "A" can be various types of carbonyl (aldehyde or
ketone) or imine groups. In one example, addition of a suitably
elaborated organometallic R1 group (e.g. R1-MgX) to aldehyde G9
(A=CHO) would result in G10 with J=C(H)OH. Reduction of this
alcohol gives rise to G11 with M=CH2. Similar types of
transformations could be employed by one skilled in the art if G9
contained A=ketone or imine.
##STR00030##
[0099] Alternatively, the C--C bond forming reaction between the Ar
and R1 groups could be accomplished by displacement of a leaving
group on the R1 by a nucleophile present in the tether region M
(Scheme G4) of G12. The activating group could be either removed to
provide Z.dbd.H (Z.dbd.CO2R--decarboxylation of or Z.dbd.CN,
decyanation) or these could be further transformed to other
functional groups e.g. Z.dbd.CH2)H or CH2NH2. When M-Z is
CH2-halide or CH2-O-sulfonate, R1 fragment can be introduced via
formation of ether linkage. This allows attachment of R1 to the
central aromatic ring by spacers (M) of varying lengths and
compositions. (Scheme A4)
##STR00031##
[0100] The R1 group could also be assembled form an acyclic
intermediate to form a heterocylic or heteroaromatic ring. Examples
of these chemistries include formation of 5-membered heteroaryls
such as oxadiazole, thiadiazole, triazole (G17) form acyl hydrazide
(G16); thiazole from 2-halo-ketone or dipolar cycloaddition
reactions from olefin or acetylic group to form 5-membered
heterocycles or 5-membered heteroaryls (G18) [Scheme A5].
Alternatively the 6-membered heteroaryl or heterocyclic rings could
be formed using Diels-Alder or hetero-Diels-Alder chemistries using
appropriately substituted alkyl aryl ether bearing either a
dienophile or a diene functionalities. The necessary acyclic
precursors could be synthesized by standard methods according to
previously described intermediates (e.g. aldehyde, alkyl halide)
schemes.
##STR00032##
[0101] When the R2 group is linked to the Ar group thru a
heteroatom (N), these biaryl systems could be prepared by
organometallic mediated aza-coupling reactions or other
nucleophilic aromatic substitution-based procedures (Scheme G6).
The Ar--(N)R2 biaryl may be formed from intermediate G6 where R1
group is already in place. Alternatively, the (N)R2 ring can be
added to the central Ar ring first, R1 can be attached through a
variety of means using approaches described in previous schemes.
Examples of (HN)R2 heteroaryl or heterocyclic rings include, but
not limited to, imidazole, pyrrole, pyrazole, pyrrolidine, or
triazole. The R2 functional group can be fully elaborated prior to
addition of the (N)R2 to the Ar, or suitably elaborated after
formation of the key C--N bond.
##STR00033##
[0102] The diverse selection of substituents present in R1 and R2
could be formed by standard functional group transformations that
are well know in the art. Some of these include formation of amide,
sulfonamide, ureas, imidazolone, oxazolones, carbamates from the
R2, R3, or Ar ring fragments bearing appropriate amine, carboxylic
acid, alcohol, or phenol groups. A particularly useful aromatic
ring functionalization technique, in which either the R2 or R1
rings can be employed, is the nucleophilic displacement of
ortho-halo N-containing aromatic rings (G20, scheme A7). Examples
of ring substrates useful in this type of transformation include
2-halo-pyridine, 2-halo-pyrimidine and 2-halo-imidazole.
Additionally, other leaving groups besides halogens (X) may be used
such as sulfonate esters (OTf, ONf). These displacement reactions
can be carried out using alkali or tertiary amine bases, or could
be mediated through the use of an organometallic reagent such as
palladium or aluminum reagents. Examples of nucleophiles (R'')
useful in this type of transformation include amines (primary,
secondary, acyclic, or cyclic), alcohols, phenols, NH-containing
heterocycle groups (imidazole, or pyrrazole) groups capable of
performing nucleophilic displacement.
##STR00034##
[0103] When R1 group contains additional functional groups, such as
amine, ester/acid/alcohols many of which may have be masked or
protected during the previous chemistries, these could be used for
further functional group manipulations. A wide variety of
modifications of R1 functionalities may be achieved using well
established synthetic procedures including, but not limited to,
alkylation, reductive amination, nucleophilic displacement,
cyclization, saponification, and oxidation/reduction. Additionally,
like these functional group manipulations, Ar1 mono-cyclic may be
further transformed to a bi-cyclic ring. Examples of such ring
transformations may be represented by elaboration of pyridine
derivatives to imidazo[1,2-a]pyridine and imidazo[1,5-a]pyridine.
These functional group manipulations and bicyclic ring elaborations
may be accomplished at any chemically suitable point in the
synthesis prior to or post incorporation of R2 or other synthetic
transformations.
[0104] These above transformations could be carried out from
alkylated phenols containing or lacking fluoro substituents in the
central Ar ring. Several of these approaches are also applicable to
3-alkoxy pyridines as the Ar ring starting materials. The
non-limiting specific examples described in later schemes are meant
to serve as examples of the broad scope of possible reactions.
Similarly, analogs where W.dbd.CH2OH, COOH, CN, CONH2 etc. (or
suitably protected precursors) could be derived by following
similar chemistries (schemes A1-A7) and these functional groups
could be derived form an ester or amide derived starting
material.
[0105] The following examples of compounds of the invention were
prepared.
TABLE-US-00001 TABLE 1 ##STR00035## Except Examples P-093 and P-094
where R6 = F, for all other Examples in Table 1 R6 = H. Example X
R3 M Rb Ra P-001 C--H CH3 CH2 3-NO2 4-F P-002 C--H CH3 CH2 3-CO2CH3
4-F P-003 C--H CH3 CH2 3,4-OCH2O 4-F P-004 C--H CH3 CH2 3,4-NON 4-F
P-013 C--H CH3 CH2 3,4-NON 3,4-NON P-021 N CH3 CH2 3-NO2 3,4-OCH2O
P-023 N CH3 CH2 3-NO2 4-F P-049 C--F CH3 C.dbd.O 3-NO2 4-F P-050
C--F CH3 CH2 3-NO2 4-F P-051 C--F CH3 CH(OH) 3-NO2 4-F P-054 N-O
CH3 CH2 3-NO2 4-F P-057 N CHF2 CH2 3-NO2 4-F P-065 N CH3 CH2 3-CF3
4-F P-067 C--H CHF2 CH2 3-NO2 4-F P-079 C--H CF3 CH(OH) 3-NO2 4-F
P-080 C--H CF3 CH2 3-NO2 4-F P-093 C--H CH3 CH(OH) 3-NO2 4-F P-094
C--H CH3 CH.sub.2 3-NO2 4-F P-095 C--OCH3 CH3 C.dbd.O 3-NO2 4-F
P-096 C--OH CH3 C.dbd.O 3-NO2 4-F P-097 C--OCH3 CH3 CH2 3-NO2 4-F
P-098 C--F CH3 CH2 3-NH2 4-F P-099 C--OH CH3 CH2 3-NO2 4-F P-102
C--H CH3 CH2 3-NO2 3-OH P-103 C--H CH3 CH2 3-NO2 3-CH2OH P-105 C--H
CH3 CH2 3-NO2 2-OH P-107 C--F CH3 CH2 3-NO2 4-NHCOCH3 P-112 C--H
CH3 CH2 3-NO2 4-NHCOOC(CH3)3 P-113 C--H CH3 CH2 3-NO2 4-NH2 P-114
C--H CH3 CH2 3-NO2 4-NHCOCH3 P-116 C--F CHF2 CH2 3-NO2 4-F P-117
C--H CH3 CH(OH) 3-[2-Oxadiazole] 4-F P-118 C--H CH3 CH2
3-[2-Oxadiazole] 4-F P-119 C--H CH3 CH2 3-NO2 2-OH, 4-F P-121 C--H
CH3 CH2 3-NO2 N(SO2CH3)2 P-122 C--H CH3 CH2 3-NO2 NHCOCH2CH2COOH
P-123 C--H CH3 CH2 3-NO2 4-NHSO2CH3 P-133 C--H CH3 CH2 3-NO2
2-CH2NH2 P-134 C--H CH3 CH2 3-NO2 2-CH2OH P-135 C--H CH3 CH2 3-NO2
3-CH2OH, 4-F P-136 C--F CH3 CH2 3-NO2 4-NH2 P-137 C--OH CH3 CH(OH)
3-NO2 4-CN P-138 C--OH CH3 CH2 3-NO2 4-CN P-139 C--F CH3 CH2 3-Br
4-F P-140 C--H CH3 CH2 3-COCH3 4-F P-141 C--H CH3 CH2 3,4-OCF2O 4-F
P-142 C--H CH3 CH2 3-NO2 4-OH P-143 C--H CH3 CH2 3-NO2
4-NHCOCH2NHCOOC(CH3)3 P-144 C--H CH3 CH2 3-NO2 4-NHCOCH2N(CH3)2
P-145 C--H CH3 CH2 3-NO2 4-NHCOCH2NH2 P-146 C--H CH3 CH2 3-NO2
4-NHCOCH2CH2N(CH2)5 P-147 C--F CH3 CH2 3-NO2 4-NHCOCH2N(CH3)2 P-148
C--F CH3 CH2 3-NO2 4-CH2NH2 P-151 C--H CH3 CH2 3-SCH3 4-F P-157
C--OH CH3 CH2 3-NO2 4-N(CH3)2 P-158 C--H CH3 CH2 3-NO2 2-CH2NHCHO
P-159 C--H CH3 CH2 3-NO2 4-NHCOCH2CH2NH2 P-160 C--H CH3 CH2 3-NO2
3-CH2NHCOOC(CH3)3 P-161 C--H CH3 CH2 3-NO2 3-CH2NH2 P-163 C--CN CH3
CH2 3-NO2 4-F P-164 C--H CH3 CH2 3-NO2 4-OCH2CH2N(CH3)2 P-165 C--H
CH3 CH2 3-NO2 4-OCH2CH2-N(pyrrolidine) P-166 C--H CH3 CH2 3-NO2
4-OCH2CH2-N(piperidine) P-167 C--F CH3 CH2 3-NH2 4-NHCOCH3 P-168
C--F CH3 CH2 3-Br 4-NHCOCH3 P-170 C--H CH3 CH2 3-COCH3, 4- 4-F OCH3
P-171 C--H CH3 CH2 3-NO2 4-OCH2CH2-N(morpholine) P-173 C--OH CH3
CH2 3-NO2 4-(N-pyrazole) P-175 C--F CH3 CH2 3-NO2
4-CH2NHCOCH2N(CH3)2 P-176 C--NH.sub.2 CH3 CH2 3-NO2 4-F P-180 C--OH
CH3 CH2 3-NO2 4-CHO P-181 C--F CH3 CH2 3-NO2 4-NHCONH2 P-183 C--OH
CH3 CH2 3-NO2 4-CH2OH P-187 C--F CH3 CH2 3-Cl 4-F P-189 C--H CH3
CH2--S 3-NO2 4-F P-190 C--OH CH3 CH2 3-NO2 4-NHCOCH3 P-191 C--H CH3
CH2--SO2 3-NO2 4-F P-192 C--H CH3 CH2--SO 3-NO2 4-F P-193 C--H CH3
O 3-NO2 4-F P-194 C--F CH3 CH2--O 3-Br 4-NHCOCH3 P-199 C--F CH3
CH2--O 3-Br 4-NH2 P-200 C--F CH3 CH2 3-Br 4-NHSO2CH3 P-202 C--F CH3
CH2--O 3-Br 4-NHSO2CH3 P-216 C--F CH3 CH2 3-Cl 4-OH P-217 C--F CH3
CH2 3-Cl 3-OH P-219 C--F CH3 CH2 3-Cl 4-OCH2CH2-N(morpholine) P-220
C--F CH3 CH2 3-Cl 3-OCH2CH2-N(morpholine) P-221 C--F CH3 CH2 3-Cl
4-OCONH2 P-222 C--F CH3 CH2 3-Cl 3-OCONH2 P-227 C--F CH3 CH2 3-Cl
4-NHSO2CH3 P-228 C--F CH3 CH2 3-Cl 4-NHCOCH3 P-230 C--H CH3 O 3-Cl
4-F P-231 C--F CH3 CH2--O 3-Cl 3-NHCOCH3 P-232 C--F CH3 CH2--O 3-Cl
3-NH2 P-233 C--F CH3 CH2 3-Cl 3-NHCOCH3 P-234 C--F CH3 CH2 3-Cl
3-NH2 P-237 C--F CH3 CH2 3-NO2 4-CH2NHCONH2 P-238 C--F CH3 CH2 3-Cl
4-NHCOCH2N(CH3)2 P-239 C--F CH3 CH2 3-Cl 4-NHSO2NH2 P-240 C--H CH3
CH2 3-Cl 4-CONH2 P-241 C--H CH3 CH2 3-Cl 4-N(CH3)2 P-242 C--F CH3
CH2 3-Cl 3,4-OCH2O P-243 C--F CH3 CH2 3-Cl 4-NHCONH2 P-246 C--H CH3
CH2 3-Cl 4-NHSO2CH3 P-247 C--H CH3 CH2 3-Cl 4-NHCH2CH3 P-249 C--F
CH3 CH2 3-COCH3 4-NHSO2CH3 P-250 C--F CH3 CH2 3-Cl 4-NHCONHCH2CH3
P-254 C--F CH3 O 3-Cl 4-NHSO2CH3 P-255 C--H CH3 CH2 3-Cl 3-NH2
P-256 C--F CH3 CH2 3-Cl 3-OH, 4-NH2 P-257 C--F CH3 CH2 3-Cl 3-OH,
4-NO2 P-260 C--H CH3 NH 3-COCH3 4-NH2 P-261 C--F CH3 CH2 3-COCH3
4-NH2 P-262 C--F CH3 CH2 3-Cl 3-OH, 4-NHCONH2 P-264 C--F CH3 CH2
3-Cl 3-OH, 4-NHSO2CH3 P-265 C--F CH3 CH2 3-Cl 3-OSO2CH3, 4-NHSO2CH3
P-266 C--H CH3 CH2 3-Cl 4-SO2NH2 P-267 C--H CH3 NH 3-COCH3
4-NHSO2CH3 P-268 C--H CH3 NH 3-COCH3 4-NHCONH2 P-269 C--F CH3 CH2
3-COCH3 4-NHCONH2 P-270 C--H CH3 CH2 3-Cl 3-NHCONH2 P-271 C--H CH3
CH2 3-Cl 3-NHSO2CH3 P-273 C--F CH3 CH2 3-Cl 4-NHCOCH2NH2 P-274 C--F
CH3 CH2 3-Cl 3-F, 4-CN P-275 C--F CH3 CH2 3-Cl 3-F, 4-CH2NH2 P-276
C--F CH3 CH2 3-Cl 3-OH, 4-NHSO2NH2 P-280 C--H CH3 NH 3-Cl 4-NH2
P-282 C--H CH3 CH2 3-Cl 3-CONH2 P-283 C--F CH3 O 3-COCH3 4-NH2
P-286 C--F CH3 CH2 3-Cl 3-F, 4-CH2NHSO2CH3 P-287 C--F CH3 CH2 3-Cl
3-F, 4-CH2NHCONH2 P-288 C--H CH3 N(CH3) 3-Cl 4-NH2 P-289 C--F CH3
CH2 3-Cl 4-NHCOCH2NHCH3 P-293 C--H CH3 N(CH3) 3-Cl 4-NHCONH2 P-294
C--H CH3 NH 3-Cl 4-NHCONH2 P-295 C--F CH3 CH2 3-Cl 3-OH, 4-CN P-296
C--F CH3 CH2 3-Cl 3-OH, 4-CH2NH2 P-299 C--F CH3 CH2 3-Cl 3-OH,
4-CH2NHSO2CH3 P-300 C--F CH3 CH2 3-Cl 3-F, 4-CH2NHCOCH3 P-301 C--F
CH3 CH2 3-Cl 3-OH, 4-CH2NHCONH2 P-302 C--F CH3 CH2 3-Cl 3-OH,
4-CH2NHCOCH3 P-303 C--F CH3 CH2 3-Cl 4-N(CH3)2 P-304 C--F CH3 CH2
3-COCH3 4-SO2NH2 P-305 C--F CH3 CH2 3-COCH3 4-CONH2 P-311 C--F CH3
CH2 3-Cl 4-NHCH3 P-312 C--F CH3 CH2 3-COCH3 4-NHSO2NH2 P-313 C--F
CHF2 CH2 3-Br 4-NHCOCH3 P-316 C--F CHF2 CH2 3-NO2 4-NHCONH2 P-317
C--F CHF2 CH2 3-Br 4-NH2 P-319 C--F CH3 CH2 3-COCH3 4-COOCH3 P-320
C--F CH3 CH2 3-COCH3 4-COOH P-322 C--F CH2CH3 CH2 3-Br 4-NHCOCH3
P-323 C--F CHF2 CH2 3-Br 4-NHCONH2 P-324 C--F CH3 CH2 3-Cl 3-OH,
5-NH2 P-326 C--F CH3 CH2 3-COCH3 4-N(CH3)2 P-329 C--F CH3 CH2
3-COCH3 3-F, 4-CH2NHCOCH3 P-330 C--F CH3 CH2 3-COCH3 3-F,
4-CH2NHCONH2 P-331 C--F CH3 CH2 3-COCH3 4-NHCH3 P-334 C--F CH2CH3
CH2 3-COCH3 4-NH2 P-335 C--F CH2CH3 CH2 3-COCH3 4-NHCONH2 P-338
C--F CH3 CH2 3-COCH3 4-N(CH3)CONH2 P-340 C--F CH3 CH2 3-CH(OH)CH3
4-NHCONH2 P-347 C--F CH3 CH2 3-Br 4-NHCONH2 P-348 C--F CH3 CH2 3-Br
4-NHCONHCH2COOH P-349 C--F CH3 CH2 3-Br 4-NHCONHCH2CH2COOH P-376 N
CH3 CH2 3-Cl 4-NHCONH2 P-378 C--H CH3 CH2 3-Cl 4-NHCONH2 P-380 C--H
CH3 CH2 N1-(3-Cl 4-F Pyrrazole) P-381 C--F CH3 CH2 N-Pyrrolidine
4-NHCOCH3 P-385 C--H CH3 CH2 N-morpholine 4-F P-390 C--F CH3 CH2
N-morpholine 4-NHCOCH3 P-394 C--H CH3 CH2 3-CN 4-NHCONH2 P-404 C--F
CH3 CH2 3-Cl 4-(N1-tetrazole) P-413 C--F CH3 CH2 3-CN 4-NHCONH2
P-418 C--F CH3 CH.dbd.CH 3-Cl 4-F P-419 C--F CH3 CH.dbd.CH 3-Cl 4-F
P-420 C--H CHF2 CH2 3-Cl 4-NHCONH2 P-421 CH H CH2 3-Cl 4-NHCONH2
P-434 C--F CH3 C.dbd.O 3-Cl 4-NHCONH2 P-441 C--F CH3 C(CH3)(OH)
3-Cl 4-NHCONH2 P-447 C--H CH3 S 3-Cl 4-NH2 P-448 C--H CH3 S 3-Cl
4-NHCONH--Et P-449 C--H CH3 SO 3-Cl 4-NHCONH--Et P-450 C--H CH3 SO2
3-Cl 4-NHCONH--Et P-451 C--F H CH2 3-NO2 4-F P-453 C--F CH3 CH2
3-Br 4-NH2 P-454 C--H CH3 CH2 3-Cl 4-NH(2-Thiazolyl) P-466 C--F CH3
CH2 3-Cl 4-NH(2-Thiazolyl) P-467 C--H CH3 CH2 3-Cl 4-NH(N-Methyl
2-imidazolyl) P-468 C--F H CH2 3-Cl 4-NHCOCH3 P-476 C--H CH3 CH2
3-Cl 4-NHCH3 P-477 C--H CH3 CH2 3-Cl 3-NHCOCH3 P-453 C--F CH3 CH2
3Br 4-NH2 P-494 C--H H CH2 3-NO2 4-F P-496 C--F H CH2 3-Br 4-F
P-497 C--F CH3 CH2 3-Br 4-F P-498 C--H CH3 CH2 3-NO2 4-OH P-501
C--H CH3 CH2 3-NO2 2-CH2NHCOH P-502 C--F CH3 CH2 3-NO2
4-CH2NHCOCH2NMe2 P-505 C--F CH3 CH2-NH 3-Cl 4-NHACc P-508 C--F H
CH2 3-NO2 4-NHCONH2 P-516 C--H CD3 CH2 3-Cl 4-NHCONH2 P-530 C--F
CH3 C(CH3)(OH) 3-Cl 4-NHAc P-532 C--F CH3 CD2 3-Cl 4-NHCONH2 P-537
C--F CH3 CD(OH) 3-Cl 4-NO2 P-538 C--F CH3 CD(OH) 3-Cl 4-NH2 P-539
C--F CH3 CD(OH) 3-Cl 4-NHCONH2 P-540 C--H CH3 S 3-Cl 4-NHCONH2
P-541 C--H CH2CH3 CH2 3-Cl 4-NHCONH2 P-542 C--H H2NCH2CH2-- CH2
3-Cl 4-NHCONH2 P-543 C--H 2- CH2 3-Cl 4-NHCONH2 (Tetarhydro-
furanyl)CH2 P-547 C--H CH3 CD2 3-Cl 4-NHCONH2 P-548 C--H
(Me)CNCH2CH2-- CH2 3-Cl 4-NHCONH2 P-550 C--H CH3 CH2 3-Cl 4-NHCONH2
P-553 C--H 3- CH2 3-Cl 4-NHCONH2 (thiatenyl) P-554 C--H 3- CH2 3-Cl
4-NHCONH2 (azetidinyl) P-555 C--H 3- CH2 3-Cl 4-NHCONH2 (oxetanyl)
P-556 C--H 3-(N- CH2 3-Cl 4-NHCONH2 methyl pyrrolidinyl) P-557 C--H
H2NCOCH2- CH2 3-Cl 4-NHCONH2 P-558 C--H CH3 C(.dbd.O) 3-Cl P-560
C--F CH3 C(CH3)(OH)- 3-Cl 4-NHCOAc enantiomer-A P-561 C--F CH3
C(CH3)(OH)- 3-Cl 4-NHCOAc enantiomer-B P-562 C--H 3- CH2 3-Cl 4-NH2
(Oxetanyl) P-563 C--H ((S)-1- CH2 3-Cl 4-NHCONH2 pyrrolidin-
2-CH2-- P-564 C--H CH3 C[(CH2CH2) 3-Cl 4-F N(CH3)) CH2CH2)]
P-565 C--H 3-(N- CH2 3-Cl 4-NHCONH2 emthyl pyrrolidine) P-566 C--H
CH3 CH2 3-Cl NHCONH(2-Tetrahydrofuran) P-575 C--F CH3 CH2--O 3-Cl
4-NO2 P-576 C--F CH3 CH2--O 3-Cl 4-NH2 P-578 C--H CH3 CO 3,4- 4-NH2
OCH2CH2O-- P-579 C--H CH3 CO 3-F 4-NH2 P-580 C--H CH3 CO 3,4-F2
4-NH2 P-583 C--H CH3 CD(OH) 3-Cl 4-NO2 P-584 C--H CH3 CD(OH) 3-Cl
4-NHCONH2 P-589 C--F CH3 CH2--O 3-Cl 4-NHCONH2 P-594 C--F CH3 CH--O
3-Cl 4-NHAc P-620 C--F H CH2 3-Br 4-NHAc
TABLE-US-00002 TABLE 2 ##STR00036## Ar1.dbd.2Het(6)--Ra Example X
R3 M Rb P Q U V W Ra P-008 C--H CH3 CH2 3-NO2 CH CH CH CH N --
P-009 C--H CH3 CH2 3-NO2 N CH NH CH CO -- P-011 C--H CH3 CH2
3,4-NON CH CH CH CH N -- P-012 C--H CH3 CH2 3,4-NON N NH CH CH CO
-- P-015 C--H CH3 O 3-NO2 N CH NH CH CO -- P-016 C--OH CH3 C.dbd.O
3-NO2 CH CH CH CH N -- P-017 C--OH CH3 CH2 3-NO2 CH CH CH CH N --
P-018 C--H CH2CH2OCH3 CH2 3-NO2 N CH N CH CO (U)--CH2CH2OCH3 P-019
N CH3 CH2 3-NO2 CH CH CH CH N -- P-020 C--H CONH2 CH2 3-NO2 N CH NH
CH CO -- P-106 C--OH CH3 CH2 3-NO2 CH CH N CH CH -- P-109 C--OH CH3
CH2 3-NO2 C CH N CH CH (P)--Cl P-110 C--H CH3 CH2 3-NO2 CH CH N CH
C (W)--NHCO2-tBu P-111 C--H CH3 CH2 3-NO2 CH CH N CH C (W)--NH2
P-124 C--OH CH3 C.dbd.O 3-NO2 CH CH N CH C (W)--OCH3 P-125 C--OH
CH3 CH2 3-NO2 CH CH N CH C (W)--OCH3 P-126 C--OH CH3 CH2 3-NO2 CH
CH N CH C (W)--Cl P-150 C--OH CH3 CH2 3-NO2 CH CH N CH C (W)--
OCH2CH2N(CH3)2 P-152 C--F CH3 CH2 3-NO2 CH CH N CH C (W)--Cl P-177
C--OH CH3 CH2 3-NO2 CH CH N CH C (W)--NHCH2CO2H P-178 C--OH CH3 CH2
3-NO2 CO CH NH CH CH -- P-182 C--OH CH3 CH2 3-NH2 C CH N CH CH
(P)--Cl P-185 C--OH CH3 CH2 3-NH2 CO CH NH CH CH -- P-224 C--H CH3
CH2--O 3-NO2 CH N CH CH CH -- P-225 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--OCH3 P-226 C--F CH3 CH2 3-Cl CH CH N CH C (W)--Cl P-252 C--F
CH3 CH2 3-Cl CH CH N CH C (W)--NH2 P-258 C--F CH3 CH2 3-Cl CH CH N
CH C (W)--NHSO2CH3 P-259 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONH2 P-272 C--F CH3 CH2 3-Cl CH CH N CH C (W)--NHSO2NH2
P-277 C--F CH3 CH2 3-COCH3 CH CH N CH C (W)--NH2 P-278 C--F CH3 CH2
3-Cl CH CH N N C (W)--NH2 P-279 C--F CH2CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONH2 P-281 C--F CH3 CH2 3-COCH3 CH CH N N C (W)--NH2 P-284
C--F CH3 CH2 3-COCH3 CH CH N N C (W)--NHSO2CH3 P-290 C--F CH3 CH2
3-COCH3 CH CH N CH C (W)--NHCONH2 P-291 C--F CH3 CH2 3-Cl CH CH N N
C (W)--NHCONH2 P-292 C--F CH3 CH2 3-Cl CH CH N N C (W)--NHSO2CH3
P-297 C--F CH3 CH2 3-COCH3 CH CH N CH C (W)--NHSO2CH3 P-298 C--F
CH3 CH2 3-Cl CH CH N N C (W)--NHSO2NH2 P-307 C--F CH3 CH2 3-COCH3
CH CH N CH C (W)--NHSO2NH2 P-308 C--F CH3 CH2 3-Cl CH CH CH N--O C
(W)--NHCONH2 P-309 C--F CH3 CH2 3-Cl CH CH N N--O C (W)--NHCONH2
P-314 C--F CH3 CH2 3-COCH3 CH CH N N C (W)--NHSO2NH2 P-315 C--F CH3
CH2 3-COCH3 CH CH N N C (W)--NHCONHEt P-318 C--F CH3 CH2 3-Cl CH CH
CH N C (W)--NHEt P-321 C--F CH3 CH2 3-COCH3 CH CH N CH C
(W)--CO2CH3 P-325 C--F CH3 CH2 3-COCH3 CH CH N N C (W)--N(CH3)2
P-327 C--F CH3 CH2 3-COCH3 CH CH N CH C (W)--CO2H P-328 C--F CH3
CH2 3-COCH3 CH CH N CH C (W)--CONH2 P-332 C--F CH3 CH2 3-COCH3 CH
CH N CH C (W)--N(CH3)2 P-336 C--F CH3 CH2 3-COCH3 CH CH N CH C
(W)--NHCH3 P-337 C--F CH3 CH2 3-COCH3 CH CH N CH C (W)--NHCONHEt
P-339 C--F CH3 CH2 3-COCH3 CH CH N CH C (W)--NHEt P-344 C--F CH3
CH2 3-Cl CH CH N CH C (W)--CH2NH2 P-345 C--F CH3 CH2 3-COCH3 CH CH
N CH C (W)--NHCOCH3 P-355 C--F CH3 CH2 3-Cl CH CH N CH C (W)--CN
P-356 C--F CH3 CH2 3-Cl CH CH N CH C (W)--NHCONHEt P-357 C--F CH3
CH2 3-Cl CH CH N CH C (W)--NHCO2Et P-358 C--F CH3 CH2 3-Cl CH CH N
CH C (W)--NHCONHCH2CO2H P-359 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--N(Et)CO2Et P-360 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONHCH2CH2CO2Et P-361 C--F CH3 CH2 3-COCH3 CH CH N CH C
(W)--1N-2- imidazolidinone P-362 C--F CH3 CH2 3-COCH3 CH CH N N C
(W)--NHCONH2 P-365 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONHCH2CH2CO2H P-366 C--F CH3 CH2 3-COCH3 CH CH N N C
(W)--NHCONHCH2CH2Cl P-367 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CH2NHCO2Et P-368 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CH2NHCONH2 P-371 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CH2NHCON(CH3)2 P-372 C--F CH3 CH2 3-Cl CH CH N CH C (W)--
CH2NHCONHEt P-373 C--F CH3 CH2 3-Cl CH CH N CH C (W)--CH2NHCO(4-
Me--1N-Piperazine) P-374 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CH2--1N(-2- imidazolidinone) P-375 C--F CH3 CH2 3-Cl CH CH N
CH C (W)--CH2--1N((N3--methyl-(2- imidazolidinone) P-377 C--F CH3
CH2 3-Cl CH CH N CH C (W)--N(morpholine) P-379 N CH3 CH2 3-Cl CH CH
N CH C (W)--NH2 P-382 C--F CH3 CH2 3-Cl CH CH N CH C (W)--CON(CH3)2
P-383 C--F CH3 CH2 3-Cl CH CH N CH C (W)--CO--N(Piperidine-4-
CO2Et) P-384 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CO--N(Piperidine-4- COOH) P-386 N CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONHEt P-387 C--F CH3 CH2 3-Cl CH CH N CH C (W)--NHCOCH3
P-388 C--F CH3 CH2 3-Cl CH CH N CH C (W)--1N-2- imidazolidinone
P-392 C--F CH3 CH2 3-Cl CH CH N N C (W)--Cl P-393 C--F CH3 CH2 3-Cl
CH CH N N C (W)--N-[3-OH- Azetidine] P-395 C--F CH3 CH2 CN CH CH N
N C (W)--NH2 P-397 C--F CH3 CH2 3-Cl CH CH N--O CH C (W)--NHCONHEt
P-398 C--F CH3 CH2 CN CH CH N CH C (W)--NHCO2Et P-399 C--F CH3 CH2
CN CH CH N N C (W)--NHCONHEt P-400 C--H CH3 CH2 CN CH CH N CH C
(W)--NHCONHEt P-401 C--F CH3 CH2 3-Cl CH CH N CH C (W)--CONH2 P-402
C--F CH3 CH2 3-Cl CH CH N CH C (W)--Br P-403 C--F CH3 CH2 3-Cl CH
CH N CH C (W)--NHCH2CO2H P-405 C--F CH3 CH2 CN CH CH N CH C
(W)--NHCONHEt P-406 C--F CH3 CH2 3-Cl CH CH N N C
(W)--O--[(S)--(N--Me- 3-pyrrolidine)] P-407 C--F CH3 CH2 3-Cl CH CH
N CH C (W)-4-OH-3-pyrdine P-408 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--OH P-409 C--F CH3 CH2 3-Cl CH CH N CH C (W)--N(COCH3)CH2CO2H
P-410 C--F CH3 CH2 3-Cl CH CH N CH C (W)-4-Br-3-pyrdine P-411 C--F
CH3 CH2 3-Cl CH CH N CH C (W)--NHCH2CH2OH P-412 C--F CH3 CH2 3-Cl
CH CH N CH C (W)--1N-1,2,4- triazole P-414 C--F CH3 CH2 3-Cl CH CH
N CH C (W)--CO--1N- pyrrolidine-3-CO2H) P-415 C--F CH3 CH2 CN CH CH
N CH (W)--CONH2 P-416 C--F CH3 CH2 3-Cl C CH N N CH (P)--Cl P-417
C--F CH3 CH2 CN CH CH N N C (W)--N-[3-OH- Azetidine] P-422 C--F CH3
CH2 3-Cl CH CH N CH C (W)--1N-tetrazole P-423 C--F CH3 CH2 3-Cl CH
CH N CH C (W)--1N-piperazine P-426 C--F CH3 CH2 3-Cl CH CH N N C
(W)--1N-(S)-Proline P-427 C--F CH3 CH2 3-Cl CH CH N N C
(W)--1N-(piperidine- 3-CO2H) P-428 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--1H-5-tetrazolyl P-431 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--1N-(piperazine- 4-CO2Et) P-432 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--1N-(piperazine- 4-CONH2) P-433 C--F CH3 CH2 3-Cl CH CH C CH N
(U)--CN P-437 C--F CH3 CH2 3-Cl CH CH C CH N (U)--CH2NH2 P-438 C--F
CH3 CH2 3-Cl CH CH N N C (W)--1N- (pyrrolidine-3- CO2H) P-439 C--F
CH3 O CN CH CH N CH C (W)--NH2 P-440 C--F CH3 O CN CH CH N CH C
(W)--NHCONHEt P-442 C--F CH3 CH2 3-Cl CH CH N N C (W)--1N-
(pyrrolidine-3- CO2Me P-446 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(azetidine-4- COOH) P-455 C--F CH3 CH2 3-Cl CH CH N N C
(W)-sarcosine P-456 C--F CH3 CH2 3-Cl CH CH CH N C (W)--F P-457
C--F CH3 CH2 3-Cl CH CH CH N C (W)--N(azetidine-3-OH) P-458 C--F
CH3 CH2 3-Cl CH CH N N C (W)--N(CH3)CH2CH2OH P-459 C--F CH3 CH2
3-Cl CH CH CH N C (W)--CH2NHCOCO2Et P-460 C--F CH3 CH2 3-Cl CH CH
CH N C (W)--CH2NHCONH--Me P-461 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N1(N3-ethyl- imidazolidin-2-one) P-462 C--F CH3 CH2 3-Cl CH CH
CH N(--O) C (W)--CH2NHCONH--Et P-463 C--F CH3 CH2 3-Cl CH CH CH
N(--O) C (W)--CH2--N- Oxazolidin-2-one P-464 C--F CH3 CH2 3-Cl CH
CH N N C (W)--N(azetidine- (W)--COOH) P-465 C--F CH3 CH2 3-Cl CH CH
CH N C (W)--CH2--N- Oxazolidin-2-one P-469 C--F CH3 CH2 3-Cl CH CH
CH N C (W)--N-Oxazolidin- 2-one P-470 C--F CH3 CH2 3-Cl CH CH CH N
C (W)--N1(N3-Methyl- imidazolidin-2-one) P-471 C--F CH3 CH2 3-Cl CH
CH CH N C (W)--NHCH2CONH2 P-472 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--CONHSO2CH3 P-473 C--F CH3 CH2 3-Cl CH CH CH N C (W)--N(CH3)2
P-478 C--F CH3 CH2 3-Cl N CH CH CH C (W)--NH2 P-488 C--H H CH2
3-NO2 N CH NH CH C(.dbd.O) -- P-499 C--H H CH2 3-NO2 CH CH NH CH C
(W)--OCH3 P-500 C--H H CH2 3-NO2 CH CH N CH C (W)--Cl P-507 C--F H
CH2 3-Cl CH CH N CH C (W)--NHCONH2 P-513 C--F CH3 CH2 C- CH CH N CH
C (W)--NHCONH-Et Tetrazole P-514 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--[N(CH2CH2)2N]--CONHEt P-515 C--F CH3 CH2 3-Cl CH CH C CH N
(U)--N-Piperazinyl P-518 C--F CH3 CH2 3-Cl CH CH C CH N
(U)--[N(CH2CH2)2N]--CONH2 P-519 C--F CH3 CH2 3-Cl CH CH C CH N
(U)--[N(CH2CH2)2N]--CONH--Et P-520 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CH2NHCOO--Ph P-521 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CH2NHCOCOCNH2 P-523 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--O--CH2-[(S)-2- Pyrrolidine] P-531 C--F CH3 CH2--O 3-CN CH CH C
CH N (U)--CH2NHCONH--Et P-533 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--O--CH2--[(S)-2-]**** P-567 C--H CH3 CH2 3-Cl CH CH N CH C
(W)--CH2OH P-568 C--H CH3 CH2 3-Cl CH CH N CH C (W)--N-Azetidine
P-569 C--F CH3 CH2 3-Cl CH CH N CH C (W)--N-Azetidine P-570 C--H
CH3 CH2 3-Cl CH CH N CH C (W)--CH2OCO--NH--Et P-571 C--F CH3 CH2
3-Cl CH CH N CH C (W)--N-Azetidine-2- Carboxamide P-572 C--H CH3
CH2 3-Cl CH CH N CH C (W)--N-morpholine P-573 C--F CH3 CH2 3-Cl CH
CH N CH C (W)--N-imidazole P-574 C--F CH3 CH2--O 3-Cl N CH CH CH C
(W)--Br P-577 C--F CH3 CH2 3-Cl CH CH N CH C (W)--N--[(2,5-
dimethyl)pyrrolidine] P-581 C--F CH3 CH2 3-Cl CH CH N CH C (W)-N-
(pyrrolidine(2- C(Me2)OH)] P-582 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--N--(pyrrolidine) P-585 C--F CH3 CH2--O 3-Cl CH CH N CH C
(W)--Cl P-586 C--F CH3 CH2--O 3-Cl CH CH N CH C (W)--N-Azetidine
P-587 C--F CH3 CH2 3-Cl CH CH N CH C (W)--C(CH3)2OH P-588 C--F CH3
CH2 3-Cl CH CH N CH C (W)--OCH2CH2NMe2 P-590 C--H CH3 CH2 3-Cl CH
CH N CH C (W)--CN P-591 C--H CH3 CH2 3-Cl CH CH N CH C (W)--CH2NH2
P-592 C--H CH3 CH2 3-Cl CH CH N CH C (W)--CH2NHCOOPh P-593 C--H CH3
CH2 3-Cl CH CH N CH C (W)--CH2NHCONHCH3 P-595 C--F CH3 CH2 3-Cl CH
CH N CH C (W)--C(CH3)2NH2 P-596 C--H CF2H CH2 3-Cl CH CH N CH C
(W)--CH2NH2 P-597 C--H CH2 3-Cl CH CH N CH C (W)--CH2NHCONH--Et
P-598 C--H CF2H CH2 3-Cl CH CH N CH C (W)--CH2NHCONH--Me P-599 C--F
CH3 CH2 3-Cl CH CH N CH C (W)--CH2OH P-600 C--H CH3 CH2 3-Cl CH CH
N CH C (W)--C(CH3)2NH2 P-601 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--N[pyrrolidine(3-hydrohyl)] P-602 C--H CH3 CH2 3-Cl CH CH N CH
C (W)--N[pyrrolidine(3-hydrohyl)] P-603 C--H CH3 CH2--O 3-Cl CH CH
CH C N (V)--Cl P-604 C--F CH3 CH2--O 3-Cl CH CH CH C N (V)--Cl
P-605 C--H CH3 CH2 3-Cl CH CH N CH C (W)--C(CH3)2OH P-606 C--F CH3
CH2 3-Cl CH CH N CH C (W)--CH(CH3)NH2 P-607 C--H CH3 CH2--O 3-Cl CH
CH CH C N (V)--N(pyrrolidine) P-608 C--F CH3 CH2--O 3-Cl CH CH CH C
N (V)--N(pyrrolidine) P-609 C--H CH3 CH2 3-Cl CH CH N CH C
(W)--CH(CH3)--N(azetidine) P-610 C--H CF2H CH2 3-Cl CH CH N CH C
(W)--C(CH3)2OH P-611 C--H CF2H CH2 3-Cl CH CH N CH C (W)--NH2 P-612
C--F CH3 CH2 3-Cl CH CH N CH C (W)--N[(S)proline-2-amide)] P-613
C--F CH3 CH2 3-Cl CH CH N CH C (W)--CH(CH3)NHCONH2 P-614 C--H CF2H
CH2 3-Cl CH CH N CH C (W)--N-Azetidine P-615 C--F CH3 CH2 3-Cl CH
CH N CH C (W)--N[Azetidine-2- (R)-carboxamide)] P-616 C--H CF2H CH2
3-Cl CH CH N CH C (W)--NHCONH2 P-617 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--N[Azetidine-2- (S)-carboxamide)] P-618 C--H CF2H CH2 3-Cl CH
CH N CH C (W)--NHCOCH2NMe2 P-619 C--F CH3 CH2 3-Cl CH CH N N C
(W)--NHCONH--Et P-621 C--H CF2H CH2 3-Cl CH CH N CH C
(W)--N(CH3)CH2CONH2 P-622 C--H CH3 CH2 3-Cl CH CH N CH C
(W)--N(CH3)CH2CONH2
TABLE-US-00003 TABLE 3 ##STR00037## Ex. No. Core R3 M Rb P Q U V Ra
P-062 C--H CH3 CH2 3,4-OCH2O C(CH3) C(CH3) N O -- P-073 C--H CH3
CH(OH) 3,4-OCH2O N(CH3) CH N CH -- P-075 C--H CH3 CH2 3,4-OCH2O
N(CH3) CH N CH -- P-087 C--H CH3 CH2 3-NO2 C(CH3) C(CH3) N N
(U)--CH2CO2CH2CH3 P-088 C--H CH3 CH2 3-NO2 C(CH3) C(CH3) N N
(U)--CH2CH2OH P-089 C--H CH3 CH2 3-NO2 C(CH3) C(CH3) NH N P-090
C--H CH3 CH2 3-NO2 C(CH3) C(CH3) N N (U)--CH2CF3 P-100 C--H CH3 CH2
3-NO2 C(CH3) C(CH3) N N (U)--CH2COOH P-101 C--H CH3 CH2 3-NO2
C(CH3) C(CH3) N N (U)--CH2CONH2 P-115 C--H CH3 CH2 3,4-OCF2O N CH N
CH (P)--CH3 P-128 C--F CH3 C.dbd.O 3-NO2 S CH CH CH -- P-129 C--OH
CH3 C.dbd.O 3-NO2 O CH N CH -- P-130 C--OH CH3 CH2 3-NO2 O CH N CH
-- P-174 C--OH CH3 CH2 3-NO2 C C N O (P)--CH3, (Q)--CH3 P-201 C--H
CHF2 CH2 3,4-OCH2O N CH N CH (P)--CH3 P-306 C--H CH3 CH2 3-Cl O N C
N (U)--NH2 P-310 C--F CH3 CH2 3-Cl S CH C CH (U)--OCH2CH3 P-333
C--F CH3 CH2 3-Cl S N C N (U)--NH2 P-341 C--F CH3 CH2 3-Cl N CH C S
(U)--NH2 P-342 C--F CH3 CH2 3-Cl S N C N (U)--NHCOOCH3 P-343 C--F
CH3 CH2 3-Cl S N C N (U)--NHCONHCH2CH3 P-346 C--F CH3 CH2 3-Cl N CH
C S (U)--NHCONHCH2CH3 P-350 C--F CH3 CH2 3-Cl S N C N
(U)--NHCONHCH2COOCH2CH3 P-351 C--F CH3 CH2 3-Cl S N C N
(U)--NHCONHCH2CH2COOCH2CH3 P-352 C--F CH3 CH2 3-Cl S N C N
(U)--NHCONH2 P-353 C--F CH3 CH2 3-Cl S N C N (U)--NHCONHCH2COOH
P-354 C--F CH3 CH2 3-Cl S N C N (U)--NHCONHCH2CH2COOH P-363 C--F
CH3 CH2 3-Cl S N C N (U)--NHCONH(CH2)3COOCH2CH3 P-364 C--F CH3 CH2
3-Cl S N C N (U)--NHCONH(CH2)3COOH P-369 C--F CH3 CH2 3-Cl S CH C N
(U)--NH2
TABLE-US-00004 TABLE 4 ##STR00038## Ex. No. X M Rb N(Rc) P-005 C--H
CH2 3-NO2 1N-1,2,4-Triazole P-006 C--H CH2 3,4-NON 1N-Imidazole
P-007 C--H CH2 3-NO2 1N-Benzotriazole P-010 C--H CH2 3-NO2
N(Indole) P-014 C--H CH2 3,4-NON 1N-Benzimidazole P-022 C--H CH2
3-CO2CH3 1N-1,2,4-Triazole P-024 N CH2 3-NO2 1N-1,2,4-Triazole
P-026 N CH2 3-NO2 N(Morpholine) P-029 C--H CH2 3-NO2
N(2-Pyrrolidinone) P-031 N CH2 3-NO2 N(2-Pyrrolidinone) P-033 N CH2
3-NO2 1N-imidazolidin-2-one P-034 C--H CH2 3-NO2
1N-2-imidazolidin-2-one P-035 C--H CH2 3-NO2 N-1,4-Butanesultam
P-036 C--H CH2 3-NO2 N-Succinimide P-037 C--H CH2 3,4-OCH2O
1N-Imidazole P-039 C--H CH2 3-NO2 N-Saccharin P-040 C--H CH2 3-NO2
N-Glutarimide P-041 C--H CH2 3-NO2 N-Isatin P-042 C--H CH2 3-NO2
N-Phthalimide P-044 C--H CH2 3,4-OCH2O 1N-1,2,4-Triazole P-045 C--H
CH2 3,4-OCH2O 1N-2-Pyrrolidinone P-046 C--H CH2 3-CO2CH3, 4-F
1N-1,2,4-Triazole P-048 C--H CH2 3-CO2CH3, 2-F 1N-1,2,4-Triazole
P-052 C--H CH2 3,4-OCH2O N-Phthalimide P-053 C--H CH2 3,4-OCH2O
1N-Succinimide P-055 C--H CH2 3-NO2 N-3,4-Pyridinedicarboximide
P-056 C--H CH2 3-NO2 9N-2-Amino-6-chloropurine P-058 C--H CH2 3-F
1N-1,2,4-Triazole P-059 C--H CH2 3-NO2 9N-Guanine P-060 C--H CH2
3,4-F2 1N-1,2,4-Triazole P-061 C--H CH2 3,4,5-F3 1N-1,2,4-Triazole
P-063 C--H CH2 3-CF3 1N-1,2,4-Triazole P-064 N CH2 3-CF3
1N-1,2,4-Triazole P-066 C--H CH2 3-NO2 4N-1,2,4-Triazole P-068 N
CH2 3-CF3 N-L-4-Hydroxyproline methyl ester P-069 C--H CH2 3-NO2
N-L-4-Hydroxyproline methyl ester P-070 C--H CH2 3-NO2
N-(S)-3-Pyrrolidinol P-071 C--H CH2 3-NO2 N-(R)-3-Pyrrolidinol
P-072 C--H CH2 3-NO2 N-D-Prolinol P-074 C--H CH2 3,4-OCH2O
1N-Pyrazole P-076 C--H CH2 3-NO2 3N-2-Oxazolidinone P-077 C--H CH2
3-NO2 1N-Pyrazole P-078 C--H CH2 3-CF3 N-(R)-3-Pyrrolidinol P-081
C--H CH2 3-CN 1N-1,2,4-Triazole P-082 C--H CH2 3-COCH3
1N-1,2,4-Triazole P-083 C--H CH2 3-CF3 3N-2-Oxazolidinone P-084
C--H CH2 3-OCF3 1N-1,2,4-Triazole P-085 C--H CH2 3-SCH3
1N-1,2,4-Triazole P-086 C--H CH2 3-OCH3 1N-1,2,4-Triazole P-104
C--H CH2 3-NO2 N-2-Pyridone P-108 C--H CH2 3-CH2OCH3
1N-1,2,4-Triazole P-131 C--H CH2 3-NO2
N-(S)-5-(Hydroxymethyl)-pyrrolidin-2-one P-132 C--H CH2 3-NO2
N-(R)-5-(Hydroxymethyl)-pyrrolidin-2-one P-153 C--H CH2 3-NO2
1N-5-(Hydroxymethyl)-imidazole P-154 C--H CH2 3-NO2
1N-4-(Hydroxymethyl)-imidazole P-155 C--H CH2 3-NO2
N-(S)-5-(Aminomethyl)-pyrrolidin-2-one P-156 C--H CH2 3-NO2
N-(R)-5-(Aminomethyl)-pyrrolidin-2-one P-162 C--H CH2 H
1N-2-Pyrrolidinone P-169 C--H CH2 3-SOCH3 1N-1,2,4-Triazole P-172
C--H CH2 3-COCH3 1N-2-Pyrrolidinone P-179 C--H CH2 3-COCH3
N-2-Pyridone P-184 C--H CH2 3-OCH3 1N-2-Pyrrolidinone P-186 C--H
CH2 3-[2-Oxadiazole] 1N-2-Pyrrolidinone P-188 C--H CH2 3-NO2
1N-2-piperidinone P-195 C--H CH2 3-NO2
1N-5-Carbonitrile-pyridin-2-one P-196 C--H CH2 3-NO2
1N-4-Carbonitrile-pyridin-2-one P-197 C--H CH2 3-NO2 2N-6-Methyl
pyridazin-3-one P-198 C--H CH2 3-NO2 1N-5-Amino-pyridin-2-one P-203
C--F CH2NH 3-Cl N-(4-(acetamido)-phenyl) P-204 C--H CH2 3-NO2
2N-6-Methoxyl pyridazin-3-one P-205 C--H CH2 3-NO2 2N-Pyridazinone
P-206 C--H CH2 3-NO2 1N-3-Methoxy-pyridin-2-one P-207 C--H CH2
3-NO2 1N-4-Carboxamide-pyridin-2-one P-208 C--H CH2 3-NO2
1N-Pyridin-2-one-5-urea P-209 C--H CH2 3-Cl N-Pyrrolidin-2-one
P-210 C--H CH2 3-NO2 1N-Pyridin-2-one-4-carboxylic acid P-211 C--H
CH2 3-NO2 1N-Pyridin-2-one-5-acetamide P-212 C--H CH2 3-NO2
1N-Pyridin-2-one-5-carboxamide P-215 C--H CH2 3-NO2
1N-4-Amino-pyridin-2-one P-218 C--H CH2 3-Cl N-Pyrrolidin-2-one
P-223 C--H CH2 3,4-F2 N-Pyrrolidin-2-one P-229 C--OH CH2 3-NO2
N-Pyrrolidin-2-one P-235 C--H CH2 3-Cl 1N-5-Bromo-2-pyrimidinone
P-236 C--H CH2 3-NO2 1N-6-Amino-pyridin-2-one P-244 C--H CH2CH2
3-NO2 CH2-1N-Pyrrolidin-2-one P-245 C--H CH2 SCH3
1N-Pyrrolidin-2-one P-248 C--H CH2 3-NO2
N-(S)-4-Hydroxy-pyrrolid-2-one P-253 C--H CH2 3-NO2
N-[(S)-Pyrrolid-2-one-4-carbamate P-370 C--F CH2 3-Cl
1N-Piperazine-4-carboxamide P-424 C--F CH2 3-Cl
1N-4-(4-Aminophenyl)pyrazole P-435 C--F CH2 3-Cl
1N-4-(4-Ureaphenyl)pyrazole P-436 C--F CH2 3-Cl
1N-4-(4-Ethylureaphenyl)pyrazole P-479 C--F CH2 3-Cl
N1-imidazol-4-yl]-pyridine P-481 C--H CH2 3,4(.dbd.N--O--N.dbd.)
1N-(12,4)Triazole P-482 C--H CH2 3-NO2 1N-Benztriazole P-483 C--H
CH2 3-NO2 1N-benzimidazole P-486 C--H CH2 3,4-(CHCHN(H))
1N-(12,4)Triazole P-492 C--H CH2 3-NO2 N-Glutarmide P-493 C--H CH2
3-NO2 N-(R)-prolinol P-495 C--H CH2 3-SO2CH3 1N-(12,4)Triazole
P-503 C--H CH2 3-NO2 1N-Pyrrolidin-2-one P-504 C-OH CH2 3-NO2
1N-Pyrrolidin-2-one P-511 C--F CH2 3-Cl
1N[4(4-nitrophenyl)pyrazole] P-512 C--F CH2 3-Cl
1N[4{4-(NHCO2Et)phenyl}pyrazole] P-517 C--F ch2 3-Cl
1N[3{3-pyridyl)imidazole] P-524 C--H bond 3-Cl
1N(7-aminobenzimidazole) P-527 C--F CH2 3-Cl
1N[4{2-pyridyl)imidazole] P-528 C--H CH2 3-Cl
1N[4{4-pyridyl)imidazole] P-534 C--F CH2 3-Cl
1N[imidazole-4-carboxamide] P-535 C--F CH2 3-Cl
1N[imidazole-5-carboxamide] P-536 C--F CH2 3-Cl
1N[4-nitro-imidazole] P-544 C--F CH2 3-Cl
1N[3(2-pyridinyl)pyrazole] P-545 C--F CH2 3-Cl
1N[3(2-pyrazinyl)pyrazole] P-546 C--F CH2 3-Cl
1N[4(6-pyrimidinyl)pyrazole] P-549 C--F CH2 3-Cl
1N[2(3-pyridinyl)imidazole] P-551 C--F CH2 3-Cl
1N[3-trifluoromethyl-5-(2-pyridinyl)-pyrazole] P-552 C--F CH2 3-Cl
1N[3-trifluoromethyl-5-(3-pyridinyl)-pyrazole] P-559 C--F CH2 3-Cl
1N[2(2-thienyl)imidazole] P-529 C--H bond 3-Cl
1N[(7-NHCONHEt)benzimidazole] P-623 C--F CH2 3-Cl
4N-Piperazin-2-one
TABLE-US-00005 TABLE 5 ##STR00039## Ex. No. X R3 M Rb Ra P-038 N
CH3 CH2 3-NO2 O-Cyclopentane P-091 C--H CH3 CH2 3-CF3
3-O-2-Cylopentene-1-one P-092 C--H CH3 CH2 3-NO2
3-O-2-Cylopentene-1-one P-127 C--F CH3 CH2 3-NO2
2-Tetrahydrothiophene P-120 C--H CH3 CH2 3-NO2 1-(4-Methyl-2,6,7-
trioxa-bicyclo[2.2.2]octane)
TABLE-US-00006 TABLE 6 ##STR00040## Ex. No. X R3 M Rb Ra P-025 N
CH3 CH2 3-NO2 OCH3 P-030 N CH3 CH2 3-NO2 OCH(CH3)2 P-149 C--OH CH3
CH2 3-NO2 OH P-027 C--H CH3 CH2 3-NO2 CONHCH3 P-491 N CH3 CH2 3-NO2
OH
TABLE-US-00007 TABLE 7 ##STR00041## All of the Examples in the
table below, R3.dbd.CH3 Ex. No. X Rb Ra P-028 C--H 3-NO2 Phenyl
##STR00042## P-032 C--H 3-NO2 Phenyl ##STR00043## P-043 C--H 3-NO2
Phenyl ##STR00044## P-047 C--H 3-NO2 Phenyl ##STR00045## P-213 C--H
3-NO2 Phenyl ##STR00046## P-214 C--H 3-NO2 Phenyl ##STR00047##
P-251 C--F 3-Cl Phenyl ##STR00048## P-263 C--F 3-Cl Phenyl
##STR00049## P-285 C--F 3-Cl Phenyl ##STR00050## P-425 C--F 3-Cl
Phenyl ##STR00051## P-429 C--F 3-Cl Phenyl ##STR00052## P-430 C--F
3-Cl Phenyl ##STR00053## P-445 C--F 3-Cl Phenyl ##STR00054## P-480
C--F 3-Cl Phenyl ##STR00055##
TABLE-US-00008 TABLE 8 ##STR00056## Ex. No. X Rb Ra P-389 C--F
##STR00057## 4-F Phenyl P-391 C--H ##STR00058## 4-F Phenyl P-396
C--F ##STR00059## 4-F Phenyl P-475 C--H ##STR00060## 4-F Phenyl
P-380 C--F ##STR00061## 4-F Phenyl P-396 C--H ##STR00062## 4-F
Phenyl P-525 C--H ##STR00063## 4-F Phenyl P-526 C--H ##STR00064##
4-F Phenyl P-474 C--H 3-pyridinyl 4-F Phenyl P-475 C--H 3-pyridinyl
N-oxide 4-F Phenyl
[0106] In another aspect the present invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a therapeutically effective amount of at least one
compound as described above.
[0107] Methods of the invention parallel the compositions and
formulations. The methods comprise administering to a patient in
need of treatment a therapeutically effective amount of a compound
according to the invention. The present invention also provides a
method for inhibiting phosphodiesterase 4.
[0108] In-vitro assay for PDE4 enzymes. The in-vitro activity of
PDE4 enzymes and the in-vitro potency of therapeutic agents
described in the present invention were measured using a real-time,
enzyme-coupled spectrophotometric assay. By using three different
coupling enzymes, the product of the PDE4 reaction is coupled to
the oxidation of the reduced form .beta.-nicotinamide adenine
dinucleotide (NADH), which dissipation can be monitored
spectrophotmetrically at 340 nM.
Assay description. Buffer A containing 50 mM Tris, pH 8.0, 16 mM
MgCl.sub.2 and 80 mM KCl is prepared and stored at room
temperature. Buffer B containing 50 mM Tris, pH 8.0 is prepared and
stored at room temperature. Stock solutions of the following
reagents are prepared in Buffer B and stored at -20.degree. C.:
Adenosine-5'-triphosphate (ATP), cyclic adenosine-5'-monophosphate
(cAMP), phosphoenolpyruvate (PEP) and NADH. An assay mix is
prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP,
PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate
dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is
enough for a single 96-well assay plate. Assay mix (180 .mu.L) and
test article (10 .mu.L) in 1:1 DMSO/H2O mixture is pre-incubated at
room temperature for 10 min. The enzymatic reaction is initiated by
addition of cAMP (10 .mu.L). Final concentration of all components
in the assay (200 .mu.L/well) are as follows: 10 mM MgCl.sub.2, 50
mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5
units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4.
Reaction progress curves are monitored in a plate reader capable of
measuring light absorbance at 340 nM. A decrease in light
absorbance at 340 nm is due to oxidation of NADH. Positive controls
containing no test article and negative controls containing no test
article and no cAMP are included on every assay plate. Reaction
rates are determined from the slopes of the linear portions of the
progress curves. All data is percent normalized with respect to
controls and presented as percent inhibition.
[0109] The results of testing of representative species are shown
below in Tables 9 and 10. The activities are designated A=<5
.mu.M, B=5-20 .mu.M, C=20-40 .mu.M.
TABLE-US-00009 TABLE 9 Cmpd No hPDE4D P-001 A P-002 A P-003 A P-004
A P-005 A P-006 A P-007 A P-008 A P-009 A P-010 A P-011 A P-012 B
P-014 B P-015 A P-017 A P-018 B P-019 A P-020 B P-021 A P-022 A
P-023 A P-024 A P-025 B P-026 B P-027 A P-028 A P-029 A P-030 B
P-033 B P-034 A P-035 A P-036 A P-037 A P-038 B P-040 B P-041 B
P-042 A P-043 A P-044 A P-045 C P-046 A P-047 B P-048 A P-049 A
P-050 A P-051 A P-052 A P-053 B P-054 A P-055 A P-057 A P-058 A
P-060 A P-061 A P-062 A P-063 A P-064 B P-065 A P-066 A P-067 A
P-070 A P-071 A P-072 B P-073 A P-074 A P-075 A P-076 A P-077 A
P-078 B P-079 A P-080 A P-081 A P-082 A P-083 B P-084 A P-085 A
P-086 A P-087 A P-088 A P-089 A P-090 A P-091 A P-092 A P-093 A
P-094 A P-095 C P-097 A P-098 A P-099 A P-101 A P-102 A P-103 A
P-104 A P-105 A P-106 A P-107 A P-108 A P-109 A P-111 A P-112 A
P-113 A P-114 A P-115 A P-116 A P-117 A P-118 A P-119 A P-120 A
P-121 A P-122 A P-123 A P-125 A P-126 A P-127 A P-128 A P-130 A
P-131 B P-132 C P-133 B P-134 A P-135 A P-136 A P-137 A P-138 A
P-139 A P-140 A P-141 A P-142 A P-143 A P-144 A P-145 A P-146 A
P-147 A P-148 A P-149 A P-150 B P-151 A P-152 A P-153 A P-154 A
P-155 C P-156 A P-157 A P-158 B P-159 A P-160 B P-161 B P-162 B
P-163 A P-164 A P-165 A P-166 A P-167 A P-168 A P-169 B P-170 A
P-171 A P-172 A P-173 A P-174 A P-175 A P-176 A P-177 A P-178 A
P-179 B P-180 A P-181 A P-182 B P-183 A P-184 B P-185 B P-186 C
P-187 A P-188 A P-189 B P-190 A P-192 B P-193 A P-194 A P-195 B
P-196 A P-197 B P-199 A P-200 A P-201 B P-203 A P-204 B P-205 A
P-206 A P-207 B P-208 B P-209 B P-211 B P-212 B P-213 B P-215 B
P-216 A P-217 A P-218 A P-219 A P-220 A P-221 A P-222 A P-223 B
P-224 B P-225 A P-226 A P-227 A P-228 A P-229 A P-230 B P-231 A
P-232 A P-233 A P-234 A P-235 B P-236 C P-237 A P-238 A P-240 A
P-241 A P-242 A P-243 A P-244 A P-245 B P-246 B P-247 A P-248 A
P-249 A P-250 A P-251 A P-252 A P-254 B P-255 A P-256 A P-257 A
P-258 A P-259 A P-260 A P-261 A P-262 A P-263 A P-264 A P-266 A
P-267 A P-268 A
P-269 A P-270 A P-271 B P-273 A P-274 A P-275 A P-277 A P-278 A
P-279 A P-280 A P-281 A P-282 A P-283 A P-284 A P-285 A P-286 A
P-287 A P-288 A P-289 A P-290 A P-291 A P-292 A P-293 A P-294 A
P-295 A P-296 A P-297 A P-299 A P-300 A P-301 A P-302 A P-303 A
P-304 A P-305 A P-306 B P-310 A P-311 A P-313 A P-315 A P-316 A
P-317 A P-318 A P-322 A P-323 A P-325 A P-326 A P-328 A P-329 A
P-330 A P-331 A P-332 A P-333 A P-334 A P-335 A P-336 A P-337 A
P-338 A P-339 A P-340 A P-341 A P-342 A P-343 A P-344 A P-345 A
P-346 A P-347 A P-352 A P-355 A P-356 A P-357 A P-359 A P-361 A
P-362 A P-366 A P-367 A P-368 A P-369 A P-370 A P-371 A P-372 A
P-373 A P-374 A P-375 A P-376 A P-377 A P-378 A P-379 A P-380 A
P-381 A P-382 A P-385 B P-386 A P-387 A P-388 A P-389 B P-390 B
P-391 A P-392 A P-393 A P-394 A P-395 A P-396 A P-397 A P-398 A
P-399 A P-400 A P-401 A P-402 A P-404 A P-405 A P-406 A P-407 A
P-410 A P-411 A P-412 A P-413 A P-415 A P-416 A P-417 A P-418 B
P-419 B P-420 A P-421 A P-422 A P-423 B P-424 A P-429 A P-431 A
P-432 A P-433 A P-434 A P-435 A P-437 A P-439 A P-440 A P-441 A
P-445 A P-447 A P-448 A P-449 A P-450 A P-451 A P-453 A P-454 A
P-456 A P-457 A P-458 A P-460 A P-461 A P-462 A P-463 A P-465 A
P-466 A P-467 A P-468 A P-469 A P-470 A P-471 A P-473 A P-474 A
P-475 B P-476 A P-477 A P-478 A P-479 A P-481 A P-483 A P-486 C
P-488 A P-491 C P-492 C P-493 C P-494 A P-495 C P-496 A P-497 A
P-499 A P-500 A P-501 B P-502 A P-503 B P-504 A P-505 B P-507 A
P-508 A P-513 B P-514 A P-515 A P-516 A P-517 A P-518 A P-519 A
P-520 A P-521 A P-523 A P-524 A P-525 A P-526 B P-527 A P-528 A
P-530 A P-531 A P-532 A P-533 A P-534 A P-535 A P-536 A P-537 A
P-538 A P-539 A P-540 A P-541 A P-542 C P-543 A P-544 A P-545 A
P-546 A P-547 A P-548 B P-549 A P-550 A P-552 A P-553 A P-554 B
P-555 A P-556 B P-557 A P-558 A P-559 A P-560 B P-561 A P-562 A
P-563 A P-564 B P-565 B P-566 A P-567 A P-568 A P-569 A P-570 A
P-571 A P-572 A P-573 A P-574 A P-575 B P-576 A P-577 A P-578 A
P-579 A P-580 A P-581 A
P-582 A P-583 A P-584 B P-585 A P-586 A P-587 A P-588 A P-589 A
P-590 A P-591 A P-592 A P-593 A P-594 A P-595 A P-596 A P-597 A
P-598 A P-599 A P-600 A P-601 A P-602 A P-603 A P-604 A P-605 A
P-606 A P-607 A P-608 A P-609 A P-610 A P-611 A P-612 A P-613 A
P-614 A P-615 A P-616 A P-617 A P-618 A P-619 A P-620 A P-621 A
P-622 A P-623 A
TABLE-US-00010 TABLE 10 PDE4B Activity, where A < 5 uM, B = 5-20
uM, C = 21-40 uM. Cmpd No hPDE4B P-001 A P-002 A P-004 B P-006 A
P-007 B P-008 A P-009 A P-010 A P-011 A P-012 B P-014 B P-015 C
P-017 A P-019 A P-020 C P-021 B P-022 B P-023 B P-024 C P-025 C
P-027 B P-028 A P-029 A P-030 C P-031 C P-033 B P-034 A P-035 A
P-036 B P-037 A P-038 C P-040 B P-041 A P-042 B P-043 B P-044 A
P-045 B P-046 B P-047 A P-049 A P-050 A P-051 B P-053 C P-054 A
P-055 B P-057 A P-058 B P-060 B P-061 B P-062 A P-063 B P-066 A
P-067 A P-070 C P-071 C P-072 C P-073 C P-074 B P-075 A P-076 A
P-077 A P-079 A P-081 B P-082 B P-083 B P-084 B P-085 A P-086 B
P-087 A P-088 A P-089 A P-090 A P-091 C P-092 A P-093 B P-094 A
P-099 A P-101 A P-102 A P-103 A P-104 A P-105 A P-106 A P-107 A
P-109 A P-111 A P-112 A P-113 A P-114 A P-115 A P-116 A P-117 C
P-118 A P-119 A P-120 B P-122 B P-123 A P-125 A P-126 A P-127 A
P-128 A P-130 A P-131 B P-133 B P-134 B P-135 A P-136 A P-138 A
P-140 A P-142 A P-143 A P-144 A P-145 A P-146 B P-147 A P-148 A
P-149 B P-150 B P-152 A P-153 B P-154 A P-155 B P-156 A P-159 A
P-161 B P-162 B P-164 B P-165 B P-166 A P-168 A P-171 A P-172 A
P-173 A P-174 A P-175 A P-176 A P-177 A P-178 A P-179 B P-180 A
P-181 A P-182 C P-183 A P-184 B P-185 C P-186 C P-187 A P-188 A
P-190 A P-192 B P-193 A P-195 C P-196 B P-197 B P-199 A P-200 A
P-201 C P-204 C P-205 A P-206 A P-207 A P-208 B P-209 A P-211 B
P-212 B P-213 A P-215 B P-216 A P-217 A P-218 A P-221 A P-222 A
P-223 B P-224 B P-225 A P-226 B P-227 A P-228 A P-229 A P-230 C
P-233 A P-234 A P-235 B P-236 C P-237 A P-240 B P-242 A P-243 A
P-244 A P-245 A P-246 A P-248 A P-249 A P-250 A P-251 A P-252 A
P-253 C P-254 A P-255 A P-256 B P-258 A P-259 A P-260 B P-261 A
P-262 A P-263 A P-264 B P-266 A P-267 A P-268 B P-269 A P-270 B
P-274 A P-275 B P-277 A P-278 A P-279 A P-280 A P-281 A P-282 B
P-283 A P-284 A P-285 B P-287 A P-290 A P-291 A P-292 B P-295 C
P-296 C P-297 B P-299 B P-300 A P-301 A P-302 A P-303 A P-304 A
P-305 B P-310 A P-311 A P-313 A P-315 A P-316 A P-317 A
P-318 A P-323 A P-324 C P-325 A P-328 A P-329 A P-330 A P-331 A
P-332 A P-333 A P-334 A P-335 A P-336 A P-337 A P-338 A P-339 A
P-341 A P-342 A P-343 A P-344 A P-345 A P-346 B P-347 A P-352 A
P-355 A P-356 A P-357 A P-359 B P-361 A P-362 A P-366 A P-367 A
P-368 A P-369 A P-370 B P-371 A P-372 A P-373 B P-374 A P-375 A
P-376 A P-378 A P-379 A P-382 A P-386 A P-387 A P-388 A P-392 A
P-393 A P-394 A P-395 A P-397 A P-398 A P-399 A P-400 A P-401 A
P-402 A P-404 A P-405 A P-406 A P-411 A P-412 A P-413 A P-415 A
P-416 C P-417 A P-420 A P-421 A P-422 A P-429 A P-432 A P-433 A
P-437 A P-439 A P-440 B P-441 B P-445 B P-447 A P-448 A P-451 A
P-453 A P-456 A P-457 A P-458 A P-460 A P-461 A P-462 A P-463 A
P-465 A P-467 A P-468 A P-469 A P-470 A P-471 A P-473 A P-478 A
P-479 B P-481 B P-488 B P-494 A P-496 A P-498 A P-499 B P-500 B
P-502 A P-503 B P-504 B P-507 B P-508 B P-513 C P-515 A P-516 A
P-517 B P-518 A P-519 A P-521 A P-523 A P-524 A P-526 B P-527 B
P-530 C P-531 A P-532 A P-533 A P-534 A P-535 A P-536 A P-539 C
P-540 A P-541 A P-542 C P-544 A P-545 A P-547 A P-549 B P-550 A
P-553 A P-555 A P-559 A P-560 B P-562 A P-563 B P-564 C P-565 C
P-566 A P-567 A P-568 A P-569 A P-570 A P-571 A P-573 A P-575 A
P-576 A P-578 A P-579 A P-582 A P-583 B P-585 A P-587 A P-588 A
P-590 A P-591 A P-592 A P-593 A P-594 A P-596 A P-597 A P-598 A
P-599 A P-600 C P-603 A P-604 A P-605 A P-606 A P-610 A P-611 A
P-612 A P-619 A P-620 C P-621 A P-623 B
[0110] The activity of PDE4 inhibitors described in the present
invention was also measured using in an ex-vivo assay measuring
leukotriene E4 (LTE4) in human whole blood after Sephadex
stimulation. The anti-inflammatory activity of therapeutic agents
of the present invention is demonstrated by the inhibition of
eosinophil activation as measured by sephadex bead stimulated LTE4
production in whole human blood. For each sample, 356 .mu.A of
heparinized human whole blood (Vacutainer tube #6480) is added to
wells of a 96 well plate. Then, 4 .mu.l of a series of compound
dilutions (in DMSO) are added in triplicates, suspension mixed and
allowed to incubate at 37.degree. C. for 15 min with gentle
shaking. After that, blood samples are stimulated by adding 40
.mu.L of Sephadex G-15 beads (Sigma-Aldrich, Sweden). The beads are
predissolved in PBS (0.16 g/mL PBS). After mixing, the suspension
is incubated at 37.degree. C. for 90 min. Then, 8 .mu.L of 15%
EDTA/PBS is added to each sample, mixed and plate centrifuged for 5
min at 115.times.g at 21.degree. C. and supernatants taken. In each
plate, 10 positive controls and 10 negative controls are used,
containing DMSO instead of compound solution. The positive controls
are stimulated with Sephadex as described for the samples, and in
the negative controls (unstimulated), Sephadex solution is replaced
by PBS. LTE.sub.4 levels in the resulting plasma samples are
determined using a commercial enzyme-linked immunoassay (Cayman
Chemical Company, Ann Arbor, Mich.) according to the manufacturer's
instructions. Examples P-050, P-075, P-107, P-113, P-136, P-139,
P-140, P-156, P-163, P-168, P-175, P-181, P-187, P-200, P-221,
P-222, P-227, P-237, P-239, P-242, P-243, P-250, P-269, P-287,
P-312, P-315, P-318, P-325, P-328, P-330, P-332, P-336, P-337,
P-338, P-339, P-342, P-356, P-378, P-382, P-403, P-405, P-409,
P-415, P-420 and P-439 all showed IC50<1 .mu.M in this ex-vivo
assay, whereas example P-358 had IC50>1 .mu.M. Persons of skill
in the art accept that positive results in PDE4 models are
predictive of therapeutic utility as discussed above.
[0111] The following specific non-limiting examples are
illustrative of the synthesis of compounds of the invention.
##STR00065##
Example 1
Preparation of P-065
##STR00066##
[0113] Synthesis of 2-bromo-6-methyl-pyridin-3-ol (I-2, X.dbd.Br,
Y.dbd.CH.sub.3): To 6-methyl-pyridin-3-ol (I-1, Y.dbd.CH.sub.3, 5.0
g, 45.82 mmol) in pyridine (15 mL) was added bromine (3.66 g, 22.91
mmol). The reaction was stirred at room temperature under N.sub.2
for 20 h. The crude reaction mixture was poured on to crushed
ice-water (300 mL), stirred for 3 h. The mixture was extracted with
ethyl acetate (5.times.100 mL) and the combined organic extracts
were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford 6.3 g (73%) of 2-bromo-6-methyl-pyridin-3-ol
(I-2, X.dbd.Br, Y.dbd.CH.sub.3) as light yellow solid.
[0114] Synthesis of 2-bromo-3-methoxy-6-methyl-pyridine (I-3,
X.dbd.Br, Y.dbd.R.sub.1.dbd.CH.sub.3):: To the
2-bromo-6-methyl-pyridin-3-ol (I-2) 6.0 g, 31.91 mmol) and
K.sub.2CO.sub.3 (8.82 g, 63.82 mmol) in acetone (100 mL) was added
MeI (6.79 g, 479.87 mmol). The reaction was stirred at 45.degree.
C. under N.sub.2 for 20 h. The reaction was cooled to room
temperature, filtered and concentrated. The residue was purified by
silica gel column chromatography using 1:1 dichloromethane-hexanes
as eluent to afford 2.34 g (36%) of
2-bromo-3-methoxy-6-methyl-pyridine (I-3, X.dbd.Br,
Y.dbd.R.sub.1.dbd.CH.sub.3) as off-white solid.
[0115] Synthesis of
3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine (I-4,
Y.dbd.R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.CF.sub.3): To the
2-bromo-3-methoxy-6-methyl-pyridine synthesized above (1.2 g, 5.94
mmol), 3-trifluoromethylphenylboronic acid (1.69 g, 8.91 mmol),
PPh.sub.3 (0.31 g, 1.19 mmol), K.sub.2CO.sub.3 (2.46 g, 17.82 mmol)
and Pd(OAc).sub.2 (0.13 g, 0.59 mmol) was added DME (15 mL), and
EtOH-H.sub.2O (1:1, 6 mL). Ar gas was bubbled through the stirred
reaction for 5 min. The reaction was stirred at 80.degree. C. under
Ar for 20 h. The reaction was cooled to room temperature,
concentrated, and H.sub.2O and dichloromethane (40 mL each) were
added. The organic layer was separated and the aqueous layer was
extracted with dichloromethane (2.times.25 mL). The combined
organic extracts were dried with Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography using 1:1 dichloromethane-hexanes then
dichloromethane to afford 1.36 g (86%) of
3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine (I-4,
Y.dbd.R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.CF.sub.3) as a light yellow
solid.
[0116] Synthesis of
6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine (I-5,
R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.CF.sub.3, Y.dbd.CH.sub.2Br). To
the 3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine
synthesized above (1.3 g, 4.86 mmol) and NBS (1.04 g, 5.83 mmol) in
CCl.sub.4 (25 mL) was added benzoyl peroxide (0.12 g, 0.49 mmol).
The reaction was stirred at 80.degree. C. under N.sub.2 for 20 h.
The reaction was cooled to room temperature and concentrated. The
residue was dissolved in mixture of dichloromethane and hexanes
(1:1, 8 mL) and purified by silica gel column chromatography using
1:1 dichloromethane-hexanes to afford 0.74 g (44%) of
6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine as
off-white solid.
[0117] Synthesis of
6-(4-fluoro-benzyl)-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine
(P-065): To the
6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine
synthesized above (0.2 g, 0.58 mmol), 4-fluorophenylboronic acid
(0.12 g, 0.87 mmol), PPh.sub.3 (0.03 g, 0.12 mmol), K.sub.3PO.sub.4
(0.37 g, 1.73 mmol) and Pd(OAc).sub.2 (0.013 g, 0.058 mmol) was
added DME (4.0 mL), and EtOH-H.sub.2O (1:1, 1.0 mL). The reaction
was stirred at 80.degree. C. for 20 h. The reaction was cooled to
room temperature, concentrated. The residue was purified by silica
gel column chromatography using 1:1 dichloromethane-hexanes then
dichloromethane to afford 0.056 g (22%) of
6-(4-fluoro-benzyl)-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine
(P-065) as a clear viscous liquid. .sup.1H NMR (CDCl.sub.3, 400
MHz): 8.24 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.6-7.64 (m, 1H),
7.52-7.65 (m, 1H), 7.2-7.34 (m, 4H), 6.96-7.05 (m, 2H), 4.14 (s,
2H), 3.85 (s, 3H); MS (APCI+): 362.1 (M+1),
[0118] LC-MS: 97.2%.
[0119] The following compounds were prepared according to general
scheme 1, analogous to the preparation of P-065.
TABLE-US-00011 P-005 P-060 P-169 P-248 P-010 P-061 P-184 P-253
P-014 P-063 P-188 P-370 P-019 P-064 P-195 P-376 P-021 P-068 P-196
P-379 P-022 P-069 P-197 P-386 P-023 P-070 P-198 P-422 P-024 P-071
P-204 P-424 P-026 P-072 P-205 P-435 P-028 P-076 P-206 P-436 P-029
P-078 P-207 P-031 P-081 P-208 P-033 P-082 P-209 P-034 P-083 P-210
P-084 P-085 P-211 P-035 P-086 P-212 P-036 P-104 P-213 P-044 P-108
P-214 P-045 P-131 P-215 P-046 P-132 P-218 P-048 P-153 P-229 P-053
P-154 P-233 P-054 P-155 P-235 P-057 P-156 P-236 P-058 P-162
P-245
##STR00067##
Example 2
Preparation of P-176
##STR00068##
[0121] Synthesis of 2-bromo-3-nitro-phenol (I-8, X.dbd.Br):
(Prepared by a modification of reported procedure, J. Org. Chem.
1988, 53, pp 1170-1176). To 2-amino-3-nitro-phenol (24.9 mmol, 1.0
eq.) in 24 mL of water and 12 mL of 1,4-dioxane at reflux, was
added 13 mL of HBr (48% aq.) over 10 minutes. The resulting
solution was refluxed for an additional 15 minutes, and cooled
0-5.degree. C. A solution of sodium nitrite (24.4 mmol, 0.98 eq.)
in 20 mL of water was added over 10 minutes, and stirred for 15
minutes. The reaction mixture was then heated to 60.degree. C. for
15 minutes, and allowed to cool naturally to room temperature, and
stirred for 16 hours. The reaction mixture was then extracted with
two portions of diethyl ether, and the combined ethereal layers
washed with brine, dried over magnesium sulfate, filtered through a
layer of celite and concentrated. The residue was diluted with
dichloromethane (with .about.0.1% MeOH), and purified via silica
gel plug filtration with dichloromethane to yield
2-bromo-3-nitro-phenol (I-8, X.dbd.Br) as a pale orange-brown
solid. Yield: 50% .sup.1H NMR (400 MHz; CDCl.sub.3): 6.07 (s, 1H),
7.25 (dd, J=8.4, 1.2 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.48 (dd,
J=8.0, 1.6 Hz, 1H) ppm.
[0122] Synthesis of 2-bromo-3-nitro-anisole (I-9, X.dbd.Br,
R.sub.1.dbd.CH.sub.3):: To a solution of 2-bromo-3-nitro-phenol
synthesized above (11.5 mmol, 1.0 eq.) in DMF at room temperature
was added cesium carbonate (13.8 mmol, 1.2 eq.), followed by
iodomethane (33.7 mmol, 2.9 eq.), and the resultant mixture was
stirred at room temperature for 16 hours. The reaction mixture was
poured into water, stirred for 2 hours, filtered, the cake washed
with two portions of water, and the resultant solid dried to afford
2-bromo-3-nitro-anisole (I-9, X.dbd.Br, R.sub.1.dbd.CH.sub.3) as a
pale orange solid. Yield: 97%; .sup.1H NMR (400 MHz; CDCl.sub.3):
3.97 (s, 3H), 7.07 (dd, J=8.4, 1.2 Hz, 1H), 7.32 (dd, J=8.0, 1.6
Hz, 1H), 7.40 (t, J=8.0 Hz, 1H) ppm.
[0123] Synthesis of 2-bromo-3-methoxy-aniline (I-10, X.dbd.Br,
R.sub.1.dbd.CH.sub.3): (Prepared by a modification of reported
procedure WO Patent: WO2006/7700). To a solution of
2-bromo-3-nitro-anisole synthesized above (10.3 mmol, 1.0 eq.) in
absolute ethanol and glacial acetic acid at room temperature was
added iron powder (42.1 mmol, 4.1 eq). The resultant mixture was
heated to reflux for 1.5 hours, and then cooled to room
temperature. The reaction mixture was diluted with water, and solid
sodium carbonate was added until the pH was 6-7. Dichloromethane
was added, and the mixture was filtered through celite. The dried
(sodium sulfate) organics were concentrated to afford
2-bromo-3-methoxy-aniline (I-10, X.dbd.Br, R.sub.1.dbd.CH.sub.3) as
an oil. Yield: 90%; .sup.1H NMR (400 MHz; CDCl.sub.3): 3.87 (s,
3H), 4.16 (br s, 2H), 6.31 (dd, J=8.0, 1.2 Hz, 1H), 6.42 (dt,
J=8.0, 0.8, 0.4 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H) ppm.
[0124] Synthesis of
2-amino-3-bromo-4-methoxy-phenyl)-(4-fluoro-phenyl)-methanone
(I-11, X.dbd.Br, Y.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3,
R.sub.2=4-fluorophenyl): To a solution of boron trichloride (1.0 M
in heptane; 10.0 mmol; 1.1 eq.) at 0.degree. C. in
tetrachloroethane was added a solution of 2-bromo-3-methoxy-aniline
synthesized above (9.09 mmol; 1 eq.) in tetrachloroethane over 1
minute. The resultant mixture was stirred at the same temperature
for 10 minutes, and to it was added a solution of
4-fluorobenzonitrile (18.2 mmol; 2 eq.) in tetrachloroethane and
aluminum chloride (10.0 mmol; 1.1 eq.). The reaction was heated to
110.degree. C. for 5 hours, and allowed to cool to room temperature
and stir for 16 hours. The reaction mixture was added 10 mL of 3N
HCl, and the resultant mixture was heated to 90.degree. C. for 1
hour, and cooled to room temperature. The pH was adjusted with 6N
NaOH to 11-12, and extracted with dichloromethane. The organics
were washed with a brine solution, dried over magnesium sulfate,
and filtered. The filtrate was concentrated, and the residue
purified via silica gel chromatography using 10% hexanes in
dichloromethane as eluent to afford
2-amino-3-bromo-4-methoxy-phenyl)-(4-fluoro-phenyl)-methanone
(I-11, X.dbd.Br, Y.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3,
R.sub.2=4-fluorophenyl) in 65% yield; .sup.1H NMR (400 MHz;
CDCl.sub.3): 3.95 (s, 3H), 6.25 (d, J=8.8 Hz, 1H), 6.85 (br s, 2H),
7.11-7.16 (M, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.60-7.64 (m, 2H)
ppm.
[0125] Synthesis of 2-bromo-6-(4-fluoro-benzyl)-3-methoxy-aniline
(I-12, X.dbd.Br, Y.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3,
R.sub.2=4-fluorophenyl): To a solution of trifluoroacetic acid
(21.6 mmol; 10 eq.) in dichloromethane at -15.degree. C. was added
in portions sodium borohydride (8.06 mmol; 3.7 eq.) while
maintaining internal bath temperature between -15.degree. and
-20.degree. C. (caution, strong gas evolution) The reaction mixture
was allowed to warm to 0-5.degree. C., and a solution of the above
ketone (2.16 mmol; 1.0 eq) in dichloromethane was added over
approximately 5 minutes. The resultant mixture was allowed to stir
at room temperature for 16 hours, and was quenched with 5% aq.
NaHCO.sub.3, and extracted with ethyl acetate. The combined
organics were washed with water, brine, and dried over magnesium
sulfate, and concentrated. (TLC analysis indicated a mixture of
starting ketone and desired methylene product) The residue was
taken into THF, and treated with BH.sub.3.THF (15 mmol) at room
temperature for 1 hour. The excess borane was quenched with
methanol, and the mixture concentrated. Three additional portions
of methanol were added, and the mixture concentrated. The residue
was purified via flash chromatography on silica gel using 1:1
dichloromethane-hexanes as eluent to give
2-bromo-6-(4-fluoro-benzyl)-3-methoxy-aniline (I-12, X.dbd.Br,
Y.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3, R.sub.2=4-fluorophenyl) in
40% yield; .sup.1H NMR (400 MHz; CDCl.sub.3): 3.86 (s, 2H), 3.87
(s, 3H), 4.07 (br s, 2H), 6.33 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4
Hz, 1H), 7.98 (ddd, J=8.8, 8.4, 2.0 Hz, 2H), 7.12 (ddd, J=8.0, 6.4,
1.0 Hz, 2H) ppm.
[0126] Synthesis of
3-(4-fluoro-benzyl)-6-methoxy-3'-nitro-biphenyl-2-ylamine (P-176):
A mixture of 2-bromo-6-(4-fluoro-benzyl)-3-methoxy-aniline
synthesized above (0.403 mmol; 1.0 eq.), 4-fluorophenylboronic acid
(0.605 mmol; 1.5 eq), and 2 M K.sub.2CO.sub.3 (650 mL, 3.2 eq) in
dioxane was degassed with nitrogen for 10 minutes, and
tetrakis(triphenylphosphine)palladium was added, and the resultant
mixture degassed for an additional 5 minutes. The reaction was
stirred at 70.degree. C. for 16 hours, and cooled to room
temperature. The reaction was diluted with water, and extracted
with two portions of ethyl acetate. The combined organics were
washed with three portions of water, brine, dried over magnesium
sulfate, and filtered through celite. The residue was purified via
flash chromatography on silica gel using 20% acetone in hexane as
eluent to give
3-(4-fluoro-benzyl)-6-methoxy-3'-nitro-biphenyl-2-ylamine (P-176)
in 46% yield; .sup.1H NMR (400 MHz; CDCl.sub.3): 3.70 (s, 3H), 3.86
(s, 2H), 6.42 (d, J=8.4 Hz, 1H), 6.97-7.02 (m, 2H), 7.04 (d, J=8.4
Hz, 1H), 7.17 (dd, J=5.2, 3.2 Hz, 2H), 7.60-7.67 (m, 2H), 8.18-8.20
(m, 2H) ppm;
[0127] LC/MS (86.9%); (ESI+). Found 353.6 (M+1), Calcd 352.4
m/z.
##STR00069##
Example 3
Preparation of P-404
##STR00070##
[0129] Synthesis of 3'-chloro-6-fluoro-2-methoxy-biphenyl (I-16,
R.sub.1.dbd.CH.sub.3, R.sub.2=Cl, Y.dbd.F): To
2-bromo-3-fluoroanisole (1.0 g, 4.88 mmol), 3-chlorophenylboronic
acid (0.91 g, 5.88 mmol), PPh.sub.3 (0.64 g, 2.44 mmol),
K.sub.2CO.sub.3 (0.27 g, 1.95 mmol) and Pd(OAc).sub.2 (0.13 g, 0.58
mmol) was added dioxane (8 mL), and EtOH-H.sub.2O (1:1, 4 mL). Ar
gas was bubbled through the stirred reaction for 5 min. The
reaction was heated at 180.degree. C. using microwave oven (Biotage
Intiator II) for 20 min. The reaction was cooled to room
temperature, combined with another 0.5 g scale run, concentrated.
The residue was purified by silica gel column chromatography using
1:1 dichloromethane-hexanes to afford 1.33 g (77%)
3'-chloro-6-fluoro-2-methoxy-biphenyl (I-16, R.sub.1.dbd.CH.sub.3,
R.sub.2=Cl, Y.dbd.F) as a viscous liquid.
[0130] Synthesis of
N-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide
(I-19, R.sub.1.dbd.CH.sub.3, R.sub.2=Cl, Y.dbd.F,
R.sub.3=4-acetylaminophenyl): To a stirred suspension of
4-acetylaminobenzoic acid (Aldrich, 1.32 g, 5.58 mmol) in anhydrous
THF (20 mL) was added SOCl.sub.2 (1.19 g, 10.04 mmol) and DMF (4
drops). The reaction mixture was stirred at room temperature for 3
h, concentrated under vacuum to afford 4-acetylaminobenzoyl
chloride (I-18, R.sub.3=4-acetylaminophenyl) as a light yellow
solid.
[0131] To a stirred solution of nitrobenzene (12 mL) was added
AlCl.sub.3 (2.23 g, 16.73 mmol) portion wise over 10 min, then the
solution was stirred at room temperature for 20 min. A solution of
4-acetylaminobenzoyl chloride synthesized above (1.32 g, 5.58 mmol)
in dichloromethane (4 mL) was added one portion to this reaction
mixture, stirred for 72 h. The reaction mixture was poured on to
crushed ice-water (250 mL), Extracted with dichloromethane
(2.times.60 mL). The combined organic layers were washed with brine
(60 mL), dried (Na.sub.2SO.sub.4), filtered and then purified by
silica gel column chromatography using dichloromethane then 3%
methanol-dichloromethane to afford 1.97 g (89%)
N-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide
(I-19, R.sub.1.dbd.CH.sub.3, R.sub.2=Cl, Y.dbd.F,
R.sub.3=4-acetylaminophenyl) as light brown solid.
[0132] Synthesis of
(4-amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanone
hydrochloride (I-19, R3=4-aminophenyl). To a stirred suspension of
N-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide
synthesized above (1.75 g, 4.44 mmol) in ethanol (40 mL) was added
con. HCl (40 mL). The reaction was refluxed for 2 h, cooled to room
temperature, filtered, washed with water than hexanes to afford
0.82 g (48%) of
(4-amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-me-
thanone hydrochloride as light yellow solid.
[0133] Synthesis of
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl)-met-
hanone: To a stirred suspension of
(4-amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanone
hydrochloride synthesized above (0.4 g, 1.02 mmol) and sodium azide
(0.2 g, 3.06 mmol) in glacial acetic acid (10 mL) was added
trimethylorthoformate (0.32 g, 3.06 mmol). The reaction was stirred
at room temperature for 3 h, diluted with cold water (60 mL), than
basified with ammonium hydroxide solution (28%). Extracted with
dichloromethane (2.times.40 mL), the combined dichloromethane
solution was washed with brine (40 ml), dried with
Na.sub.2SO.sub.4, filtered, and concentrated to afford 0.38 g (90%)
of
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl)-met-
hanone as light yellow solid.
[0134] Synthesis of
1-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-1H-tetraz-
ole (P-404): To
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl)-met-
hanone synthesized above (0.1 g, 0.24 mmol) in TFA (1.5 mL) was
added triethylsilane (0.28 g, 2.4 mmol). The reaction mixture was
stirred at room temperature for 20 h. The reaction mixture was
cooled to 0.degree. C., diluted with water (3 mL), basified with
ammonium hydroxide solution (28%), filtered, washed with water
dried to afford 0.08 g (81%) of
1-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-1H-tetraz-
ole (P-404) as off-white solid. .sup.1H NMR (DMSO-d.sub.6, 400
MHz): 7.2-7.4 (m, 6H), 7.04-7.12 (s, 3H), 6.7 (d, J=8.4 Hz, 1H),
3.95 (s, 2H), 3.77 (s, 3H) ppm; MS (APCI+): 365.1 (M-28),
[0135] LC-MS: 95.9%.
[0136] The following compounds were prepared by incorporation of
various R3 groups analogous to the preparation of P-404.
TABLE-US-00012 P-434 P-003 P-187 P-152 P-441 P-004 P-051 P-124
P-099 P-013 P-256 P-125 P-137 P-032 P-257 P-106 P-138 P-095 P-262
P-109 P-157 P-096 P-263 P-126 P-173 P-097 P-264 P-150 P-180 P-049
P-265 P-177 P-183 P-050 P-276 P-178 P-190 P-116 P-285 P-182 P-001
P-098 P-016 P-185 P-002 P-139 P-017 P-163
##STR00071##
##STR00072##
Example 4
Preparation of P-443
[0137] Synthesis of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30).
In a 3-necked 250 mL round-bottomed flask equipped with nitrogen
lines and a stir bar was placed 2-bromo-1-fluoro-3-methoxy-benzene
(I-29, 2.0 g, 9.75 mmol) and dichloromethane (48 mL). The solution
was cooled in an ice water bath for 15 minutes and then titanium
tetrachloride (5.02 mL, 45.8 mmol) and dichloromethyl methyl ether
(1.32 mL, 14.6 mmol) were added and the reaction mixture was
allowed to warm to room temperature and react for 2 hours. The
reaction mixture was slowly added to ice water (250 mL) and
extracted with dichloromethane (2.times.100 mL). The organic
portions were combined, washed with a saturated sodium bicarbonate
solution (75 mL), water (75 mL) and brine (75 mL), dried
(MgSO.sub.4) and concentrated. The crude material was triturated
with hexanes (15 mL) to produce 1.67 g of
3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30) as an off-white
solid in 74% yield. MS (ESI+): 233.2 (M+)
[0138] Synthesis of (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol
(I-31). In a 100 mL round bottomed flask equipped with a stir bar
was placed 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30, 1.67 g,
7.17 mmol), methanol (12 mL), dichloromethane (12 mL) and sodium
borohydride. The reaction mixture was allowed to stir at room
temperature for 17 hours, quenched with water (10 mL) and 1M HCl (5
mL) and extracted with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The crude material was triturated
with hexanes (15 mL) to produce 955 mg (57%) of
(3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31) as a white
solid.
[0139] Synthesis of
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32). Into
a 100 mL round bottom flask was added
(3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31, 1.04 g, 4.0
mmol), 3-chlorophenylboronic acid (0.76 g, 4.8 mmol),
Pd(PPh.sub.3).sub.4 (0.45 g, 0.41 mmol), Na.sub.2CO.sub.3 (6 mL, 2M
aq), toluene, (32 mL), and EtOH (11 mL). The reaction was degassed
with N.sub.2, then stirred at 80.degree. C. for 24 hours. Water was
added and the product was extracted with ethyl acetate. The
combined organics were concentrated and filtered through a
SiO.sub.2 plug eluting with 50% ethyl acetate/hexanes. The solid
was triturated with ether and filtered. The filtrate was
concentrated and triturated with ether and filtered. The filter
cakes were combined and purified by flash column chromatography
eluting with 20% acetone/hexanes to give
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 0.79
g, 67%) as a white solid.
[0140] Synthesis of
3-bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl (I-33). Into a
250 mL round bottom flask was added
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol synthesized
above (1.21 g, 4.54 mmol), dichloromethane (20 mL), PPh.sub.3 (1.19
g, 4.54 mmol), and the solution was cooled to 0.degree. C. NBS
(0.81 g, 4.54 mmol) was added and the reaction stirred for 2 hours
at 0.degree. C. The organics were washed with H.sub.2O and
concentrated. The residue was purified by flash column
chromatography eluting with 8% ethyl acetate/hexanes to give
3-bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 956 mg,
64%) as an off-white solid.
[0141] Synthesis of
3'-chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (I-34). In
a 40 mL vial equipped with a stir bar was placed
3-bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 400 mg,
1.21 mmol), 4-nitrophenylboronic acid (420 mg, 1.45 mmol),
potassium phosphate (tribasic) (514 mg, 2.42 mmol), dimethoxyethane
(3.5 mL) and 50% aqueous ethanol (3.5 mL). After degassing with
nitrogen for 15 minutes, tetrakis(triphenylphosphine)palladium(0)
(140 mg, 0.121 mmol) was added. The mixture was heated to
60.degree. C. for 18 hours and then the palladium catalyst was
removed by filtering through Celite. To the filtrate were added
water (50 mL) and a saturated ammonium chloride solution (50 mL).
After extracting with ethyl acetate (3.times.50 mL), the organic
portions were combined, washed with brine (75 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
silica gel chromatography utilizing 20% ethyl acetate/hexanes as
eluent to produce 342 mg (76%) of
3'-chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (I-34) as
a yellow solid. MS (APCI-): 370.1 (M-1).
[0142] Synthesis of
4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
(I-35): In an 18 mL vial equipped with a stir bar was placed iron
powder (179 mg, 3.20 mmol), ethanol (5.0 mL) and water (1.2 mL).
The mixture was heated to 85.degree. C. in an oil bath and then the
above product
3'-Chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (6) (340
mg, 0.914 mmol) was added and the reaction was continued at
85.degree. C. for 2 hours. The reaction mixture was cooled to room
temperature and filtered through Celite. To the filtrate was added
water (50 mL) and extractions were performed with ethyl acetate
(2.times.60 mL). The organic portions were combined, washed with
brine (50 mL), dried (MgSO.sub.4) and concentrated to produce 245
mg of
4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
(I-35) as a yellow, viscous oil in 79% yield. MS (APCI+): 342.0
(M+1).
[0143] Synthesis of
[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-thiazol-2-y-
l-amine. (P-443): In an 8 mL vial equipped with a stir bar was
placed
4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
(I-35) synthesized above (100 mg, 0.293 mmol), 2-bromothiazole
(52.1 .mu.L, 0.585 mmol), 10% aqueous ethanol (1.5 mL) and
concentrated hydrochloric acid (48.8 .mu.L, 0.585 mmol). The
mixture was heated to 90.degree. C. for 18 hours and then cooled to
room temperature. After water (30 mL) and 5% aqueous potassium
carbonate (30 mL) were added, the aqueous portion was extracted
with ethyl acetate (2.times.35 mL) and the organic portions were
combined, washed brine (30 mL), dried (magnesium sulfate) and
concentrated. The crude material was purified by column
chromatography utilizing 3% acetone/dichloromethane as the eluent
to produce 57 mg of
[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-thiazol-2-y-
l-amine. (P-443) as white solid in 45% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.75 (s, 3H), 3.94 (s, 2H), 6.62 (d, J=4 Hz,
1H), 6.70 (dd, J=8, 1 Hz, 1H), 7.10 (t, J=9 Hz, 1H), 7.20-7.22 (m,
2H), 7.26-7.40 (m, 8H) ppm; MS (APCI+): 425.0 (M+1), LC-MS: 89%
Example 5
Preparation of P-238
[0144] Synthesis of
N-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-2-dimethy-
lamino-acetamide (P-238). In a 8 ml vial was charged with
4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
(I-35) (70 mg, 0.2 mmol, HCl salt), N,N-dimethylglycine/HCl salt
(31 mg, 0.3 mmol, 1.5 eq.) EDCI (80 mg, 0.4 mmol, 2 eq.), HOBt (41
mg, 0.3 mmol, 1.5 eq.), Et.sub.3N (0.2 ml, 1.43 mmol, 5.3 eq.),
N,N-dimethylforamide (2 ml). The resulting mixture was stirred at
rt overnight. The mixture was poured into water and extracted with
EtOAc. Evaporation of solvent gave a residue, which was purified by
chromatography on silica gel using dichloromethane in methanol
(33:1) as eluent to give the free base product, which was converted
into HCl salt by treating with 2N HCl in ether. 65 mg of
N-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-2-dimethy-
lamino-acetamide (P-238) as HCl salt in 75% yield. .sup.1H NMR
(CDCl.sub.3, 400 MHz): 9.04 (br s, 1H), 7.46-7.52 (m, 2H),
7.37-7.43 (m, 1H), 7.24-7.36 (m, 3H), 7.14-7.23 (m, 2H), 7.01-7.12
(m, 1H), 6.64-6.74 (m, 1H), 3.86-3.98 (m, 2H), 3.73 (s, 3H), 3.05
(s, 2H), 2.36 (s, 6H) ppm; LCMS: 96%.
Example 6
Preparation of P-243
[0145] Synthesis of
[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-243). A mixture of
4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
(I-35) (100 mg, 0.26 mmol, 1 eq.), sodium cyanate (74 mg, 0.52
mmol, 2 eq.) in HOAc (1 ml) and water (1 ml) was sonicated at rt
for 20 min. then was shaken at rt overnight. The mixture was
diluted with water. The precipitate was collected by filtration and
washed with water. After dried, 71 mg of crude product containing a
less polar by product (presumably the corresponding acetamide) was
obtained. Trituration of the crude product with acetone/hexane gave
56 mg of
[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-243) as white solid in 56% yield. .sup.1H NMR (DMSO-d.sub.6, 400
MHz): 8.42 (s, 1H), 7.40-7.47 (m, 2H), 7.36 (m, 1H), 7.23-7.32 (m,
4H), 7.07 (m, 2H), 6.92 (m, 1H), 5.76 (s, 2H), 3.83 (s, 2H), 3.72
(s, 3H) ppm.
##STR00073##
Example 7
Preparation of P-252
[0146] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine
P-252. A solution of I-145 (1.20 g, 3.70 mmol) and
2-aminopyridine-5-boronic acid pinacol ester (894 mg, 4.06 mmol) in
N,N-dimethylformamide (8 mL) was degassed using a nitrogen stream
for 10 min. To the solution was added potassium carbonate (1.54 g,
11.1 mmol), allylpalladium(II) chloride dimer (203 mg, 0.555 mmol),
and bis(diphenylphosphino)pentane (489 mg, 1.11 mmol) under
nitrogen and the suspension was stirred at 65.degree. C. under
nitrogen for 15 h. To the reaction was added ethyl acetate (50 mL)
and water (50 mL) and the biphasic suspension was filtered through
celite (.about.15 g). The celite was washed with ethyl acetate
(2.times.20 mL), and water (2.times.20 mL) and the filtrate was
separated. The aqueous layer was extracted with ethyl acetate (100
mL) and the organic extracts were combined. The organic solution
was washed with water (200 mL) and brine (200 mL), dried over
sodium sulfate, filtered, and the solvent removed under vacuum. The
residue was purified by flash silica gel column chromatography
(10-33% acetone in dichloromethane), triturated in diethyl ether (5
mL), filtered, washed with hexanes (5 mL) and diethyl ether (2 mL)
to give P-252 (190 mg, 15% yield) as a beige powder. .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.97 (d, J=2.4 Hz, 1H), 7.39-7.27 (m, 5H),
7.07 (t, J=8.6 Hz, 1H), 6.69 (dd, J=8.8 Hz, 1.2 Hz, 1H), 6.45 (d,
J=8.8 Hz, 1H), 4.32 (s, 2H), 3.82 (s, 2H), 3.75 (s, 3H) ppm.
LCMS=96.6% purity. MS (APCI+)=343.0 (M+1).
Example 8
Preparation of P-258
[0147] Synthesis of
N-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-met-
hanesulfonamide (P-258). To a solution of
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine
(P-252) synthesized above (70 mg, 0.18 mmol) in pyridine (2 ml) was
added methanesulfonyl chloride (23 mg, 0.20 mmol) at 0 C under
nitrogen, and stirred at room temperature for 20 h. The reaction
mixture was diluted with water, neutralized with 6N HCl, extracted
with ethyl acetate, washed with water and brine, and dried over
Na2SO4. After it was concentrated in vacuo, the residue was
purified by a chromatography on silica gel to yield
N-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
l]-methanesulfonamide (P-258) (25 mg, 32%). .sup.1H NMR (400 MHz,
CDCl.sub.3) 8.15 (s, 1H), 7.58 (dd, J=8.8, 2.1 Hz, 1H), 7.38 (s,
1H), 7.34 (t, J=6.6 Hz, 3H), 7.24-7.31 (m, 2H), 7.11 (t, J=8.5 Hz,
1H), 6.73 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.77 (s, 3H), 3.09 (s,
3H) ppm.
Example 9
Preparation of P-429
[0148] Synthesis of
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridi-
ne-2-carboxylic acid ethyl ester (I-37). Into a 20 mL vial with
stir bar was added
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2--
ylamine (P-252, 565 mg, 1.65 mmol), ethyl bromopyruvate (0.52 mL,
4.12 mmol), and 5 mL of DME. The reaction was stirred at room
temperature for 18 hours, then basified with NaHCO.sub.3 (aq. sat).
The product was extracted with ethyl acetate and concentrated.
Purification by flash column chromatography (5%
acetone/dichloromethane) provided a tan solid which was triturated
with ether to obtain
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridi-
ne-2-carboxylic acid ethyl ester (I-37) (198 mg, 27%) as an
off-white solid.
[0149] Synthesis of
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridi-
ne-2-carboxylic acid amide (P-429). Into an 8 mL vial was added
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridi-
ne-2-carboxylic acid ethyl ester (I-37) synthesized above (37 mg,
0.084 mmol) and 2 mL of 7N NH.sub.3/MeOH. After stirring for 20
hours at 60.degree. C., the reaction was concentrated. Trituration
with ether provided
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-
-a]pyridine-2-carboxylic acid amide (P-429) (24.5 mg, 71%) as a
white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.42 (s, 1H),
8.30 (s, 1H), 7.64 (br s, 1H), 7.53 (d, J=4.6 Hz, 1H), 7.42 (m,
5H), 7.30 (m, 1H), 7.23 (dd, 1H, J=9.6, 1.6 Hz), 6.97 (d, 1H), 8.4
Hz), 3.95 (s, 2H), 3.74 (s, 3H) ppm. LC/MS=83.4%, 410.0
(APCI+).
Example 10
Preparation of P-456
[0150] Synthesis of
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456). A flask was charged with
3-Bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl (I-32, 3.3 g,
10 mmol), 2-fluoro-pyridine-5-boronic acid (1.4 g, 10 mmol),
toluene (40 mL), 2M aq. Na.sub.2CO.sub.3 (10 mL, 20 mmol), ethanol
(10 mL) and Pd(PPh.sub.3).sub.4 (577 mg, 0.5 mmol). The reaction
mixture was bubbled with nitrogen gas for 5 minutes. Then the
yellow reaction mixture was stirred at 80.degree. C. After
overnight stirring the reaction mixture was cooled to room
temperature and concentrated in-vacuo. The residue was diluted in
EtOAc (20 mL) and washed with water (30 mL). The aqueous layer was
extracted with EtOAc (2.times.20 mL). The combined organic layers
were washed with brine (50 mL), dried over Na2SO4 and concentrated
in-vacuo. The crude was purified by silica gel column
chromatography, eluted with hexane/EtOAc (9:1) to produce 3.23 g
(93% yield) of
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456) as a colorless solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
3.73 (s, 3H), 3.98 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.11 (dd,
J=8.4, 2.8 Hz, 1H), 7.25-7.51 (m, 5H), 7.82 (td, J=8.2, 2.4 Hz,
1H), 8.14 (s, 1H), 8.32 (s, 1H) ppm.
Example 11
Preparation of P-446
[0151] Synthesis of
1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-aze-
tidine-2-carboxylic acid (P-446). A vial was charged with
D,L-azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and DMF (1 mL).
Then NaH (60% dispersion in mineral oil, 33 mg, 0.84 mmol) was
added slowly (gas evolution). After 2 min. of stirring at room
temperature was added
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456). The heterogeneous white reaction mixture was stirred and
heated at 120.degree. C. After overnight stirring the reaction
mixture was cooled to rt and was diluted in EtOAc (5 mL). The
mixture was poured into a reparatory funnel with 0.5M HCl (1 mL)
and water (5 mL). The aqueous layer was extracted with EtOAc
(3.times.5 mL). The combined organic layers were washed with brine
(15 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was
purified by silica gel column chromatography, eluted with
dichloromethane in methanol (9:1) to produce 7.7 mg (6% yield) of
1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-
-2-yl]-azetidine-2-carboxylic acid (P-446) as a cream solid.
Example 12
Preparation of P-445
[0152] Synthesis of
N-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-oxalamic acid ethyl ester (I-40). Into a 20 mL vial was added
[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-carbamic acid ethyl ester (P-367) (152 mg, 0.43 mmol),
dichloromethane (4 mL), TEA (0.11 mL, 0.85 mmol). The solution was
cooled to 0.degree. C. and Ethyl chlorooxoacetate (71 uL, 0.64
mmol) was added. After 20 minutes at room temperature, the organic
solution was washed with H.sub.2O and brine, and then concentrated.
Ethyl acetate was added to the residue, which produced a solid and
was filtered. The solid was triturated with ether and dried to give
N-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-oxalamic acid ethyl ester (I-40) (69 mg, 35%) as a gray-blue
solid.
[0153] Synthesis of
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,5-a]pyridi-
ne-3-carboxylic acid ethyl ester (I-41). Into a 4 mL vial was added
the above compound (12) (44 mg, 0.096 mmol), dichloromethane (1
mL), pyridine (31 uL, 0.48 mmol), and POCl.sub.3 (13 uL, 0.14
mmol). The reaction was stirred for 18 hours at room temperature
and then H.sub.2O was added. The product was extracted with
dichloromethane and then concentrated. Purification using FCC
eluting with 20% acetone/hexane provided a yellow semi-solid which
was triturated with hexane to give
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,5-a]pyridi-
ne-3-carboxylic acid ethyl ester (I-41) (8.2 mg, 19%) as a tan
solid.
[0154] Synthesis of
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,5-a]pyridi-
ne-3-carboxylic acid amide (P-445). Into a 4 mL vial was added I-41
(7 mg, 0.016 mmol) and 2 mL of 7N NH.sub.3/MeOH. The reaction was
stirred at 60.degree. C. for 18 hours, and then concentrated to
afford
6-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,5-a]pyridi-
ne-3-carboxylic acid amide (P-445) (6.6 mg, 99%) as a tan solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.29 (s, 1H), 7.82 (br s, 1H),
7.71 (d, J=9.3 Hz, 1H), 7.52 (s, 1H), 7.49-7.33 (m, 5H), 7.33-7.26
(m, 1H), 6.95 (s, 2H), 3.97 (s, 2H), 3.74 (s, 3H) ppm. LC/MS=88.6%,
410.0 (APCI+).
##STR00074##
Example 13
Preparation of P-378
[0155] Synthesis of [4-(3-bromo-4-methoxy-benzyl)-phenyl]-urea
(I-44). To a 40 mL vial equipped with a teflon screw cap and a
magnetic stir bar was added 2-bromo-4-bromomethyl-1-methoxybenzene
(649 mg, 2.32 mmol),
[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (577
mg, 2.20 mmol) and potassium phosphate (933 mg, 4.40 mmol). To the
vial was then added dimethoxyethane (15 mL), ethanol (3.7 mL) and
water (3.7 mL). To this stirring solution was added
tetrakis(triphenylphosphine) palladium (127 mg, 0.11 mmol) and the
solution was degassed by bubbling N.sub.2 gas through the solution
for 20 min. The vial was capped and placed in an oil bath with
stirring at 65.degree. C. for 12.5 h. The cooled reaction mixture
was concentrated under a stream of N.sub.2 gas to a total volume of
.about.5 mL and then diluted with ethyl acetate (20 mL) and water
(10 mL). Upon shaking a white solid precipitates. The solid is
filtered and dried to afford 272 mg (34%) of
[4-(3-bromo-4-methoxy-benzyl)-phenyl]-urea (I-44) as a white
solid.
[0156] Synthesis of
[4-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea (P-378).
To a 20 mL vial equipped with a magnetic stir bar and a screw cap
was added [4-(3-bromo-4-methoxy-benzyl)-phenyl]-urea (I-44)
synthesized above compound (250 mg, 0.746 mmol), dimethoxyethane (5
mL), ethanol (1 mL) and water (1 mL). To this mixture were added
3-chlorophenylboronic acid (140 mg, 0.895 mmol), potassium
phosphate (316 mg, 1.49 mmol) and tetrakis(triphenylphosphine)
palladium (30 mg, 0.0254 mmol). The stirring reaction mixture was
degassed by bubbling N.sub.2 gas through the solution for 10 min.
The vial was capped and placed in an oil bath with stirring at
80.degree. C. for 16 h. The cooled reaction mixture was
concentrated to dryness, then diluted with water (5 mL) and ethyl
acetate (15 mL). The aqueous layer was extracted with ethyl acetate
(2.times.5 mL) and the combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered and concentrated under a stream of
N.sub.2 gas. The residue was purified by flash chromatography on
silica gel (35 g) utilizing 9:1 dichloromethane/acetone as eluent.
Fractions pure by TLC were combined and concentrated to give 139 mg
(51%) of [4-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-378) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 3.74 (s, 3H), 3.83 (s, 2H), 5.75 (br s, 2H), 7.03 (d, J=8.4
Hz, 1H), 7.08 (m, 2H), 7.15 (d, J=2.4 Hz, 1H), 7.18 (dd, J=8.4, 2.4
Hz, 1H), 7.28 (m, 2H), 7.36-7.41 (m, 3H), 7.48 (m, 1H), 8.40 (br s,
1H) ppm.
[0157] MS (APCI+): 367.0 (M.sup.++1); LC-MS: 95.9% purity.
[0158] The following compounds were prepared analogous to the
Examples shown above.
TABLE-US-00013 P-008 P-199 P-296 P-339 P-392 P-011 P-202 P-297
P-340 P-394 P-067 P-216 P-298 P-344 P-395 P-102 P-217 P-299 P-345
P-399 P-103 P-219 P-300 P-347 P-400 P-105 P-220 P-301 P-348 P-401
P-110 P-221 P-302 P-349 P-402 P-111 P-222 P-304 P-355 P-403 P-112
P-225 P-305 P-356 P-407 P-113 P-226 P-308 P-357 P-408 P-114 P-231
P-309 P-358 P-409 P-119 P-232 P-312 P-359 P-410 P-121 P-233 P-313
P-360 P-411 P-122 P-234 P-314 P-361 P-412 P-123 P-240 P-315 P-362
P-413 P-134 P-242 P-316 P-365 P-414 P-135 P-252 P-317 P-366 P415
P-140 P-258 P-318 P-367 P-420 P-141 P-259 P-319 P-368 P-421 P-142
P-261 P-320 P-371 P-423 P-143 P-266 P-321 P-372 P-428 P-144 P-272
P-322 P-373 P-431 P-145 P-274 P-323 P-374 P-432 P-146 P-275 P-324
P-375 P-433 P-151 P-277 P-325 P-377 P-437 P-159 P-278 P-327 P-378
P-269 P-164 P-279 P-328 P-381 P-239 P-165 P-281 P-329 P-382 P-166
P-284 P-330 P-383 P-170 P-286 P-331 P-384 P-171 P-287 P-334 P-385
P-189 P-290 P-335 P-387 P-191 P-291 P-336 P-388 P-192 P-292 P-337
P-390 P-194 P-295 P-338 P-391
##STR00075##
Example 14
Preparation of P-268
##STR00076##
[0160] Synthesis of 3-iodo-4-methoxy-phenylamine (I-45, X.dbd.I,
Y.dbd.H, Z.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3): In a 3-neck 250 mL
round-bottomed flask equipped with a stir bar, condenser and
N.sub.2 lines was placed iron powder (3.50 g, 62.7 mmol), ammonium
chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and water (23 mL).
The mixture was heated to 85.degree. C. and then
2-iodo-1-methoxy-4-nitro-benzene (5.0 g, 17.9 mmol) was added
portion wise over a period of about 2 minutes. The mixture was
allowed to stir at 85.degree. C. for 2 hours and then filtered
through celite. The celite was washed with EtOH (100 mL) and the
filtrate was concentrated. To the concentrated material was added
water (100 mL) and ethyl acetate (150 mL). The organic portion was
removed and the aqueous portion was re-extracted with ethyl acetate
(150 mL). The organic portions were combined, washed with brine
(150 mL), dried (MgSO.sub.4) and concentrated. The crude material
was purified by column chromatography utilizing 50% EtOAc/hexanes
as the eluent to produce 3.92 g of 3-iodo-4-methoxy-phenylamine
(I-45, X.dbd.I, Y.dbd.H, Z.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3) as a
brown semi-solid in 88% yield. MS (ESI+): 250.1 (M+1)
[0161] Synthesis of 1-(5'-amino-2'-methoxy-biphenyl-3-yl)-ethanone
(I-47, Y.dbd.H, Z.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3,
R.sub.2.dbd.COCH.sub.3): In a 3-neck 100 mL round-bottomed flask
equipped with a condenser, stir bar and N.sub.2 lines was placed
3-iodo-4-methoxy-phenylamine synthesized above (2.92 g, 11.7 mmol),
3-acetylylphenylboronic acid (2.11 g, 12.9 mmol), potassium
carbonate (4.85 g, 35.1 mmol), triphenylphosphine (921 mg, 3.51
mmol), 1,4-dioxane (23 mL), 50% aqueous ethanol (23 mL) followed by
palladium (II) acetate (263 mg, 1.17 mmol). The mixture was heated
to 90.degree. C. for 16 hours and then cooled to room temperature.
The palladium catalyst was removed via filtration and to the
filtrate was added 1M HCl (50 mL) and water (50 mL). The aqueous
portion was Extracted with ethyl acetate (2.times.75 mL), the
organic portions were combined, washed with brine (75 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
column chromatography utilizing 50% EtOAc/hexanes as the eluent to
produce 1.18 g of (5'-amino-2'-methoxy-biphenyl-3-yl)-ethanone
(I-47, Y.dbd.H, Z.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3,
R.sub.2.dbd.COCH.sub.3) as a pale orange oil in 42% yield.
[0162] MS (APCI+): 242.0 (M+1).
[0163] Synthesis of
1-[2'-methoxy-5'-(4-nitro-phenylamino)-biphenyl-3-yl]-ethanone
(I-49, Y.dbd.H, Q=NH, R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.COCH.sub.3,
R.sub.3.dbd.NO.sub.2): To a 40 mL vial equipped with a stir bar was
placed 1-iodo-4-nitrobenzene (1.26 g, 5.07 mmol), cesium carbonate
(2.20 g, 6.76 mmol),
(.+-.)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (316 mg,
0.507 mmol), and a solution of
(5'-amino-2'-methoxy-biphenyl-3-yl)-ethanone (I-47, Y.dbd.H,
Z.dbd.NH.sub.2, R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.COCH.sub.3)
synthesized above (816 mg, 3.38 mmol) in toluene (13.5 mL). The
mixture was stirred for 10 minutes and then
tris(dibenzylideneacetone)dipalladium(0) (310 mg, 0.338 mmol) and
the mixture was heated to 110.degree. C. for 16 hours. The reaction
was cooled to room temperature and then filtered through Celite.
The filtrate was treated with water (40 mL), 1M HCl (40 mL) and
then Extracted with ethyl acetate (2.times.75 mL). The organic
portions were combined, washed with brine (75 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
column chromatography utilizing 35% EtOAc/hexanes as the eluent to
produce 277 mg of
1-[2'-methoxy-5'-(4-nitro-phenylamino)-biphenyl-3-yl]-ethanone
(I-49, Y.dbd.H, Q=NH, R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.COCH.sub.3,
R.sub.3.dbd.NO.sub.2) as a dark orange solid in 23% yield.
[0164] Synthesis of
1-[5'-(4-amino-phenylamino)-2'-methoxy-biphenyl-3-yl]-ethanone
hydrochloride: In an 18 mL vial equipped with a stir bar was placed
iron powder (148 mg, 2.66 mmol), ammonium chloride (207 mg, 3.87
mmol), absolute EtOH (3.1 mL) and water (1.0 mL). The mixture was
heated to 85.degree. C. and then was added
-[2'-methoxy-5'-(4-nitro-phenylamino)-biphenyl-3-yl]-ethanone
(I-49, Y.dbd.H, Q=NH, R.sub.1.dbd.CH.sub.3, R.sub.2.dbd.COCH.sub.3,
R.sub.3.dbd.NO.sub.2) synthesized above (275 mg, 0.759 mmol) was
added and the mixture was heated for 2 hours. The reaction was
cooled to room temperature, filtered through Celite and Extracted
with ethyl acetate (2.times.40 mL). The organic portions were
combined, washed with brine (40 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by column
chromatography utilizing 75% EtOAc/hexanes as the eluent to produce
207 mg of the free base as a dark orange oil in 82% yield. The free
base was treated with 4.0 M HCl in 1,4-dioxane (1.0 mL) and stirred
for 3 hours at room temperature. The reaction mixture was treated
with diethyl ether (4 mL) and the solid was collected via suction
filtration. After washing the solid with diethyl ether (3.times.2
mL), 100 mg of
1-[5'-(4-amino-phenylamino)-2'-methoxy-biphenyl-3-yl]-ethanone
hydrochloride was isolated as a brown solid in 44% yield.
[0165] MS (APCI-): 366.9 (M-2); LC-MS: 85%
[0166] Synthesis of
[4-(3'-acetyl-6-methoxy-biphenyl-3-ylamino)-phenyl]-urea (P-268):
In an 8 mL vial equipped with a stir bar was placed
1-[5'-(4-amino-phenylamino)-2'-methoxy-biphenyl-3-yl]-ethanone
synthesized above (free base) (60.0 mg, 0.180 mmol), water (600
.mu.L), acetic acid (300 .mu.L) and sodium cyanate (46.8 mg, 0.720
mmol). The mixture was stirred at room temperature for 4 hours and
then water (20 mL) was added followed by an P-traction with
(2.times.30 mL). The organic portions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated. The crude
material was purified by column utilizing 75% acetone/DCM as the
eluent to produce 32 mg of
[4-(3'-acetyl-6-methoxy-biphenyl-3-ylamino)-phenyl]-urea (P-268) as
a light brown solid in 47% yield.
[0167] MS (APCI+): 376.1 (M+1); LC-MS: 94%.
##STR00077##
Example 15
Preparation of P-447
[0168] 1-Methoxy-4-phenmylsulfanyl-(4'-nitrobenzene) (I-51). A
solution of 4-methoxybenzenethiol (500 mg, 3.57 mmol) and
4-iodonitrobenzene (1.07 g, 4.28 mmol) in dimethylformamide (10 mL)
was stirred at room temperature. To the orange solution was added
solid cesium carbonate (3.48 g, 10.7 mmol). The resulting purple
solution was stirred at room temperature overnight. The solution
was diluted with ethyl acetate (50 mL) and washed with water (50
mL). The aqueous wash was extracted with ethyl acetate (50 mL). The
organic washes were combined, washed with saturated aqueous sodium
bicarbonate (100 mL), water (100 mL), and brine (100 mL), dried
over sodium sulfate, decanted, and the solvent removed under
vacuum. The resultant solid was purified by flash silica gel column
chromatography using 10% ethyl acetate in hexanes as eluant to give
product I-51 (933 mg, 99% yield).
[0169] 2-Bromo-methoxy-4-(4'-nitro-phenyl-sulfanyl)-benzene (I-52).
A 10% v/v solution of bromine (1 mL) in glacial acetic (9 mL) acid
was prepared. A solution of I-51 (780 mg, 2.99 mmol) in glacial
acetic acid (7.8 mL) was stirred at room temperature. To this
solution was added the 10% bromine in acetic acid solution (3.53 mL
total solution, 6.87 mmol of bromine). The reaction was allowed to
stir at room temperature for 2 h. The reaction was combined with a
previous pilot run of this reaction (100 mg 0.383 mmol). The
previous run had been reacted under the same conditions and TLC
showed similar results. The combined reactions were diluted with
ethyl acetate (100 mL), and washed with water (100 mL). The organic
extract was then washed with saturated aqueous sodium bicarbonate
(2.times.100 mL), water (100 mL), and brine (100 mL), dried over
sodium sulfate, decanted, and removed under vacuum. The resulting
yellow residue was purified by flash silica gel column
chromatography (10% ethyl acetate in hexanes as the eluant) to give
I-52 (550 mg, 48% overall yield) and a second less pure crop (420
mg).
[0170] 3'-Chloro-2-methxoy-5-(4-nitro-phenyl-sulfonyl)-biphenyl
(I-53). A solution of the above compound I-52 (550 mg, 1.62 mmol)
and 3-chlorobenzeneboronic acid (278 mg, 1.78 mmol) in toluene (6
mL) was degassed with a nitrogen stream for 15 min. To the reaction
was added ethanol (800 uL) and 2 M aqueous sodium carbonate
solution (1.6 mL) and the reaction was degassed under the nitrogen
stream. To the reaction was added
tetrakis(triphenylphosphine)palladium(0) (93.4 mg, 8.08.times.10-2
mmol) and the reaction was heated to 100.degree. C. under nitrogen
for 5 h. The reaction was cooled to room temperature and diluted
with ethyl acetate (50 mL). The organic suspension was washed with
water (50 mL). The aqueous wash was extracted into ethyl acetate
(50 mL), the organic extractions combined, washed with water
(2.times.30 mL) and brine (30 mL), dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The resulting crude
red oil was purified by flash silica gel column chromatography (10%
ethyl acetate in hexanes) to give I-53 (329.9 mg, 55% yield) as a
yellow powder.
[0171]
4-(3'-Chloro-6-methoxy-biphenyl-3-ylsulfanyl)-phenylaammonium
chloride (P-447). A suspension of compound I-53 (315 mg, 0.847
mmol), iron powder (166 mg, 2.97 mmol) and solid ammonium chloride
(231 mg, 4.32 mmol) in ethanol (5 mL) and water (1.5 mL) was heated
to 80.degree. C. for 21 h. The solvent was removed under vacuum and
the dark residue was dissolved in ethyl acetate (30 mL) and water
(30 mL). The layers were separated, and the aqueous layer was
extracted with ethyl acetate (30 mL). The organic extracts were
combined, washed with water (50 mL) and brine (50 mL), dried over
sodium sulfate, filtered, and the solvent removed under vacuum. The
residue was dried under high vacuum overnight. The orange oil was
dissolved in dioxane (2 mL), stirred, and 4 N hydrogen chloride in
dioxane (1 mL) was added. The reaction was stirred for 3 h at room
temperature, and the solvent was removed under vacuum to give
product (P-447) (257.8 mg, 81% yield) as a brown powder. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) 7.95-7.49 (m, 1H), 7.46-7.37 (m, 3H),
7.34 (dd, J=8.6, 2.2 Hz, 1H), 7.26-7.23 (m, 3H), 7.16 (d, J=8.8 Hz,
1H), 6.96-6.95 (m, 2H), 3.78 (s, 3H) ppm.
[0172] LCMS=97.5% purity. MS (APCI+)=342.0 (M+1).
Example 16
Preparation of P-448
[0173]
1-[4-(3'-Chloro-6-methoxy-biphenyl-3-ylsulfanyl)-phenyl]-3-ethyl
urea (P-448). A solution of the above compound (P-447) (195 mg,
0.520 mmol) in pyridine (3 mL) was stirred at room temperature. To
the reaction was added ethyl isocyanate (110 mg, 1.56 mmol). The
solution was stirred at room temperature for 22.5 h. The reaction
was diluted in ethyl acetate (50 mL), and washed with water (50
mL). The aqueous wash was extracted into ethyl acetate (50 mL), and
the organic extracts combined. The ethyl acetate solution was
washed with 1 N aqueous hydrochloric acid (50 mL), water
(2.times.50 mL), and brine (50 mL), dried over sodium sulfate, and
the solvent removed under vacuum. The resultant solid was
triturated with diethyl ether (5 mL), filtered, washed with diethyl
ether (2.times.3 mL), and dried to give product (P-448) (109.2 mg,
51% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.49-7.48 (m, 1H),
7.39-7.29 (m, 5H), 7.26-7.19 (m, 4H), 6.94 (d, J=8.8 Hz, 1H), 6.19
(s, 1H), 4.60 (m, 1H), 3.82 (s, 3H), 3.32-3.25 (m, 2H), 1.15 (t,
J=7.4 Hz, 3H) ppm. LCMS=97.3% purity. MS (APCI+)=413.0 (M+1).
Example 17
Preparation of P-449
[0174]
1-[4-(3'-Chloro-6-methoxy-biphenyl-3-sulfinyl)-phenyl]-3-ethyl urea
(P-449). A solution of 10% v/v 30% aqueous hydrogen peroxide (w/w)
(1 mL) in glacial acetic acid (9 mL) was made. To a slurry of the
above compound (P-448) (41.3 mg, 0.100 mmol) in acetic acid (300
uL) was added the hydrogen peroxide solution (96.7 uL, 0.100 mmol
hydrogen peroxide). The solution was stirred for 1 hour at room
temperature. The solvent was removed under vacuum, and the residue
purified by silica gel thin layer chromatography (eluting with 10%
acetone in dichloromethane), triturated with diethyl ether (5 mL),
filtered, and dried to give the product (P-449) (29.3 mg, 68%
yield) as a brown gum. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
7.55-7.44 (m, 5H), 7.36-7.32 (m, 5H), 7.20 (s, 1H), 7.04 (d, J=8.4
Hz, 1H), 5.27 (m, 1H), 3.84 (s, 3H), 3.29-3.22 (m, 2H), 1.12 (t,
J=7.4 Hz, 1H) ppm. LCMS=97.6% purity. MS (APCI+)=429.1 (M+1).
Example 18
Preparation of P-450
[0175]
1-[4-(3'-Chloro-6-methoxy-biphenyl-3-sulfonyl)-phenyl]-3-ethyl-urea
(P-450). A solution of
1-[4-(3'-Chloro-6-methoxy-biphenyl-3-ylsulfanyl)-phenyl]-3-ethyl
urea (P-448) (41.3 mg, 0.100 mmol) in glacial acetic acid (300 uL)
was stirred at room temperature. To the solution was added 290 uL
of 10% v/v (30% w/w hydrogen peroxide in water) in acetic acid. The
resulting solution was stirred for 1.5 h at room temperature. The
solvent was removed under vacuum, and the residue was purified by
silica gel thin layer chromatography (eluting with 25% acetone in
dichloromethane) and dried to give the product (P-450) (20.2 mg,
45% yield) as a yellow grease. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
7.55-7.44 (m, 5H), 7.35-7.31 (m, 4H), 7.28 (s, 1H), 7.04 (d, J=8.4
Hz, 1H), 5.32 (t, J=5.6 Hz, 1H), 3.84 (s, 3H), 3.28-3.21 (m, 2H),
1.11 (t, J=7.4 Hz, 1H) ppm. LCMS=97.9% purity. MS (APCI+)=473.1
(M+28), 443.0 (M+1).
Example 19
Preparation of P-540
[0176] P-540 Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylsulfanyl)-phenyl]-urea. A
solution of PR195 (200 mg, 0.585 mmol) and sodium cyanate (76 mg,
1.17 mmol) in water (10 mL) and glacial acetic acid (5 mL) was
stirred at room temperature overnight. Water (20 mL) was added to
the gummy suspension, and the reaction was extracted into ethyl
acetate (2.times.20 mL). The organic extracts were combined, washed
with 1 N aqueous hydrochloric acid (2.times.20 mL), saturated
aqueous sodium bicarbonate (2.times.20 mL), water (20 mL), and
brine (20 mL), dried over sodium sulfate, and the solvent removed
under vacuum to give crude PR199 as a yellow gum. The crude
material was purified by preparatory thin layer chromatography
(silica) eluting with dichloromethane and developed twice to give
PR199 (53.1 mg, 22.5% yield) as a white powder. .sup.1H NMR (400
MHz, CDCl.sub.3) 7.49-7.48 (m, 1H), 7.41-7.28 (m, 5H), 7.23 (s,
4H), 6.95 (d, J=8.0 Hz, 1H), 6.31 (s, 1H), 4.57 (s, 2H), 3.83 (s,
3H) ppm. LCMS=95.3% purity. MS=385.1 (M+1).
[0177] The following compounds were prepared analogous to the
Examples shown above.
TABLE-US-00014 P-260 P-294 P-193 P-283 P-267 P-288 P-230 P-254
P-280 P-293 P-240
##STR00078##
Example 20
Preparation of P-380
##STR00079##
[0179] 2-Bromo-4-(4-fluoro-benzyl)-1-methoxy-benzene: In a 250 mL
round-bottomed flask equipped with a stir bar was placed
3-bromo-4-methoxybenzyl bromide (5.0 g, 17.9 mmol),
4-fluorophenylboronic acid (2.76 g, 19.7 mmol), potassium phosphate
(tribasic) (7.60 g, 35.8 mmol), dimethoxyethane (30 mL) and 50%
aqueous ethanol (30 mL). The mixture was degassed with nitrogen for
30 minutes and then added tetrakis(triphenylphosphine)palladium(0)
(5.17 g, 4.48 mmol). The mixture was heated to 60.degree. C. for 4
hours and then the palladium catalyst was filtered off. To the
filtrate were added water (100 mL) and a saturated ammonium
chloride solution (150 mL). After extracting with ethyl acetate
(3.times.100 mL), the organic portions were combined, washed with
brine (150 mL), dried (MgSO.sub.4) and concentrated. The crude
material was purified by column utilizing 5% EtOAc/hexanes as the
eluent to produce 2.12 g of
2-bromo-4-(4-fluoro-benzyl)-1-methoxy-benzene as a colorless oil in
40% yield.
[0180]
4-Chloro-1-[5-(4-fluoro-benzyl)-2-methoxy-phenyl]-1H-pyrazole
(P-380): In a 2-5 mL microwave vial equipped with a stir bar was
placed the above product (250 mg, 0.847 mmol), 4-chloro-1H-pyrazole
(172 mg, 1.69 mmol), potassium carbonate (234 mg, 1.69 mmol), CuI
(48.4 mg, 0.254 mmol) and N-methyl-2-pyrrolidone (2.8 mL). The
mixture was heated to 190.degree. C. in a Biotage Initiator
microwave reactor for 1 hour. The mixture was quenched with water
(30 mL) and a saturated ammonium chloride solution (30 mL) followed
by an P-traction with ethyl acetate (2.times.30 mL). The organic
portions of the product (P-380) as a viscous, yellow oil in 35%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.87 (s, 3H), 3.93
(s, 2H), 6.94-6.98 (m, 3H), 7.08 (dd, J=8, 2 Hz, 1H), 7.12-7.16 (m,
2H), 7.55 (d, J=2 Hz, 1H), 7.60 (s, 1H), 8.04 (s, 1H) ppm.
[0181] MS (APCI+): 317.0 (M+1); LC-MS: 97%
Example 21
Preparation of P-389
##STR00080##
[0183] Synthesis of
4-{1-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-1H-pyrazol-4-yl}-pyridine
(P-389). In a 2-5 mL microwave vial equipped with a stir bar was
placed I-185 (250 mg, 0.847 mmol), 4-(1H-pyrazol-4-yl)-pyridine
(245 mg, 1.69 mmol), potassium carbonate (234 mg, 1.69 mmol) and
N-methyl-2-pyrrolidone (2.8 mL). The mixture was degassed with
nitrogen for 10 minutes and then CuI (48.4 mg, 0.254 mmol) was
added. The mixture was heated to 190.degree. C. in a Biotage
Initiator microwave reactor for 1 hour. The mixture was quenched
with water (50 mL) and a saturated ammonium chloride solution (50
mL) followed by an extraction with ethyl acetate (2.times.100 mL).
The organic portions were combined, dried (MgSO.sub.4) and
concentrated. The residue was purified via column chromatography
utilizing 15% acetone/dichloromethane as the eluent. After a failed
recrystallization attempt with dichlormethane/hexanes, 41 mg of
P-389 as a viscous, yellow oil in 13% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.91 (s, 3H), 3.96 (s, 2H), 6.95-7.02 (m, 3H),
7.10-7.18 (m, 3H), 7.42-7.45 (m, 2H), 7.62 (d, J=2 Hz, 1H), 8.04
(s, 1H), 8.41 (s, 1H), 8.57-8.59 (m, 2H) ppm. MS (APCI+): 360.1
(M+1); LC-MS: 90%.
Example 22
Preparation of P-396
##STR00081##
[0185] Synthesis of
1-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-3-trifluoromethyl-1H-pyrazole
(P-396). In a 2-5 mL microwave vial equipped with a stir bar was
placed I-185 (250 mg, 0.847 mmol), 3-trifluoromethyl-1H-pyrazole
(230 mg, 1.69 mmol), potassium carbonate (234 mg, 1.69 mmol) and
N-methyl-2-pyrrolidone (2.8 mL). The mixture was degassed with
nitrogen for 10 minutes and then CuI (48.4 mg, 0.254 mmol) was
added. The mixture was heated to 190.degree. C. in a Biotage
Initiator microwave reactor for 1 hour. The mixture was quenched
with water (30 mL) and a saturated ammonium chloride solution (30
mL) followed by an extraction with ethyl acetate (2.times.60 mL).
The organic portions were combined, dried (MgSO.sub.4) and
concentrated. The residue was purified via column chromatography
utilizing 20% ethyl acetate/hexanes as the eluent to produce 20 mg
of P-396 as a viscous, yellow oil in 7% yield. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 3.86 (s, 3H), 3.94 (s, 2H), 6.65 (d, J=2
Hz, 1H), 6.95-6.99 (m, 3H), 7.10-7.16 (m, 3H), 7.57 (d, J=2 Hz,
1H), 8.03 (m, 1H) ppm. MS (APCI+): 351.0 (M+1); LC-MS: 92%.
##STR00082##
Example 23
Preparation of P-117
##STR00083##
[0187] 2-(3-Iodo-phenyl)-[1,3,4]oxadiazole: A mixture containing
3-iodo benzoylhydrazide (4.5 g, 17.17 mmol) and 85.6 ml of
triethylorthoformate (30 equivalents) was refluxed for 16 hours.
The reaction mixture was concentrated to a solid residue and
triturated with 15 ml mixture of diethyl ether/heptane=1:1. After
filtration and drying, 3.9 g white solid was obtained. The mother
liquor was concentrated and recrystallized from a mixture of
methanol/water=1:3 to give another 200 mg of the product, a total
of 4.1 g.
[0188] 6-Methoxy-3'-[1,3,4]oxadiazol-2-yl-biphenyl3-carbaldehyde. A
mixture of 5-formyl-2-methoxyphenyl boronic acid (414 mg, 2.29
mmol), the above product, 2-(3-iodo-phenyl)-[1,3,4]oxadiazole, (626
mg, 2.29 mmol), aqueous 2N K.sub.2CO.sub.3 (3.4 mL, 3 equivalents),
Pd(PPh.sub.3).sub.2Cl.sub.2 (50 mg, 0.068 mmol) in DME (15 mL) was
stirred at room 80.degree. C. for 7 hours. Reaction mixture was
cooled to r.t., then it was diluted with ethyl acetate (45 mL) and
washed with water, brine and dried over Na.sub.2SO.sub.4. After
removal of solvent, 700 mg of crude was obtained. Purification by
column chromatography gave 350 mg of the product (Yield: 55%).
[0189]
(4-Fluoro-phenyl)-(6-methoxy-3'-[1,3,4]oxadiazol-2-yl-biphenyl-3-yl-
)-methanol (P-117). To a solution of the above aldehyde,
6-Methoxy-3'-[1,3,4]oxadiazol-2-yl-biphenyl3-carbaldehyde (86 mg,
0.307 mmol) in anhydrous THF (1 mL) was added dropwise a solution
of 4-fluorophenyl magnesium bromide in THF (0.46 ml, 1M) at
-78.degree. C. After the addition was complete, the resulting
mixture was allowed to warm to room temperature and stirred for 40
minutes. Then saturated NH.sub.4Cl aq. was added. The mixture was
extracted with EtOAc (2.times.10 ml). The combined organic layers
were washed with water and dried over Na.sub.2SO.sub.4. Removal of
solvent gave a residue, which was purified by chromatography on
silica gel to give 112 mg of the product (P-117). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 3.82 (s, 3H), 5.85 (s, 1H), 6.97 (d,
J=8.4 Hz, 1H), 6.98-7.05 (m, 2H), 7.31-7.39 (m, 4H), 7.54 (t, 1H),
7.67-7.7 (m, 1H), 8.01-8.04 (m, 1H), 8.23 (s, 1H), 8.46 (s, 1H)
ppm; LCMS (ESI+): 377 (M+1).
[0190] The following compounds were prepared analogous to the
example shown above.
Example 24
Preparation of P-118
[0191]
2-[5'-(4-Fluoro-benzyl)-2'-methoxy-biphenyl-3-yl]-[1,3,4]oxadiazole
(P-118). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.80 (s, 3H),
3.95 (s, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.97-6.99 (m, 2H), 7.13-7.17
(m, 4H), 7.54 (t, 1H), 7.68-7.7 (m, 1H), 8.01-8.03 (m, 1H), 8.23
(s, 1H), 8.46 (s, 1H) ppm; MS (APCI+): 361 (M+1), LCMS: 96.7%.
Example 25
Preparation of P-093
[0192]
(4-Fluoro-6-methoxy-3'-nitro-biphenyl-3-yl)-(4-fluoro-phenyl)-metha-
nol (P-093). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.35 (t,
J=2.0 Hz, 1H), 8.15-8.19 (m, 1H), 7.75-7.79 (m, 1H), 7.55 (t, J=8.0
Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.38-7.41 (m, 2H), 7.01-7.06 (m,
2H), 6.72 (d, J=12 Hz, 1H), 6.13 (br s, 1H), 3.82 (s, 3H) ppm.
Calc. 373.36;
[0193] APCI.sup.- (M-2): 371.0; >85%.
Example 26
Preparation of P-094
[0194] 4-Fluoro-5-(4-fluoro-benzyl)-2-methoxy-3'-nitro-biphenyl
(P-094). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.33 (br s,
1H), 8.15-8.17 (m, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz,
1H), 7.12-7.18 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.97 (t, J=8.4 Hz,
2H), 6.74 (d, J=11.6 Hz, 1H), 3.95 (s, 2H), 3.81 (s, 3H) ppm. Calc.
357.36; APCI.sup.- (M-1): 356.1, .sup.-(M-2): 355.2, 93%.
Example 27
Preparation of P-079
[0195]
(4-Fluoro-phenyl)-(3'-nitro-6-trifluoromethoxy-biphenyl-3-yl)-metha-
nol (P-079). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.29 (1H, d,
J=3.2 Hz), 5.91 (1H, d, J=3.2 Hz), 7.06 (2H, m), 7.37 (3H, m), 7.44
(1H, dd, J=8.4, 2.4 Hz), 7.49 (1H, d, J=2 Hz), 7.61 (1H, dd, J=8
and 8 Hz), 7.78 (1H, m), 8.25 (1H, m), 8.32 (1H, m) ppm.
Example 28
Preparation of P-080
[0196] 5-(4-Fluoro-benzyl)-3'-nitro-2-trifluoromethoxy-biphenyl
(P-080).
[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.02 (2H, s), 7.01
(2H, m), 7.16 (2H, m), 7.24 (2H, m), 7.31 (1H, m), 7.60 (1H, dd,
J=8, 8 Hz), 7.77 (1H, m), 8.24 (1H, m), 8.30 (1H, m) ppm.
##STR00084##
Example 29
Preparation of P-009
##STR00085##
[0199] (3-Bromo-4-methoxy-phenyl)-acetonitrile; To a mixture of
compound 4-methoxyphenyl acetonitrile (5.88 g, 40 mmol), KBr (9.52
g, 80 mmol), tetrabutylammonium chloride (332 mg, 1.2 mmol) in
dichloroethane (80 mL), was added 21% w/w nitric acid (48 g, 160
mmol). The reaction mixture was stirred at rt for 20 h, diluted
with dichloromethane (80 mL) and washed with sat. NaHCO.sub.3 aq.
(2.times.50 mL), water (2.times.50 mL), brine and dried over
Na.sub.2SO.sub.4. After removal of solvent under vacuum, the
residue was triturated with Et.sub.2O (10 ml)/hexanes (40 ml) to
give 6.32 g of product; Yield: 70%.
[0200] (6-Methoxy-3'-nitro-biphenyl-3-yl)-acetonitrile; A reaction
mixture of the above product (2.26 g, 10 mmol), 3-nitrophenyl
boronic acid (1.67 g, 10 mmol), triphenylphosphine (262 mg, 1
mmol), K.sub.2CO.sub.3 (4.14 g, 30 mmol), Pd(OAc).sub.2 (112 mg,
0.5 mmol) in 1,2-dimethoxyethane (80 mL), ethanol (10 mL) and water
(10 mL) was stirred at 80.degree. C. for 20 hrs under Ar. After
removal of solvent under vacuum, reaction mixture was diluted with
ethyl acetate (80 mL) and washed with water (2.times.40 mL), brine
and dried over Na.sub.2SO.sub.4. After removal of solvent, the
residue was triturated with Et.sub.2O (20 mL) to give 2.18 g of
product; Yield: 81%.
[0201]
(6-Chloro-pyridazin-3-yl)-(6-methoxy-3'-nitro-biphenyl-3-yl)-aceton-
itrile; To a mixture of the above product (1072 mg, 4 mmol)
3,6-dichloropyridazine (1311 mg, 8.8 mmol) in DMF (15 mL), was
added portion wise NaH (400 mg, 60% in oil, 10 mmol) at 0.degree.
C. under Ar. The reaction mixture was stirred at 0.degree. C. for 1
hr and allowed to slowly warm to rt and then stirred at rt for 16
hrs. Reaction mixture was cooled to 0.degree. C. and added sat.
NH.sub.4Cl aq. (50 mL)/water (150 mL) and stirred at rt for 10 min.
The resulting solid was filtered, dissolved in ethyl acetate (80
mL) and then washed with water (2.times.40 mL), brine, and dried
over Na.sub.2SO.sub.4. After removal of solvent, the residue was
purified by silica gel column chromatography with ethyl
acetate/hexane as eluent to give 1.4 g of product; Yield: 92%.
[0202]
6-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2H-pyridazin-3-one
(P-009). A reaction mixture of the above product (600 mg, 1.58
mmol) in acetic acid (10 mL), concentrated HCl (20 mL) and water
(10 mL) was refluxed for 18 hrs. After cooling to r.t., water (200
mL) was added to reaction mixture and stirred at rt. for 20 min.
The resulted solid was filtered and dried at r.t. over night. The
solid was dissolved in dichloromethane (50 ml) and filtered off
solid. After removal of dichloromethane, the solid was washed with
diethyl ether (20 mL) to give 310 mg of product (P-009); Yield:
58%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.83 (3H, s), 3.92
(2H, s), 6.88 (1H, d, J=9.6 Hz), 6.98 (1H, d, J=8.4 Hz), 7.13 (1H,
d, J=9.6 Hz), 7.18 (1H, m), 7.22 (1H, dd, J=8.4.2 Hz), 7.56 (1H,
dd, J=8, 8 Hz), 7.82 (1H, m), 8.18 (1H, m) ppm; MS (ESI+): 338.6
(M+1); LC-MS: 96%.
[0203] The following compounds were prepared analogous to the
example shown above.
Example 30
Preparation of P-012
[0204]
6-(3-Benzo[1,2,5]oxadiazol-5-yl-4-methoxy-benzyl)-2H-pyridazin-3-on-
e (P-012). .sup.1H NMR (400 MHz, CDCl.sub.3) 6, 3.85 (3H, s), 3.92
(2H, s), 6.89 (1H, d, J=9.6 Hz), 6.99 (1H, d, J=8.4 Hz), 7.14 (1H,
d, J=9.6 Hz), 7.23 (1H, d, J=2 Hz), 7.27 (1H, m), 7.60 (1H, m),
7.81 (1H, m), 7.85 (1H, m), 10.42 (1H, br s).
Example 30
Preparation of P-018
[0205]
6-[6-(2-Methoxy-ethoxy)-3'-nitro-biphenyl-3-ylmethyl]-2-(2-methoxy--
ethyl)-2H-pyridazin-3-one (P-018). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.34 (3H, s), 3.36 (3H, s), 3.68 (2H, m), 3.80
(2H, t, J=5.5 Hz), 3.92 (2H, s), 4.14 (2H, m), 4.36 (2H, t, J=5.5
Hz), 6.84 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=8 Hz), 7.05 (1H, d,
J=9.5 Hz), 7.19-7.22 (2H, m), 7.55 (1H, dd, J=8 and 8 Hz), 7.87
(1H, m), 8.17 (1H, m), 8.49 (1H, m).
Example 31
Preparation of P-020
[0206] Carbamic acid
3'-nitro-5-(6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-biphenyl-2-yl
ester (P-020). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6, 3.92 (2H, s),
6.82 (1H, dd, J=9.6 and 2.4 Hz), 6.82 (1H, br s), 7.15 (1H, br s),
7.18 (1H, J=8.4 Hz), 7.32 (1H, dd, J=8 and 2 Hz), 7.41 (1H, d, J=10
Hz), 7.44 (1H, d, J=2 Hz), 7.75 (1H, dd, J=8 and 8 Hz), 7.88 (1H,
m).
##STR00086##
Example 32
Preparation of P-224
##STR00087##
[0208] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethoxy)-pyridine (P-224). Into
a 20 mL vial with stir bar was added I-70 (230 mg, 0.71 mg),
2-hydroxypyridine (91 mg, 0.59 mmol), Ag.sub.2CO.sub.3 (236 mg,
0.89 mmol), and 4 mL of benzene. The reaction was stirred for 18
hours at 80.degree. C. protected from light. An additional 204 mg
of 2-hydroxypyridine and 515 mg of Ag.sub.2CO.sub.3 was added and
the reaction stirred for 3 more days at 80.degree. C. The reaction
was filtered and the filtrate was concentrated. The residue was
purified by flash column chromatography eluting with 20% ethyl
acetate/hexanes to give 63 mg (32%) of P-224 as a light yellow oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) 8.42 (s, 1H), 8.22-8.13 (m, 2H),
7.87 (d, J=7.8 Hz, 1H), 7.63-7.53 (m, 2H), 7.52-7.44 (m, 2H), 7.02
(d, J=8.3 Hz, 1H), 6.89 (dd, J=5.4, 6.2 Hz, 1H), 6.80 (d, J=8.3 Hz,
1H), 5.37 (s, 2H), 3.85 (s, 3H) ppm. LC/MS=90.0%, 337.1
(APCI+).
Example 33
Preparation of P-479
##STR00088##
[0210]
3-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazol-
-4-yl]-pyridine (P-479). A flask was charged with
3-(1H-Imidazol-4-yl)-pyridine (165 mg, 0.75 mmol) and THF (5 mL).
Then NaH (60% dispersion in mineral oil, 60 mg, 1.5 mmol) was added
slowly (gas evolution). After 2 min. of stirring at room
temperature 3-Bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl
(165 mg, 0.5 mmol) was added. The reaction mixture was stirred at
rt. After overnight stirring the reaction mixture was quenched with
water (20 mL). The mixture was extracted with EtOAc (3.times.10
mL). The combined organic layers were washed with brine (50 mL),
dried over Na.sub.2SO.sub.4 and concentrated in-vacuo. The crude
was purified by silica gel column chromatography, eluted with
dichloromethane/MeOH (200:5) to produce 77.1 mg (39% yield) of the
product (P-479) as a pale yellow solid. .sup.1H NMR (400 MHz,
DMSO-d) .delta. 3.75 (s, 3H), 5.26 (s, 2H), 7.02 (d, J=, 8.59 Hz,
1H), 7.28-7.50 (m, 6H), 7.78-7.88 (m, 2H), 8.04-8.11 (m, 1H), 8.38
(dd, J=4.7, 1.2 Hz, 1H), 8.96 (d, J=1.5 Hz, 1H) ppm.
##STR00089##
Example 34
Preparation of P-120
[0211] (6-Methoxy-3'-nitro-biphenyl-3-yl)-acetic acid (I-71) Into a
100 mL round bottom flask with stir bar was added
5-bromomethyl-2-methoxy-3'-nitro-biphenyl (I-70) (0.60 g, 1.86
mmol), NaCN (0.18 g, 3.72 mmol), and dry DMF (20 mL). The reaction
was stirred at room temperature for 20 hours after which 20 mL of
water and 20 mL of dichloromethane were added. The layers were
separated and the aqueous was extracted with 20 mL of
dichloromethane. The combined organic were washed with water
(3.times.20 mL) and concentrated to afford the corresponding
nitrile which was used as is in the next reaction. Into a 100 mL
round bottom flask with a stir bar was added the crude nitrile, 10
mL of ethanol, and 5 mL of 2 N KOH. The suspension dissolved upon
heating and the solution was stirred at reflux for 18 hours. The
reaction was cooled to room temperature and the ethanol was removed
under reduced pressure. The remaining aqueous portion was washed
with 2.times.10 mL of dichloromethane then acidified to pH=1 using
6 N HCl. The precipitate that formed was filtered and washed with
water (2.times.10 mL). After drying in a 40.degree. C. vacuum oven
for 4 hours, 0.32 g (60%) of I-71 was obtained as a yellow
solid.
[0212] (6-Methoxy-3'-nitro-biphenyl-3-yl)-acetic acid
3-methyl-oxetan-3-ylmethyl ester (I-73). Into a 20 mL vial with
stir bar were added the above acid (I-71) (0.12 g, 1.15 mmol), 2 mL
dichloromethane, 3-Hydroxymethyl-3-methyl-oxetane (0.30 g, 1.04
mmol), DMAP (38 mg, 0.31 mmol), DCC (0.24 g, 1.15 mmol), and 2 mL
of dichloromethane. After the reaction was stirred at room
temperature for 30 minutes, 10 mL of hexanes were added and the
reaction was stirred an additional 10 minutes. The suspension was
filtered through celite and the celite pad was washed with 5:1
hexane:dichloromethane (3.times.10 mL). The filtrate was
concentrated and the residue purified by flash column
chromatography using 30% ethyl acetate/hexanes to give 0.33 g (85%)
of I-73 as a colorless semi-solid.
[0213]
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-4-methyl-2,6,7-trioxa-bi-
cyclo[2.2.2]octane (P-120); Into a 100 mL round bottom flask with
stir bar was added I-73 (0.32 g, 0.86 mmol) and 10 mL of dry
dichloromethane. The solution was cooled to -15.degree. C. and
BF.sub.3-OEt.sub.2 (270 uL, 2.2 mmol) was added. The reaction was
allowed to slowly attain room temperature over 4 hours then cooled
again to 0.degree. C. Triethylamine (0.48 mL, 3.45 mmol) was added
and the reaction was concentrated. The product was purified by
flash column chromatography using 2% ethyl acetate in 50% ethyl
acetate/hexanes to afford 9.8 mg (3%) of the product (P-120) as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 2.99 (s, 3H), 3.81
(s, 3H), 3.90 (s, 6H), 6.93 (d, J=8.3 Hz, 1H), 7.27-7.35 (m, 2H),
7.54 (t, J=8.0 Hz, 1H), 7.87 (d, J=7.8 Hz, 2H), 8.15 (dd, J=8.3,
1.3 Hz, 2H), 8.43 (t, J=1.8 Hz, 1H) ppm. MS (APCI+) 372.1.
##STR00090##
Example 35
Preparation of P-341
##STR00091##
[0215]
1-Bromo-3-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-propan-2-one-
; Into a 20 mL vial with stir bar was added
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid (I-74,
R1=Me, Y.dbd.F) (306 mg, 1.04 mmol), dichloroethane (4 mL), thionyl
chloride (151 uL, 2.08 mmol) and the solution was stirred at
80.degree. C. for 1 hour. The solution was cooled to 0.degree. C.,
4 mL of dichloromethane were added, and a solution of
(trimethylsilyl)diazomethane (1.56 mL, 3.11 mmol, 2.0 M in ether)
was added and the reaction stirred at room temperature for 16
hours. The reaction was cooled to 0.degree. C. and 0.5 mL HBr (48%
in H.sub.2O) was added. After 30 minutes at 0.degree. C.,
Na.sub.2CO.sub.3 was added until bubbling ceased and the reaction
was dried by the addition of Na.sub.2SO.sub.4. The suspension was
filtered and concentrated to yield product (390 mg, 99%) as a brown
oil, which was used as is.
[0216]
4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-thiazol-2-ylam-
ine (P-341). Into a 20 mL vial were added the above compound (390
mg, 1.05 mmol), ethanol (4 mL), and thiourea (160 mg, 2.10 mmol).
The reaction was stirred for 2 hours at 75.degree. C., then cooled
to room temperature. Water (10 mL) and 10 mL of brine were added
and the product was extracted with ethyl acetate. The organics were
dried with Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by flash column chromatography eluting with 3%
methanol/dichloromethane to afford crude product as a yellow solid.
The solid was triturated with 1:5 ether:hexane to give pure product
(135 mg, 37%) as a tan solid. The solid was dissolved in ether:THF
and a solution of 2.0 M HCl/ether were added. The suspension was
concentrated to give the title compound (P-341). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.89 (br s, 1H), 7.52-7.42 (m, 2H), 7.38
(s, 1H), 7.37-7.27 (m, 2H), 6.98 (d, J=8.6 Hz, 1H), 6.42 (s, 1H),
4.00-3.55 (br s, 2H), 3.87 (s, 2H), 3.75 (s, 3H). MS: 349.0
(APCI+).
Example 36
Preparation of P-346
##STR00092##
[0218]
1-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-thiazol-2-y-
l]-3-ethyl-urea (P-346). Into an 8 mL vial was added P-341 (40 mg,
0.11 mmol), pyridine (2 mL), and ethylisocyanate (24 mg, 0.34
mmol). The solution was stirred at 50.degree. C. for 3 days, then
an additional 40 mg ethyl isocyanate was added and the reaction was
stirred at 80.degree. C. for 2 hours. After cooling to room
temperature, water was added and the product was extracted with
ethyl acetate. The organics were concentrated and the residue was
purified by flash column chromatography eluting with 15-20%
acetone/hexane to give the product (P-346) (31 mg, 64%) as an
off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.42
(br s, 1H), 7.45-7.42 (m, 2H), 7.37 (s, 1H), 7.30-7.25 (m, 2H),
6.93 (d, J=8.4 Hz, 1H), 6.57 (s, 2H), 3.86 (s, 2H), 3.73 (s, 3H),
3.14-3.11 (m, 2H), 1.04 (t, J=7.2 Hz, 3H). LC/MS=95.4%, 420.0
(APCI+).
##STR00093##
Example 37
Preparation of P-369
[0219]
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-thiazol-2-yl]-
-carbamic acid tert-butyl ester (I-78). Into an 8 mL vial was added
I-33 (70 mg, 0.21 mmol),
(5-tributylstannanyl-thiazol-2-yl)-carbamic acid tert-butyl ester
(I-77, 104 mg, 0.21 mmol), 4A molecular sieves (100 mg), and THF (2
mL). The mixture was degassed for 10 minutes with N.sub.2 and then
Pd(PPh.sub.3).sub.4 (25 mg, 0.021 mmol) was added. After stirring
for 18 hours at 80.degree. C., the suspension was filtered and the
filter cake was washed with EtOAc. The filtrate was washed with
water and then concentrated. Purification by flash column
chromatography (15% acetone/hexanes) provided I-78 (11 mg, 12%) as
a white semi-solid.
[0220]
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-thiazol-2-ylam-
ine (P-369). Into a 4 mL vial was added I-78 (10 mg, 0.022 mmol)
and 1 mL of 4N HCl/dioxane. After stirring for 8.5 hours the
reaction was concentrated to obtain P-369 (6.8 mg, 77%) .sup.1H NMR
(400 MHz, DMSO-d.sub.6) 9.69 (br s, 2H), 7.52-7.45 (m, 2H),
7.43-7.36 (m, 2H), 7.32 (d, J=4.6 Hz, 1H), 7.29 (d, J=6.3 Hz, 1H),
7.08-7.01 (m, 2H), 5.29 (s, 2H), 3.77 (s, 3H) ppm. LC/MS=94.4%,
349.0 (APCI+).
##STR00094##
Example 38
Preparation of P-333
##STR00095##
[0222]
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadia-
zol-2-ylamine (P-333). A mixture of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid (I-79)
(0.998 mmol, 1.0 eq.) and thiosemicarbazide (2.99 mmol; 3 eq.) in
excess phosphorous oxychloride was heated to 120.degree. C. for 45
minutes, and allowed to cool to room temperature. The resultant
mixture was added to water, and extracted with 2 portions of ethyl
acetate. The organics were washed with brine, and dried over
magnesium sulfate. The residue was purified via flash
chromatography on silica gel using 5% (1N NH.sub.3 in MeOH) in
dichloromethane as eluent to afford the desired product (P-333) in
39% yield.
[0223] .sup.1HNMR (DMSO-d.sub.6, 400 MHz): 3.75 (s, 3H), 4.17 (s,
2H), 6.98 (d, J=8.0 Hz, 1H), 7.29 (d, J=6.4 Hz, 1H), 7.37-7.41 (m,
2H), 7.43-7.49 (m, 2H), 7.58-7.76 (br s, 2H)
Example 39
Preparation of P-342
##STR00096##
[0225] Synthesis of Methyl
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazol-2-
-yl]-carbamate (P-342). To P-333 (0.286 mmol; 1.0 eq.) was added a
solution of methyl chloroformate (0.388 mmol; 1.4 eq.) in benzene.
The mixture was heated to reflux for 10 h, and allowed to cool to
room temperature. The resultant mixture was diluted with ethyl
ether, filtered, and washed with ethyl ether. The solids were dried
at 30-35.degree. C. under vacuum for 4 h to afford the title
compound, P-342, in 41% yield.
[0226] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.73 (s, 3H), 3.75 (s,
3H), 4.32 (s, 2H), 4.74 (br s, 1H), 6.99 (d, J=8.8 Hz, 1H), 7.29
(d, J=6.4 Hz, 1H), 7.38 (s, 1H) 7.42-7.47 (m, 3H) ppm. LC/MS
(94.0%) APCI.sup.+ found: 408.0; calc'd: 407.9 m/z
Example 40
Preparation of P-343
##STR00097##
[0228] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazol-
-2-yl]-3-ethyl-urea (P-343). To a solution of P-333 (0.214 mmol;
1.0 eq.) in pyridine was added ethyl isocyanate (0.643 mmol; 3
eq.), and the resultant solution stirred at room temperature for 4
days. The reaction was diluted with water, and stirred for 1 h. The
solids were filtered, washed with water, and dried under high
vacuum to afford the title compound, P-343, in 47% yield. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): 1.04 (t, J=7.2 Hz, 3H), 3.12 (q, J=5.6
Hz, 2H), 3.75 (s, 3H), 4.26 (s, 2H), 6.53 (br s, 1H), 6.99 (d,
J=8.8 Hz, 1H), 7.29 (dd, J=6.4, 1.2 Hz, 1H), 7.38 (s, 1H),
7.40-7.48 (M, 3H), 10.71 (s, 1H) ppm. LC/MS=94.8% purity APCI.sup.+
found: 421.0; calc'd: 420.9 m/z
Example 41
Preparation of P-352
##STR00098##
[0230] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazol-2-
-yl]-urea (P-352). To a solution of P-333 (0.177 mmol; 1 eq) in THF
at room temperature was added trimethylsilyl isocyanate (0.886
mmol; 5 eq), and the resultant solution was stirred overnight. The
reaction was then heated to 60.degree. C. for 5 h, additional
trimethylsilyl isocyanate (0.460 mmol; 2.6 eq) was added, and the
reaction allowed to proceed overnight at 60.degree. C. The reaction
was cooled, and poured into excess aqueous 5% sodium bicarbonate.
The resultant suspension was stirred at room temperature for 1 h,
filtered, and washed with water. The solid was dried in vacuo to
obtain the title compound, P-352, as a white solid in 46% yield.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.75 (s, 3H), 4.26 (s, 2H),
6.30 (br s, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.29 (d, J=6.4 Hz, 1H),
7.38 (s, 1H), 7.40-7.48 (m, 4H), 10.72 (s, 2H) ppm. LC/MS=91.1%
purity. APCI.sup.+ found: 393.0; calc'd: 392.8 m/z.
##STR00099##
Example 42
Preparation of P-015
##STR00100##
[0232] Acetic acid 4-methoxy-phenyl ester (I-85, R1=Me, Y.dbd.H); A
mixture of 4-methoxyphenol (6.2 g, 50 mmol), K.sub.2CO.sub.3 (10 g,
72 mmol) and acetic anhydride (6.12 g, 60 mmol) in acetone (150 ml)
was stirred at RT. over night. The solid was filtered off and
washed with acetone (50 ml). After removal of acetone, 8.6 g of
product was obtained. Yield: 100%.
[0233] Acetic acid 3-bromo-4-methoxy-phenyl ester (I-86, R1=Me,
Y.dbd.Br); To a mixture of the above product (4.15 g, 25 mmol) in
acetonitrile (100 ml), was added NBS (5.34 g, 30 mmol) at rt. The
reaction mixture was stirred at rt. over night and more NBS (5.34
g, 30 mmol) was added and the reaction mixture was stirred at
75.degree. C. over night. After removal of solvent, the crude
product directly went to next step.
[0234] 3-Bromo-4-methoxy-phenol (I-87, R1=Me, Y.dbd.Br); A mixture
of crude the above product (25 mmol) in MeOH (100 mL) and 2N NaOH
aq. (30 mL) was stirred at r.t. for 40 min. The pH of reaction
mixture was adjusted to acidic by adding 2N HCl aq. and extracted
with dichloromethane (4.times.60 mL). The dichloromethane layer was
dried over Na.sub.2SO.sub.4. After removal of solvent, the residue
was purified by silica gel column chromatography with
dichloromethane as eluent to give 2.9 g of product Yield: 57% (for
two steps)
[0235] 3-(3-Bromo-4-methoxy-phenoxy)-6-chloro-pyridazine; To a
mixture of the above product (1420 mg, 7 mmol)
3,6-dichloropyridazine (1252 mg, 8.4 mmol) in DMSO (15 ml), was
added K.sub.2CO.sub.3 (1159 mg, 8.4 mmol) at rt. The reaction
mixture was stirred at 110.degree. C. for 3 hr under Ar. After
cooling to rt, water (50 mL) was added to reaction mixture and
extracted with ethyl acetate (3.times.50 mL). The combined ethyl
acetate layer was washed with water (3.times.50 mL), brine and
dried over Na.sub.2SO.sub.4. After removal of solvent, the solid
was washed with diether (20 mL) to give 1650 mg of the product
Yield: 75%
[0236] 6-(3-Bromo-4-methoxy-phenoxy)-2H-pyridazin-3-one; A reaction
mixture of the above product (455 mg, 1.4 mmol) in acetic acid (10
mL), was stirred at 110.degree. C. for 7 hrs. After removal of
solvent, the solid was washed with ethyl acetate (10 mL) to give
340 mg of product. Yield: 82%; MS (ESI+): 297.3 (M+1); LC-MS:
94%.
[0237] 6-(6-Methoxy-3'-nitro-biphenyl-3-yloxy)-2H-pyridazin-3-one
(P-015); A reaction mixture of the above product (85 mg, 0.29
mmol), 3-nitrophenyl-boronic acid (72 mg, 0.43 mmol),
triphenylphosphine (16 mg, 0.06 mmol), K.sub.2CO.sub.3 (124 mg, 0.9
mmol), Pd(OAc).sub.2 (7 mg, 0.03 mmol) in 1,2-dimethoxyethane (6
ml), ethanol (0.5 ml) and water (0.5 ml) was stirred at 80.degree.
C. for 20 hrs under Ar. Reaction mixture was diluted with water (40
ml) and extracted with ethyl acetate (2.times.40 mL). The combined
organic phase was washed with water (2.times.30 mL), brine and
dried over Na.sub.2SO.sub.4. After removal of solvent, the residue
was purified by silica gel column chromatography with ethyl
acetate/hexane as eluent to give 39 mg g of the product (P-015)
Yield: 40%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=3.85 (3H, s),
7.03 (1H, d, J=10 Hz), 7.04 (1H, d, J=8.8 Hz), 7.16-7.20 (2H, m),
7.22 (1H, d, J=10 Hz), 7.57 (1H, dd, J=8, 8 Hz), 7.86 (1H, m), 8.19
(1H, m), 8.41 (1H, m), 9.62 (1H, br s). MS (ESI+): 340.6 (M+1);
LC-MS: 92%.
##STR00101## ##STR00102##
Example 43
Preparation of P-439 and P-440
[0238] Synthesis of
2'-Fluoro-3'-hydroxy-6'-methoxy-biphenyl-3-carbonitrile (I-89,
R1=Me, R2=3-CN, R3=H). A solution of I-88a (2.00 g, 8.22 mmol) and
3-cyanophenylboronic acid (1.45 g, 9.87 mmol) in toluene (30 mL)
was purged with a nitrogen stream for 15 min To the solution was
added ethanol (5 mL) and 2 M aqueous sodium carbonate (8.2 mL), a
suspension formed and palladium(0)tetrakis(triphenylphosphine) (475
mg, 0.411 mmol) was added. The reaction was heated to 108.degree.
C. and stirred at this temperature overnight. The reaction was
diluted with ethyl acetate (200 mL) and water (200 mL). The layers
were separated and the aqueous layer extracted with ethyl acetate
(200 mL). The organic extracts were combined, washed with water
(400 mL) and brine (300 mL), dried over sodium sulfate, filtered,
and the solvent removed under vacuum to give crude product. The
crude material was purified by flash silica gel column
chromatography (0-5% methanol in dichloromethane) to give I-89a
(1.53 g, 77% yield) as a beige powder.
[0239] 1H NMR (400 MHz CDCl.sub.3) d: 7.74-7.73 (m, 1H), 7.67-7.64
(m, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.01 (t, J=9.4 Hz, 1H), 6.691 (dd,
J=9.2, 2.0 Hz, 1H), 4.91 (br m, 1H), 3.77 (s, 3H) ppm. LCMS=100%
purity. MS (APCI-)=224.0 (M-19).
[0240] Synthesis of
2'-Fluoro-6'-methoxy-3'-(6-nitro-pyridin-3-yloxy)-biphenyl-3-carbonitrile
(I-89b). A solution of I-89a (500 mg, 2.06 mmol) and
5-bromo-2-nitropyridine (379 mg, 1.87 mmol) in n-methylpyrrolidine
(10 mL) was purged with a nitrogen stream. To the solution was
added cesium carbonate (1.22 g, 3.74 mmol), copper(I) chloride
(92.4 mg, 0.934 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione
(43.1 mg, 0.234 mmol) under nitrogen. The reaction was heated to
60.degree. C. overnight. The reaction was diluted with ethyl
acetate (75 mL) and water (75 mL), and the layers separated. The
aqueous wash was extracted with ethyl acetate (75 mL), and the
organic extracts combined. The organic extracts were washed with 1
N aqueous sodium hydroxide (100 mL), water (100 mL), and brine (100
mL), dried over sodium sulfate, decanted, and the solvent removed
under reduced pressure to give crude product. The material was
purified by flash silica gel column chromatography (0-50% ethyl
acetate in hexanes) to give I-89b (541.8 mg, 79% yield) as a yellow
powder. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.34 (d, J=2.8 Hz, 1H),
8.26 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.69-7.64 (m, 2H), 7.55 (t,
J=7.8 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.26 (t, J=9.0 Hz,
1H), 6.86 (dd, J=9.2, 1.6 Hz, 1H), 3.85 (s, 3H) ppm. LCMS=74.2%
purity. MS (APCI+)=(M-29).
[0241] Synthesis of
5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-yloxy)-pyridin-2-yl-ammonium
chloride (P-439). A suspension of I-89b (R1=Me, R2=3-CN,
R3=2-N0.sub.2-3-pyridyl) (250 mg, 0.684 mmol) and tin(II), chloride
(567 mg, 2.51 mmol) in isopropyl alcohol (2.5 mL) and concentrated
hydrochloric acid (1.25 mL) was stirred at reflux for 3 h. To the
reaction was added ethyl acetate (50 mL) and aqueous saturated
sodium bicarbonate (50 mL). The layers were separated and the
aqueous layer extracted with ethyl acetate (50 mL). The combined
organic extracts were washed with water (50 mL) and brine (50 mL),
dried over sodium sulfate, filtered, and the solvent removed under
vacuum. The residue was purified by flash silica gel column
chromatography (eluting with 50% ethyl acetate in toluene) to give
the free base as an orange gum. The gum was dissolved in dioxane (1
mL) and 4 N hydrochloric acid in dioxane was added (2 mL). The
suspension was stirred for 2 h at room temperature and subsequently
the solvent was removed under reduced pressure. The residue was
triturated with diethyl ether (5 mL), filtered, and washed with
diethyl ether (2.times.1 mL) to give P-439 (55.1 mg, 22% yield) as
a pale yellow solid.
[0242] 1H NMR (400 MHz d6-DMSO) d: 7.89-7.84 (m, 4H), 7.75 (d,
J=7.6 Hz, 1H), 7.68 (t, J=8.2 Hz, 1H), 7.32 (t, J=9.4 Hz, 1H),
7.02-6.99 (m, 2H), 3.77 (s, 3H). LCMS=96.2% purity. MS
(APCI+)=336.1 (M+1).
[0243] Synthesis of
1-[5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-yloxy)-pyridin-2-yl]-3-ethyl-
-urea (P-440). A solution of P-439 (85.0 mg, 0.230 mmol) and ethyl
isocyanate (49.0 mg, 0.690 mmol) in pyridine (1.5 mL) was stirred
at room temperature over night. The reaction was neutralized with
water (50 mL) and extracted with ethyl acetate (2.times.50 mL). The
combined extracts were washed with water (50 mL) and brine (50 mL),
dried over sodium sulfate, filtered, and the solvent removed under
vacuum. The residue was purified by preparatory silica gel thin
layer chromatography (5% acetone in dichloromethane), triturated
with diethyl ether (3 mL), filtered, and washed with diethyl ether
(2 mL) to give P-440 (32.0 mg, 34% yield) as a white powder.
[0244] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.10 (s, 1H), 7.99 (t,
J=1.8 Hz, 1H), 7.90 (s, 1H), 7.87 (dt, J=7.5 Hz, 1.50 Hz, 1H), 7.76
(d, J=8.0 Hz, 1H), 7.69-7.65 (m, 2H), 7.46 (d, J=2.00 Hz, 1H), 7.25
(t, J=9.2 Hz, 1H), 6.99 (dd, J=9.2 Hz, 1.60 Hz, 1H), 3.76 (s, 2H),
3.31 (s, 3H), 3.15 (2H), 1.07 (t, J=7.4 Hz, 3H).
[0245] LCMS=97.9% purity. MS (APCI+)=407.1 (M+1).
##STR00103##
Example 44
Preparation of P-203
##STR00104##
[0247] 3-Bromo-2-fluoro-4-methoxy-benzaldehyde and
N-{4-[(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-amino]-phenyl}-a-
cetamide To a hot (80.degree. C.) solution of
hexamethylenetetramine (13.7 g, 97.5 mmol) in TFA (50 ml) was added
a solution of 3-bromo-2-fluoro-4-methoxy-benzene (10 g, 48.8 mmol)
in TFA (40 ml) over 1 hour. The resultant solution was continued to
stir at 80.degree. C. for 1 h. After it was cooled to room
temperature, the reaction mixture was poured to water, and stirred
for 30 min. The products were collected on a filter and dried in
vacuo to yield desired aldehyde (I-91) and a dimeric amine impurity
(total weight: 11 g), as an inseparable mixture. 1H-NMR indicated
the molar ratio of these two products is about 1:1.
[0248] 3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-carbaldehyde (I-92),
A mixture of the above products (1.0 g, 4.3 mmol),
3-chlorophenylboronic acid (1.34 g, 8.6 mmol), K.sub.2CO.sub.3
(1.36 g, 12.9 mmol) and (Ph.sub.3P).sub.4Pd (1.49 g, 1.29 mmol) in
dioxane/H.sub.2O (5:1, 40 ml) was heated to 85 C for 20 h under
nitrogen. After it was cooled to room temperature, the mixture was
diluted with water, extracted with ethyl acetate, washed with water
and brine, and dried over Na.sub.2SO.sub.4. After it was
concentrated in vacuo, the residue was purified by a column
chromatography on silica gel to yield the title compound (I-92)
(0.4 g).
[0249] 3-Hydroxymethyl-6-methoxy-3'-nitro-biphenyl-2-ol To a
solution of above product (I-92) (0.4 g, 1.5 mmol) in methanol (8
ml) was added 4'-aminoacetanilide (0.34 g, 2.3 mmol) and
p-toluenesulfonic acid mono-hydrate (0.013 g, 0.08 mmol). The
resulting mixture was stirred at room temperature for 20 h. After
the solvent was removed, the residue was dissolved in acetic acid
(4 ml), and sodium cyanoboronhydride (0.28 g, 4.5 mmol) at 0 C. The
resultant stirred at room temperature for 2 h. The mixture was
poured into ice-water, extracted with ethyl acetate, washed with
water and brine, and dried over Na.sub.2SO.sub.4. After it was
concentrated in vacuo, the residue was purified by a column
chromatography on silica gel to yield the product (I-93, R1=Me,
Y.dbd.F) (0.4 g, 67%).
[0250]
N-{4-[(3'-Chloro-2-fluoro-6-hydroxy-biphenyl-3-ylmethyl)-amino]-phe-
nyl}-acetamide (P-203). To a solution of the above product (0.17 g,
0.43 mmol) in methylene chloride (20 mL) was added BBr.sub.3 (0.32
g, 1.28 mmol) at -78.degree. C. After it was stirred at -78.degree.
C., the resultant was allowed to warm to room temperature, and
continued to stir for 3 h. The reaction was quenched with ice-water
and basified with Na.sub.2CO.sub.3. The resulting mixture was
extracted with ethyl acetate, washed with brine, and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo to yield the
product P-203 (150 mg, 95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
10.06 (br s, 1H), 7.46-7.61 (m, 4H), 7.40-7.47 (m, 2H), 7.30 (s,
1H), 7.25 (d, J=6.3 Hz, 1H), 7.07-7.16 (m, 2H), 7.01 (d, J=8.7 Hz,
1H), 4.40 (s, 2H), 2.03 (s, 3H) ppm.
[0251] The following compound was prepared by procedure similar to
the one described above.
Example 45
Preparation of P-251
[0252]
N-{4-[(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-sulfamoyl]-
-phenyl}-acetamide (P-251) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.71
(d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.45 (br s, 1H),
7.26-7.37 (m, 2H), 7.17-7.25 (m, 2H), 7.12-7.19 (m, 1H), 6.68 (d,
J,=,8.6 Hz, 1H) 4.83 (t, J=6.2 Hz, 1H) 4.19 (d, J,=,6.3 Hz, 2H)
3.75 (s, 3H) 2.21 (s, 3H) ppm.
##STR00105##
Example 46
Preparation of P-025
##STR00106##
[0254] 2-iodo-3-methoxy-6-methyl-pyridine (I-95): To
2-iodo-6-methyl-pyridin-3-ol (I-94) (1.0 g, 4.25 mmol) and
K.sub.2CO.sub.3 (1.18 g, 8.51 mmol) in acetone (20 mL) was added
MeI (0.91 g, 6.38 mmol). The reaction was stirred at 45.degree. C.
under N.sub.2 for 20 h. The reaction was cooled to room temperature
and concentrated. The residue was purified by silica gel column
chromatography using dichloromethane to afford 1.04 g (98%) of the
product (I-95, R1=Me) as light yellow solid.
[0255] 3-methoxy-6-methyl-2-(3-nitro-phenyl)-pyridine (I-96): To
the above product (I-95, R1=Me) (0.5 g, 2.0 mmol),
3-nitrophenylboronic acid (2) (0.5 g, 3.06 mmol), PPh.sub.3 (0.11
g, 0.4 mmol), K.sub.2CO.sub.3 (0.83 g, 6.0 mmol) and Pd(OAc).sub.2
(0.045 g, 0.2 mmol) was added DME (16 mL), and EtOH-H.sub.2O (1:1,
4 mL). Ar gas was bubbled through the stirred reaction for 5 min.
The reaction was stirred at 60.degree. C. under Ar for 18 h. The
reaction was cooled to room temperature, concentrated, and H.sub.2O
and dichloromethane (40 mL each) were added. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.25 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 1:1
dichloromethane-hexanes then dichloromethane to afford 0.22 g (44%)
of the product (I-96, R1=Me) as a light yellow solid.
[0256] 6-bromomethyl-3-methoxy-2-(3-nitro-phenyl)-pyridine (I-97):
To the above product (I-96, R1=Me) (0.21 g, 0.86 mmol) and NBS
(0.17 g, 0.95 mmol) in CCl.sub.4 (10 mL) was added benzoylperoxide
(0.02 g, 0.08 mmol). The reaction was stirred at 60.degree. C.
under N.sub.2 for 18 h. The reaction was cooled to room temperature
and concentrated. The residue was dissolved in mixture of
dichloromethane and hexanes (1:1, 8 mL) and purified by silica gel
column chromatography using 1:1 dichloromethane/hexanes then
dichloromethane to afford 0.15 g (55%) of the product as a light
brown solid.
[0257] 3-methoxy-6-methoxymethyl-2-(3-nitro-phenyl)-pyridine
(P-025): To the above product (0.08 g, 0.25 mmol), methanol (0.11
g, 2.5 mmol), and CsCO.sub.3 (0.24 g, 0.74 mmol) was added DMF (2
mL). The vial was capped and stirred at room temperature for 20 h.
The reaction was diluted with 1:1 ethyl acetate-H.sub.2O (60 mL).
The organic layer was separated and the aqueous was extracted with
ethyl acetate (2.times.20 mL). The combined organic extracts were
dried with Na.sub.2SO4, filtered, and concentrated to afford 0.066
g (97%) of the product (P-025) as off white solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz): 8.88 (dd, J=2.0, 1.6 Hz, 1H), 8.3-8.35 (m,
1H), 8.2-8.24 (m, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.8 Hz,
1H), 7.37 (d, J=8.4 Hz, 1H), 3.61 (s, 2H), 3.92 (s, 3H), 3.50 (s,
3H); MS (APCI+): 275.1 (M+1), LC-MS: 96.1%.
##STR00107##
Example 47
Preparation of P-091
[0258] 2-methoxy-5-methyl-3'-trifluoromethyl-biphenyl (I-100) A
reaction mixture of 2-methoxy-5-methylphenyl boronic acid (I-99) (5
g, 30.3 mmol), 3-iodobenzenetrifluoride (8.24 g, 30.3 mmol),
K.sub.2CO.sub.3 (8.3 g, 60.6 mmol), palladium acetate (350 mg, 1.5
mmol) in methanol (200 ml) and water (40 ml) was stirred at room
temperature over night. Reaction mixture was concentrated to a 1/3,
and then it was diluted with ethyl acetate (300 ml) and washed with
0.6 N sodium hydrogen sulfate solution (300 ml), water (2.times.150
ml), brine and dried over Na.sub.2SO.sub.4. After removal of
solvent, 7.75 g of product (I-100) was obtained as oil. Yield:
100%.
[0259] 5-Bromomethyl-2-methoxy-3'-trifluoromethyl-biphenyl (I-101);
To a 250 mL round bottom flask equipped with stirring bar was added
I-100 (5 g, 18.79 mmol) and CCl.sub.4 (125 mL). To this solution 1
g of NBS and 100 mg of AIBN were added. The flask was connected to
a condenser and the mixture was reflux under the sun lamp for one
hour. To the reaction mixture 1 g of NBS and 100 mg AIBN were
[0260] added and this stirred at reflux, under N.sub.2 for 2 more
hours. After 2 hours another portion of NBS (1.3 g) and 108 mg of
AIBN were added and mixture was refluxed for 2 more hours. The
reaction mixture was cooled to RT, concentrated to half and
filtered off. The solid was washed with 100 mL of CCl.sub.4. After
removal of solvent 6.76 g of crude product (I-101) was
obtained.
[0261]
3-(6-Methoxy-3'-trifluoromethyl-biphenyl-3-ylmethoxy)-cyclopent-2-e-
none (P-091). To a solution of 1,3-cyclopentanedione (110 mg, 1.11
mmol) in 1.5 ml anhydrous DMF was added at 0.degree. C. NaH (60%
dispersion in mineral oil, 45 mg, 1.11 mmol). The suspension was
stirred for 30 minutes, then a solution of I-101 (350 mg, 0.76
mmol) in 1.5 ml DMF was added. The reaction mixture was stirred at
RT, overnight. The reaction mixture was quenched with saturated
NH.sub.4Cl solution and extracted with methylene chloride. Combined
organic layers were washed with brine, dried over sodium sulfate,
filtered, concentrated to give 300 mg crude. Purification was done
using preparative silica gel plate (1500 um) to afford 125 mg of
product P-091. .sup.1H NMR (CDCl.sub.3, 400 MHz): 2.45 (t, 2H),
2.66 (t, 2H), 3.05 (d, 1H), 3.84 (s, 3H), 5 (s, 2H), 5.43 (s, 1H),
7.02 (d, J=8.4 Hz, 1H), 7.33 (d, J=2 Hz, 1H), 7.38 (dd, J=8.4, 2.4
Hz, 1H), 7.53 (t, 1H), 7.6 (d, J=8.4 Hz, 1H), 7.7 (d, J=8.4 Hz,
1H), 7.77 (s, 1H). LCMS (APCI+): 363 (M+1), 90%.
Example 48
Preparation of P-092
##STR00108##
[0263] Synthesis of
3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethoxy)-cyclopent-2-enone
(P-092). Into a 50 mL round bottom flask with stir bar added I-70
(284 mg, 0.83 mmol), 1,3-cyclopentadione (217 mg, 2.21 mmol),
K.sub.2CO.sub.3 (305 mg, 2.21 mmol), and 5 mL DMF. The reaction was
stirred at room temperature for 18 hours. 5 mL of dichloromethane
and 5 mL water were added. The layers were separated and the
aqueous extracted with 10 mL dichloromethane. The combined organics
were washed with water (4.times.10 mL), dried over sodium sulfate,
and concentrated. The residue was purified by flash column
chromatography using 0-2% methanol/dichloromethane. Obtained 112 mg
(37%) P-092 as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
2.41-2.54 (m, 2H) 2.60-2.71 (m, 2H) 3.86 (s, 3H) 5.01 (s, 2H) 5.44
(s, 1H) 7.04 (d, J=8.5 Hz, 1H) 7.37 (d, J=2.2 Hz, 1H) 7.41 (dd,
J=8.5, 2.2 Hz, 1H) 7.58 (t, J=8.0 Hz, 1H) 7.86 (d, J=7.8 Hz, 1H)
8.20 (dd, J=8.3, 1.3 Hz, 1H) 8.41 (t, J=1.7 Hz, 1H). LC/MS=92.0%,
340.1 (APCI+)
##STR00109##
Example 49
Preparation of P-128
[0264]
(2-fluoro-6-methoxy-3'-nitro-biphenyl-3-yl)-thiophen-2-yl-methanone
(I-103) To a 25 mL vial which contained a solution of
thiophene-2-carbonyl chloride (90 mg, 0.6 mmol) in nitrobenzene
(0.5 mL) was added AlCl.sub.3 (75 mg, 0.75 mmol) at -10.degree. C.
After stirring at 0.degree. C. for 2 h,
6-Fluoro-2-methoxy-3'-nitro-biphenyl (31) (125 mg, 0.5 mmol) in
nitrobenzene (0.5 mL) was added at rt. The reaction mixture was
allowed to stir at rt for 24 hours. The reaction mixture was cooled
to -10.degree. C. and quenched with ice-water (10 mL, extracted
with ethyl acetate (10 mL), washed with water (2.times.10 mL),
NaHCO.sub.3 (sat., 10 mL), brine (30 mL) and dried over
Na.sub.2SO.sub.4. After removal of solvent, the crude was purified
by crystallization from ether-hexane to give 100 mg of I-103 in 60%
yield. LCMS: Calc. 357.4; APCI.sup.-(M): 356.9, 342 (M-16-1)
97.4%
[0265]
2-(2-fluoro-6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-tetrahydro-thio-
phene (P-128). To a 25 mL vial which contained compound I-103 (90
mg, 0.25 mmol) in triethylsilane (1 mL) was added TFA (1 mL) at
-10.degree. C. The reaction mixture was allowed to warm to rt and
stir at rt for 72 h. The reaction mixture was poured onto 30 mL
ice-water, extracted with ethyl acetate (3.times.30 mL), washed
with NaHCO.sub.3 (sat. 30 mL), water (20 mL), brine (30 mL) and
dried over Na.sub.2SO.sub.4. After removal of solvent, the residue
was purified by silica gel column chromatography with ethyl
acetate/hexane as eluent to give 30 mg of product (P-128) in 30%
yield. 1H NMR (CDCl.sub.3,400 MHz): 8.33 (br s, 1H), 8.22-8.26 (m,
1H), 7.59-7.76 (m, 5H), 7.15 (t, J=4.0 Hz, 1H), 6.91 (d, J=9.2 Hz,
1H), 3.89 (s, 3H)
[0266] LCMS: Calc. 347.4; APCI.sup.- (M) 347.0: 99%.
Example 50
Preparation of P-481
##STR00110##
[0268] Synthesis of
5-(2-Methoxy-5-[1,2,4]triazol-1-ylmethyl-phenyl)-benzo[1,2,5]oxadiazole
(P-481). A suspension of
1-(3-Bromo-4-methoxy-benzyl)-1H-[1,2,4]triazole (I-104, 402 mg,
1.50 mmol), benzo[1,2,5]oxadiazole-5-boronic acid (I-105, 246 mg,
1.50 mmol), palladium(0) bis(dibenzylideneacetone) (43 mg, 0.075
mmol), and triphenyl phosphine (39.3 mg, 0.15 mmol) in
dimethylformamide (15 mL) and 1 M aqueous cesium carbonate (4.5 mL,
4.5 mmol) was heated to 85.degree. C. with stirring overnight. The
solvent was removed under vacuum and the residue suspended in ethyl
acetate (15 mL). The organic suspension was washed with water
(3.times.15 mL) and brine, dried over sodium sulfate, decolorized
over activated carbon, filtered, and the solvent removed under
vacuum to give crude material. The residue was purified by
recyrstalization from dichloromethane (2 mL) and hexanes (10 mL) to
give P-481 (180 mg, 39% yield). 1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 3.88 (s, 4H) 5.51 (s, 2H) 7.06 (d, J=7.8 Hz, 1H)
7.41-7.54 (m, 3H) 7.59 (d, J=9.3 Hz, 1H) 7.71-8.03 (m, 3H) 8.25 (s,
1H) 9.34 (br. s., 1H), LCMS=95.7% purity.
Example 51
Preparation of P-482
##STR00111##
[0270] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-benzotriazole
(P-482). A suspension of
1-(3-Bromo-4-methoxy-benzyl)-1H-benzotriazole (I-106) (477 mg, 1.50
mmol), 3-nitrophenylboronic acid (250 mg, 1.50 mmol), palladium(0)
bis(dibenzylideneacetone) (43 mg, 0.075 mmol), and triphenyl
phosphine (39 mg, 0.15 mmol) in dimethylformamide (10 mL) and 1 M
aqueous sodium carbonate (4.5 mL, 4.5 mmol) was heated to
85.degree. C. with stirring overnight. The solvent was removed
under vacuum and the residue suspended in ethyl acetate (20 mL).
The organic suspension was washed with water (3.times.20 mL) and
brine, dried over sodium sulfate, decolorized over activated
carbon, and the solvent removed under vacuum to give crude
material. The residue was purified dissolving in ethyl acetate (5
mL) and adding hexanes (25 mL) until a solid formed. This was
repeated 3 times to give P-482 (210 mg, 39% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .sup.1H NMR (400 MHz, CDCl.sub.3): 3.82 (s,
3H), 5.86 (s, 2H), 6.98 (d, J=8.2 Hz, 1H), 7.30-7.37 (m, 2H),
7.37-7.52 (m, 3H), 7.52-7.59 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.12
(d, J=8.3 Hz, 1H), 8.18 (dd, J=8.2, 1.2 Hz, 1H), 8.35 (d, J=1.6 Hz,
1H) ppm. LCMS=93.9% purity.
##STR00112##
Example 52
Preparation of P-010, P-483, P-014
[0271] Synthesis of 2-Bromo-4-bromomethyl-1-methoxy-benzene (I-42).
To solution of potassium bromide (29.6 g, 248 mmol) in nitric acid
(21% by volume, 149 g, 497 mmol), was added dichloroethane (188 mL)
and tetrabutylammonium chloride (1.04 g, 3.73 mmol) followed by
4-(bromomethyl)anisol (25.0 g, 124 mmol) in dichloroethane (62 mL),
and the reaction was stirred at room temperature for 5 h. The
organic layer was separated, washed with water (2.times.100 mL,
2.times.150 mL), 2% aqueous potassium carbonate (150 mL), dried
over sodium sulfate, and the solvent removed under vacuum. The
residue was purified by being run through a flash silica gel plug
(10% ethyl acetate in hexanes) to give the title compound (I-42)
(9.22 g, 26% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.59 (d, 1H), 7.30 (dd, J=8.2, 2.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H),
4.44 (s, 2H), 4.44 (s, 3H).
[0272] Synthesis of 1-(3-Bromo-4-methoxy-benzyl)-1H-indole (I-107,
X.dbd.CH). A solution of indole (250 mg, 2.14 mmol) in DMF (15 mL)
was cooled in an ice bath. To this solution was added sodium
hydride (64.3 mg, 2.68 mmol), followed by
2-Bromo-4-bromomethyl-1-methoxy-benzene (500 mg, 1.79 mmol). The
reaction was warmed to room temperature and stirred overnight. To
the reaction was added saturated aqueous ammonium chloride (75 mL)
and the layers separated. The organic extract was washed with
saturated aqueous ammonium chloride (2.times.75 mL), water
(3.times.75 mL) and brine (50 mL). The extract was dried over
sodium sulfate, and the solvent removed under reduced pressure. To
residue was purified by flash silica gel column chromatography
eluting with 1:3 hexanes: dichloromethane to give the title
compound (I-107, X.dbd.CH)(490 mg, 87% yield) which was taken into
further reactions.
[0273] 1H NMR (400 MHz CDCl.sub.3) d: 7.659-7.635 (m, 1H), 7.391
(dd, J=1.60 Hz, 0.80 Hz, 1H), 7.215-7.092 (m, 4H), 6.996-6.969 (m,
1H), 6.794 (d, J=8.40 Hz, 1H), 6.549 (dd, J=3.00 Hz, 1.00 Hz, 1H),
5.234 (s, 2H), 3.850 (s, 3H).
[0274] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-indole (P-010). A
suspension of 1-(3-Bromo-4-methoxy-benzyl)-1H-indole (150 mg, 0.474
mmol), palladium bis(triphenylphosphine)dichloride (13.3 mg, 0.0190
mmol), and 3-nitrophenylboronic acid (94.9 mg, 0.569 mmol) in
dioxane (10 mL) and 1 M aqueous sodium carbonate (1.1 mL) was
stirred at 85.degree. C. for 22 h. To the reaction was added ethyl
acetate (30 mL). The organic suspension was washed with water
(4.times.30 mL), brine (2.times.30 mL), dried over sodium sulfate,
and the solvent removed under vacuum. The residue was purified by
flash silica gel column chromatography (10% ethyl acetate in
hexanes as the elutant) to yield
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-indole P-010 (23.6
mg, 17% yield).
[0275] 1H NMR (400 MHz, CDCl.sub.3) d: 8.36 (t, J=1.60, 1H), 8.16
(dt, J=6.40, 0.90, 1H), 7.76 (dd, J=6.40, 0.80, 1H), 7.65 (d,
J=6.40, 1H), 7.53 (t, J=6.20, 1H), 7.326 (d, J=6.40, 1H), 7.26-7.10
(m, 5H), 6.92 (d, J=7.20, 1H), 6.55 (d, J=2.40, 1H), 5.32 (s, 2H),
3.797 (s, 3H). LCMS=87.7% purity. MS (APCI+)=359.1 (M+1).
[0276] Synthesis of 1-(3-Bromo-4-methoxy-benzyl)-1H-benzoimidazole
(I-107, X.dbd.N). A suspension of 1H-benzoimidazole (317 mg, 2.68
mmol) and potassium carbonate (495 mg, 3.58 mmol) in DMF (10 mL)
was stirred at 45.degree. C. for 1 h. To the heated suspension was
added 2-Bromo-4-bromomethyl-1-methoxy-benzene (500 mg, 1.79 mmol)
and the reaction was stirred at 45.degree. C. for 4 h, cooled to
room temperature and stirred at room temperature overnight. About
half of the solvent was removed under vacuum, and ethyl acetate (30
mL) was added. The organic solution was washed with saturated
aqueous ammonium chloride (3.times.30 mL), water (2.times.15 mL),
and brine (15 mL). The organic extract was dried over anhydrous
sodium sulfate and the solvent removed under vacuum to give crude
product as an orange oil. The product was purified by flash silica
gel column chromatography eluting with 5% methanol in
dichloromethane to give the title compound (282.5 mg; 48% yield)
and a second crop of 50% pure
2-Bromo-4-bromomethyl-1-methoxy-benzene (207.1 mg).
[0277] 1H NMR (400 MHz CDCl.sub.3) 7.93 (s, 1H0 7.84-7.82 (m, 1H),
7.45 (d, J=2.40 Hz, 1H), 7.30-7.26 (m, 3H) 7.07 (dd, J=8.60 Hz,
2.20 Hz, 1H), 6.84 (d, J=8.40 Hz, 1H), 5.28 (s, 2H), 3.87 (s,
3H).
[0278] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-benzoimidazole
(P-483). A suspension of
1-(3-Bromo-4-methoxy-benzyl)-1H-benzoimidazole (I-107, X.dbd.N)
(250 mg, 0.788 mmol), 3-nitrophenylboronic acid (132 mg, 0.788 mg),
triphenylphosphine (20.6 mg, 0.0788 mmol), solid potassium
carbonate (326 mg, 2.37 mmol) in 1,2-dimethoxyethane (6 mL), water
(1 mL), and ethanol (1 mL) was flushed with argon gas and the
palladium acetate (8.9 mg, 0.0394 mmol) was added. The reaction was
heated to 80.degree. C. over night. Additional palladium acetate
(8.9 mg, 0.039 mmol) and triphenylphosphine (20.6 mg, 0.0788 mmol)
was added and the mixture was stirred an additional night at
80.degree. C. The solvent was removed under vacuum and taken up in
ethyl acetate (50 mL). The organic solution was washed with
saturated aqueous ammonium chloride (2.times.75 mL), water
(3.times.75 mL) water, and the combined aqueous layers were
extracted with ethyl acetate (50 mL). The combined organic extracts
were washed with brine (75 mL), decolorized using activated carbon,
dried over sodium sulfate, and the solvent removed under vacuum.
The residue was taken up in dichloromethane (5 mL), hexanes (20 mL)
were added and the yellow powder was filtered to give crude P-483.
This was purified by flash silica gel column chromatography eluting
with 10-20% acetone in dichloromethane, and the excess boronic acid
removed by taking up the residue in dichloromethane (3 mL), and
washing with 1 N aqueous sodium hydroxide solution. This wash was
extracted into dichloromethane (5 mL), the combined extracts dried
over sodium sulfate, and the solvent removed under vacuum to give
P-483 (23.9 mg, 8.4% yield) as an orange tacky powder.
[0279] 1H NMR (400 MHz, DMSO-d.sub.6) d: 8.44 (s, 1H), 8.27 (t,
J=2.00 Hz, 1H), 8.21-8.178 (m, 1H), 7.924-7.898 (m, 1H), 7.711 (t,
J=8.00 Hz, 1H), 7.646-7.597 (m, 2H), 7.523 (d, J=2.40 Hz, 1H),
7.398 (dd, J=8.40 Hz, 2.00 Hz, 1H), 7.219-7.127 (m, 3H), 5.485 (s,
2H), 3.764 (s, 3H). LCMS=93.1% purity. MS (ESI+)=360.9 (M+1).
[0280] Synthesis
5-(5-Benzoimidazol-1-ylmethyl-2-methoxy-phenyl)-benzo[1,2,5]oxadiazole
(P-014). A suspension of
1-(3-Bromo-4-methoxy-benzyl)-1H-benzoimidazole (I-107, X.dbd.N)
(250 mg, 0.778 mmol), 1 N aqueous cesium carbonate (2.4 mL), and
triphenylphosphine (20.7 mg, 0.0788 mmol) in DMF (5 mL) was
stirred. To the suspension was added benzo[1,3]dioxol-5-yl-boronic
acid (155 mg, 0.946 mmol), the reaction purged with nitrogen, and
bis(dibenzylideneacetone)palladium(0) (22.7 mg, 0.0394 mmol) was
added under nitrogen. The reaction was stirred at 100.degree. C.
overnight. After cooling to room temperature, ethyl acetate (50 mL)
was added. The organic suspension was washed with saturated aqueous
ammonium chloride (2.times.50 mL), 1 N aqueous sodium hydroxide
(3.times.50 mL), water (50 mL), and brine (50 mL), decolorized over
activated carbon, dried over sodium sulfate, and removed under
vacuum to give crude product. The product was purified by flash
silica gel column chromatography eluting with 1% methanol in
dichloromethane to give P-014 (102.1 mg, 36% yield) as an off white
powder. .sup.1H NMR (400 MHz, d6-DMSO) d: 8.446 (s, 1H),
8.054-8.020 (m, 2H), 7.715 (dd, J=9.60 Hz, 1.60 Hz, 1H),
7.651-7.649 (m, 2H), 7.605 (d, J=2.40 Hz, 1H), 7.440 (dd, J=8.60
Hz, 2.20 Hz, 1H), 7.244-7.147 (m, 3H), 5.485 (s, 2H), 3.787 (s,
3H).
[0281] LCMS=99.5% purity. MS (ESI+)=357.8 (M+1).
Example 53
Preparation of P-005
##STR00113##
[0283] Synthesis of 2-Bromo-4-chloromethyl-1-methoxy-benzene
(I-109). I-109 was synthesized from 4-chloromethylanisole (25.0 g,
159.6 mmol) using the same conditions as I-42, and was purified by
dissolution in diethyl ether (50 mL) and hexanes (50 mL) and
crystallization by removing the diethyl ether under vacuum to give
I-109 (19.1 g, 51% yield) as a yellow powder.
[0284] 1H NMR (400 MHz CDCl.sub.3) d: 7.584 (d, J=2.40 Hz, 1H),
7.296 (dd, J=8.40 Hz, 2.00 Hz, 1H), 6.871 (d, J=8.40 Hz, 1H), 4.520
(s, 2H), 3.901 (s, 3H).
[0285] Synthesis of 1-(3-Bromo-4-methoxy-benzyl)-1H-[1,2,4]triazole
(I-110). A suspension of 1,2,4-triazole (5.72 g, 82.8 mmol),
3-bromo-4-methoxybenzylchloride (I-109) (13.0 g, 55.2 mmol), and
solid cesium carbonate (27.0 g, 82.8 mmol) in DMF (225 mL) was
stirred at room temperature overnight. The reaction was diluted
with ethyl acetate (400 mL) Dilute with 400 ml EA, and washed with
water (300 mL). The aqueous wash was extracted with ethyl acetate
(2.times.150 mL), and all the ethyl acetate extracts combined,
washed with saturated aqueous ammonium chloride (3.times.300 mL),
water (2.times.300 mL), and brine (300 mL), dried over sodium
sulfate and the solvent removed under vacuum to give I-110 as a
yellow oil (11.39 g; 77% yield) which solidified to a greasy yellow
solid.
[0286] .sup.1H NMR (400 MHz CDCl.sub.3) d: 8.060 (s, 1H), 7.969 (s,
1H), 7.492 (d, J=2.00 Hz, 1H), 7.212 (dd, J=8.60 Hz, 2.20 Hz, 1H),
6.890 (d, J=8.40 Hz, 1H).
[0287] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-1,2,4]triazole
(P-005). A solution of I-110 (12.8 g, 47.6 mmol) and
3-nitrophenylboronic acid (9.53 g, 57.1 mmol) in DMF (250 mL) was
purged with nitrogen for 10 min at room temperature and 1 N aqueous
sodium carbonate (143 mL), triphenylphosphine (2.49 g, 9.51 mmol),
and bis(dibenzylideneacetone)palladium(0) (2.73 g, 4.75 mmol under
nitrogen. The reaction was heated to 80.degree. C. and stirred
overnight. The reaction did not go to completion, so it was heated
to 100.degree. C. with vigorous stirring for 2 h. The diluted with
ethyl acetate (1 L) and washed with water (3.times.1 L) and brine
(500 mL), dried over sodium sulfate and the solvent removed under
vacuum to give a brown oil. The oil was purified by silica gel
column chromatography eluting with 0-5% acetone in dichloromethane,
and the residue dissolved in ethyl acetate (300 mL), washed with
water (2.times.300 mL), and brine (300 mL) to give a 30% mixture of
I-110 and P-005. This mixture was added to a solution of
3-nitrophenylboronic acid (8.00 g, 47.9 mmol) and
triphenylphosphine (2.24 g, 8.58 mmol) in 1,2-dimethoxyethane (150
mL). Argon was bubbled through for 10 min, and methanol (15 mL),
water (15 mL), solid potassium carbonate (17.8 g, 129 mmol), and
palladium acetate (960 mg, 4.29 mmol) were added under argon gas,
and the argon stream was continued for 10 min. The reaction stirred
at 80.degree. C. under nitrogen overnight. The solvent was removed
under vacuum, and the residue dissolved in ethyl acetate (300 mL)
and washed with water (300 mL). The water was extracted with ethyl
acetate (2.times.300 mL), and the extracts combined. The organic
extracts were washed with water (2.times.500 mL), saturated aqueous
sodium bicarbonate (2.times.500 mL), and brine (500 mL), dried over
sodium sulfate, and removed under vacuum to give crude product as a
brown oil. The product was purified by flash silica gel column
chromatography eluting with 0-25% acetone in dichloromethane to
give slightly impure P-005. The material was triturated with
dichloromethane (30 mL) in hexanes (300 mL), then in
dichloromethane (15 mL) and hexanes (10 mL) and washed with hexanes
(20 mL) to give pure P-005 (5.26 g, 36% yield) as a white powder.
.sup.1H NMR (400 MHz, CDCl.sub.3): 3.84 (s, 3H), 5.34 (s, 2H), 7.02
(d, J=8.5 Hz, 1H), 7.28 (d, 1H), 7.32 (dd, J=8.5, 2.2 Hz, 1H), 7.57
(t, J=8.0 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.97 (s, 1H), 8.09 (s,
1H), 8.19 (dd, J=8.3, 1.3 Hz, 1H), 8.38 (t, J=1.7 Hz, 1H) ppm.
LCMS=100.0% purity.
[0288] MS (APCI+)=311.1 (M+1).
[0289] HPLC (220 nm); 99.95%. [Mobile Phase A and Mobile Phase
B=Water and Acetonitrile, Symmetry C18, (250.times.4.6 mm, 5 um),
Flow=1.0 mL/min, Inj. Wash=ACN, Inj. Vol.=10 uL. Retention
time=22.16 min]
[0290] Elemental Analysis (Calc): C, 61.93; H, 4.55; N, 18.05
(Found), C, 61.92; H, 4.62; N, 17.88.
[0291] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-1,2,4]triazole
hydrochloride salt (P-005). A solution of I-111 (200 mg, 0.645
mmol) in tetrahydrofuran (6 mL) was stirred at room temperature. To
this was added 2 M hydrogen chloride in diethyl ether at room
temperature. The reaction turned cloudy after 10 sec. The reaction
was allowed to stir at room temperature for 45 min, and the
reaction filtered and washed with diethyl ether to give P-005
(189.0 mg, 85% yield) as a white solid.
[0292] 1H NMR. (400 MHz d6-DMSO) d: 8.736 (s, 1H), 8.282 (t, J=2.00
Hz, 1H), 8.219-8.192 (m, 1H), 8.026 (s, 1H), 7.941-7.922 (m, 1H),
7.724 (t, J=8.00 Hz, 1H), 7.434 (d, J=2.40 Hz, 1H), 7.389 (dd,
J=8.40 Hz, 2.40 Hz, 1H), 7.175 (d, J=8.80 Hz, 1H), 5.417 (s, 2H),
3.797 (s, 3H).
[0293] LCMS=100.0% purity. MS (APCI+)=311.1 (M+1).
[0294] Elemental Analysis (Calc): C, 55.42 H, 4.36, N, 16.16, Cl,
10.22 (Found): C, 55.23; H, 4.39; N, 16.00, Cl, 11.06
Example 54
Preparation of P-486
##STR00114##
[0296] Synthesis of
5-(2-Methoxy-5-[1,2,4]triazol-1-ylmethyl-phenyl)-1H-indole (P-486).
P-486 was synthesized from 1H-indole-3-boronic acid (240 mg, 1.49
mmol) and I-110 (200 mg, 0.746 mmol) using conditions similar to
those that were used for I-111. The reaction was worked up by
diluting the reaction with ethyl acetate (50 mL), washing with 1 N
aqueous sodium hydroxide (3.times.30 mL), water (2.times.30 mL),
and brine (30 mL). The organic portion was concentrated and the
residue was purified by flash silica gel column chromatography
eluting with 2% methanol in dichloromethane, followed by flash
silica gel column chromatography eluting with 0-20% ethyl acetate
in hexanes, and then separation on a silica gel preparatory plate
eluting with 50% ethyl acetate in hexanes to give P-486 (51.6 mg,
23% yield).
[0297] 1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 3.82 (s, 3H) 5.33
(s, 2H) 6.58 (br. s., 1H) 6.98 (d, J=8.33 Hz, 1H) 7.18-7.25 (m, 2H)
7.29-7.35 (m, 2H) 7.38-7.44 (m, 1H) 7.73 (s, 1H) 7.96 (s, 1H) 8.06
(s, 1H) 8.17 (br. s., 1H)
[0298] LCMS=100.0% purity. MS (APCI+)=305.1 (M+1).
Example 55
Preparation of P-488
##STR00115##
[0300] Synthesis of 6-(6-Hydroxy-3'-nitro-biphenyl-3-yl
methyl)-2H-pyridazin-3-one (P-488). To a mixture of compound P-009
(260 mg, 0.77 mmol) in dichloroethane (15 ml), boron tribromide (1
M in dichloromethane, 2.3 ml, 2.3 mmol) was added at -70.degree. C.
The reaction mixture was allowed to slowly warm up to rt and then
stirred at rt for 2 hrs. Water (100 ml) and sat. NaHCO3 aq. (20 ml)
were added to the reaction mixture and it was stirred at rt for 1
hr. The resulting solid was filtered and washed with water (50 ml)
to give 236 mg (95%) of P-488.
[0301] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.83 (2H, s), 6.79 (1H,
dd, J=9.6 and 2 Hz), 6.94 (1H, d, J=8.4 Hz), 7.10 (1H, dd, J=8.4
and 2 Hz), 7.29 (1H, d, J=2.4 Hz), 7.33 (1H, d, J=9.6 Hz), 7.70
(1H, dd, J=8 and 8 Hz), 8.00 (1H, m), 8.16 (1H, m), 8.40 (1H, m),
9.83 (1H, s), 12.80 (1H, br). MS (ESI-): 322.5 (M-1) LC-MS:
97%.
Example 56
Preparation of P-487 and P-018
[0302] Synthesis of
6-[6-(2-Methoxy-ethoxy)-3'-nitro-biphenyl-3-ylmethyl]-2H-pyridazin-3-one
P-018 and
6-[6-(2-Methoxy-ethoxy)-3'-nitro-biphenyl-3-ylmethyl]-2-(2-meth-
oxy-ethyl)-2H-pyridazin-3-one P-487. A reaction mixture of compound
P-488 (97 mg, 0.3 mmol), Bromoethyl methyl ether (63 mg, 0.45 mg)
and K.sub.2CO.sub.3 (124 mg, 0.9 mmol) in 2-butanone (15 ml) was
stirred at 80.degree. C. under argon for 18 hrs. After cooling to
rt, water (10 ml) was added to the reaction mixture and the pH was
adjusted to acidic by addition of 2 N HCl aq. and then extracted
with ethyl acetate (40 ml). The organic layer was washed with water
(20 ml), brine, and dried over Na.sub.2SO.sub.4. After removal of
solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/Hexane as eluent to give 30 mg of
product P-487 (3a) and 20 mg of product P-018 (3b).
[0303] P-487: .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.24 (3H, s),
3.61 (2H, m), 3.89 (2H, s), 4.15 (2H, m), 6.81 (1H, d, J=9.6 Hz),
7.13 (1H, d, J=8.8 Hz), 7.26 (1H, dd, J=8.8 and 2 Hz), 7.35 (2H,
m), 7.71 (1H, dd, J=8 and 8 Hz), 8.00 (1H, m), 8.18 (1H, m), 8.43
(1H, m) ppm. MS (ESI-): 380.6 (M-1) LC-MS: 98%.
[0304] P-018: .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.34 (3H, s), 3.36
(3H, s), 3.68 (2H, m), 3.80 (2H, t, J=5.5 Hz), 3.92 (2H, s), 4.14
(2H, m), 4.36 (2H, t, J=5.5 Hz), 6.84 (1H, d, J=9.5 Hz), 6.98 (1H,
d, J=8 Hz), 7.05 (1H, d, J=9.5 Hz), 7.19-7.22 (2H, m), 7.55 (1H,
dd, J=8 and 8 Hz), 7.87 (1H, m), 8.17 (1H, m), 8.49 (1H, m) ppm. MS
(APCI+): 440.1 (M+1)
##STR00116##
Example 57
Preparation of P-017
[0305] Synthesis of 2,6-dimethoxy-3'-nitro-biphenyl (I-81). To
1-bromo-3-nitrobenzene (2.02 g, 10.0 mmol),
2,6-dimethoxyphenylboronic acid (2.70 g, 15.0 mmol),
triphenylphosphine (0.52 g, 2.0 mmol), K.sub.2CO.sub.3 (4.14 g,
30.0 mmol) and palladium(II) acetate (0.009 g, 0.04 mmol) was added
DME (80 mL) and EtOH/H.sub.2O (1:1, 20 mL). Argon gas was bubbled
through the stirred reaction for 5 min. The reaction was stirred at
80.degree. C. under argon for 20 h. The reaction was cooled to room
temperature, concentrated, and H.sub.2O (60 mL) and dichloromethane
(80 mL) were added. The layers were separated and the aqueous was
extracted with dichloromethane (2.times.40 mL). The combined
organic extracts were dried with Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography using 10% ethyl acetate/hexanes as eluent to afford
1.69 g (65%) of I-81 as a white solid.
[0306] Synthesis of
(2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-pyridin-4-yl-methanone
(I-112). I-81 (0.26 g, 1.0 mmol), 4-nicotinyl chloride (0.18 g, 1.0
mmol), and dichloromethane (2 mL) were stirred for 5 min at room
temperature. AlCl.sub.3 (0.33 g, 2.47 mmol) was added in portions
over 30 min under argon, then argon gas was bubbled through the
reaction mixture for an additional 2 min. The vial was capped and
stirred at room temperature for 30 min, then at 50.degree. C. for 4
h. The reaction was cooled to room temperature and poured onto
cooled concentrated HCl (3 mL). The resulting aqueous mixture was
extracted with dichloromethane (2.times.30 mL), the aqueous layer
was separated, made basic through the addition of 50% aqueous NaOH,
and extracted with ethyl acetate (2.times.30 mL). The combined
organics were dried with Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography using 2% MeOH/dichloromethane as eluent to afford
0.02 g (6%) of I-112 as an off-white solid. 1H NMR (CDCl.sub.3, 400
MHz): 12.53 (s, 1H), 8.84 (dd, J=4.4, 1.6 Hz, 2H), 8.3-8.32 (m,
1H), 8.21-8.25 (m, 1H), 7.74-7.78 (m, 1H), 7.48-7.63 (m, 4H), 6.61
(d, J=8.8 Hz, 1H), 3.87 (s, 3H); MS (ESI-): 349.3 (M-1), LC-MS:
94.3%.
[0307] Synthesis of
6-methoxy-3'-nitro-3-pyridin-4-ylmethyl-biphenyl-2-ol (P-017). To a
cooled (0.degree. C.) and stirred solution of TFA (2.5 ml) under
N.sub.2 was added NaBH.sub.4 (0.12 g, 3.09 mmol) in portions over
20 min. The reaction mixture was warmed to 15.degree. C., and a
solution of I-112 (0.055 g, 0.15 mmol) in dichloromethane (2.5 mL),
was added over 30 min. The reaction was stirred at room temperature
for 20 h, poured onto ice-water (10 mL), made basic (pH 8-10)
through the addition of 50% aqueous NaOH, and extracted with ethyl
acetate (3.times.40 mL). The combined organic extracts were washed
with brine (60 mL), dried with Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography using 2% MeOH/dichloromethane as eluent to afford
0.039 g (74%) of P-017 as a foamy solid. 1H NMR (CDCl.sub.3, 400
MHz): 8.41 (d, J=4.4 Hz, 1H), 8.2-8.26 (m, 2H), 7.6-7.74 (m, 2H),
7.1-7.18 (m, 3H), 6.57 (d, J=8.0 Hz, 1H), 5.3 9 s, 1H), 3.96 (s,
2H), 3.73 (s, 3H); MS (ESI-): 335.1 (M-1), LC-MS: 92.5%.
Example 58
Preparation of P-019
##STR00117##
[0309] Synthesis of 2-iodo-3-methoxy-6-methyl-pyridine (I-95). To
2-iodo-6-methyl-pyridin-3-ol (1.0 g, 4.25 mmol) and K.sub.2CO.sub.3
(1.18 g, 8.51 mmol) in acetone (20 mL) was added MeI (0.91 g, 6.38
mmol). The reaction was stirred at 45.degree. C. under N.sub.2 for
20 h. The reaction was cooled to room temperature and concentrated.
The residue was purified by silica gel column chromatography using
dichloromethane to afford 1.04 g (98%) of I-95 as light yellow
solid.
[0310] Synthesis of 3-methoxy-6-methyl-2-(3-nitro-phenyl)-pyridine
(I-113). To I-95 (0.5 g, 2.0 mmol), 3-nitrophenylboronic acid (0.5
g, 3.06 mmol), triphenylphosphine (0.11 g, 0.4 mmol),
K.sub.2CO.sub.3 (0.83 g, 6.0 mmol) and palladium(II) acetate (0.045
g, 0.2 mmol) was added DME (16 mL), and EtOH-H.sub.2O (1:1, 4 mL).
Argon gas was bubbled through the stirred reaction for 5 min. The
reaction was stirred at 60.degree. C. under argon for 18 h. The
reaction was cooled to room temperature, concentrated, and H.sub.2O
and dichloromethane (40 mL each) were added. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.25 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 1:1
dichloromethane-hexanes then dichloromethane to afford 0.22 g (44%)
of I-113 as a light yellow solid.
[0311] Synthesis of
6-bromomethyl-3-methoxy-2-(3-nitro-phenyl)-pyridine (I-114). To
I-113 (0.21 g, 0.86 mmol) and NBS (0.17 g, 0.95 mmol) in CCl.sub.4
(10 mL) was added benzoylperoxide (0.02 g, 0.08 mmol). The reaction
was stirred at 60.degree. C. under N.sub.2 for 18 h. The reaction
was cooled to room temperature and concentrated. The residue was
dissolved in a mixture of dichloromethane and hexanes (1:1, 8 mL)
and purified by silica gel column chromatography using 1:1
dichloromethane:hexanes then dichloromethane to afford 0.15 g (55%)
of I-114 as a light brown solid.
[0312] Synthesis of
3-methoxy-2-(3-nitro-phenyl)-6-pyridin-4-ylmethyl-pyridine (P-019).
To I-114 (0.1 g, 0.31 mmol), 4-pyridylboronic acid (0.057 g, 0.46
mmol), Triphenylphosphine (0.008 g, 0.031 mmol), K.sub.3PO.sub.4
(0.13 g, 0.62 mmol) and palladium(II)acetate (0.004 g, 0.015 mmol)
was added DME (4 mL), and EtOH-H.sub.2O (1:1, 1 mL). Argon gas was
bubbled through the stirred reaction for 5 min. The reaction was
stirred at 80.degree. C. under argon for 18 h. The reaction was
cooled to room temperature, concentrated, and diluted with H.sub.2O
and dichloromethane (40 mL each). The organic layer was separated
and the aqueous was extracted with dichloromethane (2.times.25 mL).
The combined organic extracts were dried with Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by preparative
TLC using 3% MeOH in dichloromethane to afford 0.051 g (51%) of
P-019 as a light brown viscous liquid. 1H NMR (CDCl.sub.3, 400
MHz): 8.89 (dd, J=2.0, 1.6 Hz, 1H), 8.52-8.55 (m, 1H), 8.31-8.34
(m, 1H), 8.2-8.24 (m, 1H), 7.64-7.7 (m, 1H), 7.58 (t, J=8.0 Hz,
1H), 7.44-7.49 (m, 1H), 7.2-7.3 (m, 2H), 7.12 (d, J=8.4 Hz, 1H),
4.16 (s, 2H), 3.9 (s, 3H); MS (APCI+): 322.1 (M+1), LC-MS:
95.6%.
Example 59
Preparation of P-020
##STR00118##
[0314] Synthesis of Carbamic acid
3'-nitro-5-(6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-biphenyl-2-yl
ester (P-020). A reaction mixture of compound P-488 (97 mg, 0.3
mmol) and chlorosulfonyl isocyanate (64 mg, 0.45 mg) in
dichloromethane (15 ml) was stirred at rt under argon for 3 days.
The reaction mixture was diluted with water (40 ml) and washed with
dichloromethane (40 mL) and ethyl acetate (40 mL). Water was
removal under vacuum, the residue was stirred with acetone (40 mL),
and the resulting solid was filtered and washed with water (30 mL)
to give 20 mg of product P-020. The acetone mother liquid was
concentrated to 5 ml and the resulting solid was filtered to give
another 40 mg of product P-020.
[0315] Yield: 55% .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.92 (2H, s),
6.82 (1H, dd, J=9.6 and 2.4 Hz), 6.82 (1H, br), 7.15 (1H, br), 7.18
(1H, J=8.4 Hz), 7.32 (1H, dd, J=8 and 2 Hz), 7.41 (1H, d, J=10 Hz),
7.44 (1H, d, J=2 Hz), 7.75 (1H, dd, J=8 and 8 Hz), 7.88 (1H, m). MS
(ESI+): 367.5 (M+1) LC-MS: 92%.
Example 60
Preparation of P-021
##STR00119##
[0317] Synthesis of
6-benzo[1,3]dioxol-5-ylmethyl-3-methoxy-2-(3-nitro-phenyl)-pyridine
(P-021). To I-114 (0.1 g, 0.31 mmol),
3,4-methylenedioxyphenylboronic acid (0.077 g, 0.46 mmol),
Triphenylphosphine (0.008 g, 0.031 mmol), K.sub.3PO.sub.4 (0.13 g,
0.62 mmol) and palladium(II)acetate (0.004 g, 0.015 mmol) was added
DME (4 mL), and EtOH-H.sub.2O (1:1, 1 mL). Argon gas was bubbled
through the stirred reaction for 5 min. The reaction was stirred at
80.degree. C. under argon for 18 h. The reaction was cooled to room
temperature, concentrated, and diluted with H.sub.2O and
dichloromethane (40 mL each). The organic layer was separated and
the aqueous was extracted with dichloromethane (2.times.25 mL). The
combined organic extracts were dried with Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography using 1:1 dichloromethane-hexanes then
dichloromethane to afford 0.08 g (71%) of P-021 as a light brown
viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz): 8.89 (dd, J=2.0, 1.6
Hz, 1H), 8.34-8.37 (m, 1H), 8.2-8.24 (m, 1H), 7.59 (t, J=8.0 Hz,
1H), 7.22-7.28 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.78-6.8 (m, 2H),
5.93 (s, 2H), 4.09 (s, 2H), 3.88 (s, 3H) ppm. MS (APCI+): 365.1
(M+1),
[0318] LC-MS: 94.3%.
Example 61
Preparation of P-491
##STR00120##
[0320] Synthesis of
[5-methoxy-6-(3-nitro-phenyl)-pyridin-2-yl]-methanol (P-491). To
I-114 (0.06 g, 0.19 mmol), cyclopentanol (0.032 g, 0.37 mmol), and
CsCO.sub.3 (0.18 g, 0.56 mmol) was added DMF (2.5 mL). The vial was
capped and stirred at room temperature for 20 h. The reaction was
diluted with 1:1 ethyl acetate-H.sub.2O (60 mL). The organic layer
was separated and the aqueous was extracted with ethyl acetate
(2.times.20 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by preparative TLC using 2% MeOH in dichloromethane to
afford 0.015 g (31%) of P-491 as a viscous liquid. 1H NMR
(CDCl.sub.3, 400 MHz): 8.88 (dd, J=2.0, 1.6 Hz, 1H), 8.32-8.36 (m,
1H), 8.22-8.26 (m, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.39 (d, J=8.4 Hz,
1H), 7.29 (d, J=8.4 Hz, 1H), 4.78 (d, J=4.8 Hz, 2H), 3.94 (s, 3H),
3.37 (t, J=9.2 Hz, 1H); MS (APCI+): 261.1 (M+1), LC-MS: 100%.
Example 62
Preparation of P-023
##STR00121##
[0322] Synthesis of
6-(4-fluoro-benzyl)-3-methoxy-2-(3-nitro-phenyl)-pyridine (P-023).
To I-114 (0.05 g, 0.15 mmol), 4-fluorophenylboronic acid (1) (0.032
g, 0.23 mmol), triphenylphosphine (0.004 g, 0.015 mmol),
K.sub.3PO.sub.4 (0.066 g, 0.31 mmol), and palladium(II)acetate
(0.002 g, 0.008 mmol) was added DME (1.8 mL), and EtOH-H.sub.2O
(1:1, 0.6 mL). The reaction was stirred at 160.degree. C. for 5 min
using Biotage-60 Microwave Synthsizer. The reaction was cooled to
room temperature and concentrated. The residue was purified by
silica gel column chromatography using 1:1 dichloromethane-hexanes
then dichloromethane to afford 0.024 g (46%) of P-023 as a light
brown viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz): 8.89 (dd,
J=2.0, 1.6 Hz, 1H), 8.32-8.36 (m, 1H), 8.2-8.24 (m, 1H), 7.59 (t,
J=8.4 Hz, 1H), 7.22-7.3 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 6.96-7.04
(m, 2H), 4.14 (s, 2H), 3.88 (s, 3H); MS (APCI+): 339.1 (M+1),
LC-MS: 100%.
Example 63
Preparation of P-024
##STR00122##
[0324] Synthesis of
3-methoxy-2-(3-nitro-phenyl)-6-[1,2,4]triazol-1-ylmethyl-pyridine
(P-024). To I-114 (0.055 g, 0.17 mmol), 1H-[1,2,4]triazole (0.018
g, 0.26 mmol), and CsCO.sub.3 (0.17 g, 0.51 mmol) was added DMF (2
mL). The vial was capped and stirred at room temperature for 20 h.
The reaction was diluted with 1:1 ethyl acetate-H.sub.2O (60 mL).
The organic layer was separated and the aqueous was extracted with
ethyl acetate (2.times.20 mL). The combined organic extracts were
dried with Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by preparative TLC using 3% MeOH in
dichloromethane to afford 0.043 g (81%) of P-024 as an off white
solid. 1H NMR (CDCl.sub.3, 400 MHz): 8.87 (dd, J=2.0, 1.6 Hz, 1H),
8.22-8.3 (m, 3H), 7.99 (s, 1H), 7.6 (t, J=8.0 Hz, 1H), 7.34 (d,
J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.5 (s, 2H), 3.92 (s, 3H);
MS (APCI+): 312.1 (M+1),
[0325] LC-MS: 100%.
Example 64
Preparation of P-026
##STR00123##
[0327] Synthesis of
4-[5-methoxy-6-(3-nitro-phenyl)-pyridin-2-ylmethyl]-morpholine
(P-026). To I-114 (0.06 g, 0.19 mmol), morpholine (0.032 g, 0.37
mmol), and Cs.sub.2CO.sub.3 (0.18 g, 0.56 mmol) was added DMF (2.5
mL). The vial was capped and stirred at room temperature for 20 h.
The reaction was diluted with 1:1 ethyl acetate-H.sub.2O (60 mL).
The organic layer was separated and the aqueous was extracted with
ethyl acetate (2.times.20 mL). The combined organic extracts were
dried with Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by silica gel column chromatography using 5%
methanol in dichloromethane to afford 0.051 g (80%) of P-026 as a
viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz): 8.86 (dd, J=2.4, 1.6
Hz, 1H), 8.3-8.34 (m, 1H), 8.2-8.24 (m, 1H), 7.59 (t, J=8.4 Hz,
1H), 7.45 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 3.91 (s, 3H),
3.75 (t, J=4.4 Hz, 4H), 3.71 (s, 2H), 2.56 (t, J=4.4 Hz, 4H); MS
(APCI+): 330.9 (M+1), LC-MS: 97%.
Example 65
Preparation of P-030
##STR00124##
[0329] Synthesis of
6-isopropoxymethyl-3-methoxy-2-(3-nitro-phenyl)-pyridine (P-030).
To a cooled (0.degree. C.) and stirred suspension of NaH (0.016 g,
0.39 mmol) in DMF (2.0 mL) was added a solution of isopropanol
(0.033 g, 0.56 mmol) in DMF (0.5 ml). The reaction mixture was
slowly warmed to room temperature and stirred for 2 h. After
cooling to (0.degree. C.), a solution of I-114 (0.06 g, 0.19 mmol)
in DMF (1.0 mL) was added over 5 min. The reaction mixture was
slowly warmed to room temperature and stirred for 20 h. The
reaction was poured on to crushed ice-water and extracted with
ethyl acetate (2.times.40 mL). The combined organic extracts were
dried with Na.sub.2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using dichloromethane
to afford 0.027 g (47%) of P-030 as a viscous liquid. 1H NMR
(CDCl.sub.3, 400 MHz): 8.86 (dd, J=2.0, 1.6 Hz, 1H), 8.33 (dt,
J=8.0, 1.2 Hz, 1H), 8.2-8.25 (m, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.49
(d, J=8.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 4.66 (s, 2H), 3.91 (s,
3H), 3.72-3.81 (m, 1H), 1.27 (d, J=6.0 Hz, 6H); MS (APCI+): 303.1
(M+1), LC-MS: 100%.
Example 66
Preparation of P-031
##STR00125##
[0331] Synthesis of
1-[5-methoxy-6-(3-nitro-phenyl)-pyridin-2-ylmethyl]-pyrrolidin-2-one
(P-031). To I-114 (0.08 g, 0.25 mmol), pyrrolidone (0.042 g, 0.5
mmol), and Cs.sub.2CO.sub.3 (0.24 g, 0.74 mmol) was added DMF (3
mL). The vial was capped and stirred at room temperature for 20 h.
The reaction was diluted with 1:1 ethyl acetate-H.sub.2O (60 mL).
The organic layer was separated and the aqueous was extracted with
ethyl acetate (2.times.20 mL). The combined organic extracts were
dried with Na.sub.2SO4, filtered, and concentrated. The residue was
purified by prep TLC using 5% methanol in dichloromethane to afford
0.054 g (78%) of P-031 as a viscous liquid. 1H NMR (CDCl.sub.3, 400
MHz): 8.88-8.9 (m, 1H), 8.36 (dt, J=8.0, 1.2 Hz, 1H), 8.2-8.25 (m,
1H), 7.6 (t, J=8.0 Hz, 1H), 7.26-7.34 (m, 2H), 4.61 (s, 2H), 3.92
(s, 3H), 3.49 (t, J=7.2 Hz, 2H), 2.47 (t, J=8.02 Hz, 2H), 2.0-2.2
(m, 2H); MS (APCI+): 328.8 (M+1), LC-MS: 94.0%.
Example 67
Preparation of P-033
##STR00126##
[0333] Synthesis of
1-[5-methoxy-6-(3-nitro-phenyl)-pyridin-2-ylmethyl]-imidazolidin-2-one
(P-033). To I-114 (0.08 g, 0.25 mmol), imidazol-2-one (0.053 g,
0.62 mmol), and K.sub.2CO.sub.3 (0.086 g, 0.62 mmol) was added DMF
(3 mL). The vial was capped and heated at 80.degree. C. for 20 h.
The reaction was diluted with 1:1 ethyl acetate-H.sub.2O (60 mL).
The organic layer was separated and the aqueous was extracted with
ethyl acetate (2.times.20 mL). The combined organic extracts were
dried with Na.sub.2SO4, filtered, and concentrated. The residue was
purified by prep TLC using 5% methanol in dichloromethane to afford
0.015 g (18%) of P-033 as an off white foamy solid. 1H NMR
(CDCl.sub.3, 400 MHz): 8.88-8.95 (m, 1H), 8.36 (dt, J=7.6, 1.6 Hz,
1H), 8.2-8.24 (m, 1H), 7.6 (t, J=8.4 Hz, 1H), 7.35 (s, 2H), 4.55
(s, 1H), 4.53 (s, 2H), 3.92 (s, 3H), 3.44-3.58 (m, 4H); MS (APCI+):
329.0 (M+1), LC-MS: 90.7%.
Example 68
Preparation of P-038
##STR00127##
[0335] Synthesis of
6-cyclopentyloxymethyl-3-methoxy-2-(3-nitro-phenyl)-pyridine
(P-038). To a cooled (0.degree. C.) and stirred suspension of NaH
(0.016 g, 0.39 mmol) in DMF (2.0 mL) was added a solution of
cyclopentanol (0.048 g, 0.56 mmol) in DMF (0.5 ml). The reaction
mixture was slowly warmed to room temperature and stirred for 2 h.
After cooling to 0.degree. C., a solution of I-114 (0.06 g, 0.19
mmol) in DMF (1.0 mL) was added over 5 min. The reaction mixture
was slowly warmed to room temperature and stirred for 20 h. The
reaction was poured on to crushed ice-water and extracted with
ethyl acetate (2.times.40 mL). The combined organic extracts were
dried with Na.sub.2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using dichloromethane
to afford 0.047 g (77%) of P-038 as a viscous liquid. 1H NMR
(CDCl.sub.3, 400 MHz): 8.86 (dd, J=2.4, 1.6 Hz, 1H), 8.3-8.34 (m,
1H), 8.2-8.24 (m, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.4 Hz,
1H), 7.36 (d, J=8.4 Hz, 1H), 4.63 (s, 2H), 4.07-4.12 (m, 1H), 3.91
(s, 3H), 1.7-1.84 (m, 8H); MS (APCI+): 329.7 (M+1), LC-MS:
96.1%.
Example 69
Preparation of P-064
##STR00128##
[0337] Synthesis of 2-bromo-6-methyl-pyridin-3-ol (I-115). To
6-methyl-pyridin-3-ol (5.0 g, 45.82 mmol) in pyridine (15 mL) was
added bromine (3.66 g, 22.91 mmol). The reaction was stirred at
room temperature under N.sub.2 for 20 h. The crude reaction mixture
was poured on to crushed ice-water (300 mL) and stirred for 3 h.
The reaction was extracted with ethyl acetate (5.times.100 mL),
washed with brine, dried with Na.sub.2SO.sub.4, filtered, and
concentrated to afford 6.3 g (738%) of I-115 as light yellow
solid.
[0338] Synthesis of 2-bromo-3-methoxy-6-methyl-pyridine (I-116). To
crude I-115 (6.0 g, 31.91 mmol) and K.sub.2CO.sub.3 (8.82 g, 63.82
mmol) in acetone (100 mL) was added methyl iodide (6.79 g, 479.87
mmol). The reaction was stirred at 45.degree. C. under N.sub.2 for
20 h. The reaction was cooled to room temperature, filtered and
concentrated. The residue was purified by silica gel column
chromatography using 1:1 dichloromethane-hexanes to afford 2.34 g
(36%) of I-116 as an off-white solid.
[0339] Synthesis of
3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine (I-117).
To I-116 (1.2 g, 5.94 mmol), 3-trifluoromethylphenylboronic acid
(1.69 g, 8.91 mmol), Triphenylphosphine (0.31 g, 1.19 mmol),
K.sub.2CO.sub.3 (2.46 g, 17.82 mmol) and palladium(II)acetate (0.13
g, 0.59 mmol) was added DME (15 mL) and EtOH-H.sub.2O (1:1, 6 mL).
Argon gas was bubbled through the stirred reaction for 5 min. The
reaction was stirred at 80.degree. C. under argon for 20 h. The
reaction was cooled to room temperature, concentrated, and H.sub.2O
and dichloromethane (40 mL each) were added. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.25 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 1:1
dichloromethane-hexanes then dichloromethane to afford 1.36 g (86%)
of I-117 as a light yellow solid.
[0340] Synthesis of
6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine
(I-118). To I-117 (1.3 g, 4.86 mmol) and NBS (1.04 g, 5.83 mmol) in
CCl.sub.4 (25 mL) was added benzoyl peroxide (0.12 g, 0.49 mmol).
The reaction was stirred at 80.degree. C. under N.sub.2 for 20 h.
The reaction was cooled to room temperature and concentrated. The
residue was dissolved in a mixture of dichloromethane and hexanes
(1:1, 8 mL) and purified by silica gel column chromatography using
1:1 dichloromethane-hexanes to afford 0.74 g (44%) of I-118 as an
off-white solid.
[0341] Synthesis of
3-methoxy-6-[1,2,4]triazol-1-ylmethyl-2-(3-trifluoromethyl-phenyl)-pyridi-
ne (P-064). To I-118 (0.2 g, 0.58 mmol), 1H-[1,2,4]triazole (0.048
g, 0.26 mmol), and Cs.sub.2CO.sub.3 (0.56 g, 1.73 mmol) was added
DMF (4 mL). The vial was capped and stirred at room temperature for
20 h. The reaction was diluted with crushed ice-H.sub.2O (60 mL),
stirred for 5 h, filtered, and dried to afford 0.14 g (73%) of
P-064 as an off white solid. 1H NMR (CDCl.sub.3, 400 MHz): 8.28 (s,
1H), 8.21 9 s, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.65 (d,
J=8.0 Hz, 1H), 7.52-7.59 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.22 (d,
J=8.4 Hz, 1H), 5.49 (s, 2H), 3.89 (s, 3H) ppm. MS (APCI+): 335.1
(M+1), LC-MS: 91.4%.
##STR00129##
Example 70
Preparation of P-492
[0342] Synthesis of
1-(3-Bromo-4-methoxy-benzyl)-piperidine-2,6-dione (I-119). A
suspension of sodium hydride (56.0 mg, 2.34 mmol) in anhydrous DMF
(12 mL) was stirred under nitrogen for 5 min. To the suspension was
added piperidine-2,6-dione (264 mg, 2.34 mmol) and the reaction was
stirred under nitrogen for 5 additional minutes. After gas
evolution ceased, I-109 (500 mg, 2.12 mmol) was added and the
reaction stirred for 24 h under nitrogen at ambient temperature.
The reaction was diluted with saturated aqueous ammonium chloride
(100 mL) and the suspension was extracted with ethyl acetate (100
mL). The purple organic extract was washed with water (3.times.50
mL) water, saturated aqueous ammonium chloride (3.times.50 mL),
brine (50 mL) dried over anhydrous sodium sulfate, and the solvent
removed under vacuum to afford 476.1 mg of I-119 as a purple powder
in 72% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.59 (d, J=2.40 Hz,
1H), 7.33 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.80 (d, J=8.40 Hz, 1H), 4.85
(s, 2H), 3.86 (s, 3H), 2.67 (t, J=6.6 Hz, 4H), 1.95-1.92 (m,
2H).
[0343] Synthesis of
1-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-piperidine-2,6-dione
(P-492). A solution of I-119 (200 mg, 0641 mmol) and
benzo[1,3]dioxol-5-yl-boronic acid (117 mg, 0.705 mmol) in
1,4-dioxane were degassed with a nitrogen stream for 10 min.
Subsequently, triphenylphosphine (33.5 mg, 0.128 mmol), solid
potassium carbonate (265 mg, 1.92 mmol) and a mixture of ethanol
and water (1:1, 1 mL) was added, and the reaction was stirred under
nitrogen for 10 min. To the reaction was added
palladium(II)acetate, and the reaction heated to 80.degree. C. with
stirring overnight. The solvent was removed under vacuum and the
residue was suspended in saturated aqueous ammonium chloride (50
mL), and the aqueous slurry was extracted with ethyl acetate
(2.times.50 mL). The combined extracts were washed with water
(3.times.50 mL) and brine (30 mL), dried over sodium sulfate,
decolorized using activated charcoal, and the solvent removed under
vacuum. The residue was purified by chromatography on flash silica
gel eluting with 0-10% acetone in dichloromethane followed by
trituration with diethyl ether (10 mL) to afford 50.9 mg of P-492
as an off white solid in 22% yield). .sup.1H NMR (CDCl.sub.3 400
MHz). 7.29 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 6.95 (dd, J=8.1 Hz,
J=1.7 Hz, 1H), 6.86 (t, J=8.2 Hz, 2H), 5.98 (s, 2H), 4.92 (s, 2H),
3.78 (s, 3H), 2.66 (t, J=6.6 Hz, 4H), 1.93 (m, 2H). LCMS=100.0%
purity. MS (APCI-) 350.0 (M-H).
Example 71
Preparation of P-070
##STR00130##
[0345] Synthesis of
(S)-1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-3-ol
(P-070). Into a 20 mL vial with stir bar was added I-114 (0.30 g,
0.93 mmol), (S)-pyrrolidin-3-ol (54 mg, 0.62 mmol),
Cs.sub.2CO.sub.3 (0.20 g, 0.62 mmol), and DMF (2 mL). The reaction
was stirred for 4 days at room temperature and then 10 mL water was
added. The product was extracted with ethyl acetate (3.times.10 mL)
and the organics were combined and concentrated. The residue was
purified by flash column chromatography using 0-5%
methanol/dichloromethane to afford 27.7 mg (14%) of P-070 as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.75 (m, 1H)
2.14-2.27 (m, 1H) 2.29-2.41 (m, 1H) 2.56 (dd, J=10.1, 5.1 Hz, 1H)
2.68 (d, J=9.8 Hz, 1H) 2.88 (td, J=8.6, 5.3 Hz, 1H) 3.63 (s, 2H)
3.83 (s, 3H) 4.29-4.43 (m, 1H) 6.96 (d, J=8.3 Hz, 1H) 7.28-7.38 (m,
2H) 7.56 (t, J=8.0 Hz, 1H) 7.86 (d, J=7.7 Hz, 1H) 8.17 (dd, J=8.2,
1.9 Hz, 1H) 8.42 (s, 1H) ppm. LC/MS=98.5%, 329.1 (APCI+)
Example 72
Preparation of P-071
##STR00131##
[0347] Synthesis of
(R)-1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-3-ol
(P-071). The same procedure was used as described for P-070 except
using (R)-Pyrrolidin-3-ol. P-071 was obtained 44.2 mg (22%) as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 1.75 (m, 1H)
2.13-2.28 (m, 1H) 2.29-2.41 (m, 1H) 2.56 (dd, J=10.0, 5.0 Hz, 1H)
2.69 (d, J=9.8 Hz, 1H) 2.88 (td, J=8.6, 5.2 Hz, 1H) 3.63 (s, 2H)
3.83 (s, 3H) 4.29-4.41 (m, 1H) 6.96 (d, J=8.3 Hz, 1H) 7.28-7.38 (m,
2H) 7.56 (t, J=8.0 Hz, 1H) 7.86 (d, J=7.8 Hz, 1H) 8.17 (dd, J=8.2,
1.3 Hz, 1H) 8.42 (t, J=1.7 Hz, 1H) ppm. LC/MS=99.0%, 329.1
(APCI+)
Example 73
Preparation of P-493
##STR00132##
[0349] Synthesis of
[(R)-1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-yl]-methanol
(P-493). The same procedure was used as described for P-070 except
using (R)-1-Pyrrolidin-2-yl-methanol to obtain P-493 (110 mg, 52%).
.sup.1H NMR (400 MHz, CDCl.sub.3) 1.63-1.77 (m, 2H) 1.78-1.89 (m,
1H) 1.89-2.03 (m, 1H) 2.28-2.37 (m, 1H) 2.74 (m, 1H) 3.01 (ddd,
J=9.1, 6.0, 3.4 Hz, 1H) 3.37 (d, J=13.0 Hz, 1H) 3.44 (dd, J=10.7,
2.0 Hz, 1H) 3.66 (dd, J=10.7, 3.5 Hz, 1H) 3.83 (s, 3H) 3.95 (d,
J=13.0 Hz, 1H) 6.97 (d, J=8.3 Hz, 1H) 7.25 (d, J=2.0 Hz, 1H) 7.32
(dd, J=8.3, 2.0 Hz, 1H) 7.56 (t, J=8.0 Hz, 1H) 7.85 (d, J=7.8 Hz,
1H) 8.18 (dd, J=8.3, 1.3 Hz, 1H) 8.41 (t, J=1.8 Hz, 1H) ppm.
LC/MS=98.9%, 343.1 (APCI+)
Example 74
Preparation of P-072
##STR00133##
[0351] Synthesis of
[(S)-1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-yl]-methanol
(P-072). The same procedure was used as described for P-070 except
using (R)-1-Pyrrolidin-2-yl-methanol to obtain P-072 (68 mg, 32%).
.sup.1H NMR (400 MHz, CDCl.sub.3) 1.63-1.78 (m, 2H) 1.84 (td,
J=13.2, 5.6 Hz, 1H) 1.89-2.02 (m, 1H) 2.33 (q, J=9.0 Hz, 1H)
2.69-2.82 (m, 1H) 2.95-3.07 (m, 1H) 3.38 (d, J=12.9 Hz, 1H) 3.44
(d, J=10.6 Hz, 1H) 3.66 (dd, J=10.7, 3.4 Hz, 1H) 3.83 (s, 3H) 3.96
(d, J=13.0 Hz, 1H) 6.97 (d, J=8.3 Hz, 1H) 7.24-7.26 (m, 1H)
7.29-7.36 (m, 1H) 7.56 (t, J=8.0 Hz, 1H) 7.85 (d, J=7.8 Hz, 1H)
8.18 (dd, J=8.2, 1.3 Hz, 1H) 8.41 (t, J=1.7 Hz, 1H) ppm.
LC/MS=98.8%, 343.1 (APCI+)
Example 75
Preparation of P-076
##STR00134##
[0353] Synthesis of
3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-oxazolidin-2-one
(P-076). Into a dry 100 mL round bottom flask with stir bar was
added oxazolidinone (0.15 g, 1.74 mmol) and dry THF (8 mL). The
solution was cooled to 0.degree. C. and NaH (83 mg, 2.09 mmol) was
added. The suspension was stirred for 10 minutes at 0.degree. C.
and 20 minutes at room temperature, and then cooled to 0.degree. C.
I-114 (0.56 g, 1.74 mmol) in 2 mL dry THF was added to the above
mixture and the reaction was stirred for 16 hours at room
temperature. 10 mL of aqueous saturated NH.sub.4Cl was added and
the THF was removed under reduced pressure. An additional 10 mL of
water was added and the product was extracted with ethyl acetate
(3.times.10 mL). The combined organics were dried over sodium
sulfate, concentrated, and purified by flash column chromatography
using 35%-75% ethyl acetate/hexanes to obtain 94 mg (16%) of P-076
as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.47 (t, J=8.1 Hz, 2H)
3.84 (s, 3H) 4.32 (t, J=7.8 Hz, 2H) 4.44 (s, 2H) 7.00 (d, J=8.4 Hz,
1H) 7.26 (s, 1H) 7.33 (dd, J=8.5, 2.2 Hz, 1H) 7.57 (t, J=8.0 Hz,
1H) 7.83 (d, J=7.7 Hz, 1H) 8.19 (dd, J=8.2, 1.3 Hz, 1H) 8.40 (t,
J=1.8 Hz, 1H) ppm. LC/MS=98.0%, 328.1 (APCI-)
Example 76
Preparation of P-001
##STR00135## ##STR00136##
[0355] Synthesis of 2-Methoxy-5-methyl-3'-nitro-biphenyl (I-69): A
reaction mixture of 2-methoxy-5-methylphenyl boronic acid (1.65 g,
10 mmol), 3-nitro-iodobenzen (2.49 g, 10 mmol), K.sub.2CO.sub.3
(2.76 g, 20 mmol), palladium(II)acetate (112 mg, 0.5 mmol) in
methanol (75 ml) and water (15 ml) was stirred at rt overnight. The
reaction mixture was diluted with ethyl acetate (300 ml) washed
with diluted Na.sub.2S.sub.2O.sub.7 aq., water, brine, and dried
over Na.sub.2SO.sub.4. After removal of solvent, 2.5 g (100%) of
I-69 was obtained.
[0356] Synthesis of 5-Bromomethyl-2-methoxy-3'-nitro-biphenyl
(I-70): To a mixture of compound I-69 (2.43 g, 10 mmol) in carbon
tetrachloride (150 mL), was added bromine (1.76 g, 11 mmol) at rt.
The reaction mixture was stirred at 80.degree. C. under a sun lamp
for 1 hr. After removal of solvent, the residue was washed with
diethylether (15 mL)/Hexane (15 mL) to give 2.1 g (65%) of compound
I-70.
[0357] Synthesis of 5-(4-Fluoro-benzyl)-2-methoxy-3'-nitro-biphenyl
(P-001): A reaction mixture of I-70 (300 mg, 0.93 mmol),
4-fluorophenyl-boronic acid (196 mg, 1.4 mmol), triphenylphosphine
(52 mg, 0.2 mmol), K.sub.3PO.sub.4 (394 mg, 1.86 mmol),
palladium(II)acetate (22 mg, 0.1 mmol) in DME (5 ml), ethanol (0.5
ml) and water (0.5 ml) was stirred at 80.degree. C. overnight under
argon. The reaction mixture was diluted with diethylether (40 ml),
washed with water, brine, and dried over Na.sub.2SO.sub.4. After
removal of solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/Hexane as eluent to give 200 mg
(60%) of P-001 .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.77 (s, 3H),
3.94 (s, 2H), 7.05-7.14 (m, 3H), 7.22-7.34 (m, 4H), 7.65-7.78 (m,
1H), 7.92 (d, J=7.8 Hz, 1H), 8.18 (dd, J=8.2, 1.34 Hz, 1H), 8.28
(t, J=1.8 Hz, 1H) ppm. LCMS=97.4% purity TSI(+)=308.6 (M-29).
Example 77
Preparation of P-494
[0358] Synthesis of 5-(4-Fluoro-benzyl)-3'-nitro-biphenyl-2-ol
(P-494): To a mixture of compound P-001 (200 mg, 0.59 mmol) in
dichloromethane (15 ml) was added BBr.sub.3 (1M in dichloromethane,
1.78 ml, 1.78 mmol) at -78.degree. C. under N.sub.2. The reaction
mixture was stirred at -78.degree. C. to rt overnight. The reaction
mixture was diluted with water and extracted with dichloromethane
(2.times.20 ml). The dichloromethane layer was washed with water
(2.times.40 ml), brine, and dried over Na.sub.2SO.sub.4. After
removal of solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/Hexane as eluent to give 180 mg
(94%) of P-494. .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.94 (2H, s),
4.83 (1H, s), 6.87 (1H, d, J=8 Hz), 6.99 (2H, m), 7.07-7.17 (4H,
m), 7.60 (1H, dd, J=8 and 8 Hz), 7.85 (1H, m), 8.21 (1H, m), 8.40
(1H, m). MS (APCI-): 322.1 (M-1) LC-MS: 97%.
Example 78
Preparation of P-067
[0359] Synthesis of (7)
2-Difluoromethoxy-5-(4-fluoro-benzyl)-3'-nitro-biphenyl (P-067): To
a mixture of compound P-494 (100 mg, 0.3 mmol) and NaOH (40 mg, 1
mmol) in DMF (6 ml), was added sodium chlorodifluoroacetate (228
mg, 1.5 mmol). The reaction mixture was stirred at 50.degree. C.
overnight. After removal of solvent, the residue was diluted with
water (40 mL) and extracted with dichloromethane (2.times.30 mL).
The combined organic extracts were washed with water (4.times.30
ml), brine, and dried over Na.sub.2SO.sub.4. After removal of
solvent, the residue was purified by silica gel column
chromatography with dichloromethane/Hexane as eluent to give 45 mg
(40%) of P-067. .sup.1H-NMR (400 MHz, CDCl.sub.3) 4.00 (2H, s),
6.37 (1H, t, J=7.3 Hz), 7.00 (2H, m), 7.15 (2H, m), 7.22 (1H, m),
7.59 (1H, dd, J=8 and 8 Hz), 7.80 (1H, m), 8.22 (1H, m), 8.32 (1H,
m) ppm. MS (APCI-): 373.1 (M-1) LC-MS: 98%.
Example 79
Preparation of P-022
##STR00137##
[0361] Synthesis of
2'-Methoxy-5'-[1,2,4]triazol-1-ylmethyl-biphenyl-3-carboxylic acid
methyl ester (P-022). A nitrogen stream was bubbled through a
solution of I-110 (810 mg, 3.02 mmol) and
3-methoxycarbonylphenylboronic acid (816 mg, 4.53 mmol) in
1,4-dioxane (50 mL) for 45 min. To this solution was added
bis(triphenylphosphine)palladium(II) dichloride (106 mg, 0.151
mmol) and 1 M aqueous sodium carbonate (9 mL) under nitrogen. The
reaction was heated to 85.degree. C. overnight. The reaction was
cooled to room temperature and diluted with ethyl acetate (150 mL).
The organic solution was washed with water (5.times.100 mL), brine
(100 mL), dried over sodium sulfate, and the solvent removed under
vacuum. The residue was purified by flash silica gel column
chromatography eluting with 0-2% methanol in dichloromethane
followed by flash silica gel column chromatography with 50% ethyl
acetate in hexanes, and the residue wash dissolved in ethyl acetate
(10 mL). The organic solution was washed with water (2.times.10 mL)
and the wash extracted with ethyl acetate (2.times.10 mL). The
combined ethyl acetate extracts were washed with water (3.times.10
mL), dried over sodium sulfate, and the solvent removed under
vacuum. The product was recrystallized by dissolving in hot diethyl
ether (2 mL), adding hexanes (3 mL), and removing the diethyl ether
under a nitrogen stream. The product was filtered and washed with
hexanes (3.times.3 mL) to give P-022 (233.6 mg, 23.9% yield) as a
white solid.
[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) d: 8.15 (t, J=1.60 Hz,
1H), 8.066 (s, 1H), 8.019-7.999 (m, 1H), 7.97 (s, 1H), 7.69-7.67
(m, 1H), 7.47 (t, J=7.60 Hz, 1H), 7.29-7.26 (m, 2H), 6.989 (d,
J=9.20, 1H), 5.33 (s, 2H), 3.93 (s, 3H), 3.82 (s, 3H) ppm.
[0363] LCMS=99.0% purity. MS (APCI+)=324.1 (M+1).
Example 80
Preparation of P-044
##STR00138##
[0365] Synthesis of
1-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-1H-[1,2,4]triazole
(P-044). A nitrogen stream was bubbled through a solution of I-110
(500 mg, 1.87 mmol) and benzo[1,3]dioxol-5-yl-boronic acid (345 mg,
2.08 mmol) in DMF (40 mL) for 10 min. To the solution was added
bis(dibenzylideneacetone)palladium(0) (120 mg, 0.208 mmol),
triphenylphosphine (109 mg, 0.416 mmol), and 1 M aqueous sodium
carbonate (6.25 mL) under nitrogen. The reaction was heated to
80.degree. C. under a nitrogen atmosphere and stirred for 16 h.
Approximately three quarters of the solvent was removed under
vacuum and the remaining suspension was diluted with ethyl acetate
(50 mL). The organic solution was washed with water (3.times.50
mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL),
dried over sodium sulfate, and the solvent removed under reduced
pressure. The product was twice purified by flash silica gel column
chromatography eluting with 0-1% methanol in dichloromethane,
followed by 0-25% acetone in dichloromethane to give P-044 (296.1
mg, 51% yield) as a yellow oil. 1H NMR (400 MHz, CDCl.sub.3) 8.05
(s, 1H), 7.96 (s, 1H), 7.24-7.21 (m, 2H), 7.01 (d, J=2.0 Hz, 1H),
6.98-6.89 (2H), 6.85 (d, J=8.0 Hz, 1H), 5.99 (s, 2H), 5.31 (s, 2H),
3.82 (s, 3H) ppm. LCMS=100.0% purity. MS (APCI+)=310.1 (M+1). HPLC
(220 nm); 97.7%. [Water and acetonitrile with 0.05% trifluoroacetic
acid, Column: Symmetry C18 (250.times.4.6 mm, 5 um), Gradient,
Flow=1.0 ml/min, Wash=CAN, Inj vol.=10 ul, Retention time=21.2
min]
Example 81
Preparation of P-058
##STR00139##
[0367] Synthesis of
1-(3'-Fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole
(P-058). A nitrogen stream was bubbled through a solution of I-110
(300 mg, 1.12 mmol) and 3-fluorophenylboronic acid (172 mg, 1.23
mmol) in 1,2-dimethoxyethane (5 mL) for 10 min. To this solution
was added triphenylphosphine (58.8 mg, 0.112 mmol), solid potassium
carbonate (463 mg, 3.36 mmol), ethanol (1 mL), water (1 mL), and
palladium(II)acetate (25.1 mg, 0.112 mmol) under nitrogen. The
reaction was stirred at 100.degree. C. for 18 h. The solvent was
removed under vacuum and the residue taken up in ethyl acetate (50
mL). The organic solution was washed with saturated aqueous
ammonium chloride (50 mL), the residual palladium was filtered, and
the organic extract was washed with water (2.times.50 mL), brine
(50 mL), dried over sodium sulfate, and removed under vacuum. The
crude product was purified by flash silica gel column
chromatography eluting with 5% methanol in dichloromethane,
followed by a second flash silica gel column eluting with 5%
acetone in dichloromethane. The solid thus obtained was
recrystallized in diethyl ether (5 mL) and hexanes (10 mL),
filtered, and washed with hexanes (5 mL) to give P-058 (65 mg; 21%
yield) as a white powder. .sup.1H NMR (400 MHz CDCl.sub.3): .delta.
8.07 (s, 1H), 7.97 (s, 1H), 7.36 (dt, J=8.0 Hz, J=6.0 Hz, 1H), 7.25
(m, 2H), 7.03 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 5.32 (s, 2H), 3.83
(s, 3H) ppm. LCMS=100.0% purity. MS: (APCI+)=284.1 (M+1).
Example 82
Preparation of P-081
##STR00140##
[0369] Synthesis of
2'-Methoxy-5'-[1,2,4]triazol-1-ylmethyl-biphenyl-3-carbonitrile
(P-081). A nitrogen stream was bubbled through a solution of I-110
(200 mg, 0.746 mmol) and 3-cyanophenylboronic acid (121 mg, 0.821
mmol) in 1,2-dimethoxyethane (5 mL) for 15 min. To the solution was
added ethanol (0.5 mL) and water (0.5 mL) and degassing was
continued for 5 min. To the solution was added solid potassium
carbonate (309 mg, 2.24 mmol), triphenylphosphine (39.1 mg, 0.149
mmol), and palladium(II)acetate (16.7 mg, 0.0746 mmol)
simultaneously under nitrogen. The reaction was heated to
80.degree. C. and stirred with heating overnight. The reaction was
cooled to room temperature and the solvent removed under vacuum.
The residue was diluted with ethyl acetate (30 mL), washed with
water (2.times.30 mL), the spent catalyst was filtered off, and the
combined aqueous layers extracted with ethyl acetate (30 mL). The
combined organic extracts were washed with saturated aqueous
ammonium chloride (50 mL), water (2.times.50 mL), brine (50 mL),
dried over sodium sulfate, and the solvent removed under vacuum.
The residue was purified by flash silica gel column chromatography
eluting with 3-15% acetone in dichloromethane to give a white
solid, which was triturated with diethyl ether (10 mL), filtered
and washed with diethyl ether (2.times.5 mL) to give P-081 (112.8
mg, 52% yield) as a white solid.
[0370] 1H NMR (400 MHz CDCl.sub.3) 8.08 (s, 1H), 7.97 (s, 1H), 7.81
(t, J=1.8 Hz, 1H), 7.69 (dt, J=8.0 Hz, 1.5, 1H), 7.61 (dt, J=8.0
Hz, 1.3, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.31 (dd, J=8.6, 2.2 Hz, 1H),
7.22 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.33 (s, 2H), 3.83
(s, 3H) ppm. MS (ESI+)=291.4 (M+1).
Example 83
Preparation of P-082
##STR00141##
[0372] Synthesis of
1-(2'-Methoxy-5'-[1,2,4]triazol-1-ylmethyl-biphenyl-3-yl)-ethanone
(P-082). A nitrogen stream was bubbled through a solution of I-110
(200 mg, 0.746 mmol) and 3-acetylphenlyboronic acid (135 mg, 0.821
mmol) in 1,2-dimethoxyethane (5 mL) for 20 min. To the solution was
added ethanol (0.5 mL) and water (0.5 mL) and degassing was
continued for 5 min. To the solution was added solid potassium
carbonate (309 mg, 2.24 mmol), triphenylphosphine (39.1 mg, 0.149
mmol) and palladium(II)acetate (16.7 mg, 0.0746 mmol)
simultaneously under nitrogen. The reaction was heated to
80.degree. C. and stirred with heating overnight. The reaction was
cooled to room temperature and the solvent removed under vacuum.
The residue was diluted with ethyl acetate (50 mL). The organic
solution was washed with water (3.times.50 mL), saturated aqueous
ammonium chloride (50 mL), brine (50 mL), dried over sodium
sulfate, decolorized in activated carbon, and the solvent removed
under vacuum. The residue was purified by flash silica gel column
chromatography eluting with 3-15% acetone in dichloromethane
followed by silica gel preparatory plate eluting with 10% acetone
in dichloromethane to give P-082 (109.1 mg, 48% yield) as a tacky
gum. 1H NMR (400 MHz, CDCl.sub.3) 8.08-8.07 (m, 2H), 7.97 (s, 1H),
7.94-7.92 (m, 1H), 7.70-7.68 (m, 1H), 7.50 (t, J=7.8 Hz, 1H),
7.30-7.26 (m, 2H), 67.00 (d, J=8.0 Hz, 1H), 5.33 (s, 2H), 3.83 (s,
3H), 2.63 (s, 3H) ppm. LCMS=99.5% purity.
[0373] MS (APCI+)=308.1 (M+1).
Example 84
Preparation of P-084
##STR00142##
[0375] Synthesis of
1-(6-Methoxy-3'-trifluoromethoxy-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole
(P-084). P-084 was synthesized from I-110 (200 mg, 0.746 mmol) and
3-trifluoromethoxyphenylboronic acid (169 mg, 0.821 mmol) by the
same reaction conditions that were used for P-081. After removal of
the solvent under vacuum, the residue was diluted with ethyl
acetate (30 mL) and washed with water (30 mL). The aqueous wash was
extracted with ethyl acetate (30 mL), and the combined organic
extracts were washed with water (2.times.50 mL), saturated aqueous
ammonium chloride (50 mL), brine (50 mL), dried over sodium
sulfate, decolorized over activated charcoal, and the solvent
removed under vacuum. The residue was purified by flash silica gel
column chromatography eluting with 5% acetone in dichloromethane to
give P-084 as a yellow oil (187.3 mg, 54% yield). 1H NMR (400 MHz,
DMSO-d.sub.6) 8.45 (s, 1H), 7.87 (s, 1H), 7.57-7.53 (m, 2H),
7.48-7.48 (brm, 1H), 7.43-7.39 (m, 2H), 7.31-7.29 (m, 1H), 7.14 (d,
J=8.4 Hz, 1H), 5.45 (s, 2H), 3.84 (s, 3H) ppm. LCMS=100.0% purity.
MS (APCI+)=350.1 (M+1).
Example 85
Preparation P-085
##STR00143##
[0377] Synthesis of
1-(6-Methoxy-3'-methylsulfanyl-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole
(P-085). P-085 was synthesized from I-110 (200 mg, 0.746 mmol) and
3-methylsulfanylphenylboronic acid (138 mg, 0.821 mmol) using the
same conditions as P-081. The reaction was worked up by diluting
with ethyl acetate (30 mL) and washing with water (30 mL). The
aqueous wash was extracted with ethyl acetate (30 mL), and the
organic extractions combined, washed with water (2.times.50 mL),
saturated aqueous ammonium chloride (50 mL), brine (50 mL),
decolorized with activated carbon, dried over sodium sulfate, and
the solvent removed under vacuum. The residue was purified by flash
silica gel column chromatography eluting with 5% acetone in
dichloromethane to give P-085 (117.1 mg, 50% yield) as a yellow
gum. 1H NMR (400 MHz, CDCl.sub.3) 8.06 (s, 1H), 7.97 (s, 1H), 7.37
(t, J=1.4 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.26-7.23 (m, 4H), 6.97
(d, J=8.4 Hz, 1H), 5.32 (s, 2H), 3.81 (s, 3H), 2.50 (s, 3H)
ppm.
[0378] LCMS=100.0% purity. MS (APCI+)=312.1 (M+1).
Example 86
Preparation of P-086
##STR00144##
[0380] Synthesis of
1-(6,3'-Dimethoxy-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole (P-086).
P-086 was synthesized from I-110 (200 mg, 0.746 mmol) and
3-methoxyphenylbronic acid (125 mg, 0.821 mmol) using the same
conditions as P-081. The reaction was cooled to room temperature
and the solvent removed under vacuum. The residue was suspended in
ethyl acetate (30 mL), washed with water (30 mL), the aqueous wash
extracted with ethyl acetate (30 mL), and the organic extracts
combined. The organic extracts were washed with water (3.times.30
mL), saturated aqueous ammonium chloride (30 mL), brine (30 mL),
decolorized with activated carbon, dried over sodium sulfate, and
the solvent removed under vacuum. The product was purified by flash
silica gel column chromatography eluting with 5% acetone in
dichloromethane to obtain P-086 (148.9 mg, 68% yield) as a yellow
oil. .sup.1H NMR (400 MHz, acetone-d.sub.6) 8.45 (s, 1H), 7.86 (s,
1H), 7.36-7.28 (m, 3H), 7.10-7.03 (m, 3H), 6.91-6.88 (m, 1H), 5.43
(s, 2H), 3.82 (s, 6H) ppm. LCMS=100% purity MS (APCI+)=296.1
(M+1).
Example 87
Preparation of P-102
##STR00145##
[0382] Synthesis of
3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenol (P-102). Into a
20 mL vial with stir bar was added I-70 (0.30 g, 0.93 mmol),
3-hydroxyphenylboronic acid (0.19 g, 1.40 mmol), triphenylphosphine
(49 mg, 0.19 mmol), K.sub.3PO.sub.4 (0.40 g, 1.86 mmol), DME (5
mL), water (0.5 mL), and ethanol (0.5 mL). N.sub.2 gas was bubbled
through the stirred reaction for 10 minutes. Palladium(II) acetate
(21 mg, 0.09 mmol) was added and N.sub.2 was bubbled through for an
additional 5 minutes. The reaction was stirred at 80.degree. C.
under N.sub.2 for 18 hours. The reaction was cooled to room
temperature and 20 mL of water and 20 mL of ethyl acetate were
added. The layers were separated and the aqueous was extracted with
ethyl acetate (3.times.15 mL). The organics were combined, dried
with sodium sulfate, and concentrated. The residue was purified by
flash column chromatography using 15% ethyl acetate/Hexanes to
obtain 177 mg (57%) of P-102 as a light-yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) 3.81 (s, 3H) 3.93 (s, 2H) 4.72 (s, 1H)
6.62-6.72 (m, 2H) 6.79 (d, J=7.7 Hz, 1H) 6.94 (d, J=8.3 Hz, 1H)
7.11-7.23 (m, 3H) 7.54 (t, J=8.0 Hz, 1H) 7.82 (d, J=7.8 Hz, 1H)
8.16 (dd, J=8.2, 1.34 Hz, 1H) 8.39 (t, J=1.8 Hz, 1H) ppm. MS:
(APCI-) 335.1
Example 88
Preparation of P-103
##STR00146##
[0384] Synthesis of
[3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenyl]-methanol
(P-103). The same procedure that was used for P-102 was used,
except using 3-hydroxybenzylboronic acid. The title compound P-103
was obtained (209 mg, 64%) as a yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) 1.62 (t, J=5.8 Hz, 1H) 3.81 (s, 3H) 3.99 (s, 2H) 4.67
(d, J=5.6 Hz, 2H) 6.94 (d, J=8.3 Hz, 1H) 7.10-7.24 (m, 5H)
7.27-7.34 (m, 1H) 7.54 (t, J=8.0 Hz, 1H) 7.83 (d, J=7.7 Hz, 1H)
8.16 (dd, J=8.3, 1.0 Hz, 1H) 8.38 (s, 1H) ppm. LC/MS=96.8%, (APCI-)
349.1
Example 89
Preparation of P-104
##STR00147##
[0386] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(P-104). Into a 20 mL vial with stir bar was added
2-hydroxypyridine (74 mg, 0.78 mmol), K.sub.2CO.sub.3 (0.24 g, 1.71
mmol), I-70 (0.30 g, 0.94 mmol), and 3 mL of DME. The mixture was
stirred at 80.degree. C. for 18 hours, and then cooled to room
temperature, filtered to remove the solids, and concentrated. The
residue was purified by flash column chromatography using 30%-75%
ethyl acetate/hexanes to obtain 124 mg (40%) of P-104 as a
tan-colored solid.
[0387] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.38 (t, J=1.9 Hz, 1H),
8.17 (dd, J=1.3, 8.2 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.56 (t,
J=7.9 Hz, 1H), 7.40-7.27 (m, 5H), 6.99 (d, J=8.6 Hz, 1H), 6.60 (d,
J=8.9 Hz, 1H), 6.17 (td, J=1.2, 6.7 Hz, 1H), 5.14 (s, 2H), 3.82 (s,
3H) ppm.
[0388] .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 162.8, 156.4,
148.3, 139.8, 139.6, 137.3, 135.8, 130.9, 130.1, 129.3, 129.1,
128.7, 124.7, 122.2, 121.6, 111.9, 106.5, 55.9, 51.7 ppm.
LC/MS=96.7%, 337.1 (APCI+).
Example 90
Preparation of P-105
##STR00148##
[0390] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenol (P-105), Into a
20 mL vial with stir bar was added I-70 (0.30 g, 0.93 mmol),
2-hydroxyphenylboronic acid (GS39) (0.19 g, 1.40 mmol),
triphenylphosphine (49 mg, 0.19 mmol), K.sub.3PO.sub.4 (0.40 g,
1.86 mmol), DME (5 mL), water (0.5 mL), and ethanol (0.5 mL).
N.sub.2 gas was bubbled through the stirred reaction for 10
minutes. palladium(II) acetate (21 mg, 0.09 mmol) was added and
N.sub.2 was bubbled through for an additional 5 minutes. The vial
was capped and the reaction was stirred at 80.degree. C. for 18
hours. The reaction was cooled to room temperature and 5 mL of
water and 5 mL of ethyl acetate were added. The layers were
separated and the aqueous was extracted with ethyl acetate
(3.times.10 mL). The organics were combined, dried with sodium
sulfate, and concentrated. The residue was purified by flash column
chromatography using 15% ethyl acetate/hexanes to afford 120 mg
(38%) of P-105 as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
3.80 (s, 3H) 3.99 (s, 2H) 4.74 (s, 1H) 6.78 (d, J=7.8 Hz, 1H) 6.90
(t, J=7.5 Hz, 1H) 6.94 (d, J=8.2 Hz, 1H) 7.09-7.17 (m, 2H)
7.19-7.25 (m, 2H) 7.53 (t, J=8.0 Hz, 1H) 7.82 (d, J=7.8 Hz, 1H)
8.15 (dd, J=8.2, 1.2 Hz, 1H) 8.38 (t, J=1.8 Hz, 1H) ppm. MS: 334.1
(APCI-)
Example 91
Preparation of P-119
##STR00149##
[0392] Synthesis of
5-Fluoro-2-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenol (P-119).
Into a 20 mL vial with stir bar was added I-70 (0.30 g, 0.93 mmol),
4-fluoro-2-hydroxyphenylboronic acid (0.22 g, 1.40 mmol),
triphenylphosphine (49 mg, 0.19 mmol), K.sub.3PO.sub.4 (0.40 g,
1.86 mmol), DME (5 mL), water (0.5 mL), and ethanol (0.5 mL).
N.sub.2 gas was bubbled through the stirred reaction for 10
minutes. palladium(II) acetate (21 mg, 0.09 mmol) was added and
N.sub.2 was bubbled through for an additional 5 minutes. The vial
was capped and the reaction was stirred at 80.degree. C. for 18
hours. The reaction was cooled to room temperature and 5 mL of
water and 5 mL of ethyl acetate were added. The layers were
separated and the aqueous was extracted with ethyl acetate
(3.times.10 mL). The organics were combined, dried with sodium
sulfate, and concentrated. The residue was purified by flash column
chromatography using 15% ethyl acetate/hexanes followed by
preparative TLC using 1:1 dichloromethane/Hexanes to obtain 24.3 mg
(7%) of P-119 as a light-yellow oil.
[0393] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.81 (s, 3H) 3.94 (s, 2H)
5.07 (br s, 1H) 6.55 (dd, J=9.8, 2.6 Hz, 1H) 6.61 (td, J=8.4, 2.55
Hz, 1H) 6.94 (d, J=8.3 Hz, 1H) 7.07 (dd, J=8.3, 6.7 Hz, 1H)
7.17-7.24 (m, 2H) 7.54 (t, J=8.0 Hz, 1H) 7.81 (d, J=7.7 Hz, 1H)
8.16 (dd, J=8.3, 1.3 Hz, 1H) 8.38 (t, J=1.8 Hz, 1H) ppm.
LC/MS=97.2%, 352.1 (APCI-)
Example 92
Preparation of P-134
##STR00150##
[0395] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzoic acid methyl
ester (I-121). Into a 20 mL vial with stir bar was added I-70 (0.30
g, 0.93 mmol), 2-methoxycarbonylphenylboronic acid (0.18 g, 1.02
mmol), triphenylphosphine (49 mg, 0.19 mmol), K.sub.3PO.sub.4 (0.40
g, 1.86 mmol), DME (5 mL), water (0.5 mL), and ethanol (0.5 mL).
N.sub.2 gas was bubbled through the stirred reaction for 10
minutes. Palladium(II) acetate (21 mg, 0.09 mmol) was added and
N.sub.2 was bubbled through for an additional 5 minutes. The vial
was capped and the reaction was stirred at 80.degree. C. for 18
hours. The reaction was cooled to room temperature and 5 mL of
water and 5 mL of ethyl acetate were added. The layers were
separated and the aqueous was extracted with ethyl acetate
(3.times.10 mL). The organics were combined, dried with sodium
sulfate, and concentrated. The residue was purified by flash column
chromatography using 10% acetone/hexanes to afford 241.0 mg (69%)
of I-121 as a colorless oil.
##STR00151##
[0396] [2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenyl]-methanol
(P-134). Into a 20 mL vial with stir bar was added I-121 (126.5 mg,
0.34 mmol) and 4 mL dry THF. The solution was cooled to 0.degree.
C. and DIBAL-H (0.84 mL, 0.84 mmol, 1.0 M in hexane) was added. The
reaction was stirred at 0.degree. C. for 30 minutes. Aqueous 1 N
HCl (1 mL) was added followed by 5 mL of water. The aqueous
solution was extracted with ethyl acetate (3.times.10 mL). The
organic were combined, dried over sodium sulfate, and concentrated.
The product was purified by flash column chromatography using 12%
acetone/hexane to afford 71 mg (66%) of P-134 as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) 1.44 (t, J=5.9 Hz, 1H), 3.80 (s,
3H), 4.10 (s, 2H), 4.70 (d, J=5.8 Hz, 2H), 6.92 (d, J=8.9 Hz, 1H),
7.10-7.16 (m, 2H), 7.16-7.22 (m, 1H), 7.27-7.30 (m, 2H), 7.39-7.45
(m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 8.15 (dd,
J=8.2, 1.3 Hz, 1H), 8.38 (t, J=1.7 Hz, 1H). LC/MS=99.9%, 349.1
(APCI-).
Example 93
Preparation of P-108
##STR00152##
[0398] Synthesis of
1-(6-Methoxy-3'-methoxymethyl-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole
(P-108). P-108 was synthesized from I-110 (200 mg, 0.746 mmol) and
3-methoxymethylphenylboronic acid (136 mg, 0.821 mmol) using the
same conditions as P-081. The reaction was cooled to room
temperature and the solvent removed under vacuum. The residue was
suspended in ethyl acetate (30 mL), washed with water (30 mL), the
aqueous wash extracted with ethyl acetate (30 mL), and the organic
extracts combined. The organic extracts were washed with water
(3.times.30 mL), saturated aqueous ammonium chloride (2.times.30
mL), brine (30 mL), decolorized with activated carbon, dried over
sodium sulfate, and the solvent removed under vacuum. The product
was purified by flash silica gel column chromatography eluting with
0-25% acetone in dichloromethane, and was run on a silica gel
preparatory plate eluting with 1% acetone in dichloromethane for
three developments to obtain P-108 (49.0 mg, 19% yield) as a yellow
oil.
[0399] .sup.1H NMR (CDCl.sub.3) d: 8.444 (s, 1H), 7.849 (s, 1H),
7.44-7.354 (m, 4H), 7.295-7.280 (m, 2H), 7.104-7.086 (m 1H), 5.435
(s, 2H), 4.472 (s, 2H), 3.805 (s, 3H), 3.350 (s, 3H).
[0400] LCMS=100.0% purity. MS (APCI+)=310.1 (M+1).
Example 94
Preparation of P-495
##STR00153##
[0402] Synthesis of
1-(3'-Methanesulfonyl-6-methoxy-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole
(P-495). P-495 was synthesized from I-110 (200 mg, 0.746 mmol) and
3-methanesulfonylphenylboronic acid (136 mg, 0.821 mmol) by a
similar procedure to P-081. Upon completion, the residue was
suspended in ethyl acetate (20 mL), washed with (20 mL), and the
aqueous wash was extracted with ethyl acetate (2.times.30 mL). The
organic extracts were combined and washed with water (3.times.50
mL), saturated aqueous ammonium chloride (2.times.50 mL), and brine
(50 mL), dried over sodium sulfate, and the solvent removed under
vacuum. The impure product was purified by flash silica gel column
chromatography eluting with 5-15% acetone in dichloromethane, and
by separation on a silica gel preparatory plate eluting with 5%
acetone in dichloromethane to give P-495 (145.0 mg, 57% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) d: 8.09-8.08 (m, 2H), 7.97 (s,
1H), 7.97-7.90 (m, 1H), 7.79-7.77 (m, 1H), 7.60 (t, J=6.4 Hz, 1H),
7.32-7.26 (m, 2H), 7.01 (d, J=6.8 Hz, 1H), 5.34 (s, 2H), 3.83 (s,
3H), 3.09 (s, 3H).
[0403] LCMS=100.0% purity. MS (APCI+)=344.0 (M+1).
Example 95
Preparation of P-163
##STR00154##
[0405] Synthesis of
2-bromo-6-(4-fluoro-benzoyl)-3-methoxy-benzonitrile (I-123). To a
cooled (0.degree. C.) solution of
(2-amino-3-bromo-4-methoxy-phenyl)-(4-fluoro-phenyl)-methanone
(I-122, 0.32 g, 1.0 mmol) in con. HCl (1.5 mL) was added a solution
of NaNO.sub.2 (0.065 g, 0.95 mmol). The reaction mixture was
stirred for 10 min at 0.degree. C., then added to a suspension of
Cu(I)CN (0.031 g, 1.2 mmol) in water (0.5 mL) and toluene (1 mL)
over 5 min at 0.degree. C. The reaction mixture was slowly warmed
to room temperature, stirred at room temperature for 2 h, then at
50.degree. C. for 30 min. The reaction was extracted with
dichloromethane (3.times.5 mL), and the combined organic extracts
were washed with brine, dried with Na.sub.2SO4, filtered, and
concentrated under vacuum. The residue was purified by silica gel
column chromatography using 1:1 dichloromethane-hexanes then
dichloromethane to afford I-123 (0.201 g, 61% yield) as white
solid.
[0406] Synthesis of
2-bromo-6-(4-fluoro-benzyl)-3-methoxy-benzonitrile (I-124): To a
solution of I-123 (0.15 g, 0.45 mmol) in trifluoroacetic acid (1.0
mL) was added triethylsilane (0.55 g, 4.5 mmol). The reaction
mixture was stirred at room temperature for 20 h, then concentrated
under vacuum to afford I-124 (0.14 g, 94% yield) as white
solid.
[0407] Synthesis of
3-(4-fluoro-benzyl)-6-methoxy-3'-nitro-biphenyl-2-carbonitrile
(P-163): To I-124 (0.14 g, 0.42 mmol), 3-nitrophenylboronic acid
(0.07 g, 0.44 mmol), PPh.sub.3 (0.05 g, 0.21 mmol), K.sub.2CO.sub.3
(0.02 g, 0.16 mmol) and Pd(OAc).sub.2 (0.01 g, 0.06 mmol) was added
dioxane (10 mL) and EtOH-H.sub.2O (1:1, 5 mL). The reaction was
degassed with an Argon stream for 5 min. The reaction was then
stirred at 85.degree. C. under Ar for 18 h. The reaction was cooled
to room temperature, concentrated under vacuum, and H.sub.2O (40
mL) and dichloromethane (40 mL) were added. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.25 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
residue was purified by silica gel column chromatography using
dichloromethane to afford P-163 (0.07 g, 46% yield) as an off-white
solid. 1H NMR (CDCl.sub.3, 400 MHz): 8.12-8.26 (m, 2H), 7.54-7.62
(m, 2H), 7.1-7.2 (m, 3H), 6.9-7.04 (m, 2H), 6.86 (d, J=8.4 Hz, 1H),
4.07 (s, 2H), 3.71 (s, 3H); MS (APCI+): 383.1 (M+1).
Example 96
Preparation of P-169
##STR00155##
[0409] Synthesis of
1-(3'-Methanesulfinyl-6-methoxy-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole
(P-169). A 30% hydrogen peroxide by weight in water solution (1 mL)
was diluted with glacial acetic acid (9 mL). A solution of P-085
(38.1 mg, 0.111 mmol) in glacial acetic acid (300 uL) was stirred
at room temperature, and the hydrogen peroxide solution was added
(107 uL total solution, 3.78 mg hydrogen peroxide, 0.111 mmol)
dropwise. The reaction was stirred for 1 h at room temperature.
Following completion, solid sodium carbonate was added (.about.100
mg) to the mixture. The reaction was diluted with water (500 uL),
and extracted with ethyl acetate (3.times.1 mL). The organic
extracts were combined, dried over sodium sulfate, and the solvent
removed under vacuum. The residue was dried under high vacuum
overnight to give P-169 (25.6 mg, 70% yield).
[0410] 1H NMR (400 MHz, CDCl.sub.3) 8.08 (s, 1H), 7.97 (s, 1H),
7.79-7.78 (m, 1H), 7.64-7.54 (m, 3H), 7.31-7.28 (m, 2H), 7.00 (d,
J=8.40 Hz, 1H), 5.33 (s, 2H), 3.83 (s, 3H), 2.76 (s, 3H) ppm.
LCMS=96.4% purity. MS (APCI+)=328.1 (M+1).
Example 97
Preparation of P-530
##STR00156##
[0412] Synthesis of
(4-Amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanone
(I-127). A suspension of I-126 (108 mg, 0.28 mmol), Fe powder (55
mg, 0.98 mmol), NH.sub.4Cl (75 mg, 1.40 mmol), in ethanol (3 mL),
and water (1 mL) was stirred for 2 hours at 80.degree. C. Upon
completion the reaction was filtered through Celite, washed with
ethyl acetate, and concentrated under vacuum. The residue was taken
up in ethyl acetate and washed with saturated aqueous NaHCO.sub.3.
The combined extracts were concentrated under vacuum to afford
compound I-127 (90 mg, 90% yield) as a yellow gum.
##STR00157##
[0413] Synthesis of
N-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide
(I-128). A solution of I-127 (88 mg, 0.25 mmol) in pyridine (2 mL),
and acetic anhydride (35 uL, 0.37 mmol) was stirred at room
temperature for 2 hours. The reaction was diluted with ethyl
acetate, and was washed with 1N aqueous HCl. The combined extracts
were dried over Na.sub.2SO.sub.4 and concentrated to a solid which
was triturated with diethyl ether to give I-128 (21 mg, 21% yield)
as a white solid.
##STR00158##
[0414] Synthesis of
N-{4-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-1-hydroxy-ethyl]-phe-
nyl}-acetamide (P-530). A mixture of I-128 (18.4 mg, 0.046 mmol)
and methylmagnesium bromide (46 uL, 0.14 mmol, 3.0M in ether) in
THF (1 mL) was stirred at room temperature for 10 min, The reaction
was quenched by the addition of saturated aqueous NH.sub.4Cl. The
reaction was extracted with ethyl acetate, and the combined
extracts washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated under vacuum. The residue was filtered through
SiO.sub.2 to remove any remaining inorganic impurities to give
P-530 (4.6 mg, 24% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.85 (s, 1H), 7.70 (t, J=9.1 Hz, 1H), 7.50-7.34 (m,
4H), 7.29-7.21 (m, 3H), 7.21-7.12 (m, 1H), 6.97 (d, J=8.9 Hz, 1H),
3.74 (s, 3H), 2.00 (s, 3H), 1.82 (s, 3H)
[0415] Purification of P-560 and P-561.
##STR00159##
[0416] The enantiomers of P-530 were separated by semi-preparative
chiral HPLC. The sample for injections was dissolved in warm EtOH.
The column used was a Chiralpack AD (250.times.20 mm, 10 um). The
mobile phase was 15% EtOH, 85% hexane (with 0.2% DEA), isocratic at
9.9 mL/min. The injection volume was 385 uL and the fractions were
collected by manually changing fractions. The run time was 60
minutes and the UV detection was set at 254 nm. The retention time
of the first enantiomer collected was 33.2 min which is P-560, and
the second enantiomer was 41.5 min which is P-561.
[0417] The chiral purity of each fraction was then determined by
analytical scale chiral HPLC using a Chiralpack AD column
(250.times.4.6 mm, 5 um). The mobile phase was 15% EtOH, 85% hexane
(with 0.2% DEA), isocratic at 1.0 mL/min. The injection volume was
10 uL, the run time was 30 min, and the UV detection was set at 254
nm. A sample of the original racemic mixture was injected and the
retention times were 12.3 and 14.9 minutes, respectively. The
retention time of P-560 was 12.3 minutes and the enantiomeric
excess was determined to be 100.0%. The retention time of P-561 was
15.0 minutes and the enantiomeric excess was determined to be
99.2%.
[0418] The absolute stereochemistry of P-560 and P-561 is not
known. The stereochemistry of the structures was drawn
arbitrarily.
N-{4-[(R)-1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-1-hydroxy-ethyl]--
phenyl}-acetamide (P-560)
[0419] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.85 (s, 1H), 7.70 (t,
J=9.1 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.41-7.37 (m, 2H), 7.29-7.22
(m, 3H), 7.19-7.14 (m, 1H), 6.97 (d, J=8.9 Hz, 1H), 5.67 (br. s.,
1H), 3.74 (s, 3H), 2.00 (s, 3H), 1.82 (s, 3H)
N-{4-[(S)-1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-1-hydroxy-ethyl]--
phenyl}-acetamide (P-561)
[0420] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.85 (s, 1H), 7.70 (t,
J=9.1 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.41-7.36 (m, 2H), 7.29-7.21
(m, 3H), 7.20-7.15 (m, 1H), 6.97 (d, J=8.9 Hz, 1H), 5.67 (br s,
1H), 3.74 (s, 3H), 2.00 (s, 3H), 1.82 (s, 3H)
Example 98
Preparation of P-547
##STR00160##
[0422] Synthesis of 3'-Chloro-2-methoxy-biphenyl (I-16). A
suspension of 2-iodoanisol (3.00 g, 12.8 mmol),
3-chlorophenylboronic acid (2.41 g, 15.4 mmol), and potassium
carbonate (3.54 g, 25.6 mmol) in water (10 mL) and methanol (50 mL)
was purged with a nitrogen stream for 20 min. To the suspension was
added palladium(II) acetate (57.6 mg, 0.2564 mmol) and the solution
was stirred at room temperature overnight (18 h). To the reaction
was added ethyl acetate (100 mL) and water (100 mL). The layers
were separated, the aqueous layer extracted with ethyl acetate (100
mL), and the organic extracts were combined. The organic solution
was washed with water (2.times.150 mL) and brine (150 mL),
decolorized with activated charcoal, dried over sodium sulfate, and
the solvent removed under reduced pressure. The resulting residue
was purified by flash silica gel column chromatography eluting with
10-30% ethyl acetate in hexanes to give I-16 (2.50 g, 89% yield) as
colorless oil. 1H NMR (400 MHz CDCl.sub.3) 7.53 (t, J=1.8 Hz, 1H),
7.40 (dt, J=7.2 Hz, 1.6 Hz, 1H), 7.38-7.28 (m, 4H), 7.05-6.97 (m,
2H), 3.82 (s, 3H).
[0423] Synthesis of
(3'-Chloro-6-methoxy-biphenyl-3-yl)-(4-nitro-phenyl)-methanone
(I-129). A solution of I-16a (1.50 g, 6.86 mmol) in nitrobenzene (6
mL) was cooled to 0.degree. C. in an ice water bath. Aluminum
trichloride (1.10 g, 8.23 mmol) was added portionwise, and the
solution stirred at 0.degree. C. for 1 h. To the solution was
added, 4-nitro-benzoylchloride (1.53 g, 8.23 mmol) and the reaction
was stirred for 20 h allowing warming to room temperature. The
solution was poured into 100 mL of an ice-water mixture and stirred
for 2 h. The yellow oil was extracted into ethyl acetate
(2.times.100 mL), and the organic extracts combined. The extracts
were washed with saturated aqueous sodium bicarbonate (100 mL),
water (2.times.150 mL), and brine (150 mL), dried over sodium
sulfate, and the solvent removed under vacuum to give crude I-129
The resultant oil was purified by flash silica gel column
chromatography (10-33% ethyl acetate in hexanes) to give I-129
(1.66 g, 66% yield).
[0424] 1H NMR (400 MHz CDCl.sub.3) d: 8.35-8.34 (m, 2H), 7.92-7.91
(m, 2H), 7.84-7.81 (m, 2H), 7.51-7.51 (m, 1H), 7.37-7.34 (m, 3H),
7.08 (d, J=6.8 Hz, 1H), 3.94 (s, 3H).
[0425] MS (APCI+)=304.1 (M-63.0)
[0426] Synthesis of
3'-Chloro-2-methoxy-5-[bisdeutero-(4-nitro-phenyl)-methyl]-biphenyl
(I-130). A solution of I-129 (500 mg, 1.36 mmol) in dichloromethane
(10 mL) was purged with nitrogen. To the solution was added
duetro-trifluoroacetic acid (3.91 g, 34.0 mmol) and the resultant
orange solution was cooled to 0.degree. C. in a ice water bath. To
the solution was slowly added sodium borodeuteride (569 mg, 13.6
mmol) portion wise over 45 min. The reaction was stirred overnight
allowing the mixture to warm to room temperature. The reaction was
basified to pH 9 with saturated aqueous sodium bicarbonate, and
extracted into ethyl acetate (75 mL). The extract was washed with
water (2.times.50 mL) and brine (50 mL), dried over sodium sulfate,
and the solvent removed under vacuum. The crude material was
purified by flash silica gel column chromatography (10% ethyl
acetate in hexanes) to give I-130 (500 mg, quantitative yield.)
[0427] 1H NMR (400 MHz CDCl.sub.3) 8.16-8.14 (m, 2H), 7.489-7.48
(m, 1H), 7.37-7.26 (m, 5H), 7.13 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.10
(d, J=2.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 3.80 (s, 3H).
[0428] Synthesis of
4-[Bisdeutero-(3'-chloro-6-methoxy-biphenyl-3-yl)-methyl]-phenylamine
(I-131). A suspension of I-130 (440 mg, 1.24 mmol), iron powder
(241 mg, 4.33 mmol), and ammonium chloride (337 mg, 6.31 mmol) in
ethanol (5 mL) and water (1.6 mL) was stirred at room temperature
for 1 h and at 100.degree. C. for 30 min. The ethanol was removed
under reduced pressure, the reaction diluted with water (50 mL),
and extracted with ethyl acetate (2.times.50 mL). The combined
extracts were washed with water (2.times.50 mL) and brine (50 mL),
dried over sodium sulfate, and the solvent removed under vacuum to
give I-131 (279 mg, 70% yield) as an orange oil.
[0429] 1H NMR (400 MHz CDCl.sub.3) d: 7.43 (m, 1H), 7.31-7.19 (m,
3H), 7.07-7.04 (m, 2H), 6.93-6.910 (m, 2H), 6.82 (d, J=8.4 Hz, 1H),
6.57-6.55 (m, 2H), 3.72 (s, 2H), 3.50 (s, 2H).
[0430] Synthesis of
{4-[Bisduetero-(3'-chloro-6-methoxy-biphenyl-3-yl)-methyl]-phenyl}-urea
(P-547). A suspension of I-131 (270 mg, 0.829 mmol) and sodium
cyanate (107.7 mg, 1.66 mmol) in water (15 mL) and glacial acetic
acid (7.5 mL) was stirred at room temperature over night. To the
solution was added aqueous saturated sodium bicarbonate (10 mL),
and the reaction was extracted with ethyl acetate (50 mL, 25 mL).
The extracts were combined, washed with water (50 mL) and brine (50
mL), dried over sodium sulfate, and the solvent removed under
vacuum to give P-547 as an orange gum. The material was purified by
flash silica gel column chromatography (eluting with 10-25% ethyl
acetate in dichloromethane) and recrystallized by in water (10 mL)
and isopropanol (8 mL) to give P-547 (111 mg, 36% yield) as a white
powder.
[0431] 1H NMR (400 MHz, d6-DMSO): 8.40 (s, 1H), 7.48-7.36 (m, 4H),
7.29-7.27 (m, 2H), 7.20-7.10 (m, 2H0, 7.09-7.08 (m, 2H), 7.03 (d,
J=8.8 Hz, 1H), 5.75 (s, 2H), 3.74 (s, 3H).
[0432] LCMS=96.9% purity. MS (APCI+)=369.1 (M+1), 326.1
(M-42.0).
[0433] HPLC (254 nm); 96.6%. [Mobile Phase A and Mobile Phase
B=Water and Acetonitrile, Symmetry C18, (250.times.4.6 mm, 5 um),
Flow=1.0 mL/min, Inj. Wash=ACN, Inj. Vol.=10 uL. Retention
time=28.37 min]
Example 99
Preparation of P-537, P-538, and P-539
##STR00161##
[0435] Synthesis of
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-nitro-phenyl)-methanone
(I-133). To a solution of 4-nitro-benzoyl chloride (1900 mg, 10.2
mmol) in nitrobenzene (6 mL) was added aluminum trichloride (1360
mg, 10.2 mmol) at 0.degree. C. The mixture was allowed to warm to
room temperature and stirred at room temperature for 1 h, cooled to
0.degree. C., and 3'-chloro-6-fluoro-2-methoxy-biphenyl (2.01 g,
8.5 mmol) in nitrobenzene (1 mL) was added at 0.degree. C. The
reaction mixture was allowed to warm to room temperature and
stirred 24 h. The reaction mixture was cooled to -10.degree. C. and
quenched with ice-water (50 mL), extracted with ethyl acetate
(2.times.25 mL), washed with water (2.times.10 mL), saturated
aqueous sodium bicarbonate (10 mL), brine (30 mL), and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
crude was purified by crystallization from ether-hexane to give
I-133 (3.00 g, 91% yield).
[0436] Synthesis of
deutero-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-nitro-phenyl)-met-
hanol (P-537). To a mixture of I-133 (500 mg, 1.25 mmol) in
THF-D.sub.2O (1:1, mL) was added NaBD.sub.4 (190 mg, 3.1 mmol) at
0.degree. C. The reaction mixture was allowed to warm to room
temperature and stirred for 24 h. The mixture was poured into
ice-water (100 mL), neutralized with aqueous saturated NH.sub.4Cl
(5 mL), extracted with ethyl acetate (3.times.30 mL), washed with
water (20 mL), brine (30 mL) and dried over Na.sub.2SO.sub.4. After
filtration and removal of solvent, the residue was purified by
silica gel column chromatography with ethyl acetate-hexane as
eluent to give P-537 (350 mg, 70% yield).
[0437] 1H NMR (CDCl.sub.3,400 MHz) 8.21 (d, J=8.8 Hz, 2H), 7.62 (d,
J=8.8 Hz, 2H), 7.23-7.37 (m, 5H), 6.78 (dd, J=8.8, 1.2 Hz, 1H),
3.77 (s, 3H), 2.39 (s, 1H). Calc. 388.8; APCI.sup.+ (M-OH): 371.1,
100%.
[0438] Synthesis of
deutero-(4-amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-met-
hanol (P-538). To a mixture of P-537 (300 mg, 0.7 mmol) in ethyl
acetate (10 mL) was added Pd/C (10%, 450 mg, 4 mmol) at room
temperature. The reaction vessel was sealed and the mixture was
shaken under a Hydrogen atmosphere (30 psi) for 60 min. The solid
was filtered, and the filtrate was concentrated to give crude
product. The crude was purified by silica gel column chromatography
with ethyl acetate-hexane as eluent and then was further purified
by a preparation TLC to yield P-538 (45 mg, 16% yield).
[0439] 1H NMR (CDCl.sub.3,400 MHz) 7.46 (t, J=8.4 Hz, 1H),
7.23-7.37 (m, 4H), 7.18 (d, J=8.4 Hz, 2H), 6.77 (dd, J=8.8, 1.2 Hz,
1H), 6.55 (d, J=8.4 Hz, 2H), 3.77 (s, 3H), 2.10 (s, 1H). Calc.
358.8; APCI.sup.+ (M-OH): 341.1, 91%.
[0440] Synthesis of
(4-amino-phenyl)-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanone
(I-134). To a solution of I-133 (500 mg, 1.2 mmol) in EtOH-H.sub.2O
(1:1, 15 mL) was added solid NH.sub.4Cl (200 mg, 4 mmol) and iron
powder (150 mg, 3 mmol), and the reaction was stirred at room
temperature for 72 h. The mixture was poured into water (50 mL),
extracted with ethyl acetate (3.times.30 mL), washed with water (20
mL) and brine (30 mL), and dried over Na.sub.2SO.sub.4, and
filtered. The solvent was removed under vacuum to yield I-134 (380
mg, 82% yield).
[0441] Synthesis of
[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-urea
(P-434). To a solution of I-134 (220 mg, 0.7 mmol) in pyridine (1
mL) and THF (4 mL) was added trimethylsilylisocyanate (1 mL,
excess) and the reaction stirred at room temperature for 36 h. The
mixture was poured into 25 mL ice-water solution. To the suspension
was added saturated aqueous sodium bicarbonate (5 mL), and the
resultant mixture was stirred at room temperature for 2 h. The
mixture was extracted with ethyl acetate (3.times.30 mL), washed
with water (20 mL), and brine (30 mL), dried over Na.sub.2SO.sub.4,
and filtered. The solvent was removed under vacuum, and the crude
product was purified by silica gel column chromatography with ethyl
acetate-hexane as eluent to yield P-434 (50 mg, 20% yield).
[0442] Synthesis of
{4-[(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-hydroxy-deutero-methyl]--
phenyl}-urea (P-539). To a mixture of P-434 (50 mg, 0.13 mmol) in
THF (5 mL) and D.sub.2O (2 mL) was added NaBD.sub.4 (50 mg, 0.25
mmol) at 0.degree. C. The reaction mixture was allowed to warm to
room temperature and stirred for 24 h. The reaction mixture was
poured into 20 mL ice-water, neutralized with NH.sub.4Cl (sat. 2
mL), extracted with ethyl acetate (3.times.10 mL), and washed with
water (10 mL) and brine (10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and the solvent removed under vacuum.
After removal of solvent, the residue was purified by a preparation
TLC to give P-539 (12 mg, 26% yield). 1H NMR (DMSO-d6, 400 MHz) d:
8.45 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.41-7.44 (m, 2H), 7.24-7.34
(m, 4H), 7.17 (d, J=8.8 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H) 5.79 (s,
1H), 3.73 (s, 3H) ppm. Calc. 401.85; APCI.sup.+ (M-OH): 384.1,
98.6%.
Example 100
Preparation of P-541
##STR00162##
[0444] [4-(3'-Chloro-6-ethoxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-541). A suspension of P-421 (66 mg, 0.19 mmol), K.sub.2CO.sub.3
(39 mg, 0.28 mmol), and EtI (23 uL, 0.28 mmol) in acetone (2 mL)
was stirred for 16 hours at 50.degree. C. An additional 50 uL of
EtI and 80 mg of K.sub.2CO.sub.3 were added and the reaction was
stirred for 4 h at 50.degree. C. To the reaction was added 80 mg of
Cs.sub.2CO.sub.3 and 50 uL of EtI, the reaction stirred 2 h at
60.degree. C., and the reaction was concentrated. The crude product
was purificated by flash column chromatography eluting with 20%-30%
Acetone/DCM afforded the title compound P-541 (37 mg, 51%) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=8.40 (s,
1H), 7.53 (s, 1H), 7.45-7.39 (m, 2H), 7.39-7.34 (m, 1H), 7.28 (d,
J=8.3 Hz, 2H), 7.19-7.13 (m, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.01 (d,
J=8.1 Hz, 1H), 5.75 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.82 (s, 2H),
1.31-1.18 (m, 3H). LC/MS=96.5%, 381.1 (APCI+).
Example 101
Preparation of P-542
##STR00163##
[0446]
{4-[6-(2-Amino-ethoxy)-3'-chloro-biphenyl-3-ylmethyl]-phenyl}-urea
(P-542). A suspension of P-421 (100 mg, 0.28 mmol),
2-bromoethylamine hydrobromide (204 mg, 8.8 mmol), Cs.sub.2CO.sub.3
(600 mg, 18.4 mmol), and sodium iodide (20 mg) in acetone (10 mL)
was stirred at reflux for 20 h. The reaction mixture was then
portioned between dichloromethane and water, and the organic layer
was extracted with 1N NaOH followed by 1 N HCl. The acidic extract
was adjusted to pH 10 by addition of NaOH followed by extraction
with dichloromethane. The solvent was removed in vacuo and the
residue was chromatographed with dichloromethane:methanol (9:1) to
yield P-542 (9 mg, 8.1% yield) as a solid.
[0447] .sup.1H NMR (CDCl.sub.3) 7.50-7.52 (m, 1H), 7.28-7.32 (m,
2H), 7.17-7.23 (m, 3H), 7.11-7.13 (m, 2H), 7.09-7.11 (m, 1H),
6.89-6.92 (m, 2H), 3.96 (t, J=5 Hz, 2H), 3.93 (s, 2H), 2.99 (t, J=5
Hz, 2H), APCI (M+1; 396.1) LCMS 95%.
Example 102
Preparation of P-543
##STR00164##
[0449]
{4-[3'-Chloro-6-(tetrahydro-furan-2-ylmethoxy)-biphenyl-3-ylmethyl]-
-phenyl}-urea (P-543). A mixture of phenol P-421 (100 mg, 0.28
mmol), tetrahydrofurfuryl bromide (50 mg, 0.28 mmol), and
K.sub.2CO.sub.3 (78 mg, 0.56 mmol) in DMF (2 mL) was heated at
80.degree. C. for 24 h. To this mixture, K.sub.2CO.sub.3 (78 mg),
NaI (10 mg), and tetrahydrofurfuryl bromide (50 mg) were added and
the reaction was run at 100.degree. C. for 6 h. The mixture was
cooled to room temperature and partitioned between dichloromethane
and water, the dichloromethane layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by preparative plate with dichloromethane:methanol (95:5)
to yield P-543 (55 mg, 45% yield).
[0450] .sup.1H NMR (400 MHz, DMSO-d6) 8.39 (s, 1H), 7.58 (s, 1H),
7.37-7.43 (m, 3H), 7.28 (d, J=7.2 Hz, 1H), 7.14-7.17 (m, 2H), 7.08
(d, J=7.2 Hz, 2H), 7.02 (d, J=7.2 Hz, 1H), 4.07 (m, 1H), 3.94 (t,
J=5 Hz, 2H), 3.82 (s, 2H), 3.6-3.69 (m, 2H), 1.88-1.93 (m, 1H),
1.73-1.77 (m, 2H), 1.62-1.69 (m, 1H).
[0451] APCI (M+1; 437) LCMS 93.5%;
Example 103
Preparation of P-548 and P-557
##STR00165##
[0453] Synthesis of
{4-[3'-Chloro-6-(2-dimethylamino-ethoxy)-biphenyl-3-ylmethyl]-phenyl}-ure-
a (P-548). A suspension of P-421 (100 mg, 0.283 mmol),
dimethylaminoethylbromide hydrobromide (198 mg, 0.850 mmol), and
cesium carbonate (600 mg, 1.84 mmol) in acetone (10 mL) was stirred
at reflux for 17 h. The suspension was diluted with dichloromethane
(50 mL), washed with 0.5 N aqueous hydrochloric acid (100 mL), and
the solvent removed under vacuum. The crude orange oil was purified
by preparatory thin layer chromatography (silica gel) eluting with
10% acetone in dichloromethane followed by eluting with 10%
methanol in dichloromethane to give P-548 (13.4 mg, 11% yield) as a
colorless gum.
[0454] 1H NMR (400 MHz CDCl.sub.3) d: 7.54 (m, 1H), 7.39-7.36 (m,
1H), 7.31-7.08 (m, 8H), 6.90-6.89 (m, 1H), 6.23 (s, 1H), 4.57 (s,
2H), 4.05 (t, J=5.8 Hz, 2H), 3.92 (s, 2H), 2.68 (t, J=5.60 Hz, 2H),
2.27 (s, 6H).
[0455] LCMS=97.3% purity. MS (APCI+)=424.2 (M+1)
##STR00166##
[0456] Synthesis of
2-[3'-Chloro-5-(4-ureido-benzyl)-biphenyl-2-yloxy]-acetamide
(P-557). A suspension of P-421 (150 mg, 0.425 mmol),
2-bromoacetamide (175 mg, 1.28 mmol), and cesium carbonate (900 mg,
2.76 mmol) in acetone (15 mL) was stirred at reflux overnight. The
solvent was removed under a nitrogen stream, and the dry residue
was suspended in ethyl acetate (50 mL). The organic solution was
washed with water (50 mL) and brine (15 mL), dried over sodium
sulfate, decanted, and the solvent removed under vacuum to give
crude product. The solid was triturated in a mixture of
dichloromethane (5 mL), methanol (5 mL), and acetone (2 mL) to give
P-557 (58.9 mg, 34% yield) as a white powder.
[0457] 1H NMR (400 MHz, DMSO-d.sub.6) 8.40 (s, 1H), 7.65 (t, J=2.0
Hz, 1H), 7.52-7.50 (m, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.43-7.37 (m,
2H), 7.28 (d, J=8.4 Hz, 1H), 7.20-7.15 (m, 3H), 7.09 (d, J=8.4 Hz,
1H), 6.90 (d, J=8.0 Hz, 1H), 5.75 (s, 2H), 4.42 (s, 2H), 3.83 (s,
2H). LCMS=93.63% purity. MS (APCI+)=410.1 (M+1).
Example 104
Preparation of P-554
##STR00167##
[0459]
3-[3'-Chloro-5-(4-ureido-benzyl)-biphenyl-2-yloxy]-azetidine-1-carb-
oxylic acid tert-butyl ester (I-136). A mixture of phenol P-421
(150 mg, 0.42 mmol), 3-methanesulfonyloxy-azetidine-1-carboxylic
acid t-butyl ester (200 mg, 0.79 mmol), and Cs.sub.2CO.sub.3 (277
mg, 0.85 mmol) in DMF (2 mL) was heated at 100.degree. C. for 18 h.
The mixture was cooled to room temperature and partitioned between
dichloromethane and water. The water layer was extracted twice with
dichloromethane. The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by preparative plate with
dichloromethane:methanol (95:5) to yield I-136 (200 mg,
quantitative yield) as an oil.
[0460]
{4-[6-(Azetidin-3-yloxy)-3'-chloro-biphenyl-3-ylmethyl]-phenyl}-ure-
a (P-554). To a solution of I-136 (200 mg, 0.393 mmol)
dichloromethane (2 mL), at 0.degree. C. was added trifluoroacetic
acid (0.5 mL). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was concentrated under vacuum,
diluted with water, saturated aqueous Na2HCO3 (0.5 mL) was added
and the mixture was extracted with dichloromethane (3.times.5 mL).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum The residue was purified by
preparative plate thin layer chromatography eluting with
dichloromethane:methanol (95:5) to yield P-554 (20 mg, 12% yield)
as a solid.
[0461] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.51 (t, 1H), 7.38-7.41
(m, 1H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 5H), 7.06 (dd, J=8.4, 2.4
Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.22 (br s, 1H), 4.97 (m, 1H),
4.56 (br s, 1H), 3.91 (s, 2H), 3.85-3.89 (t, 2H), 3.73-3.75 (m,
2H), 3.48-3.52 (m, 1H) ppm.
[0462] APCI (M+1; 408) LCMS 97%;
Example 105
Preparation of P-553
##STR00168##
[0463]
{4-[3'-Chloro-6-(thietan-3-yloxy)-biphenyl-3-ylmethyl]-phenyl}-urea
P-553). Compound P-553 was synthesized by a route analogous to that
reported for P-5M (Example 104)
[0464] 1H NMR (CDCl.sub.3) .delta.: 7.48 (t, 1H), 7.34-7.38 (m,
1H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 5H), 7.06 (dd, J=8.4, 2.4 Hz,
1H), 6.73 (d, J=8.4 Hz, 1H), 6.28 (bs, 1H), 5.19 (m, 1H), 4.59 (bs,
1H), 3.92 (s, 2H), 3.46-3.53 (t, 2H), 3.23-3.31 (m, 2H).
APCI (M+1; 425)
Example 106
Preparation of P-555
##STR00169##
[0465]
{4-[3'-Chloro-6-(oxetan-3-yloxy)-biphenyl-3-ylmethyl]-phenyl}-urea
(P-555). Compound P-555 was synthesized by a route analogous to
that reported for P-554
[0466] 1H NMR (DMSO-d.sub.6) .delta. 8.39 (s, 1H), 7.57 (t, 1H),
7.38-7.48 (m, 3H), 7.28 (d, J=8.4 Hz, 2H), 7.22 (d, J=2.4 Hz, 1H),
7.09-7.14 (m, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.4 Hz, 1H),
5.75 (s, 2H), 5.25 (m, 1H), 4.87 (t, J=5 Hz, 2H), 4.46 (m, 2H),
3.82 (s, 2H).
[0467] APCI (M+1; 409) LCMS 97%.
Example 107
Preparation of P-556
##STR00170##
[0469]
4-[3'-Chloro-6-((S)-1-methyl-pyrrolidin-3-yloxy)-biphenyl-3-ylmethy-
l]-phenyl}-urea (P-556). Compound P-556 was synthesized by a route
analogous to that reported for P-554 (Example 104).
[0470] 1H NMR (400 MHz, CDCl.sub.3) 7.51 (t, 1H), 7.37-7.39 (m,
1H), 7.27-7.33 (m, 2H), 7.12-7.22 (m, 5H), 7.06 (dd, J=8.4, 2.4 Hz,
1H), 6.8 (d, J=8.4 Hz, 1H), 6.29 (br s, 1H), 4.76 (m, 1H), 4.59 (br
s, 1H), 3.91 (s, 2H), 3.02 (m, 1H), 2.6 (t, 2H), 2.35 (s, 3H),
2.17-2.24 (m, 2H). APCI (M+1; 436)
Example 108
Preparation of P-562
##STR00171##
[0471]
4-[3'-Chloro-6-(oxetan-3-yloxy)-biphenyl-3-ylmethyl]-phenylamine
(P-562). Compound P-562 was synthesized by a route analogous to
that reported for P-554 (Example 104)
[0472] 1H NMR (400 MHz, DMSO-d.sub.6) 7.56 (t, 1H), 7.57 (t, 1H),
7.37-7.48 (m, 3H), 7.18 (d, J=2 Hz, 1H), 7.01 (dd, J=8.4, 2 Hz,
1H), 6.88 (d, J=8.4 Hz, 2H), 6.61 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.4
Hz, 1H), 5.75 (s, 2H), 5.25 (m, 1H), 4.93 (br s, 2H), 4.87 (t, J=5
Hz, 2H), 4.46 (m, 2H), 3.72 (s, 2H) ppm. APCI (M+1; 366) LCMS
97%;
Example 109
Preparation of P-563
##STR00172##
[0473]
{4-[3'-Chloro-6-((S)-1-pyrrolidin-2-ylmethoxy)-biphenyl-3-ylmethyl]-
-phenyl}-urea (P-563). Compound P-562 was synthesized by a route
analogous to that reported for P-554 (Example 104)
[0474] 1H NMR (400 MHz, DMSO-d.sub.6) 9.25 (br s, 1H), 8.77 (br s,
1H), 8.49 (s, 1H), 7.57 (s, 1H), 7.37-7.46 (m, 3H), 7.28 (d, J=8.4
Hz, 1H), 7.19 (overlap, 2H), 7.08 (d, overlap, J=8.4 Hz, 3H),
4.09-4.22 (m, 2H), 3.84 (overlap, 1H), 3.13 (m, 1H), 2.97 (m, 1H),
2.05 (m, 1H), 1.71-1.83 (m, 3H) ppm.
Example 110
Preparation of P-565
##STR00173##
[0475]
{4-[3'-Chloro-6-((R)-1-methyl-pyrrolidin-3-yloxy)-biphenyl-3-ylmeth-
yl]-phenyl}-urea (P-565). Compound P-562 was synthesized by a route
analogous to that reported for P-554 (Example 104)
[0476] 1H NMR (400 MHz, CDCl.sub.3) 7.51 (t, 1H), 7.35-7.38 (m,
1H), 7.23-7.31 (m, 4H), 7.13 (d, J=8.4 Hz), 7.11 (s, 1H), 7.06 (dd,
J=8.4, 2.4 Hz, 1H), 6.95 (br s, 1H), 6.78 (d, J=8.4 Hz, 1H), 4.8
(br s, 2H), 4.75 (m, 1H), 3.89 (s, 2H), 3.06 (t, 2H), 2.62 (m, 2H),
2.36 (s, 3H), 2.17-2.24 (m, 1H), 1.93-1.98 (m, 1H) ppm. APCI (M+1;
436) LCMS 98%.
Example 111
Preparation of P-550
##STR00174##
[0478] Synthesis of
1-bromo-5-bromomethyl-3-fluoro-2-methoxy-benzene (I-137). To a
heated (80.degree. C.) and stirred solution of
4-bromomethyl-2-fluoro-1-methoxy-benzene (1.0 g, 4.57 mmol) in
acetic acid (4 mL) was added a solution of bromine (1.09 g, 6.85
mmol) in acetic acid (2 mL) over 30 min. The reaction mixture was
stirred at 80.degree. C. for 18 h, cooled to room temperature, and
poured on to crushed ice-water (50 mL). Ammonium hydroxide solution
(28%) was added to pH 8, extracted with dichloromethane (2.times.40
mL), washed with water, dried over Na.sub.2SO.sub.4, filtered, and
concentrated under vacuum. The residue was purified by silica gel
column chromatography using 5% ethyl acetate in hexanes to afford
I-137 (0.43 g, 31% yield) as a viscous liquid.
[0479] Synthesis of
4-(3-bromo-5-fluoro-4-methoxy-benzyl)-phenyl]urea (I-138): To I-137
(0.2 g, 0.67 mmol),
[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea
(0.19 g, 0.74 mmol), and Pd(Ph.sub.3P).sub.4 (0.04 g, 0.04 mmol),
was added toluene (8 mL), EtOH (2 mL) and 2 M aqueous
Na.sub.2CO.sub.3 solution (0.7 mL, 1.4 mmol). The suspension was
degassed by bubbling argon gas for 15 min. The reaction was stirred
at 60.degree. C. under an argon atmosphere for 24 h. The reaction
was cooled to room temperature, and H.sub.2O (20 mL) and ethyl
acetate (30 mL) were added. The layers were separated and the
aqueous wash extracted with ethyl acetate (2.times.20 mL). The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered, and concentratedunder vacuum. The residue was triturated
with dichloromethane to afford I-138 (0.18 g, 77% yield) as yellow
solid.
[0480] Synthesis of
[4-(3'-chloro-5-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-550): To a suspension of I-138 (0.11 g, 0.31 mmol),
3-chlorophenylboronic acid (0.05 g, 0.34 mmol) and
Pd(Ph.sub.3P).sub.4 (0.02 g, 0.02 mmol) was added toluene (6 mL),
EtOH (1.5 mL) and 2 M aqueous NaCO.sub.3 solution (0.31 mL, 0.62
mmol). The reaction was degassed with an argon stream for 15 min.
The reaction was stirred at 80.degree. C. under an argon atmosphere
for 18 h. The reaction was cooled to room temperature, and H.sub.2O
(20 mL) and ethyl acetate (20 mL) were added. The layers were
separated and the aqueous wash was extracted with ethyl acetate
(2.times.10 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
residue was purified by preparative thin layer chromatography using
8% methanol in dichloromethane to afford P-550 (0.064 g, 53% yield)
as an off-white solid. 1H NMR (DMSO-d.sub.6, 400 MHz): 8.42 (s,
1H), 7.41-7.54 (m, 4H), 7.30 (d, J=8.4 Hz, 2H), 7.1-7.17 (m, 3H),
7.08 (s, 1H), 5.77 (s, 2H), 3.85 (s, 2H), 3.64 (s, 3H); MS (APCI+):
485.1 (M+1), LC-MS: 99.1%; HPLC 96.8% pure.
Example 112
Preparation of P-558
##STR00175##
[0482] Synthesis of
(4-amino-phenyl)-(3'-chloro-6-methoxy-biphenyl-3-yl)-methanone
(P-558). To a solution of I-129 (500 mg, 1.3 mmol) in EtOH-H.sub.2O
(1:1, 15 mL) was added NH.sub.4Cl (200 mg, 4 mmol) and iron powder
(150 mg, 3 mmol). The reaction mixture was stirred at room
temperature for 72 h. The mixture was poured into water (50 mL),
extracted with ethyl acetate (3.times.30 mL), washed with water (20
mL) and brine (30 mL), dried over Na.sub.2SO.sub.4, and filtered.
The solvent was removed under vacuum to yield P-558 (420 mg, 85%
yield). 1H NMR (DMSO-d.sub.6, 400 MHz) 7.70 (dd, J=8.4, 2.4 Hz,
1H), 7.40-7.57 (m, 7H), 7.25 (d, J=8.8 Hz, 1H), 6.61 (d, J=8.8 Hz,
2H), 6.09 (s, 2H), 3.88 (s, 3H) ppm. Calc. 337.8; APCI.sup.+ (M+1):
338, 98%.
Example 113
P-566
##STR00176##
[0484]
1-[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-3-(tetrahydr-
o-furan-2-yl)-urea (P-566). 1H NMR (DMSO-d.sub.6,400 MHz): 8.27 (s,
1H), 7.47-7.50 (m, 1H), 7.34-7.45 (m, 3H), 7.27-7.32 (m, 2H),
7.09-7.21 (m, 4H), 7.03 (d, J=8.4 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H),
5.52-5.48 (m, 1H), 3.84 (s, 2H), 3.73 (s, 3H), 3.70-3.79 (m, 1H),
3.62-3.69 (m, 1H), 1.99-2.11 (m, 1H), 1.79-1.91 (m, 2H), 1.57-1.69
(m, 1H) ppm.
Example 114
Preparation of P-523 and P-533
##STR00177##
[0486] Synthesis of
(R)-2-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylo-
xymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (I-139). A
mixture of N-boc-D-prolinol (225 mg, 1.12 mmol) and sodium hydride
(60% weight dispersion, 66 mg, 1.68 mmol) in dimethylformamide (2
mL) was stirred until gas evolution ceased. After 2 min of stirring
P-456 (194 mg, 0.56 mmol) was added, and the reaction heated at
120.degree. C. overnight. The reaction was cooled to room
temperature, diluted ethyl acetate (10 mL), washed with water (10
mL), and the aqueous wash extracted with ethyl acetate (25 mL). The
combined extracts were dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The residue was purified by silica
gel column chromatography (9:1 hexanes/ethyl acetate) to give I-139
(60.4 mg, 25% yield) as a thick colorless oil.
[0487] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-(R)-1-pyrrolidin-2-
-ylmethoxy)-pyridine (P-523). A biphasic solution of I-139 (60 mg,
0.11 mmol) and trifluoroacetic acid (851 mg, 0.75 mmol) in
dichloromethane (2 mL) and water (0.5 mL) was heated to 80.degree.
C. for 4 h. The mixture was concentrated under vacuum, and the
residue purified by silica gel column chromatography (9:1
dichloromethane/methanol) to give P-523 (32.4 mg, 69% yield).
LCMS=100% purity.
[0488] Synthesis of
(R)-2-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylo-
xymethyl]-pyrrolidine-1-carboxylic acid ethylamide (P-533). A
solution of P-523 (235 mg, 0.55 mmol) and ethyl isocyanate (0.2 mL,
2.8 mmol) in pyridine (1 mL) was stirred at room temperature
overnight. The reaction was diluted with water (5 mL), extracted
with ethyl acetate (2.times.3 mL), and the extracts combined. The
organic solution was dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The residue was purified by silica
gel column chromatography (19:1 dichloromethane/methanol) to give
P-533 (92.1 mg, 34% yield). A portion of P-533 (19.0 mg) was
further purified by a sodium bicarbonate wash, and silica gel
preparatory thin layer chromatography (9:1
dichloromethane/methanol) to give (14.1 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 1.03 (t, J=7.2 Hz, 3H), 1.80-1.95 (m, 4H), 3.07 (m,
2H), 3.18 (m, 1H), 3.30 (m, 1H), 3.72 (s, 3H), 3.87 (s, 2H), 3.97
(m, 1H), 4.05 (m, 1H), 4.28 (m, 1H), 6.22 (t, J=5.2 Hz, 1H), 6.76
(d, J=8.4 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.26-7.32 (m, 2H), 7.36
(s, 1H), 7.39-7.50 (m, 2H), 7.55 (dd, J=8.4, 2.2 Hz, 1H), 8.03 (d,
J=2.01 Hz, 1H) ppm. MS (APCI+): 498.2 (M+1), LC-MS: 92.2%.
Example 115
Preparation of P-568
##STR00178##
[0490] Synthesis of
2-azetidin-1-yl-5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine
(P-568): To a mixture of I-140 (0.15 g, 0.46 mmol) and azetidine
(0.09 g, 0.92 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.35 g, 2.29 mmol). The reaction mixture was stirred and at
85.degree. C. for 15 min. The reaction was then cooled to room
temperature, diluted with dichloromethane (6 mL), washed with 0.5 N
aqueous HCl (2.times.4 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by silica gel column
chromatography using 3% methanol in dichloromethane followed by
preparative thin layer chromatography using 5% methanol in
dichloromethane to afford P-568 (0.05 g, 30% yield) as a viscous
liquid. 1H NMR (DMSO-d.sub.6, 400 MHz): 7.99 (d, J=1.6 Hz, 1H),
7.34-7.49 (m, 5H), 7.14-7.2 (m, 2H), 7.04 (d, J=8.8 Hz, 1H), 6.28
(dd, J=8.4, 0.8 Hz, 1H), 3.86 (t, J=7.2 Hz, 4H), 3.77 (s, 2H), 3.74
(s, 3H), 2.22-2.32 (m, 2H);
[0491] MS (APCI+): 365.1 (M+1), LC-MS: 100%.
Example 116
Preparation of P-571
##STR00179##
[0493] Synthesis of
1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-aze-
tidine-2-carboxylic acid amide (P-571): To a cooled (0.degree. C.)
solution of I-141 (0.23 g, 0.54 mmol) in THF (10 mL) was added
N-methylmorpholine (0.05 g, 0.54 mmol). The reaction mixture was
stirred for 5 min, and isobutylchloroformate (0.07 g, 0.54 mmol)
was added. The reaction was stirred at 0.degree. C. for 45 min, and
ammonium hydroxide (28%, 4.0 mL) was added. The reaction was warmed
to room temperature, stirred for 1.5 h, and diluted with water (5
mL). The organic layer was separated, the aqueous layer extracted
with ethyl acetate (2.times.20 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by silica gel column chromatography using 5%
methanol in dichloromethane, and preparative thin layer
chromatography using 5% methanol in dichloromethane to afford P-571
(0.03 g, 13% yield) as off-white solid. 1H NMR (DMSO-d.sub.6, 400
MHz): 7.99 (d, J=2.0 Hz, 1H), 7.51 (br s, 1H), 7.4-7.48 (m, 3H),
7.36 (s, 1H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.8 Hz,
1H), 6.34 (d, J=8.4 Hz, 1H), 4.39 (dd, J=9.2, 6.4 Hz, 1H), 3.7-3.9
(m, 2H), 3.8 (s, 2H), 3.72 (s, 3H), 2.26-2.46 (m, 2H); MS (APCI+):
426.1 (M+1), LC-MS: 94.3%.
Example 117
Preparation of P-572
##STR00180##
[0495] Synthesis of
4-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-morpholine
(P-572). To I-140 (0.15 g, 0.46 mmol) and morpholine (0.08 g, 0.92
mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 g, 2.29
mmol). The reaction mixture was stirred at 160.degree. C. for 6 h.
The reaction was cooled to room temperature, diluted with
dichloromethane (6 mL), washed with 0.5 N aqueous HCl (2.times.4
mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum. The residue was purified by silica gel column
chromatography using 3% methanol in dichloromethane to afford P-572
(0.042 g, 23% yield) as a viscous liquid. 1H NMR (DMSO-d.sub.6, 400
MHz): 8.07 (d, J=2.8 Hz, 1H), 7.38-7.45 (m, 5H), 7.16-7.24 (m, 2H),
7.04 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 3.8 (s, 2H), 3.74
(s, 3H), 3.67 (t, J=4.8 Hz, 4H), 3.36 (t, J=4.8 Hz, 4H); MS
(APCI+): 395.1 (M+1), LC-MS: 95.1%.
Example 118
Preparation of P-581
##STR00181##
[0497] Synthesis of
2-{(S)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2--
yl]-pyrrolidin-2-yl}-propan-2-ol (P-581). To a cooled (0.degree.
C.) and solution of I-142 (0.05 g, 0.11 mmol) in THF (8.0 mL) was
added methylmagnesium bromide (3M sol, 0.26 mL, 0.88 mmol). The
reaction mixture was slowly warmed to room temperature, and stirred
for 3 h. The reaction was then cooled to 0.degree. C., and
saturated aqueous ammonium chloride solution (5 mL), was added. The
aqueous suspensions was extracted with diethyl ether (2.times.30
mL), washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to afford P-581 (0.046 g,
88% yield) as an off-white solid. 1H NMR (DMSO-d.sub.6, 400 MHz):
7.90 (d, J=2.4 Hz, 1H), 7.75 (br s, 1H), 7.36-7.48 (m, 4H),
7.26-7.32 (m, 2H), 6.92 (d, J=8.8 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H),
6.33 (br s, 1H), 4.0-4.08 (m, 1H), 3.79 (s, 2H), 3.72 (s, 3H),
3.3-3.45 (m, 2H), 1.7-2.0 (m, 4H), 1.11 (s, 3H), 0.98 (s, 3H);
[0498] MS (APCI+): 455.1 (M+1), LC-MS: 97.5%.
Example 119
Preparation of P-601
##STR00182##
[0500] Synthesis of
1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pyr-
rolidin-3-ol (P-601). To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456, 0.3 g, 0.87 mmol) and 3-pyrrolidinol (2) (0.15 g, 1.74
mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.66 g,
4.34 mmol). The reaction mixture was stirred and heated at
100.degree. C. for 2.5 h, cooled to room temperature, diluted with
dichloromethane (8 mL), washed with 0.5 N HCl (2.times.4 mL), dried
with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane to afford 0.27 g (75%) of P-601 as white solid. 1H
NMR (DMSO-d.sub.6, 400 MHz): 7.95 (s, 1H), 7.2-7.46 (m, 6H), 6.91
(d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.9 (d, J=3.6 Hz, 1H),
4.32-4.4 (m, 1H), 3.76 (s, 2H), 3.71 (s, 3H), 3.12-3.45 (m, 4H),
1.8-2.05 (m, 2H) ppm; MS (APCI+): 413.1 (M+1), LC-MS: 91.6%.
Example 120
Preparation of P-602
##STR00183##
[0502] Synthesis of
1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pyrrolidin-3-
-ol (P-602): To
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(I-140, 0.22 g, 0.67 mmol) and 3-pyrrolidinol (2) (0.12 g, 1.34
mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.51 g,
3.36 mmol). The reaction mixture was stirred and heated at
100.degree. C. for 1.5 h, cooled to room temperature, diluted with
dichloromethane (8 mL), washed with 0.5 N HCl (2.times.4 mL), dried
with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane to afford 0.13 g (49%) of P-602 as white solid. 1H
NMR (DMSO-d.sub.6, 400 MHz): 7.9 (d, J=2.4 Hz, 1H), 7.3-7.49 (m,
5H), 7.12-7.2 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.8 Hz,
1H), 4.89 (d, J=3.6 Hz, 1H), 4.35 (br s, 1H), 3.76 (s, 2H), 3.73
(s, 3H), 3.2-3.45 (m, 4H), 1.8-2.05 (m, 2H) ppm; MS (APCI+): 395.1
(M+1), LC-MS: 99.1%.
Example 121
Preparation of P-612
##STR00184##
[0504] Synthesis of
(S)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-pyrrolidine-2-carboxylic acid amide (P-612): To a cooled
(0-5.degree. C.) and stirred solution of
(S)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-pyrrolidine-2-carboxylic acid (I-143, 0.15 g, 0.34 mmol) in THF (2
mL) was added diisopropylethylamine (0.05 g, 0.37 mmol). The
reaction mixture was stirred for 5 min, isobutylchloroformate (0.05
g, 0.37 mmol) was added, stirred at 0-5.degree. C. for 45 min.
Ammonium hydroxide (28%, 4.0 mL) was added, the reaction warmed to
ambient temperature, stirred for 1.5 h. The reaction mixture was
diluted with water (5 mL). The organic layer was separated, the
aqueous layer was extracted with ethyl acetate (2.times.20 mL). The
combined organic layers were dried with Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by silica gel column
chromatography using 5% methanol in dichloromethane followed by
preparative thin layer chromatography using 5% methanol in
dichloromethane to afford 0.074 g (49%) of P-612 as an off-white
solid. 1H NMR (DMSO-d.sub.6, 400 MHz): 8.27 (d, J=2.4 Hz, 1H),
7.34-7.46 (m, 4H), 8.2 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz,
1H), 7.4-7.46 (m, 2H), 7.37 (br s, 1H), 7.26-7.38 (m, 2H), 6.94 (d,
J=8.0 Hz, 1H), 3.92-3.98 (m 3H), 3.93 (s, 2H), 3.73 (s, 3H), 2.55
(t, J=8.4 Hz, 2H), 1.98-2.06 (m, 2H) ppm; MS (APCI+): 441.1 (M+1),
LC-MS: 97.0%; HPLC 97.1% pure.
Example 122
Preparation of P-615
##STR00185##
[0506] Synthesis of
(S)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid amide (P-615). To a cooled (0-5.degree.
C.) and stirred solution of
(S)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid (I-143, 0.22 g, 0.54 mmol) in THF (2.5
mL) was added N,N-diisopropylethylamine (0.07 g, 0.57 mmol). The
reaction mixture was stirred for 5 min, isobutylchloroformate (0.08
g, 0.57 mmol) was added, stirred at 0-5.degree. C. for 45 min.
Ammonia in methanol (7M sol, 1.0 mL, 7.0 mmol) was added, the
reaction warmed to room temperature, and stirred for 0.5 h. The
reaction mixture was diluted with water (5 mL). The organic layer
was separated, the aqueous layer was extracted with ethyl acetate
(2.times.20 mL). The combined organic layers were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane, followed by preparative thin layer chromatography
using 5% methanol in dichloromethane to afford 0.06 g (27%) of
P-615 as an off-white solid. 1H NMR (DMSO-d.sub.6, 400 MHz): 7.99
(d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.34-7.46 (m, 4H), 7.24-7.3 (m,
2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz,
1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.8 (s, 2H),
3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm;
[0507] MS (APCI+): 426.6 (M+1), LC-MS: 98.0%.
Example 123
Preparation of P-617
##STR00186##
[0509] Synthesis of
(R)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid amide (P-617). To a cooled 0-5.degree.
C. and stirred solution of
(R)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid (I-144, 0.14 g, 0.33 mmol) in THF (2.5
mL) was added N,N-diisopropylethylamine (0.09 g, 0.69 mmol). The
reaction mixture was stirred for 5 min, isobutylchloroformate (0.05
g, 0.36 mmol) was added, and the reaction stirred at 0-5.degree. C.
for 30 min. Ammonium hydroxide solution (28%, 1.0 mL, 8.0 mmol) was
added, the reaction warmed to room temperature, and stirred for 0.5
h. The reaction mixture was diluted with water (5 mL). The organic
layer was separated, the aqueous layer was extracted with ethyl
acetate (2.times.20 mL). The combined organic layers were dried
with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane, followed by preparative thin layer chromatography
using 5% methanol in dichloromethane to afford 0.07 g (47%) of
P-617 as an off-white solid. 1H NMR (DMSO-d.sub.6, 400 MHz): 7.99
(d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.38-7.46 (m, 3H), 7.4 (br s,
1H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H),
6.34 (d, J=8.0 Hz, 1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m,
2H), 3.84 (s, 2H), 3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm; MS (APCI+):
426.9 (M+1), LC-MS: 100%.
Example 124
Preparation of P-615-HCl
##STR00187##
[0511] Synthesis of
(S)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid amide hydrochloride (P-615-HCl). To a
cooled (0-5.degree. C.) and stirred solution of
(S)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid amide (P-615, 0.04 g, 0.1 mmol) in
ether (2 mL) was added 2M HCl in ether (0.5 ml, 1.0 mmol), and the
reaction, stirred for 1 h. The ether layer was removed, again
triturated with ether (2.0 mL), concentrated to afford 0.045 g
(98%) of P-615-HCl as a white solid. 1H NMR (DMSO-d.sub.6, 400
MHz): 7.92 (d, J=2.0 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.69 (br s,
1H), 7.26-7.48 (m, 6H), 6.95 (d, J=8.8 Hz, 1H), 6.72 (d, J=9.2 Hz,
1H), 4.8-4.9 (m, 1H), 4.0-4.18 (m, 2H), 3.89 (s, 2H), 3.73 (s, 3H),
2.64-2.74 (m 1H), 2.26-2.34 (m, 1H) ppm; MS (APCI+): 426.16 (M+1),
LC-MS: 98.8%; HPLC 98.3% pure.
Example 125
Preparation of P-617-HCl
##STR00188##
[0513] Synthesis of
(R)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-azetidine-2-carboxylic acid amide hydrochloride (P-617-HCl): To a
cooled (0-5.degree. C.) and stirred solution of
(R)-1-[5-(3'-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]--
azetidine-2-carboxylic acid (P-617, 0.057 g, 0.13 mmol) in ether (2
mL) was added 2M HCl in ether (0.65 ml, 1.3 mmol) and the reaction
stirred for 1 h. The ether layer was removed, again triturated with
ether (2.0 mL), concentrated to afford 0.059 g (98%) of P-617-HCl
as a white solid. 1H NMR (DMSO-d.sub.6, 400 MHz): 7.92 (d, J=2.0
Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.69 (br s, 1H), 7.26-7.48 (m,
6H), 6.95 (d, J=8.8 Hz, 1H), 6.72 (d, J=7.62 Hz, 1H), 4.8-4.9 (m,
1H), 4.0-4.16 (m, 2H), 3.89 (s, 2H), 3.73 (s, 3H), 2.64-2.74 (m
1H), 2.26-2.36 (m, 1H) ppm; MS (APCI+): 426.16 (M+1), LC-MS: 95.8%;
HPLC 97.3% pure.
##STR00189##
Example 126
Preparation of P-569
[0514] Synthesis of
5-(3'Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456). In a 250 mL round bottomed flask equipped with a
condenser, nitrogen lines and a stir bar was placed carbonic acid
3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl methylcarbonate
(I-145, 3.61 g, 11.1 mmol), 2-fluoropyridineboronic acid (1.72 g,
12.2 mmol), potassium carbonate (4.60 g, 33.3 mmol),
1,5-bis(diphenylphosphino)pentane (1.47 g, 3.33 mmol) and DMF (56
mL). The reaction mixture was degassed for 15 minutes by bubbling
nitrogen and then allylpalladium(II) chloride dimer (609 mg, 1.67
mmol) was added. The reaction mixture was heated to 85.degree. C.
for 18 hours. To the reaction mixture was added water (80 mL), and
saturated ammonium chloride (150 mL). The aqueous portion was
extracted with ethyl acetate (3.times.125 mL). The organic portions
were combined, washed with brine (150 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by column
chromatography utilizing 10% hexanes/dichloromethane as the eluent
to produce 2.45 g of P-456 as a pale yellow solid in 64% yield.
[0515] Synthesis of
2-Azetidin-1-yl-5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyri-
dine (P-569). In an 8 mL vial equipped with a stir bar was placed
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456,150 mg, 0.434 mmol), azetidine (88.0 uL, 1.30 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (306 uL, 2.17 mmol). The mixture
was heated to 160.degree. C. for 1 hour and then cooled to room
temperature. The reaction mixture was treated with water (4 mL) and
1M HCl (6 mL). The aqueous portion was extracted with
dichloromethane (2.times.30 mL), the organic portions were
combined, washed with brine (15 mL), dried (MgSO.sub.4) and
concentrated to produce 156 mg of P-569 as a white solid in 94%
yield.
[0516] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.37-2.44 (m,
2H), 3.73 (s, 3H), 3.87 (s, 2H), 4.19 (t, J=8 Hz, 4H), 6.76 (bd,
J=9 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 7.28 (bd, J=7 Hz, 1H), 7.33 (d,
J=8 Hz, 1H), 7.36 (bs, 1H), 7.42-7.48 (m, 2H), 7.76 (bd, J=9 Hz,
1H), 7.86 (s, 1H) ppm. MS (APCI+): 383.1 (M+1) LC-MS: 96%
Example 127
Preparation of P-577
[0517] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-((2S,5S)-2,5-dimet-
hyl-pyrrolidin-1-yl)-pyridine (P-577): In an 8 mL vial equipped
with a stir bar was placed
5-(3'Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456, 100 mg, 0.289 mmol), (2S,5S)-2,5-dimethyl-pyrrolidine (176
mg, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (367 uL, 2.60
mmol). The mixture was heated to 160.degree. C. for 3 hours and
then cooled to room temperature. The reaction mixture was treated
with water (4 mL) and 1M HCl (6 mL). The aqueous portion was
extracted with dichloromethane (2.times.30 mL), the organic
portions were combined, washed with brine (15 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
silica gel column chromatography utilizing 5%
acetone/dichloromethane as the eluent to produce 10 mg of P-577 as
a pale viscous oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.05 (d, J=6 Hz, 6H), 1.56-1.61 (m, 4H), 3.72 (s, 3H), 3.75 (s,
2H), 4.07-4.12 (m, 2H), 6.38 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H),
7.27-7.32 (m, 3H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2
Hz, 1H) ppm.
[0518] MS (APCI+): 425.1 (M+1) LC-MS: 92%
Example 128
Preparation of P-582
[0519] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-pyrrolidin-1-yl-py-
ridine (P-582). In an 8 mL vial equipped with a stir bar was placed
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456,100 mg, 0.289 mmol), pyrrolidine (60.3 uL, 0.723 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (204 uL, 1.45 mmol). The mixture
was heated to 160.degree. C. for 30 minutes and then cooled to room
temperature. The reaction mixture was diluted with dichloromethane
(25 mL) and washed with 0.5M HCl (3.times.10 mL). The combined
aqueous portions were extracted with dichloromethane (15 mL), the
organic portions were combined, washed with brine (15 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
silica gel column chromatography utilizing 10%
acetone/dichloromethane as the eluent to produce 79 mg of P-582 as
a pale orange semisolid in 69% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.89-1.93 (m, 4H), 3.31-3.34 (m, 4H), 3.71
(s, 3H), 3.77 (s, 2H), 6.37 (d, J=9 Hz, 1H), 6.91 (d, J=9 Hz, 1H),
7.23-7.28 (m, 2H), 7.32 (dd, J=9, 2 Hz, 1H), 7.36 (s, 1H),
7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 397.1
(M+1) LC-MS: 98%
##STR00190##
Example 129
Preparation of P-587
[0520] Synthesis of
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid methyl ester (I-146). In a 250 mL round bottomed flask
equipped with a condenser, nitrogen lines and a stir bar was placed
carbonic acid 3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl
methylcarbonate (I-145, 3.60 g, 11.1 mmol),
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic
acid methyl ester (3.21 g, 12.2 mmol), potassium carbonate (4.60 g,
33.3 mmol), 1,5-bis(diphenylphosphino) pentane (1.47 g, 3.33 mmol)
and DMF (56 mL). The reaction mixture was degassed for 15 minutes
by bubbling nitrogen and then allylpalladium(II) chloride dimer
(609 mg, 1.67 mmol) was added. The reaction mixture was heated to
85.degree. C. for 8 hours. After the addition of water (50 mL) and
dichlormethane (100 mL), the mixture was filtered through Celite.
The layers were separated and the aqueous portion was extracted
with dichlormethane (75 mL). The organic portions were combined,
washed with brine (150 mL), dried (MgSO.sub.4) and concentrated.
The crude material was purified by column chromatography utilizing
a gradient elution of 1%, 5%, 10% acetone/dichloromethane as the
eluent to produce 3.13 g of I-146 as an orange-yellow viscous oil
with solids forming in 73% yield.
[0521] Synthesis of
2-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pro-
pan-2-ol hydrochloride (P-587). In a 100 mL round bottomed flask
was placed
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-ca-
rboxylic acid methyl ester (I-146, 2.0 g, 5.18 mmol) and
tetrahydrofuran (26 ml). The solution was cooled to 0.degree. C.
and then a solution of methylmagnesium bromide (3M in diethyl
ether) (8.6 mL, 25.9 mmol) was added over a 10 minute period. The
mixture was stirred at 0.degree. C. for 5 minutes and then at room
temperature for 3 hours. The reaction mixture was concentrated by a
stream of nitrogen, cooled to 0.degree. C. and then quenched slowly
with saturated ammonium chloride (20 mL). The aqueous portion was
extracted with ethyl acetate (3.times.40 mL), the organic portions
were combined, washed with brine (25 mL), (MgSO.sub.4) and
concentrated. The crude material was purified by column
chromatography utilizing 7% acetone/DCM as the eluent to produce a
colorless viscous oil. This product was combined with material
isolated from a 1.04 g run of the exact same reaction conditions
and purification (442 mg as a white semi-solid isolated from the
1.04 gram run). The combined lots were purified by silica gel
column chromatography utilizing a gradient elution of 50%, then 60%
ethyl acetate/hexanes as the eluent to produce 1.33 g of P-587 as a
colorless, viscous oil in 44% yield. In an 18 mL vial equipped with
a stir bar was placed P-587 (325 mg, 0.842 mmol), diethyl ether
(3.5 mL) followed by 2M HCl in diethyl ether (1.5 mL, 3.00 mmol).
The mixture was stirred for 45 minutes, concentrated by stream of
nitrogen and then dried in a high vacuum oven set at 40.degree. C.
for 18 hours to produce 355 mg of P-587 HCl salt as an off-white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.53 (s, 6H),
3.74 (s, 3H), 4.13 (s, 2H), 6.98 (d, J=8 Hz, 1H), 7.29 (bd, J=7 Hz,
1H), 7.38 (s, 1H), 7.40-7.48 (m, 3H), 7.95 (bd, J=8 Hz, 1H), 8.18
(bs, 1H), 8.56 (s, 1H) ppm. MS (APCI+): 386.1 (M+1). HPLC purity:
98.8%.
Example 130
Preparation of P-599
[0522] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-metha-
nol (P-599). In an 8 mL vial equipped with a stir bar was placed
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid methyl ester (I-146, 100 mg, 0.259 mmol) and tetrahydrofuran
(1.3 mL). The solution was cooled to 0.degree. C. and then lithium
aluminum hydride (39.3 mg, 1.04 mmol) was added resulting in strong
gas evolution. Then mixture was stirred at 0.degree. C. for 1 hour
and then concentrated with a stream of nitrogen. The solid was
diluted with dichloromethane (2 mL) and then slowly quenched with
water (7 mL). The aqueous portion was extracted with DCM (3.times.6
mL), the organic portions were combined, filtered through Celite,
dried (MgSO.sub.4) and concentrated. The crude material was
purified by silica gel column chromatography utilizing 30%
acetone/dichloromethane to produce 22 mg of P-599 as a pale orange
viscous oil in 24% yield.
[0523] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.72 (s, 3H),
3.95 (s, 2H), 4.51 (s, 2H), 5.33 (bs, 1H), 6.94 (d, J=9 Hz, 1H),
7.27-7.46 (m, 6H), 7.61 (bd, J=8 Hz, 1H), 8.38 (s, 1H) ppm. MS
(APCI+): 358.1 (M+1) LC-MS: 96%.
Example 131
Preparation of P-588
##STR00191##
[0525] Synthesis of
{2-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yloxy]-
-ethyl}-dimethyl-amine (P-588). In an 8 mL vial equipped with a
stir bar was sodium hydride (34.7 mg, 0.867 mmol), THF (1.1 mL) and
2-diemethylamino-ethanol (87.2 uL, 0.867 mmol. The mixture was
stirred for 5 minutes and then a solution of
5-(3'Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456, 100 mg, 0.289 mmol) and THF (1.1 mL) was added. After
stirring at 60.degree. C. for 2 hours, the reaction was combined
with a previous run (30 mg scale) and the quenched with water (20
mL). After extractions with ethyl acetate (2.times.30 mL),), the
organic portions were combined, dried (MgSO.sub.4), concentrated
and dried in a high vacuum oven at 60.degree. C. for 18 hours to
produce 136 mg of P-588 as a cloudy, pale yellow viscous oil in 87%
yield.
[0526] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.18 (s, 6H),
2.57 (t, J=6 Hz, 2H), 3.72 (s, 3H), 3.87 (s, 2H), 4.28 (t, J=6 Hz,
2H), 6.73 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.27-7.29 (m, 1H),
7.32 (d, J=9 Hz, 1H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.53 (dd,
J=8, 2 Hz, 1H), 8.03 (br s, 1H). MS (APCI+): 415.1 (M+1) LC-MS:
>99%.
Example 132
Preparation of P-595
##STR00192##
[0528] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-1-m-
ethyl-ethylamine (P-595). In an 18 mL vial equipped with a stir bar
was placed cerium (III) chloride (315 mg, 1.28 mmol) which was
placed under and vacuum and heated with heat gun to remove residual
moisture. Then, THF (2 mL) was added and the mixture was cooled to
0.degree. C. and stirred for 1 hour and then at room temperature
for 25 minutes. After cooling to -78.degree. C. for 15 minutes,
methyl lithium (1.6M in diethyl ether) (800 uL, 1.28 mmol) was
added and the mixture was stirred at -78.degree. C. for 15
additional minutes. After this time period, a solution of
5-(3'-Chloro2-fluoro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-ca-
rbonitrile (P-355, 150 mg, 0.425 mmol) and THF (800 uL) was added
and the mixture was stirred at -78.degree. C. for 1 hour and then
reacted at room temperature for 2 hours. Additional methyl lithium
(1.6M in diethyl ether) (530 uL, 0.850 mmol) was introduced after
cooling to 0.degree. C. and the mixture was allowed to react at
room temperature for 1 hour. The reaction was then cooled to
0.degree. C. and quenched with isopropanol (2 mL). After filtration
through Celite, the filtrate was concentrated and then combined
with material from a previous run (30 mg scale). The combined
material was purified by silica gel column chromatography utilizing
gradient elution of 10% 1M NH.sub.3 in MeOH/dichloromethane and
then 20% to produce 17 mg of P-595 as a dark orange oil in 8%
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.35 (s, 6H),
3.72 (s, 3H), 3.93 (s, 2H), 6.95 (d, J=8 Hz, 1H), 7.27-7.47 (m,
6H), 7.55 (s, 1H), 8.40 (s, 1H) ppm.
[0529] MS (APCI+): 385.1 (M+1).
##STR00193##
Example 133
Preparation of P-596
[0530] Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitri-
le (I-148). In a 40 mL vial equipped with a stir bar was placed
I-147 (1.0 g, 2.88 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
(729 mg, 3.17 mmol), tetrakis(triphenylphosphine)palladium (166 mg,
0.144 mmol), ethanol (4.4 mL) and toluene (17.6 mL). After stirring
for 5 minutes, a 2M aqueous solution of sodium carbonate (2.88 mL)
was added and the reaction mixture was degassed by bubbling
nitrogen through the mixture. After heating at 80.degree. C. for
2.5 hours, the reaction was filtered through Celite and the
filtrate was diluted with water (40 mL) and extracted with ethyl
acetate (2.times.60 mL). The organic portions were combined, dried
(MgSO.sub.4), concentrated and purified by silica gel column
chromatography utilizing 40% ethyl acetate/hexanes as the eluent to
produce 859 mg of I-148 as a yellow viscous oil in 80% yield.
[0531] Synthesis of
C-[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-meth-
ylamine (P-596). In a 40 mL vial equipped with a stir bar was
placed
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitri-
le (I-148, 860 mg, 2.32 mmol), methanol (20 mL) concentrated HCl
(967 uL, 11.6 mmol) and 10% Pd/C. The reaction is allowed to stir
at ambient temperature for 6 hours under a hydrogen atmosphere.
After filtering the mixture through Celite, the filtrate is
concentrated, diluted with 0.5M HCl (20 mL) and water (20 mL)
followed by extractions with ethyl acetate (2.times.50 mL). The
organic portions were combined, dried (MgSO.sub.4), concentrated
and purified by silica gel column chromatography utilizing 10% 1M
NH.sub.3 in MeOH/dichloromethane as the eluent to produce 121 mg of
P-596 as a pale yellow solid in 14% yield.
[0532] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.12 (bs, 2H),
3.74 (s, 2H), 3.99 (s, 2H), 7.11 (t, J=74 Hz, 1H), 7.23 (d, J=8 Hz,
1H), 7.32-7.35 (m, 2H), 7.40-7.51 (m, 5H), 7.64 (dd, J=10, 2 Hz,
1H), 8.45 (s, 1H) ppm. MS (APCI+): 375.1 (M+1), LC-MS: 99%.
Example 134
Preparation of P-598
[0533] Synthesis of
[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]--
carbamic acid phenyl ester (I-149). In an 8 mL vial equipped with a
stir bar was placed
C-[5-(3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-meth-
ylamine (P-596, 115 mg, 0.307 mmol), dichloromethane (1.5 mL) and
triethylamine (85.6 uL, 0.614 mmol). The solution was cooled to
0.degree. C. and then phenyl chloroformate (57.8 uL, 0.461 mmol)
was added and the mixture was stirred at 0.degree. C. for 15
minutes. The reaction was quenched with water (3 mL) and then the
organic portion was removed. The aqueous portion was extracted with
dichloromethane (2 mL), the organic portions were combined, washed
with brine (3 mL), dried (MgSO.sub.4), concentrated and purified by
silica gel column chromatography utilizing 70% ethyl
acetate/hexanes as the eluent to produce 78 mg of I-149 as a yellow
viscous oil in 51% yield.
[0534] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 4.01 (s, 2H),
4.32 (d, J=6 Hz, 2H), 6.92-7.39 (m, 9H), 7.41-7.48 (m, 4H), 7.51
(s, 1H), 7.71 (dd, J=8, 2 Hz, 1H), 8.292 (t, J=6 Hz, 1H), 8.51 (d,
J=2 Hz, 1H). MS (APCI+): 495.1 (M+1). LC-MS: >99%.
[0535] Synthesis of
1-[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl-
]-3-methyl-urea hydrochloride (P-598). In an 8 mL vial equipped
with a stir bar was placed
5-(3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-c-
arbamic acid phenyl ester (I-149, 74 mg, 0.150 mmol),
tetrahydrofuran (300 uL) and methylamine (40 wt. % in water)(116
uL, 1.50 mmol). The solution was stirred at room temperature for 2
hours and then concentrated by a stream of nitrogen. The solid was
triturated with diethyl ether (2 mL), collected and washed with
diethyl ether (2 mL) to produce 48 mg of P-598 as a white solid. To
P-598 (41 mg, 0.0949) was added diethyl ether (2 mL) and 2M HCl in
diethyl ether (700 uL). The mixture was stirred at ambient
temperature for 2 hours, the solids collected, washed with diethyl
ether (1 mL) and dried in a high vacuum oven to produce 35 mg of
P-598 HCl salt as a white solid in 50% yield.
[0536] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.55 (s, 3H),
4.18 (s, 2H), 4.46 (s, 2H), 6.29 (bs, 1H), 6.78 (bs, 1H), 7.13 (t,
J=74 Hz, 1H), 7.27 (d, J=8 Hz, 1H), 7.42-7.49 (m, 5H), 7.52 (s,
1H), 7.76 (d, J=8 Hz, 1H), 8.39 (d, J=8 Hz, 1H), 8.79 (s, 1H).
[0537] MS (APCI+): 432.1 (M+1-HCl). LC-MS: >99%.
##STR00194##
Example 135
Preparation of P-606
[0538] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-eth-
ylamine (P-606). In a 40 mL vial equipped with a stir bar was
placed methylmagnesium bromide (3M in diethyl ether)(1.32 mL, 3.96
mmol), nitrogen in/out lines attached and the solution was cooled
to 0-5.degree. C. After the addition of a solution of
5-(3'-Chloro2-fluoro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-ca-
rbonitrile (P-355, 700 mg, 1.98 mmol) in tetrahydrofuran (10 mL),
the reaction was warmed to ambient temperature and stirred for 40
minutes. Additional methylmagnesium bromide (3M in diethyl
ether)(660 uL, 1.98 mmol) was introduced and the reaction was
heated to 60.degree. C. for 3 hours. The reaction was cooled to
0-5.degree. C. and a slurry of lithium aluminum hydride (150 mg,
3.96 mmol) in tetrahydrofuran (1 mL) was added. The reaction was
heated to 60.degree. C. for 1 hour and then partially concentrated,
cooled to 0-5.degree. C. and quenched with water (5 mL) and 1M NaOH
(3 mL). After the addition of ethyl acetate (10 mL), the reaction
was filtered through Celite and the filtrate layers were separated.
The aqueous portion was extracted with ethyl acetate (30 mL), the
organic portions were combined, dried (MgSO.sub.4), concentrated
and purified by a 50 gram silica gel SNAP cartridge (Biotage SP4
Flash Chromatography instrument) utilizing gradient elution of
5-40% MeOH/dichloromethane to produce 124 mg of P-606 as a yellow
viscous oil in 17% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.26 (d, J=7 Hz, 3H), 3.72 (s, 3H), 3.94 (s, 2H), 3.99 (q,
J=6 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.27-7.29 (m, 1H), 7.32-7.38 (m,
3H), 7.41-7.47 (m, 2H), 7.57 (dd, J=8, 2 Hz, 1H), 8.39 (s, 1H). MS
(APCI+): 372.3 (M+2). LC-MS: 95%
Example 136
Preparation of P-606-diHCl
[0539] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-eth-
ylamine dihydrochloride (P-606-diHCl): In an 8 mL vial equipped
with a stir bar was placed
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-eth-
ylamine (P-606, 115 mg, 0.311 mmol), diethyl ether (3 mL),
1,4-dioxane (300 uL) and 2M HCl in diethyl ether (600 uL). The
mixture was stirred at ambient temperature for 15 minutes, the
solid was collected, washed with diethyl ether (3 mL) and dried to
produce 98 mg of P-606-diHCl as a light tan solid in 71% yield.
[0540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.47 (d, J=7 Hz,
3H), 3.73 (s, 3H), 4.01 (s, 2H), 4.46-4.51 (m, 1H), 6.96 (d, J=8
Hz, 1H), 7.27 (d, J=6 Hz, 1H), 7.36 (s, 1H), 7.38-7.48 (m, 4H),
7.72 (dd, J=8, 2 Hz, 1H), 8.33 (bs, 3H), 8.55 (d, J=2 Hz, 1H).
[0541] MS (APCI+): 371.5 (M+1-2 HCl)
[0542] LC-MS: 92%
Example 137
Preparation of P-613
[0543] Synthesis of
{1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-et-
hyl}-urea hydrochloride (P-613): In an 8 mL vial equipped with a
stir bar was placed
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-eth-
ylamine dihydrochloride (P-606, 55 mg, 0.124 mmol), water (800 uL),
glacial acetic acid (400 uL) followed by sodium cyanate (32.2 mg,
0.496 mmol). The mixture was stirred at room temperature for 18
hours and then slowly quenched with a saturated solution of sodium
bicarbonate (3 mL) and extracted with dichloromethane (3.times.4
mL). The organic portions were combined, dried (MgSO.sub.4),
concentrated and purified by a 10 gram silica gel SNAP cartridge
(Biotage SP4 Flash Chromatography instrument) utilizing gradient
elution of 2-20% MeOH/dichloromethane to produce 13 mg of P-613
(free base) as an off-white solid in 25% yield. To P-613 (free
base) (13 mg, 0.0314 mmol) was added diethyl ether (1 mL) and 2M
HCl in diethyl ether (300 uL). The mixture was allowed to stir at
room temperature for 10 minutes, concentrated and dried to produce
14 mg of P-613 HCl salt as an off-white solid in quantitative
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.36 (d, J=7 Hz,
3H), 3.73 (s, 3H), 4.06 (s, 2H), 4.82 (m, 1H), 5.53 (br s, 2H),
6.69 (br s, 1H), 6.97 (d, J=9 Hz, 1H), 7.29 (br d, J=6 Hz, 1H),
7.38-7.47 (m, 4H), 7.60 (br d, J=8 Hz, 1H), 8.02 (br d, J=8 Hz,
1H), 8.58 (s, 1H) ppm.
##STR00195##
Example 138
Preparation of P-610
[0544] Synthesis of carbonic acid
3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester
(I-151). Compound I-151 was synthesized following the same
procedure as that for the generation of I-223.
[0545] Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid methyl ester (I-152). In a 40 mL vial equipped with a stir bar
was placed carbonic acid
3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester
(I-151, 700 mg, 2.04 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylicaci-
d methyl ester (590 mg, 2.24 mmol), potassium carbonate (846 mg,
6.12 mmol), 1,5-bis(diphenylphosphino)pentane (270 mg, 0.612 mmol)
and DMF (10 mL). The reaction mixture was degassed for 15 minutes
by bubbling nitrogen and then allylpalladium(II) chloride dimer
(112 mg, 0.306 mmol) was added. The reaction mixture was heated to
85.degree. C. for 4 hours. To the reaction mixture was added water
(40 mL) and ethyl acetate (40 mL) and the mixture was filtered
through Celite. The layers of the filtrate were separated and the
aqueous portion was extracted with ethyl acetate (40 mL). The
organic portions were combined, washed with brine (40 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by a
50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography
instrument) utilizing gradient elution of 12-100% ethyl
acetate/hexanes to produce 458 mg of I-152 as a viscous yellow
solid in 56% yield.
[0546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.86 (s, 3H),
4.12 (s, 2H), 7.13 (t, J=74 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.37
(dd, J=8, 2 Hz, 1H), 7.57 (dt, J=7, 2 Hz, 1H), 7.44-7.52 (m, 4H),
7.88 (dd, J=8, 2 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 8.71 (s, 1H)
ppm.
[0547] MS (APCI+): 404.5 (M+1). LC/MS: 98%.
[0548] Synthesis of
2-[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-prop-
an-2-ol hydrochloride (P-610). In a 40 mL vial equipped with a stir
bar was placed
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid methyl ester (I-152, 385 mg, 0.953 mmol) and tetrahydrofuran
(8 mL). The solution was cooled to 0.degree. C. and then
methylmagnesium bromide (3M in diethyl ether) (3.2 mL, 9.53 mmol)
was added and the reaction was warmed to ambient temperature and
allowed to stir for 2 hours. The reaction was concentrated, placed
in an ice bath and slowly quenched with a saturated solution of
ammonium chloride (5 mL). After adding dichloromethane (15 mL), the
mixture was filtered through Celite, the layers of the filtrate
were separated and the aqueous portion was extracted with
dichloromethane (15 mL). The organic portions were combined, washed
with brine (40 mL), dried (MgSO.sub.4) and concentrated. The crude
material was purified by a 10 gram silica gel SNAP cartridge
(Biotage SP4 Flash Chromatography instrument) utilizing gradient
elution of 2-20% acetone/dichloromethane to produce 183 mg P-610 as
a colorless oil in 48% yield. To P-610 (175 mg, 0.433 mmol) was
added diethyl ether (1 mL) and 2M HCl in diethyl ether (700 uL).
The mixture was allowed to stir at room temperature for 20 minutes,
concentrated and dried to produce 139 mg of P-610-HCl as an
off-white solid in 73% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.53 (s, 6H), 3.82 (bs, 1H), 4.17 (s, 2H), 7.14 (t, J=74
Hz, 1H), 7.27 (d, J=9 Hz, 1H), 7.43-7.54 (m, 6H), 7.97 (bs, 1H),
8.32 (bs, 1H), 8.67 (s, 1H) ppm. MS (ESI+): 405.6 (M+1-HCl. LC/MS:
92%.
##STR00196##
Example 139
Preparation of P-611
[0549] Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine
hydrochloride (P-611). In a 40 mL vial equipped with a stir bar was
placed compound I-151 (1.0 g, 2.92 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine
(707 mg, 3.21 mmol), potassium carbonate (1.21 g, 8.76 mmol),
1,5-bis(diphenylphosphino)pentane (386 mg, 0.876 mmol) and DMF (15
mL). The reaction mixture was degassed for 15 minutes by bubbling
nitrogen and then allylpalladium(II) chloride dimer (160 mg, 0.438
mmol) was added. The reaction mixture was heated to 85.degree. C.
for 4 hours. To the reaction mixture was added water (40 mL) and
ethyl acetate (40 mL) and the mixture was filtered through Celite.
The layers of the filtrate were separated and the aqueous portion
was extracted with ethyl acetate (40 mL). The organic portions were
combined, washed with brine (40 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by a 50 gram silica
gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument)
utilizing gradient elution of I-10% methanol/dichloromethane to
produce 841 mg of P-611 as a viscous dark yellow oil in 80% yield.
To P-611 (840 mg, 2.33 mmol) was added 1,4-dioxane (8 mL) and 4M
HCl in 1,4-dioxane (2 mL). The mixture was allowed to stir at room
temperature for 20 minutes, concentrated and dried to produce 643
mg of P-611-HCl as a yellow-orange solid in 70% yield. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 3.39 (bs, 2H), 3.89 (s, 2H), 6.932
(s, 1H), 7.14 (t, J=74 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 7.36 (dd,
J=9, 2 Hz, 1H), 7.42-7.52 (m, 4H), 7.85 (dd, J=9, 2 Hz, 1H), 7.91
(br s, 1H), 7.94 (br s, 1H), 13.71 (br s, 1H) ppm. LC/MS: 94%.
Example 140
Preparation of P-616
[0550] Synthesis of
[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-urea
(P-616). In an 18 mL vial equipped with a stir bar was placed P-611
(80 mg, 0.222 mmol), glacial acetic acid (1.5 mL), water (750 uL)
and sodium cyanate (57.7 mg, 0.888 mmol). The mixture was heated to
80.degree. C. for 3 hours, cooled to room temperature, diluted with
dichloromethane (4 mL) and slowly quenched with a saturated
solution of sodium bicarbonate (20 mL) to pH 8. The layers were
separated and the aqueous portion was extracted with
dichloromethane (2.times.15 mL). The organic portions were
combined, washed with brine (15 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by silica gel column
chromatography utilizing 5% methanol/dichloromethane as the eluent
to produce a brown oil. To this material was added diethyl ether (1
mL) and 2M HCl in diethyl ether (500 uL). After stirring at room
temperature for 30 minutes, the mixture was concentrated and dried
to produce 39 mg of P-616-HCl as a yellow solid in 40% yield
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.89 (s, 2H), 6.93 (d,
J=9.0 Hz, 1H), 7.13 (t, J=74 Hz, 1H), 7.35 (dd, J=8, 2 Hz, 1H),
7.41-7.52 (m, 4H), 7.84 (d, J=2 Hz, 1H), 7.86-7.90 (m, 2H), 13.55
(s, 1H) ppm. MS (ESI+): 404.5 (M+1-HCl).
##STR00197##
Example 141
Preparation of P-621
[0551] Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(I-153). Compound I-153 was prepared in a manner analogous to P-611
(Example 138) in 70% yield. MS (ESI+): 364.4 (M+1). LC/MS: 96%.
[0552] Synthesis of
2-{[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-met-
hyl-amino}-acetamide (P-621). In an 8 mL vial equipped with a stir
bar was placed
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyrid-
ine (I-153, 210 mg, 0.577 mmol), 2-methylamino-acetamide
hydrochloride (216 mg, 1.73 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (488 uL, 3.46 mmol). The mixture
was heated to 160.degree. C. for 3 hours and then diluted with
dichloromethane (5 mL). The organic portion was washed with 0.5M
HCl (3 mL) and the aqueous washes were combined and extracted with
dichloromethane (2.times.3 mL). The organic portions were combined,
washed with brine (4 mL), dried (MgSO.sub.4) and concentrated. The
crude material was purified by Teledyne CombiFlash system utilizing
a 12 g RediSepRf silica gel cartridge and a gradient elution of
0-30% methanol/dichloromethane, followed by preparative TLC
(20.times.20 cm, 1000 microns) using 5% methanol/dichloromethane as
the eluent to produce 8 mg of P-621?? as a dark brown semi-solid in
3% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.98 (s, 3H),
3.83 (s, 2H), 4.03 (s, 2H), 6.53 (d, J=9 Hz, 1H), 7.10 (t, J=74 Hz,
1H), 7.21 (d, J=8 Hz, 1H), 7.30 (dd, J=8, 2 Hz, 1H), 7.36 (d, J=2
Hz, 1H), 7.40-7.50 (m, 5H), 8.01 (d, J=2 Hz, 1H) ppm. MS (APCI+):
432.1 (M+1). LC/MS: 86%.
Example 142
Preparation of P-618
##STR00198##
[0554] Synthesis of
N-[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-2-di-
methylamino-acetamide hydrochloride (P-618). In an 18 mL vial
equipped with a stir bar was placed dimethylglycine (58.5 mg, 0.567
mmol), dichloromethane (2.8 mL) and thionyl chloride (82.5 uL, 1.13
mmol). The solution was stirred at room temperature for 4 hours and
then concentrated. To the reaction mixture was added a solution of
P-611 (150 mg, 0.378 mmol), tetrahydrofuran (2.8 mL) and
diisopropylethylamine (263 uL, 1.51 mmol). The mixture was stirred
at ambient temperature for 2 hours and then heated to 45.degree. C.
for 60 hours. The reaction was concentrated, diluted with ethyl
acetate (3 mL) and washed with water (5 mL). The layers were
separated and the aqueous portion was extracted with ethyl acetate
(3.times.3 mL). The organic portions were combined, washed with
brine (5 mL), dried (MgSO.sub.4) and concentrated. The crude
material was purified by silica gel column chromatography utilizing
5% methanol/dichloromethane (with 1% AcOH) as the eluent, followed
by preparative TLC (20.times.20 cm, 1500 microns) using 10%
methanol/dichloromethane as the eluent to produce 27 mg of P-618 as
an orange semi-solid in 16% yield. To P-618 (45 mg, 0.0561 mmol)
was added diethyl ether (1 mL) and 2M HCl in diethyl ether (500
uL). The mixture was allowed to stir at room temperature for 20
minutes, concentrated and dried to produce 8 mg of P-618-HCl as a
pale orange solid in 30% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 2.86 (d, J=4 Hz, 6H), 4.00 (s, 2H), 4.16 (m, 2H), 7.17 (t,
J=74 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.34 (dd, J=8, 2 Hz, 1H),
7.41-7.51 (m, 5H), 7.77 (dd, J=8, 2 Hz, 1H), 7.97-7.99 (m, 1H),
8.34 (d, J=2 Hz, 1H), 9.82 (bs, 1H), 11.14 (s, 1H) ppm. MS (APCI+):
446.1 (M+1).
[0555] LC/MS: 96%
Example 143
Preparation of P-622
##STR00199##
[0557] Synthesis of
2-{[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-me-
thyl-amino}-acetamide (P-622). In an 8 mL vial equipped with a stir
bar was placed P-456 (210 mg, 0.607 mmol), 2-methylamino-acetamide
hydrochloride (227 mg, 1.82 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (513 uL, 3.64 mmol). The mixture
was heated to 160.degree. C. for 2.5 hours and then diluted with
dichloromethane (5 mL). The organic portion was washed with 0.5M
HCl (3.times.3 mL) and the aqueous washes were combined and
extracted with dichloromethane (3.times.3 mL). The organic portions
were combined, washed with brine (4 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by Teledyne
CombiFlash system utilizing a RediSepRf 12 g silica gel cartridge
and a gradient elution of 0-30% isopropanol/dichloromethane to
produce material that still contained impurities. The impure
material was purified by preparative TLC (20.times.20 cm, 1000
microns) using 10% isopropanol/dichloromethane as the eluent to
produce 89 mg of P-622 as a yellow solid in 35% yield. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 2.99 (s, 3H), 3.71 (s, 3H), 3.78
(s, 2H), 4.03 (s, 2H), 6.53 (d, J=9 Hz, 1H), 6.90-6.92 (m, 2H),
7.23-7.25 (m, 1H), 7.28 (d, J=8 Hz, 2H), 7.34-7.37 (m, 2H),
7.40-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 414.1
(M+1).
Example 144
Preparation of P-573
##STR00200##
[0559] Synthesis of
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-imidazol-1-yl-pyri-
dine (P-573). To a 20 mL vial which contained P-456 (200 mg, 0.55
mmol) and 1H-imidazole-2-carboxylic acid (202 mg, 1.8 mmol) was
added DBU (0.5 mL, excess), at rt. The vial was sealed and the
mixture was allowed to heat to 160.degree. C. and stir at
160.degree. C. for 2.5 h. The mixture was cooled to rt and then
poured onto 20 mL ice-water solution, acidified with 2N HCl to
pH=1-2, extracted with ethyl acetate (3.times.15 mL), washed with
water (3.times.15 mL), brine (20 mL) and dried over Na2SO4. After
removal of solvent, the residue was separated by a chromatography
on silica gel with dichloromathane/iPA as eluent to yield P-573 (60
mg) in 26% yield.
[0560] 1H NMR (DMSO-d.sub.6, 400 MHz): 8.48 (s, 1H), 8.40 (d, J=2.4
Hz, 1H), 7.91 (br s, 1H), 7.85 (dd, J=8.2, 2.4 Hz, 1H), 7.74 (d,
J=9.2 Hz, 1H), 7.27-7.47 (m, 5H), 7.11 (s, 1H), 6.86 (d, J=7.6 Hz,
1H), 4.01 (s, 2H), 3.73 (s, 3H) ppm.
[0561] LC/MS: 393.84 Calc. 393.8; APCI+ (M+1): 394.1, 99%
##STR00201##
Example 145
Preparation of P-590
[0562] Synthesis of
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitrile
(P-590). To a 100 mL flask which contained the mixture of I-154
(1324 mg, 4 mmol) and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
(1.1 g, 4.4 mmol) in toluene/EtOH/H.sub.2O (4/1/1, 25 mL) was added
potassium phosphate (1.7 g, 8 mmol) and
tetrakis(triphenylphosphine)palladium (0) (400 mg, 0.3 mmol) under
nitrogen. The reaction mixture was stirred at 60.degree. C. for 4
h. The reaction mixture was cooled to ambient temperature, poured
onto ice-water solution (100 mL), and extracted with ethyl acetate
(3.times.30 mL). The combined organic layers was washed with water
(30 mL), brine (25 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. The residue was separated by a
chromatography on silica gel with ethyl acetate-hexane as eluent to
afford P-590 (380 mg, 27%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.61
(s, 1H), 7.61 (d, J=1.2 Hz, 2H), 7.46-7.48 (m, 1H), 7.29-7.37 (m,
3H), 7.11 (dd, J=8.4, 2.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.94 (d,
J=8.4 Hz, 1H), 4.03 (s, 2H), 3.81 (s, 3H) ppm.
Example 146
Preparation of P-591
[0563] Synthesis of
C-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methylamine
hydrochloride (P-591). To a 50 mL flask which contained P-590 (220
mg, 0.66 mmol) in EtOH (14 mL) was added 12 N HCl (1 mL) and then
Pd/C (10%, 200 mg) at rt. The system was allowed to stir at ambient
temperature under a hydrogen atmosphere (15 psi) for 3 h. The
solids were removed by filtration and the filtrate was
concentrated. The residue was purified via chromatography on silica
gel with ethyl acetate as eluent to yield P-591 (160 mg) in 70%
yield. P-591 (25 mg) was treated with 2N HCl in diethyl ether (2
mL) to afford P-591 HCl salt (16 mg) in 60% yield. 1H NMR
(DMSO-d.sub.6,400 MHz): 8.54 (s, 1H), 8.26 (br. s, 2H), 7.76 (d,
J=8.4 Hz, 1H), 7.39-7.47 (m, 4H), 7.22-7.27 (m, 2H), 7.06 (d, J=8.4
Hz, 1H), 4.14 (br s, 2H), 3.99 (s, 2H), 3.74 (s, 3H) ppm.
[0564] Calc. 338.84; APCI.sup.+ (M+1): 339.1, 100%.
Example 147
Preparation of P-592
[0565] Synthesis of
[5-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-carbamic
acid phenyl ester (P-592). To a 20 mL vial which contained P-591
(140 mg, 0.4 mmol) and triethylamine (85 mg, 0.8 mmol) in
dichloromethane (3 mL) was added phenyl chloroformate (95 mg, 0.6
mmol) at 0-5.degree. C. The reaction mixture was allowed to warm to
ambient temperature and stir for 1 h. The mixture was poured onto
30 mL ice-water solution, extracted with dichloromethane
(3.times.15 mL). The combined organic layers were washed with water
(20 mL), brine (15 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. The residue was purified via chromatography
on silica gel with ethyl acetate-hexane as eluent to yield 150 mg
(79%) of P-592. 1H NMR (CDCl.sub.3,400 MHz): 8.46 (s, 1H),
7.48-7.52 (m, 2H), 7.11-7.37 (m, 10H), 6.92 (d, J=8.4 Hz, 1H), 6.13
(br.s, 1H), 4.55 (d, J=4.8 Hz, 2H), 3.97 (s, 2H), 3.80 (s, 3H)
ppm.
[0566] Calc. 458.9; APCI.sup.+ (M+1): 459.1, 100%.
Example 148
Preparation of P-597
[0567] Synthesis of
1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-3-ethy-
l-urea hydrochloride (P-597). To a 20 mL vial which contained P-591
(66 mg, 0.2 mmol) in pyridine (2 mL) was added isocyanato-ethane
(0.2 mL, excess) at ambient temperature, and the resultant mixture
stirred for 48 h. The mixture was poured onto 20 mL ice-water
solution and the solid was filtered, washed with water (2.times.20
mL) and air dried to afford 55 mg of P-597. The free base was
treated with 4N HCl in dioxane at ambient temperature to afford 55
mf of P-597 HCl salt in 63% yield. 1H NMR (DMSO-d.sub.6,400 MHz).
8.72 (s, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.50
(br s, 1H), 7.37-7.41 (m, 3H), 7.29-7.31 (m, 2H), 7.08 (d, J=8.8
Hz, 1H), 6.67 (s, 1H), 6.36 (s, 1H), 4.44 (s, 2H), 4.09 (s, 2H),
3.75 (s, 3H), 3.00 (d, J=7.2 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H)
ppm.
Example 149
Preparation of P-593
[0568] Synthesis of
1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-3-meth-
yl-urea hydrochloride (P-593). To a 20 mL vial which contained
P-592 (92 mg, 0.2 mmol) in THF (3 mL) was added excess methylamine
(40% in H.sub.2O, 1 mL), and the resultant mixture allowed to stir
at ambient temperature for 4 h. The solvent was removed and diethyl
ether (10 mL) was added. The solids were filtered, washed with
diethyl ether (2.times.5 mL) and air dried to afford 50 mg of
P-593. The free base was treated with 4 N HCl in dioxane (0.5 mL)
to afford 45 mg of P-593 HCl salt in 52% yield. .sup.1H NMR
(DMSO-d.sub.6,400 MHz): 8.77 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.78
(d, J=8.4 Hz, 1H), 7.51 (s, 1H), 7.31-7.44 (m, 5H), 7.08 (d, J=8.4
Hz, 1H), 6.90 (s, 1H), 4.49 (s, 1H), 4.12 (s, 3H), 3.75 (s, 3H),
2.54 (s, 2H) ppm. Calc. 395.88; APCI.sup.+ (M+1): 396.1, 100%.
Example 150
Preparation of P-600
##STR00202##
[0570] Synthesis of
1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methylamine
hydrochloride (P-600). A 50 mL flask which contained CeCl.sub.3
(370 mg, 1. mmol) was dried with a heat gun for 0.5 h. After
cooling to ambient temperature, THF (5 mL) was added and the
mixture was allowed to stir for 2 h, and cooled to -78.degree. C.
Methyl lithium (1 M in ether, 1 mL) was added at -78.degree. C. and
stirred at -78.degree. C. for 1 h and then P-590 (170 mg, 0.5 mmol)
in THF (0.5 mL) was added. The mixture was allowed to stir at
-78.degree. C. for 0.5 h, allowed to warm to ambient temperature,
and stirred for 16 h. The reaction was quenched with the addition
of isopropanol (1 mL). The solids were removed by filtration, and
the filtrate concentrated. The residue was purified via
chromatography on silica gel with ethyl acetate-EtOH as eluent to
yield 30 mg of P-600 which was treated with 2N HCl in diethyl ether
(2 mL) to afford 15 mg of P-600 HCl salt in 8% yield.
[0571] .sup.1H NMR (DMSO-d.sub.6,400 MHz): 8.59 (d, J=2.0 Hz, 1H),
8.39 (br s, 2H), 7.80 (dd, J=8.0, 2.0 Hz, 1H), 7.54 (d, J=8.4 Hz,
1H), 7.48 (br s, 1H), 7.36-7.45 (m, 3H), 7.25-7.28 (m, 2H), 7.06
(d, J=9.2 Hz, 1H), 3.99 (s, 2H), 3.74 (s, 3H), 1.57 ppm (s, 6H)
ppm. LC/MS: Calc. 409.9; APCI+ (M+1): 410.1, 100%
##STR00203##
Example 151
Preparation of P-605
[0572] Synthesis of
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
methyl ester (I-156). To a 250 mL flask which contained the mixture
of I-155 (2.0 g, 6.6 mmol) and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic
acid methyl ester (1.6 g, 6 mmol) in DME (30 mL) was added
K.sub.2CO.sub.3 (2.5 g, 18 mmol),
[Pd(y.sup.3C.sub.3H.sub.5Cl)].sub.2 (300 mg, 0.8 mmol) and DPPPent
(800 mg, 1.9 mmol) at rt under nitrogen. The reaction mixture was
heated to 85.degree. C. and stirred at 85.degree. C. for 16 h. The
reaction mixture was cooled to rt, poured onto ice-water (200 mL),
The semi-solid which formed was separated from the aq. layer to
provide the crude which was purified by a chromatography on silica
gel with dichloromethane-acetone as eluent to yield I-156 (1200 mg,
50%) 1H NMR (CDCl.sub.3, 400 MHz): 8.64 (s, 1H), 8.05 (d, J=8.0 Hz,
1H), 7.62 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.29-7.36 (m, 2H), 7.11
(d, J=8.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H),
4.04 (s, 2H), 3.99 (s, 3H), 3.80 (s, 3H) ppm. LC/MS: Calc. 367.84;
APCI+ (M+1): 368.1, 99%.
[0573] Synthesis of
2-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-propan-2-ol
HCl salt (P-605) and
1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethanone
(I-157). To a 50 mL dried flask containing I-156 (350 mg, 1 mmol)
in THF (5 mL) and cooled to 0.degree. C. was added methylmagnesium
bromide (3M in ether, 3 mL, 9 mmol). The reaction mixture was
allowed to warm to ambient temperature and stirred for 16 h, and
then poured onto 50 mL ice-water. The mixture was neutralized with
NH.sub.4Cl (sat. 10 mL), extracted with ethyl acetate (3.times.20
mL), and the organics washed with water (20 mL), brine (20 mL) and
dried over Na.sub.2SO.sub.4. After removal of solvent, the residue
was purified by silica gel column chromatography with
dichloromethane-acetone as eluent to give 100 mg of the P-605 in
28% yield and 60 mg of I-157 in 15% yield. 50 mg of P-605 was
treated with 2N HCl in diethyl ether (1 mL) to afford 55 mg of
P-605 HCl salt in 99% yield. .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
8.60 (br s, 1H), 7.85-8.24 (m, 2H), 7.30-7.52 (m, 6H), 7.08 (d,
J=6.8 Hz, 1H), 4.08 (s, 2H), 3.75 (s, 3H), 1.51 ppm (s, 6H)
ppm.
[0574] LC/MS: Calc. 367.88; APCI+ (M+1): 368.1, 96%.
Example 152
Preparation of P-609
[0575] Synthesis of
2-(1-azetidin-1-yl-ethyl)-5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyr-
idine (P-609). To a 25 mL vial which contained I-157 (52 mg, 0.15
mmol) and azetidine HCl salt (30 mg, 0.3 mmol) in MeOH (2 mL) was
added sodium cyanoborohydride (16 mg, 22 mmol) at 0.degree. C. The
reaction mixture was allowed to warm to ambient temperature and
stir for 72 h. The mixture was poured onto 5 mL 0.5 N aqueous
sodium hydroxide solution and extracted with ethyl acetate
(3.times.10 mL). The combined organics were washed with water (10
mL), brine (10 mL) and dried over Na.sub.2SO.sub.4. After removal
of the solvent, the residue was purified by a chromatography on
silica gel with dichloromethane-acetone as eluent to afford 30 mg
of P-609 in 54% yield.
[0576] .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.41 (d, J=2.0 Hz, 1H),
7.27-7.48 (m, 6H), 7.10-7.15 (m, 2H), 6.91 (d, J=8.0 Hz, 1H), 3.92
(s, 2H), 3.79 (s, 3H), 3.41-3.46 (m, 1H), 3.10-3.25 (m, 4H),
2.00-2.07 (m, 2H), 1.21 (d, J=6.4 Hz, 3H) ppm.
Example 153
Preparation of P-567
##STR00204##
[0578] Synthesis of
5-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid methyl ester (I-158). Into a 250 mL round-bottomed flask was
added I-154 (4.89 g, 15.69 mmol),
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic
acid methyl ester (4.52 g, 17.26 mmol), toluene (120 mL), EtOH (20
mL), water (20 mL), and K.sub.3PO.sub.4 (6.66 g, 31.38 mmol). The
suspension was degassed with N.sub.2 for 15 minutes and then
Pd(PPh.sub.3).sub.4 (1.81 g, 1.57 mmol) was added and the reaction
was stirred at 80.degree. C. for 1 hour. The layers were separated
and the aqueous was extracted with 50 mL EtOAc. The organics were
combined and washed with 50 mL of brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash column chromatography eluting with 10%
acetone/hexanes to afford 890 mg of I-158 as a light-yellow oil in
15% yield.
##STR00205##
[0579]
[5-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methanol
(P-567). Into a 100 mL round-bottomed flask was added I-158 (0.71
g, 1.93 mmol), THF (20 mL), and the solution was cooled to
0.degree. C. LiAlH.sub.4 (0.29 g, 7.72 mmol) was added and the
reaction was stirred at 0.degree. C. for 1 hour. 20 mL of water was
slowly added and the product was extracted with EtOAc (3.times.20
mL). The organics were combined and filtered through Celite and
then concentrated. The residue was purified by flash column
chromatography eluting with 20% acetone/hexanes to provide 352 mg
of P-567 as a light-yellow oil in 54% yield.
[0580] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.42 (d, J=1.6 Hz, 1H),
7.64 (dd, J=2.0, 7.9 Hz, 1H), 7.49 (s, 1H), 7.45-7.34 (m, 4H),
7.25-7.20 (m, 2H), 7.05 (d, J=8.6 Hz, 1H), 5.31 (t, J=5.8 Hz, 1H),
4.50 (d, J=5.9 Hz, 2H), 3.93 (s, 2H), 3.74 (s, 3H) ppm.
LC/MS=92.1%, 340.1 (APCI+).
Example 154
Preparation of P-570
##STR00206##
[0582] Ethyl-carbamic acid
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl
ester hydrochloride (P-570). Into an 18 mL vial was added P-567 (98
mg, 0.29 mmol), toluene (2 mL), and ethyl isocyanate (57 uL, 0.72
mmol). The reaction was stirred at 60.degree. C. for 6 hours and
then concentrated. The solid was triturated with ether to obtain 79
mg of P-570 as a white solid. Of this material, 68 mg was dissolved
in 4N HCl/Dioxane and then concentrated. This solid was triturated
with ether, filtered, and washed with ether to afford 50 mg of
P-570 HCl salt as a tan solid in 45% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.48 (d, J=1.5 Hz, 1H), 7.71-7.64 (m, 1H), 7.49 (s,
1H), 7.45-7.34 (m, 3H), 7.32-7.19 (m, 3H), 7.05 (d, J=9.1 Hz, 1H),
5.01 (s, 2H), 3.94 (s, 2H), 3.74 (s, 3H), 3.07-2.95 (m, 2H), 1.01
(t, J=7.2 Hz, 3H) ppm. LC/MS=100.0%, 411.0 (APCI+).
Example 155
Preparation of P-534
##STR00207##
[0584]
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazole-4-
-carboxylic acid methyl ester (I-159) and
3-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-3H-imidazole-4-carbo-
xylic acid methyl ester (I-160). Into an 18 mL vial was added
methyl 4-imidazole carboxylate (113 mg, 0.90 mmol), DMF (3 mL), and
NaH (43 mg, 1.08 mmol). After 20 minutes at room temperature I-33
(295 mg, 0.90 mmol) was added. The reaction was stirred for 2 hours
at room temperature and then water was added. The product was
extracted with EtOAc and the organics were concentrated. The
residue was purified by flash column chromatography eluting with
6%-10% acetone/dichloromethane to separate the regioisomers. The
4-substituted ester I-159 (67 mg, 20%) and the 2-substituted ester
I-160 (79 mg, 23%) were obtained as colorless oils.
##STR00208##
[0585]
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazole-4-
-carboxylic acid amide (P-534). Into an 8 mL vial was added I-159
(30 mg, 0.08 mmol) and 2 mL of 7N NH.sub.3/MeOH. The reaction was
stirred at 60.degree. C. for 6 days after which it was
concentrated. Ether was added to form a solid which was filtered
and washed with ether to afford 8 mg of P-534 as a tan solid in 28%
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.77 (s, 1H), 7.63 (s,
1H), 7.48-7.36 (m, 4H), 7.29 (d, J=6.4 Hz, 1H), 7.26 (br s, 1H),
7.05 (br s, 1H), 7.02 (d, J=8.7 Hz, 1H), 5.25 (s, 2H), 3.75 (s, 3H)
ppm.
Example 156
Preparation of P-535
##STR00209##
[0587]
3-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-3H-imidazole-4-
-carboxylic acid amide (P-535). Into an 8 mL vial was added I-160
(36 mg, 0.096 mmol) and 2 mL of 7N NH.sub.3/MeOH. The reaction was
stirred at 60.degree. C. for 6 days after which it was
concentrated. The solid was triturated with ethe, filtered, and
washed with ether to afford 7 mg of P-535 as a white solid in 20%
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.83 (s, 1H), 7.75 (br
s, 1H), 7.63 (s, 1H), 7.51-7.41 (m, 2H), 7.38 (s, 1H), 7.29 (d,
J=6.6 Hz, 1H), 7.19 (br s, 1H), 7.10-7.00 (m, 1H), 6.94 (d, J=8.7
Hz, 1H), 5.59 (s, 2H), 3.72 (s, 3H) ppm. LC/MS=92.2%, 359.1
(APCI-).
Example 157
Preparation of P-536
##STR00210##
[0589]
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-4-nitro-1H-imi-
dazole (P-536). Into a 100 mL round bottom flask was added I-33
(1.0 g, 3.03 mmol), DMF (25 mL), and the solution was cooled to
0.degree. C. Sodium hydride (145 mg, 3.64 mmol) was added followed
by 4-nitro-1H-imidazole (377 mg, 3.34 mmol). The reaction was
stirred at 0.degree. C. for 2 hours and then 10 mL of water was
added. The product was extracted with 3.times.15 mL EtOAc and the
combined organics were concentrated. The product was purified by
flash column chromatography eluting with 20% acetone/hexanes to
afford 625 mg of P-536 as an amber oil in 57% yield. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) 8.41 (d, J=0.9 Hz, 1H), 7.94 (s, 1H),
7.56-7.37 (m, 4H), 7.30 (d, J=6.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H),
5.34 (s, 2H), 3.76 (s, 3H) ppm
Example 158
Preparation of P-531
##STR00211##
[0591]
C-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-m-
ethylamine (I-161), Into a 100 ml round bottom flask was added
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
(1.0 g, 0.43 mmol), 20 mL of MeOH, conc. HCl (1.8 mL, 2.17 mmol),
and 10% Pd/C (0.2 g). The reaction was stirred under a hydrogen
atmosphere for 18 hours. The reaction was filtered through Celite,
washed with MeOH, and then concentrated to a yellow solid. The
material was used as is.
##STR00212##
[0592]
1-Ethyl-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-
-2-ylmethyl]-urea (I-162). Into a 50 mL round bottom flask was
added
C-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyla-
mine (I-161, 1 g, crude), pyridine (10 mL), and ethyl isocyanate
(0.5 mL, 6.5 mmol). The reaction was stirred at room temperature
for 30 minutes and then NaHCO.sub.3 (sat) was added. The product
was extracted with 3.times.10 mL EtOAc and the combined organics
were dried over Na.sub.2SO.sub.4, and concentrated. The residue was
purified by flash column chromatography eluting with 50%
acetone/dichloromethane--100% MeOH to afford 289 mg of I-162 as a
brown oil in 22% yield.
##STR00213##
[0593]
1-[4-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethoxy)-pyridin-2-y-
lmethyl]-3-ethyl-urea (P-531). Into an 8 mL vial was added I-163
(125 mg, 0.39 mmol),
1-ethyl-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylm-
ethyl]-urea (I-162, 119 mg, 0.39 mmol), K.sub.3PO.sub.4 (248 mg,
1.17 mmol), DME (2.5 mL), EtOH (0.5 mL), and water (0.5 mL). The
suspension was degassed with N.sub.2 and then Pd(PPh.sub.3).sub.4
was added. The reaction was stirred for 1 hour at 80.degree. C.
Water (2 mL) was added and the product was extracted with EtOAc
(3.times.2 mL). The organic extracts were combined and
concentrated. The residue was purified by flash column
chromatography eluting with 25%-50% acetone/dichloromethane to give
a tan-gray solid which was then triturated with ether. The
resulting solid was recrystallized from EtOH to provide 7 mg of
P-531 as a white solid in 4% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.26 (d, J=2.8 Hz, 1H), 7.89-7.82 (m, 2H), 7.75-7.53
(m, 3H), 7.47 (dd, J=3.0, 8.6 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.04
(d, J=8.6 Hz, 1H), 6.33 (t, J=5.8 Hz, 1H), 6.01 (t, J=5.4 Hz, 1H),
5.16 (s, 2H), 4.22 (d, J=5.9 Hz, 2H), 3.78 (s, 3H), 3.09-2.95 (m,
2H), 0.99 (t, J=7.1 Hz, 3H) ppm. LC/MS=90.7%, 435.2 (APCI+).
Example 159
Preparation of P-244
##STR00214##
[0595] 2-(3-Bromo-4-methoxy-phenyl)-ethanol (I-164). Into a 100 mL
round bottom flask was added (3-bromo-4-methoxy-phenyl)-acetic acid
(0.58 g, 2.37 mmol), THF (10 mL), and the mixture was cooled to
0.degree. C. BH.sub.3-THF (10.6 mL, 10.6 mmol, 1.0M in THF) was
added and the reaction was stirred at room temperature for 20
hours. 20 mL of MeOH was added and the solvent was removed on a
rotary evaporator. This was repeated an additional 5 times. The
residue was purified by flash column chromatography eluting with
10-20% acetone/hexanes to afford 457 mg of I-164 as a light yellow
oil in 83% yield.
##STR00215##
[0596] 2-Bromo-4-(2-bromo-ethyl)-1-methoxy-benzene (I-165). Into a
100 mL round bottom flask was added
2-(3-bromo-4-methoxy-phenyl)-ethanol (I-164, 418 mg, 1.81 mmol),
dichloromethane (15 mL), carbon tetrabromide (1.50 g, 4.52 mmol),
and triphenylphosphine (1.19 g, 4.52 mmol). After stirring for 1
hour at room temperature the reaction was concentrated. The residue
was purified by flash column chromatography eluting with hexanes to
afford 1.91 g of I-165 as a colorless oil, which was used without
further purification.
##STR00216##
[0597] 1-[2-(3-Bromo-4-methoxy-phenyl)-ethyl]-1H-pyridin-2-one
(I-166). Into a 100 mL round bottom flask was added
2-bromo-4-(2-bromo-ethyl)-1-methoxy-benzene (I-165, 1.82 g, crude),
2-hydroxypyridine (258 mg, 2.72 mmol), K.sub.2CO.sub.3 (625 mg,
4.53 mmol), and DME (20 mL). After stirring for 18 hours at
80.degree. C. the suspension was filtered and the filtrate was
concentrated. The residue was purified by flash column
chromatography eluting with 25-50% acetone/hexanes to afford 221 mg
of I-166 as a brown oil in 40% yield (2 steps).
##STR00217##
[0598]
1-[2-(6-Methoxy-3'-nitro-biphenyl-3-yl)-ethyl]-1H-pyridin-2-one
(P-244). Into a 40 mL vial were added
1-[2-(3-bromo-4-methoxy-phenyl)-ethyl]-1H-pyridin-2-one (I-166, 210
mg, 0.68 mmol), 3-nitrophenylboronic acid (125 mg, 0.75 mmol),
PPh.sub.3 (36 mg, 0.014 mmol), potassium carbonate (283 mg, 2.04
mmol), dimethoxyethane (10 mL), ethanol (1 mL), and water (1 mL).
The suspension was degassed with N.sub.2 for 5 minutes and then
palladium(II) acetate (15 mg, 0.068 mmol). After degassing for an
additional 2 minutes the reaction was stirred at 80.degree. C. for
18 hours. To the reaction was added 5 mL of water and 10 mL of
ethyl acetate. The layers were separated and the aqueous was
extracted with ethyl acetate (3.times.10 mL). The organics were
combined and concentrated. The residue was purified by flash column
chromatography eluting with 10-20% acetone/dichloromethane. The
yellow oil which was obtained (136 mg) was dissolved in 1 mL of
ether and allowed to stand at room temperature for 3 days. The tan
solid which formed was filtered, washed with ether, and dried to
afford 74 mg of P-244 in 31% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.30-8.29 (m, 1H), 8.18-8.15 (m, 1H), 7.81-7.79
(m, 1H), 7.54 (t, J=8.0 Hz), 7.37-7.33 (m, 1H), 7.19 (dd, J=8.2,
2.2 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.95-6.93 (m, 2H), 6.61 (d,
J=9.2 Hz, 1H), 6.06 (td, J=6.6, 1.2 Hz, 1H), 4.15 (t, J=7.0 Hz,
2H), 3.82 (s, 3H), 3.07 (t, J=7.0 Hz, 2H) ppm. LC/MS=99.4%, 351.6
(ESI+).
Example 160
Preparation of P-003
##STR00218##
[0600] 5-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-benzo[1,3]dioxole
(P-003). P-003 was prepared by according to the method described
for P-001. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.80 (s, 3H) 3.93 (s,
2H) 5.98 (s, 2H) 6.83-6.92 (m, 2H) 6.92-7.05 (m, 4H) 7.05-7.12 (m,
2H) 7.16 (dd, J=8.4, 5.6 Hz, 2H) ppm. LCMS=94.4% purity.
TSI(+)=365.4 (M+29).
Example 161
Preparation of P-004
##STR00219##
[0602]
5-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-benzo[1,2,5]oxadiazole
(P-004). P-004 was prepared by according to the method described
for P-001. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.84 (s, 3H), 3.97 (s,
2H), 6.91-7.05 (m, 3H), 7.13-7.24 (m, 4H), 7.62 (dd, J=9.3, 1.3 Hz,
1H) 7.75-7.87 (m, 2H) ppm. LCMS=96.2% purity. TSI (+)=365.4
(M+31).
Example 162
Preparation of P-006
##STR00220##
[0604] Synthesis of
5-(5-Imidazol-1-ylmethyl-2-methoxy-phenyl)-benzo[1,2,5]oxadiazole
(P-006). A suspension of 1-(3-bromo-4-methoxy-benzyl)-1H-imidazole
(I-167, 267 mg, 1.00 mmol), benzo[1,2,5]oxadiazole-5-boronic acid
(I-105, 164 mg, 1.00 mmol), palladium(0)bis(dibenzylideneacetone)
(28.7 mg, 0.050 mmol), and triphenylphosphine (26.2 mg, 0.10 mmol)
in dimethylformamide (20 mL) and 1 M aqueous cesium carbonate (3.0
mL, 3.0 mmol) was heated to 85.degree. C. with stirring overnight.
The solvent was removed under vacuum and the residue suspended in
ethyl acetate (25 mL). The organic suspension was washed with water
(3.times.20 mL) and brine, dried over sodium sulfate, decolorized
over activated carbon, filtered, and concentrated under. The
residue was purified by silica gel preparatory thin layer
chromatography (ethyl acetate:dichloromethane 3:1) to give 10.4 mg
of P-006 in 9.1% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.86 (s,
3H) 5.13 (s, 2H) 6.93 (s, 1H) 7.01 (d, J=8.32 Hz, 1H) 7.10 (s, 1H)
7.17-7.25 (m, 2H) 7.52-7.62 (m, 2H) 7.78-7.85 (m, 2H) ppm.
LCMS=100% purity. APCI(+)=307.1 (M+1).
##STR00221##
Example 163
Preparation of P-474
[0605] Synthesis of
3-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-pyridine (P-474). A
suspension of I-168 (158 mg, 0.53 mmol), 3-pyridineboronic acid
(61.5 mg, 0.50 mmol), palladium(0)bis(dibenzylideneacetone) (14.4
mg, 0.025 mmol), and triphenylphosphine (13.1 mg, 0.050 mmol) in
dimethylformamide (5 mL) and 1 M aqueous sodium carbonate (1.5 mL,
1.5 mmol) was heated to 85.degree. C. with stirring overnight. The
solvent was removed under vacuum and the residue suspended in ethyl
acetate (15 mL). The organic suspension was washed with water
(3.times.15 mL) and brine, dried over sodium sulfate and the
solvent removed under vacuum to give crude material. The residue
was purified by silica gel preparatory thin layer chromatography to
afford 69.1 mg (47%) of P-474
[0606] LCMS=94.6% purity.
Example 164
Preparation of P-475
[0607] Synthesis of
3-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-pyridine 1-oxide (P-475).
A vial was charged with P-474 (60 mg, 0.20 mmol), methyl ruthenium
oxide (2.5 mg, 0.010 mmol), 30% aqueous hydrogen peroxide (0.5 mL),
and dichloromethane (1.0 mL). The reaction was allowed to stir at
room temperature for 3 days. The biphasic mixture was treated with
catalytic amount of manganese dioxide (1.7 mg, 0.02 mmol) and
carefully stirred until the oxygen evolution ceased (1 h). The
phases were separated, the aqueous layer extracted into
dichloromethane (2.times.1 mL), the organic layers combined, dried
over sodium sulfate, and the solvent removed under vacuum to afford
20.9 mg of P-475 in 34% yield. .sup.1H NMR (400 MHz, CDCl.sub.3)
3.82 (s, 3H) 3.94 (s, 2H) 6.89-7.24 (m, 8H) 7.41 (d, J=8.1 Hz, 1H)
8.16 (d, J=6.3 Hz, 1H) 8.44 (s, 1H) ppm. LCMS=92.0% purity.
Example 165
Preparation of P-007
##STR00222##
[0609] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-benzotriazole
(P-007). A suspension of I-169 (477 mg, 1.50 mmol),
3-nitrophenylboronic acid (250 mg, 1.50 mmol), palladium(0)
bis(dibenzylideneacetone) (43 mg, 0.075 mmol), and triphenyl
phosphine (39 mg, 0.15 mmol) in dimethylformamide (10 mL) and 1 M
aqueous sodium carbonate (4.5 mL, 4.5 mmol) was heated to
85.degree. C. with stirring overnight. The solvent was removed
under vacuum and the residue suspended in ethyl acetate (20 mL).
The organic suspension was washed with water (3.times.20 mL) and
brine, dried over sodium sulfate, decolorized over activated
carbon, filtered and the solvent removed under vacuum to give a
residue. The residue was purified dissolving in ethyl acetate (5
mL) and adding hexanes (25 mL) until a solid formed. This was
repeated 3 times to afford 210 mg of P-007 in 39% yield.
[0610] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.83 (s, 3H), 5.87 (s,
2H), 6.99 (d, J=8.2 Hz, 1H), 7.31-7.52 (m, 4H), 7.56 (t, J=7.9 Hz,
1H), 7.76 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 8.19 (dd,
J=8.2, 1.2 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H) ppm. LCMS=93.9% purity.
APCI(+)=361.10 (M+1).
Example 166
Preparation of P-037
##STR00223##
[0612] Synthesis of
1-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-1H-imidazole (P-037).
To a solution of I-167 (484 mg, 1.80 mmol) and
benzo[1,3]dioxole-5-boronic acid (332 mg, 2.00 mmol) were added
palladium(0) bis(dibenzylideneacetone) (57.5 mg, 0.100 mmol), and
triphenylphosphine (52.4 mg, 0.200 mmol) in dimethylformamide (40
mL) and 1 M aqueous sodium carbonate (6.0 mL, 6.0 mmol) was heated
to 80.degree. C. with stirring overnight. The solvent was removed
under vacuum and the residue suspended in ethyl acetate (30 mL).
The organic suspension was washed with water (3.times.30 mL) and
brine, dried over sodium sulfate, decolorized over activated
carbon, filtered, and the solvent removed under vacuum to give a
residue. The residue was purified by reverse phase
(water:acetonitrile 3:1 to 1:1) followed by extraction with
dichloromethane and removal of solvent under reduced pressure to
afford 69.6 mg of P-037 as a clear viscous oil in 13% yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) 3.81 (s, 3H), 5.08 (s, 2H), 5.99
(s, 2H), 6.82-6.96 (m, 4H), 7.00 (d, J=1.5 Hz, 1H), 7.09 (d, J=10.2
Hz, 3H), 7.55 (s, 1H) ppm. LCMS=100% purity. APCI(+)=309.10
(M+1).
Example 167
Preparation of P-040
##STR00224##
[0614] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-piperidine-2,6-dione
(P-040). To a solution of I-70 (161 mg, 0.500 mmol) and glutarimide
(113 mg, 1.00 mmol) in dimethyl formamide (1.5 mL) was added sodium
hydride (60% weight dispersion, 40 mg, 1.00 mmol) at -78.degree. C.
After hydrogen gas evolution ceased the reaction was stirred at
120.degree. C. overnight. The reaction mixture was filtered, and
the filtrate concentrated under reduced pressure. The residue was
diluted with ethyl acetate (15 mL), washed with water, brine, dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The product was purified by trituration with hexanes (50
mL) and dichloromethane (2 mL) followed by silica gel column
chromatography (50% ethyl acetate in hexanes) to afford 79.8 mg of
P-040 in 45% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) 1.94
(quintet, J=6.4 Hz, 2H), 2.67 (t, J=6.4 Hz, 4H), 3.81 (s, 3H), 4.94
(s, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.44 (dd,
J=8.4, 2.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.81 (ddd, J=8.0, 1.6,
1.2 Hz, 1H), 8.16 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 8.39 (t, J=2.0 Hz,
1H) ppm. LCMS=92% purity.
Example 168
Preparation of P-041
##STR00225##
[0616] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-indole-2,3-dione
(P-041). To a solution of I-70 (98 mg, 0.300 mmol) and isatin (88
mg, 0.60 mmol) in dimethyl formamide (1.0 mL) was added sodium
hydride (60% weight dispersion, 24 mg, 0.6 mmol) at -78.degree. C.
After hydrogen gas evolution ceased the reaction was stirred at
room temperature overnight. The reaction mixture was filtered, and
the filtrate concentrated under reduced pressure. The residue was
diluted with ethyl acetate (15 mL), washed with water, brine, dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The crude product was purified by silica gel column
chromatography (4:1 ethyl acetate:hexanes) to afford 45.5 mg of
P-041 in 39.1% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.82 (s,
3H), 4.93 (s, 2H), 6.85 (d, J=7.9 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H),
7.07-7.14 (m, 1H), 7.29-7.40 (m, 2H), 7.49-7.65 (m, 4H), 7.79 (d,
J=7.8 Hz, 1H), 8.18 (s, 1H), 8.37 (t, J=1.74 Hz, 1H) ppm. Turb.
Spray (+)=389.60 (M+1)
Example 169
Preparation of P-042
##STR00226##
[0618] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-isoindole-1,3-dione
(P-042). To a solution of I-70 (161 mg, 0.500 mmol) and phthalimide
(147 mg, 1.00 mmol) in dimethyl formamide (1.5 mL) was added sodium
hydride (60% weight dispersion, 40 mg, 1.0 mmol) at -78.degree. C.
After hydrogen gas evolution ceased the reaction was stirred at
80.degree. C. overnight. The reaction mixture was filtered, and the
filtrate concentrated under reduced pressure. The residue was
diluted with ethyl acetate (15 mL), washed with water, brine, dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The crude product was purified by trituration several times
in hexanes (100 mL) and ethyl acetate (5 mL) to afford 43.8 mg of
P-042 as a grey-white solid in 26% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) 3.80 (s, 3H), 4.84 (s, 2H), 6.95 (d, J=,8.5 Hz, 1H),
7.43 (d, J=2.2 Hz, 1H), 7.49 (dd, J=8.5, 2.2 Hz, 1H), 7.55 (t,
J=8.0 Hz, 1H), 7.65-7.76 (m, 2H), 7.77-7.87 (m, 3H), 8.17 (dd,
J=8.2, 1.3 Hz, 1H), 8.39 (t, J=1.8 Hz, 1H) ppm. LCMS=97.1%
purity.
[0619] APCI (+)=359.1 (M-29).
Example 170
Preparation of P-043
##STR00227##
[0621] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolo[3,4-c]pyridine-1,3-dio-
ne (P-043). To a solution of I-70 (161 mg, 0.500 mmol) and
pyridinecarboximide (148 mg, 1.00 mmol) in dimethyl formamide (1.5
mL) was added sodium hydride (60% weight dispersion, 40 mg, 1.0
mmol) at -78.degree. C. After hydrogen gas evolution ceased the
reaction was stirred at 80.degree. C. overnight. The reaction was
diluted with ethyl acetate (15 mL), washed with water, brine,
decolorized with activated charcoal, dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The crude product
was purified by trituration several times in hexanes (100 mL) and
ethyl acetate (5 mL) to afford 20.9 mg of P-043 as a grey-white
solid in 11% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.81 (s, 3H),
4.86 (s, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H),
7.45-7.52 (m, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.71-7.83 (m, 3H), 8.18
(d, J=8.3 Hz, 1H), 8.38 (s, 1H), 9.06 (d, J=4.70 Hz, 1H), 9.08-9.17
(m, 2H), 9.20 (s, 1H) ppm. LCMS=95.2% purity. APCI(-)=389.1
(M).
Example 171
Preparation of P-047
##STR00228##
[0623] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2H-[1,2,4]triazolo[4,3-a]pyrid-
in-3-one (P-047. To a solution of I-70 (161 mg, 0.500 mmol) and
triazolepyridinone (135 mg, 1.00 mmol) in dimethyl formamide (1.5
mL) was added sodium hydride (60% weight dispersion, 40 mg, 1.0
mmol) at -78.degree. C. After hydrogen gas evolution ceased the
reaction was stirred at 75.degree. C. for 4 h. The reaction was
diluted water (15 mL). The resultant precipitate was isolated,
dissolved in ethyl acetate (10 mL), decolorized with activated
carbon, dried over sodium sulfate, filtered, and the solvent
removed under vacuum to afford 43.2 mg of P-047 as a cream colored
solid in 23% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.82 (s,
3H), 5.16 (s, 2H), 6.48 (ddd, J=7.1, 4.0, 3.2 Hz, 1H), 6.99 (d,
J=8.5 Hz, 1H), 7.04-7.13 (m, 2H), 7.41 (d, J=2.2 Hz, 1H), 7.47 (dd,
J=8.5, 2.2 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.73-7.86 (m, 2H), 8.17
(dd, J=8.2, 1.2 Hz, 1H), 8.39 (t, J=1.8 Hz, 1H) ppm. LCMS=98.0%
purity. APCI(+)=377.1 (M+1).
Example 172
Preparation of P-052
##STR00229##
[0625] Synthesis of
2-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-isoindole-1,3-dione
(P-052). A suspension of phthalimide (147 mg, 1.00 mmol), I-168
(138 mg, 0.500 mmol), and solid potassium carbonate (138 mg, 1.00
mmol) was stirred over 72 h. Water was added, and a precipitate was
formed. The suspension was stirred for 10 min, and the solid
collected and dissolved in ethyl acetate (20 mL). The organic
solution was dried over sodium sulfate, filtered, and the solvent
removed under vacuum to afford 173 mg of P-052 in 93% yield.
[0626] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.78 (s, 3H), 4.82 (s,
2H), 5.91-6.00 (m, 2H), 6.80-6.98 (m, 3H), 7.02 (d, J=1.3 Hz, 1H),
7.35-7.43 (m, 2H), 7.70 (dd, J=5.4, 3.0 Hz, 2H), 7.80-7.88 (m, 2H)
ppm. LCMS=95.6% purity.
Example 173
Preparation of P-055
##STR00230##
[0628] Synthesis of
6-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolo[3,4-b]pyridine-5,7-dio-
ne (P-055). A suspension of I-70 (322 mg, 1.00 mmol), quinolinimide
(148 mg, 1.00 mmol), and solid potassium carbonate (276 mg, 2.00
mmol) in dimethyl formamide (20 mL) was stirred at room temperature
overnight. The reaction was diluted water, stirred for 10 min, and
the resultant precipitate was isolated. The solid was dissolved in
ethyl acetate (20 mL), dried over sodium sulfate, filtered, and the
solvent removed under vacuum to afford 145 mg of P-055 as a pale
yellow solid in 37% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.81
(s, 3H), 4.91 (s, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.45 (d, J=2.2 Hz,
1H), 7.48-7.66 (m, 3H), 7.80 (d, J=7.8 Hz, 1H), 8.10-8.22 (m, 2H),
8.39 (t, J=1.8 Hz, 1H), 8.96 (dd, J=4.9, 1.4 Hz, 1H) ppm. LCMS=95%
purity. TSI (+)=390.40 (M+1).
Example 174
Preparation of P-062
##STR00231##
[0630] Synthesis of 2-Methoxy-3'-nitro-biphenyl (I-169). A
suspension of 2-methoxyphenylboronic acid (911 mg, 6.00 mmol),
3-nitro-iodobenzne (1.24 g, 5.00 mmol), palladium(II) acetate (22
mg, 0.10 mmol), and solid potassium carbonate (1.38 g, 10. mmol),
in methanol (25 mL), and water (5 mL) was stirred at room
temperature overnight. The reaction was diluted with ethyl acetate
(50 mL), washed with water (2.times.50 mL) and brine, dried over
sodium sulfate, filtered, and the solvent removed under vacuum to
give crude product. The product was purified by silica gel column
chromatography (hexanes/ethyl acetate 9:1) to afford 940 mg of
I-169 as a white solid in 82% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) 3.84 (s, 3H), 6.96-7.14 (m, 2H), 7.30-7.44 (m, 2H),
7.56 (t, J=8.0 Hz, 1H), 7.86 (d, J=7.7 Hz, 1H), 8.17 (dd, J=8.2,
1.2 Hz, 1H), 8.42 (s, 1H) ppm.
##STR00232##
[0631] Synthesis of
4-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-3,5-dimethyl-isoxazole
(P-062). To a solution of I-168 (138 mg, 0.500 mmol) and
3,5-dimethyl-isoxazole-4-boronic acid (70 mg, 0.500 mmol) in
dimethyl formamide (5 mL) were added palladium(0)
bis(dibenzylideneacetone (14 mg, 0.025 mmol), triphenylphosphine
(13 mg, 0.0500 mmol) and 1 M aqueous sodium carbonate (1.5 mL, 1.5
mmol). The resultant suspension was stirred at 85.degree. C. for 72
h. The reaction was concentrated under reduced pressure, diluted
with ethyl acetate (10 mL), washed with water (3.times.10 mL) and
brine, dried over sodium sulfate, filtered, and the solvent removed
under reduced pressure. The crude residue was purified by silica
gel preparatory thin layer chromatography eluting with 1:1 hexanes
and dichloromethane to afford 16.2 mg (10%) of P-062. .sup.1H NMR
(400 MHz, CDCl.sub.3) 2.11 (s, 3H), 2.31 (s, 3H), 3.64 (s, 2H),
3.79 (s, 3H), 5.98 (s, 2H), 6.80-6.94 (m, 3H), 6.94-7.05 (m, 3H)
ppm. LCMS=100% purity. APCI(+)=338.10 (M+1).
Example 175
Preparation of P-066
##STR00233##
[0633] Synthesis of
C-(6-Methoxy-3'-nitro-biphenyl-3-yl)-methylamine (I-170): A
suspension of P-052 (700 mg, 1.80 mmol) and hydrazine hydrate (0.35
mL. 7.2 mmol) in ethanol (60 mL) was stirred at reflux for 6 h. The
reaction was cooled to room temperature, filtered, and the solvent
was evaporated. The residue was dissolved in ethanol (15 mL),
precipitated with water (50 mL), and filtered to afford 97.9 mg as
a white solid in 21% yield.
##STR00234##
[0634] Synthesis of
4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-4H-[1,2,4]triazole
(P-066). A solution of formic hydrazine (25 mg, 0.41 mmol) and
N,N-dimethylformamide dimethyl acetal (0.050 mL, 0.41 mmol) in
acetonitrile (0.5 mL) was stirred at 50.degree. C. for 30 min. To
the solution was added I-170 (98 mg, 0.38 mmol) and acetic acid
(0.5 mL). The reaction was then stirred at 160.degree. C. for 6 h.
The reaction was cooled to room temperature and the concentrated
under vacuum. The reaction was diluted with water (30 mL) and
extracted with dichloromethane (2.times.30 mL), the combined
extracts were washed with brine, dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The crude material
was purified by silica gel preparatory thin layer chromatography
(9:1 dichloromethane:methanol) to afford 19.4 mg of P-066 in 17%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3): 3.86 (s, 3H), 5.19 (s,
2H), 7.03 (d, J=8.5 Hz, 1H), 7.17-7.25 (m, 2H), 7.58 (t, J=8.0 Hz,
1H), 7.79 (d, J=7.8 Hz, 1H), 8.16-8.24 (m, 3H), 8.37 (t, J=1.9 Hz,
1H) ppm.
[0635] LCMS=94.0% purity. APCI(+)=311.1 (M+1).
##STR00235##
Example 176
Preparation of P-073
[0636] Synthesis of
(3-Benzo[1,3]dioxol-5-yl-4-methoxy-phenyl)-(2-methyl-2H-pyrazol-3-yl)-met-
hanol (P-073). A solution of 1-methylpyrazole (123 mg, 1.50 mmol)
in tetrahydrofuran (10 mL) was cooled to 0.degree. C. in an ice
bath, and n-butyl lithium (2.5 M in hexanes, 0.80 mL, 2.0 mmol) was
added. The yellow solution was stirred at 0.degree. C. for 30 min
followed by the addition of I-170 (256 mg, 1.00 mmol), and the
resultant pale green solution stirred for 2 h. The reaction was
diluted with water (50 mL), and extracted with ethyl acetate
(2.times.30 mL). The combined extracts were washed with brine,
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude material was purified by silica gel column
chromatography (1:1 hexanes:dichloromethane) to afford 259.1 mg of
P-073 as a pale yellow solid in 77% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3): 3.81 (s, 3H), 3.83 (s, 3H), 5.90 (s, 1H), 5.98 (s,
2H), 6.12 (d, J=1.6 Hz, 1H), 6.82-6.89 (m, 1H), 6.91-6.98 (m, 2H),
7.03 (d, J=1.5 Hz, 1H), 7.29 (s, 2H), 7.40 (d, 1H) ppm. LCMS=98.9%;
APCI(+)=339.1 (M+1).
Example 177
Preparation of P-075
[0637] Synthesis of
5-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-1-methyl-1H-pyrazole
(P-075). To a solution of P-073 (169 mg, 0.500 mmol) in
trifluoroacetic acid (2.0 mL), was added triethylsilane (0.50 mL,
3.0 mmol). The reaction was stirred at room temperature overnight.
The reaction was diluted with water (10 mL) and extracted with
dichloromethane (2.times.10 mL). The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The crude product was purified by
silica gel column chromatography (20% methanol in dichloromethane)
to afford 39.1 mg (24%) of P-075. .sup.1H NMR (400 MHz, CDCl.sub.3)
7.40 (d, J=1.7 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.02-7.06 (m, J=2.4
Hz, 1H), 7.02 (d, J=1.7 Hz, 1H), 6.91-6.94 (m, 1H), 6.90 (s, 1H),
6.86 (t, J=8.5 Hz, 2H), 5.98 (s, 2H), 3.95 (s, 2H), 3.80 (s, 3H),
3.74 (s, 3H) ppm.
Example 178
Preparation of P-074
##STR00236##
[0639] Synthesis of
1-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-1H-pyrazole (P-074). A
suspension of pyrazole (136 mg, 2.00 mmol), I-168 (108 mg, 1.00
mmol), and solid potassium carbonate (276 mg, 2.00 mmol) was
stirred at room temperature overnight. Water (30 mL) was added, and
the suspension extracted with ethyl acetate (2.times.30 mL). The
combined organic layers were washed with brine, dried over sodium
sulfate, filtered, and the solvent removed under vacuum. The
product was purified by silica gel column chromatography (10% ethyl
acetate in hexanes) to afford 44.4 mg of P-074 as a pale yellow oil
in 14% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (d, J=1.8 Hz,
1H), 7.38 (d, J=2.3 Hz, 1H), 7.17 (dd, J=4.4, 2.2 Hz, 2H), 7.01 (d,
J=1.7 Hz, 1H), 6.91-6.94 (m, 2H), 6.82-6.87 (m, 1H), 6.26 (t, J=2.1
Hz, 1H), 5.98 (s, 2H), 5.28 (s, 2H), 3.80 (s, 3H)
Example 179
Preparation of P-077
##STR00237##
[0641] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-pyrazole (P-077). A
suspension of I-70 (322 mg, 1.00 mmol), pyrazole (136 mg, 2.00
mmol), and solid potassium carbonate (276 mg, 2.00 mmol) in
dimethyl formamide (10 mL) was stirred at room temperature
overnight. The reaction was diluted water (30 mL), and extracted
with ethyl acetate (2.times.30 mL). The combined extracts were
washed with brine, dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The residue was purified by silica
gel column chromatography (15% ethyl acetate in hexanes) to give
P-077 (148 mg, 48% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 8.27 (s, 1H), 8.17-8.22 (m, 1H), 7.89-7.94 (m, 1H),
7.83 (d, J=2.2 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.44 (d, J=1.7 Hz,
1H), 7.35 (d, J=2.1 Hz, 1H), 7.28-7.33 (m, 1H), 7.15 (d, J=8.5 Hz,
1H), 6.19-6.30 (m, 1H), 5.32 (s, 2H), 3.79 (s, 3H) ppm.
[0642] LCMS=99.7% purity. APCI (+)=310.1 (M+1)
Example 180
Preparation of P-087
##STR00238##
[0644] Synthesis of
[4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-ac-
etic acid ethyl ester (P-087). To a solution of I-171 (102 mg,
0.300 mmol) in 1,2-dimethoxyethane (5 mL), were added ethyl
hydrazinoacetate hydrochloride (93 mg, 0.60 mmol) and 4 Angstrom
molecular sieves (200 mg), and the reaction was stirred at reflux
for 3 h. The hot suspension was filtered and the solvent removed
under vacuum. The residue was dissolved in dichloromethane (10 mL)
and washed with water (30 mL). The aqueous wash was extracted with
dichloromethane (2.times.30 mL), and the extracts combined. The
organic solution was washed with brine, dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The residue was
purified by silica gel column chromatography (2:1 hexanes:ethyl
acetate) to give P-087 (97.1 mg, 76% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.38 (t, J=1.9 Hz, 1H), 8.15 (dd, J=8.2, 2.3 Hz, 1H),
7.79-7.82 (m, 1H), 7.53-7.56 (m, 1H), 7.07-7.10 (m, 2H), 6.90 (d,
J=9.1 Hz, 1H), 4.79 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.80 (s, 3H),
3.74 (s, 2H), 2.13 (s, 3H), 2.13 (s, 3H), 1.26 (t, J=7.1 Hz, 3H)
ppm. LCMS: 98.7% purity. APCI(+)=310.1 (M-29)
Example 181
Preparation of P-088
##STR00239##
[0646] Synthesis of
2-[4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]--
ethanol (P-088). To a solution of I-171 (102 mg, 0.300 mmol) in
1,2-dimethoxyethane (5 mL), were added 2-hydroxyethyl hydrazine
(0.037 mL, 0.60 mmol) and 4 Angstrom molecular sieves (200 mg), and
the reaction was stirred at reflux for 3 h. The hot suspension was
filtered and the solvent removed under vacuum. The residue was
dissolved in dichloromethane (10 mL) and washed with water (30 mL).
The aqueous wash was extracted with dichloromethane (2.times.30
mL), and the extracts combined. The organic solution was washed
with brine, dried over sodium sulfate, filtered, and the solvent
removed under vacuum. The crude material was purified by silica gel
column chromatography (2:1:0.3 hexanes:ethyl acetate:methanol) to
give P-088 (61.0 mg, 53% yield) as a yellow solid. .sup.1H NMR (400
MHz, CDCl.sub.3): 8.37 (t, J=2.0 Hz, 1H), 8.16 (dt, J=8.2, 1.1 Hz,
1H), 7.81 (dt, J=7.7, 0.8 Hz, 1H), 7.54-7.57 (m, 1H), 7.06-7.10 (m,
2H), 6.91 (d, J=9.1 Hz, 1H), 4.05-4.09 (m, 2H), 3.95-4.02 (m, 2H),
3.80 (s, 3H), 3.73 (s, 2H), 2.14 (s, 3H), 2.16 (s, 3H) ppm. LCMS:
98.2% purity. APCI(+)=382.1 (M+1)
Example 182
Preparation of P-089
##STR00240##
[0648] Synthesis of
4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-1H-pyrazole
(P-089). To a solution of I-171 (102 mg, 0.300 mmol) in
1,2-dimethoxyethane (5 mL), were added hydrazine (0.029 mL, 0.60
mmol) and 4 Angstrom molecular sieves (200 mg), and the reaction
was stirred at reflux for 3 h. The hot suspension was filtered and
the solvent removed under vacuum. The residue was dissolved in
dichloromethane (10 mL) and washed with water (30 mL). The aqueous
wash was extracted with dichloromethane (2.times.30 mL), and the
extracts combined. The organic solution was washed with brine,
dried over sodium sulfate, filtered, and the solvent removed under
vacuum. The crude material was purified by silica gel column
chromatography (1:1 hexanes:ethyl acetate) to give P-089 (67.8 mg,
67% yield) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.38 (s, 1H),
8.13-8.20 (m, 1H), 7.75-7.83 (m, 1H), 7.50-7.58 (m, 1H), 7.05-7.13,
(m, 2H), 6.91 (d, J=8.1 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 2H), 2.18
(s, 6H) ppm. LCMS=97.2% purity. APCI (+)=338.1 (M+1).
Example 183
Preparation of P-090
##STR00241##
[0650] Synthesis of
4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-1-(2,2,2-trifluor-
o-ethyl)-1H-pyrazole (P-090). To a solution of I-171 (102 mg, 0.300
mmol) in 1,2-dimethoxyethane (5 mL), were added
2,2,2-trifluoroethyl hydrazine (0.098 mL, 0.60 mmol) and 4 Angstrom
molecular sieves (200 mg), and the reaction was stirred at reflux
for 3 h. The hot suspension was filtered and the solvent removed
under vacuum. The residue was dissolved in dichloromethane (10 mL)
and washed with water (30 mL). The aqueous wash was extracted with
dichloromethane (2.times.30 mL), and the extracts combined. The
organic solution was washed with brine, dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The crude material
was purified by silica gel column chromatography (5:1 hexanes:ethyl
acetate) to give P-090 (64.5 mg, 51% yield) as a yellow-red oil.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.38 (t, J=2.0 Hz, 1H), 8.16
(ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.78-7.81 (m, 1H), 7.52-7.55 (m,
1H), 7.04-7.07 (m, 2H), 6.91 (d, J=9.1 Hz, 1H), 4.58 (q, J=8.4 Hz,
2H), 3.78-3.81 (m, 3H), 3.73 (s, 2H), 2.20 (s, 3H), 2.14 (s, 3H)
ppm. LCMS=97.6% purity. APCI (+)=420.1 (M+1).
Example 184
Preparation of P-101
##STR00242##
[0652] Synthesis of
2-[4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]--
acetamide (P-101). To a solution of P-087 (212 mg, 0.500 mmol) in
methanol (5 mL) was added ammonia (7 M in methanol, 0.5 mL, 3.5
mmol) and the solution was stirred at room temperature overnight.
The resulting suspension was concentrated under vacuum, and
dissolved in ethyl acetate (10 mL). The reaction was washed with
water (10 mL) and brine (10 mL), dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The resulting solid
was triturated in dichloromethane (1 mL) in hexanes (10 mL) to give
P-101 (85.8 mg, 44% yield) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) 8.31-8.37 (m, 1H), 8.14-8.20 (m, 1H), 7.77-7.84 (m,
1H), 7.51-7.59 (m, 1H), 7.01-7.10 (m, 2H), 6.91 (d, J=8.1 Hz, 1H),
6.05 (br s, 1H), 5.39 (br s, 1H), 4.68 (s, 2H), 3.80 (s, 3H), 3.73
(s, 2H), 2.17 (s, 3H), 2.16 (s, 3H) ppm. LCMS=98.2% purity. APCI
(+)=395.1 (M+1).
##STR00243##
Example 185
Preparation of P-115
[0653] Synthesis of
3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-benzaldehyde
(I-172). To a solution of 5-formyl-2-methoxy phenyl boronic acid
(1.0 g, 5.5 mmol) in water (6 mL) and methanol (30 mL), was added
5-bromo-2,2-difluoro-1,3-benzodioxole (0.97 mL, 7.2 mmol), solid
potassium carbonate (1.5 g, 11 mmol), and palladium(II) acetate (25
mg, 0.11 mmol). The reaction was stirred at room temperature for 16
h. The black mixture was diluted with water (30 mL) and extracted
with ethyl acetate (2.times.30 mL). The combined extracts were
decolorized with activated charcoal, dried over sodium sulfate,
filtered, and concentrated to 20 mL under vacuum. The solution was
purified by silica gel column chromatography eluting with
hexanes/ethyl acetate (11:1) to give I-172 (620 mg, 39% yield) as a
white solid.
[0654] Synthesis of
[3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-phenyl]-(2-methyl-2H-py-
razol-3-yl)-methanol (I-173). A solution of 1-methylpyrazole (123
mg, 1.5 mmol) under a positive nitrogen atmosphere was cooled to
0.degree. C. in an ice water bath. To the stirring solution was
added n-butyl lithium (2.5 M in hexanes, 0.80 mL, 2.0 mmol) The
reaction mixture was stirred at 0.degree. C. for 30 min, and I-172
(292 mg, 1.0 mmol) was added in one portion. The reaction was
stirred an additional 2 h. The reaction was diluted with water (50
mL), and extracted with ethyl acetate (2.times.30 mL). The combined
extracts were washed with brine, dried over sodium sulfate,
filtered, and the solvent removed under reduced pressure to give
I-173 (220 mg, 59% yield) as a yellow solid.
[0655] Synthesis of
5-[3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-benzyl]-1-methyl-1H-p-
yrazole (P-115). To a solution of I-173 (187 mg, 0.500 mmol) in
trifluoroacetic acid (2.0 mL), was added triethyl silane (0.50 mL,
3.0 mmol). The reaction was stirred at room temperature overnight.
The reaction was diluted with water (10 mL) and extracted with
dichloromethane (2.times.10 mL). The combined extracts were washed
with brine, dried over sodium sulfate, filtered, and the solvent
removed under vacuum. The residue was purified by silica gel column
chromatography (5:2 hexanes/ethyl acetate) and silica gel
preparatory thin layer chromatography (20:1
dichloromethane/methanol) to give P-115 (29.9 mg, 17% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): 3.74 (s, 3H), 3.81 (s, 3H), 3.96
(s, 2H), 6.02 (d, J=1.6 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 7.00-7.17
(m, 4H), 7.24 (d, J=1.5 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H) ppm.
LCMS=100% purity. APCI (+)=359.1 (M+1).
Example 186
Preparation of P-201
##STR00244##
[0657] Synthesis of
5-(3-Benzo[1,3]dioxol-5-yl-4-difluoromethoxy-benzyl)-1-methyl-1H-pyrazole
(P-201). A suspension of benzo[1,3]dioxole-5-boronic acid (108 mg,
0.65 mmol), I-174 (158 mg, 0.500 mmol), palladium(II)
triphenylphosphindichloride (35 mg, 0.050 mmol), and 1M aqueous
sodium carbontate (1.0 mL, 1.00 mmol) in xylene (3 mL) was stirred
at 150.degree. C. for 24 h. The reaction was diluted with ethyl
acetate (10 mL), washed with water (3.times.10 mL) and brine, dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The residue was purified by silica gel column
chromatography (4:1 hexanes/ethyl acetate), and then by silica gel
preparatory thin layer chromatography (5:1 dichloromethane/acetone)
to give P-201 (13.4 mg, 7% yield).
[0658] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.64 (s, 3H), 4.05 (s,
2H), 5.82 (s, 1H), 5.95 (s, 2H), 6.63-6.94 (m, 7H), 7.59 (s, 1H)
ppm. LCMS=99% purity. APCI (-)=321.1 (M-37).
Example 187
Preparation of P-306
##STR00245##
[0660] Synthesis of
5-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]oxadiazol-2-ylamine
(P-306). A solution of I-176 (277 mg, 1.00 mmol) in hydrazine
hydrate (0.5 mL) was stirred at 100.degree. C. overnight. The
reaction was concentrated under vacuum to obtain a gummy white
solid. The crude material was dissolved in 1,2-dimethoxyethane (0.5
mL) and cyanogen bromide (212 mg, 2.00 mmol) was added. The
reaction was stirred at room temperature for 3 h. The reaction was
diluted with dichloromethane (5 mL) and washed with 1 M aqueous
sodium hydroxide (5 mL). The organic layer was separated, dried
over sodium sulfate, filtered and concentrated under vacuum. The
residue was purified by silica gel preparatory thin layer
chromatography (hexanes/ethyl acetate) to give P-306 (64.2 mg, 30%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.77 (s, 3H), 4.01 (s,
2H), 6.87 (s, 2H), 7.10 (d, J=8.5 Hz, 1H), 7.21-7.29 (m, 2H),
7.36-7.47 (m, 3H), 7.50 (s, 1H) ppm. LCMS=97.1% purity. APCI(+)=316
(M).
Example 188
Preparation of P-393
##STR00246##
[0662] Synthesis
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-a-
zetidin-3-ol (P-393). A suspension of I-177 (72 mg, 0.20 mmol),
azetidin-3-ol hydrochloride (44 mg, 0.40 mmol) and potassium
carbonate (55 mg, 0.40 mmol) in dimethyl formamide (1.5 mL) was
stirred at 80.degree. C. overnight. The mixture was cooled to room
temperature, diluted with water (5 mL), and extracted with diethyl
ether (3.times.5 mL). The combined extracts were concentrated, and
the crude material purified by silica gel column chromatography
(2:1 hexanes/ethyl acetate) to give P-393 (73.3 mg, 92% yield) as a
cream white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 3.75 (s, 3H),
3.77 (s, 2H), 3.98 (dd, J=10.3, 4.3 Hz, 2H), 4.34-4.43 (m, 2H),
4.77 (br s, 1H), 6.70 (d, J=8.3 Hz, 1H), 7.08 (t, J=8.6 Hz, 1H),
7.26-7.40 (m, 4H), 8.21 (s, 2H) ppm.
[0663] LCMS=100% purity. APCI (+)=400 (M).
Example 189
Preparation of P-397
##STR00247##
[0665] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1-oxy-pyridin-2-y-
l]-3-ethyl-urea (P-397). A solution of P-356 (82.7 mg, 0.200 mmol)
in diethyl ether (5 mL) was stirred at room temperature with
peracetic acid (32% wt., 0.06 mL, 0.300 mmol) for 3 h. The mixture
was concentrated and the residue purified by silica gel column
chromatography (19:1 dichloromethane/methanol) to give P-397 (27.6
mg, 32% yield).
[0666] .sup.1H NMR (400 MHz, CDCl.sub.3): 1.12 (t, 3H) 3.17-3.35
(m, 2H), 3.72-3.80 (m, 3H), 3.87 (s, 2H), 6.64-6.78 (m, 1H), 6.86
(br s, 1H), 7.02-7.17 (m, 1H), 7.22 (s, 1H), 7.29-7.43 (m, 3H),
7.93 (s, 1H), 8.36 (d, J=8.9 Hz, 1H), 9.73 (s, 1H) ppm.
[0667] LCMS=100% purity. APCI (-)=428.1 (M-2).
Example 190
Preparation of P-398
##STR00248##
[0669] Synthesis of
[5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-carbam-
ic acid ethyl ester (P-398). A solution of I-178 (166 mg, 0.500
mmol) in tetrahydrofuran was cooled to 0.degree. C. To the reaction
was added pyridine (0.08 mL, 1 mmol), and the reaction stirred for
10 min. To the solution was added ethyl chloroformate (0.09 mmol, 1
mmol) slowly, and the yellow suspension was stirred at room
temperature overnight. The reaction was allowed to sit after the
addition of water (10 mL), and the solid that settled to the bottom
was collected by filtration. The solid was suspended in dimethyl
sulfoxide (5 mL) and water (5 mL), and filtered to give P-398 (14.6
mg, 7.2% yield) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): 1.31 (t, J=7.1 Hz, 3H), 3.76 (s, 3H), 3.91 (s, 2H),
4.23 (q, J=7.1 Hz, 2H), 6.73 (d, J=8.6 Hz, 1H), 7.12 (t, J=8.5 Hz,
1H), 7.32-7.41 (m, 1H), 7.44-7.56 (m, 2H), 7.63 (d, J=7.8 Hz, 2H),
7.70 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 8.12 (s, 1H) ppm. LCMS=94.0%
purity. APCI(+)=406.1 (M+1).
Example 191
Preparation of P-405-HCl
##STR00249##
[0671] Synthesis of
1-[5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-3-et-
hyl-urea hydrochloride salt (P-405-HCl). A solution of I-178 (166
mg, 0.500 mmol) and ethyl isocyanate (0.2 mL, 2.5 mmol) in pyridine
(0.5 mL) was stirred at room temperature overnight. To the solution
was added water (5 mL), and the reaction stirred for 1 h. The solid
that formed was filtered, triturated with tetrahydrofuran and water
to give a residue. This residue was purified by silica gel column
chromatography (100:1 dichloromethane/methanol) to give impure
P-405 (131 mg, 65% yield). The whole of the material was suspended
in diethyl ether (1.5 mL) and 4 N hydrogen chloride in dioxane
(0.75 mL, 3.0 mmol) was added. Additional hydrogen chloride
solution was added (2.25 mL, 9 mmol). The reaction mixture was
allowed to stir at room temperature overnight. The precipitate was
filtered and dried to give P-405-HCl (52.5 mg, 24% yield).
[0672] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.09 (t, J=7.2 Hz, 3H),
3.12-3.25 (m, 2H), 3.74 (s, 3H), 3.94 (s, 2H), 6.97 (d, J=8.7 Hz,
1H), 7.25-7.47 (m, 2H), 7.53-7.92 (m, 5H), 8.10 (s, 1H) ppm.
LCMS=100% purity. APCI (+)=405.1 (M+1).
Example 192
Preparation of P-406
##STR00250##
[0674] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-((R)-1-methyl-pyrr-
olidin-3-yloxy)-pyrimidine (P-406). To a solution of I-177 (65 mg,
0.18 mmol) and (R)-(-)-methyl-3-pyrrolidinol (0.039 mL, 0.36 mmol)
in tetrahydrofuran (1 mL) was added NaH (60% weight dispersion, 29
mg, 0.72 mmol) slowly. Once gas evolution ceased, the reaction was
stirred at 80.degree. C. for 4 h. The reaction was cooled to room
temperature and diluted with water (10 mL). The mixture was
extracted with ethyl acetate (3.times.2 mL), the pH of the aqueous
layer adjusted to pH 7 by addition of 1 M aqueous hydrochloric
acid, and the aqueous mixture again extracted with ethyl acetate
(2.times.2 mL). The combined extracts were dried over sodium
sulfate, filtered and the solvent removed under vacuum. The residue
was purified by silica gel column chromatography (9:1
dichloromethane/methanol) to give P-406 (46.8 mg, 61% yield) as a
thick pale yellow oil.
[0675] .sup.1H NMR (400 MHz, CDCl.sub.3): 2.03-2.48 (m, 2H), 2.54
(s, 3H), 2.72-2.93 (m, 2H), 3.00 (br s, 1H), 3.47 (dd, J=11.4, 5.9
Hz, 1H), 3.77 (s, 3H), 3.87 (s, 2H), 5.45 (t, J=6.4 Hz, 1H), 6.73
(d, J=8.5 Hz, 1H), 7.12 (t, J=8.5 Hz, 1H), 7.29-7.41 (m, 3H), 8.37
(s, 2H) ppm. LCMS=100% purity. MS (ESI+) 428.1 (M+H).
Example 193
Preparation of P-417
##STR00251##
[0677] Synthesis of
2'-Fluoro-3'-[2-(3-hydroxy-azetidin-1-yl)-pyrimidin-5-ylmethyl]-6'-methox-
y-biphenyl-3-carbonitrile (P-417). To a stirred solution of I-177
(61 mg, 0.17 mmol) and azetidin-3-ol hydrochloride (40 mg, 0.34
mmol) in dimethylformamide (0.5 mL) was added solid potassium
carbonate (48 mg, 0.34 mmol), and the pale yellow solution was
subsequently stirred at 80.degree. C. overnight. The reaction was
cooled to room temperature, diluted with water (15 mL), stirred for
30 min at room temperature, and the resulting precipitate collected
by filtration. The crude was purified by trituration in
dichloromethane/diethyl ether/hexanes to give P-417 (26 mg, 39%
yield) as a white-cream solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
3.68-3.74 (m, 5H), 3.77 (s, 2H), 4.08-4.26 (m, 2H), 4.52 (br s,
1H), 5.63 (d, J=6.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 7.32 (t, J=8.7
Hz, 1H), 7.54-7.74 (m, 2H), 7.74-7.91 (m, 2H), 8.24 (s, 2H)
ppm.
[0678] LCMS=100% purity. APCI (+)=391.1 (M+1).
Example 194
Preparation of P-513
##STR00252##
[0680] Synthesis of
1-Ethyl-3-{5-[2-fluoro-6-methoxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-ylmethy-
l]-pyridin-2-yl}-urea (P-513). A mixture of P-405 (405 mg, 1.00
mmol), sodium azide (325 mg, 5.00 mmol), and ammonium chloride (374
mg, 7.00 mmol) in dimethylformamide (10 mL) was stirred at
80.degree. C. overnight. The reaction was cooled to room
temperature, diluted with ethyl acetate (30 mL), and washed with
water (50 mL). The aqueous wash was extracted with ethyl acetate
(2.times.30 mL), the extracts combined, dried over sodium sulfate,
and the solvent removed under vacuum. The residue was purified by
silica gel column chromatography (19:1 to 4:1
dichloromethane/methanol) to give P-513 (11.5 mg, 2.5% yield) as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.05-1.10 (m,
3H), 3.11-3.21 (m, 2H), 3.72 (s, 3H), 3.88 (s, 2H), 6.93 (d, J=8.6
Hz, 1H), 7.10-7.37 (m, 3H), 7.42 (s, 1H), 7.54 (s, 1H), 7.90 (br s,
2H), 8.07 (s, 2H), 9.09 (s, 1H) ppm.
[0681] LCMS=95.9% yield. APCI (+)=448.1
Example 195
Preparation of P-456
##STR00253##
[0683] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(P-456). A suspension of I-33 (824 mg, 2.50 mmol),
2-fluoropyridin-5-boronic acid (352 mg, 2.50 mmol), 2 M aqueous
sodium carbonate (2.5 mL, 5.00 mmol), and
palladium(0)tetrakis(triphenylphosphine) (144 mg, 0.125 mmol) in
toluene (10 mL) and ethanol (2.5 mL) was stirred at 80.degree. C.
overnight under a high pressure nitrogen atmosphere. The reaction
was cooled to room temperature, diluted with water (10 mL), and
extracted with ethyl acetate (2.times.20 mL). The combined extracts
were dried over sodium sulfate, filtered, and concentrated under
vacuum. The residue was purified by silica gel column
chromatography (4:1 hexanes/ethyl acetate) to give P-456 (695 mg,
78% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
3.73 (s, 3H), 3.98 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.11 (dd,
J=8.4, 2.7 Hz, 1H), 7.25-7.51 (m, 5H), 7.82 (td, J=8.2, 2.4 Hz,
1H), 8.14 (s, 1H), 8.32 (s 1H) ppm. LCMS=97.4% purity. APCI (+)=346
(M)
Example 196
Preparation of P-457
##STR00254##
[0685] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-aze-
tidin-3-ol (P-457). A mixture of azetidin-3-ol (56 mg, 0.56 mmol)
and sodium hydride (60% weight dispersion, 33 mg, 0.84 mmol) in
dimethylformamide (1 mL) was stirred under gas evolution ceased.
After 2 min of stirring P-456 (97 mg, 0.28 mmol) was added, and the
reaction heated at 140.degree. C. overnight. The reaction was
cooled to room temperature, diluted with water (5 mL), and
extracted with ethyl acetate (2.times.5 mL). The combined extracts
were dried over sodium sulfate, filtered, and the solvent removed
under vacuum. The residue was purified by silica gel column
chromatography (1:2 hexanes/ethyl acetate followed by 9:1
dichloromethane/methanol) and trituration in ethyl acetate and
hexanes to give P-457 (22.2 mg, 19.9% yield) as a cream colored
solid.
[0686] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.61 (dd, 2H),
3.68-3.74 (m, 3H), 3.78 (s, 2H), 4.09 (t, J=7.5 Hz, 2H), 4.47-4.60
(m, 1H), 5.59 (d, J=6.6 Hz, 1H), 6.33 (d, J=8.5 Hz, 1H), 6.92 (d,
J=8.6 Hz, 1H), 7.20-7.32 (m, 2H), 7.32-7.39 (m, 2H), 7.39-7.50 (m,
2H), 7.96 (d, J=1.6 Hz, 1H) ppm. LCMS=98.5% purity. APCI (+)=399
(M).
##STR00255##
Example 197
Preparation of P-522
[0687] Synthesis of
1-(3'-Chloro-6-methoxy-biphenyl-3-yl)-6-nitro-1H-benzoimidazole
(P-522). A suspension of I-179 (328 mg, 1.00 mmol), potassium
phosphate (424 mg, 2.00 mmol), and 3-chlorophenylboronic acid (313
mg, 1.30 mmol) in ethanol (1 mL), water (1 mL), and
1,2-dimethoxyethane (2 mL) was degassed with nitrogen stream for 15
min. To the mixture was added
palladium(0)tetrakis(triphenylphosphine), and the reaction stirred
at 80.degree. C. overnight. The reaction was cooled to room
temperature, basified with 1 M aqueous sodium hydroxide (2 mL),
diluted with water (15 mL), and extracted with ethyl acetate
(2.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated under vacuum. The crude was
purified by silica gel column chromatography (4:1 to 1:1
hexanes/ethyl acetate) to give P-522 (310 mg, 82% yield) as a pale
yellow solid.
[0688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 3.90 (s, 3H), 7.36-7.51
(m, 3H), 7.60 (d, J=7.4 Hz, 1H), 7.64-7.77 (m, 3H), 7.81 (d, J=9.1
Hz, 1H), 8.23 (dd, J=9.1, 2.2 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.88
(s, 1H) ppm.
[0689] LCMS=96.1% purity. APCI (+)=380 (M).
Example 198
Preparation of P-524
[0690] Synthesis of
3-(3'-Chloro-6-methoxy-biphenyl-3-yl)-3H-benzoimidazol-5-ylamine
(P-524). A solution of P-522 (310 mg, 0.811 mmol) in ethanol (577
mg) and tetrahydrofuran (5 mL) was stirred at room temperature. To
the solution was added tin(II) chloride hydrate (900 mg, 4.00 mmol)
and the reaction stirred at 80.degree. C. for 3 h. The reaction was
then cooled to room temperature, and concentrated in vacuo. The
residue was diluted with chloroform (10 mL), washed with 1 N
aqueous sodium hydroxide (4 mL), water, and brine, dried over
sodium sulfate, filtered, and the solvent removed under vacuum. The
residue was purified by silica gel column chromatography (9:1
dichloromethane/methanol) to give P-524 (55.3 mg, 19% yield) as
off-white solid.
[0691] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.86 (s, 3H), 4.87 (s,
2H), 6.66 (dd, J=8.6, 1.9 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H),
7.25-7.35 (m, 2H), 7.38-7.65 (m, 4H), 7.66 (s, 1H), 8.30 (s, 1H)
ppm. LCMS=93.9% purity. APCI (+)=380 (M).
Example 199
Preparation of P-529
[0692] Synthesis of
1-[3-(3'-Chloro-6-methoxy-biphenyl-3-yl)-3H-benzoimidazol-5-yl]-3-ethyl-u-
rea (P-529). A solution of P-524 (35 mg, 0.10 mmol) and ethyl
isocyanate (0.04 mL, 0.5 mmol) in pyridine (0.2 mL) was stirred at
room temperature overnight. The reaction was diluted with water (2
mL), extracted with ethyl acetate (2.times.2 mL), and the extracts
combined. The extracts were dried over sodium sulfate, filtered,
and the solvent removed under vacuum. The residue was purified by
trituration in ethyl acetate and diethyl ether to give P-529 (19.0
mg, 45% yield) as an off-white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 1.07 (t, J=7.2 Hz, 3H), 3.02-3.20 (m, 2H), 3.88 (s,
3H), 5.96-6.09 (m, 1H), 7.23 (dd, J=8.7, 1.9 Hz, 1H), 7.35 (d,
J=8.9 Hz, 1H), 7.40-7.54 (m, 3H), 7.54-7.62 (m, 2H), 7.62-7.73 (m,
2H), 7.89 (d, J=1.7 Hz, 1H), 8.42 (s, 1H), 8.46 (s, 1H) ppm.
[0693] LCMS=94.17% purity. APCI (+)=421.1 (M).
Example 200
Preparation of P-473
##STR00256##
[0695] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-dimet-
hyl-amine (P-473). To a solution of pyrrolidine-3-carboxylic acid
methyl ester (185 mg, 1.12 mmol), was added sodium hydride (60%
weight dispersion, 66 mg, 1.68 mmol). After 2 min of stirring, P456
(194 mg, 0.56 mmol) was added, and the reaction stirred for 10 min
in a microwave reactor at 240.degree. C. and 15 bar. The reaction
was diluted with ethyl acetate (5 mL), washed with 0.1 N aqueous
hydrochloric acid (5 mL), and the aqueous layer was extracted with
ethyl acetate (3.times.5 mL). The combined extracts were washed
with brine, dried over sodium sulfate, filtered, and the solvent
removed under vacuum. The crude material was purified by silica gel
column chromatography (9:1 ethyl acetate/hexanes) to give P-473
(80.7 mg, 39% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 2.96 (s,
6H), 3.71 (s, 3H), 3.77 (s, 2H), 6.57 (d, J=8.6 Hz, 1H), 6.91 (d,
J=8.6 Hz, 1H), 7.18-7.50 (m, 6H), 7.98 (d, J=2.0 Hz, 1H) ppm.
[0696] LCMS=96.9% purity. APCI (+)=371.1 (M).
Example 201
Preparation of P-029
##STR00257##
[0698] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-029). A suspension of sodium hydride (15.6 mg, 0.652 mmol) in
DMF (10 mL) was allowed to stir under nitrogen for 15 min. To the
suspension was added 2-pyrrolidone (55.5 mg, 0.652 mmol) and the
reaction allowed to stir at room temperature for 15 min under
nitrogen. To the reaction was added I-70 (200 mg, 0.621 mmol) and
the reaction stirred under nitrogen at ambient temperature for 16
h. The reaction was diluted with saturated aqueous ammonium
chloride (50 mL), extracted with ethyl acetate (50 mL), and the
layers separated. The organic extract was washed with saturated
aqueous ammonium chloride (2.times.50 mL), water (3.times.50 mL),
brine (50 mL), dried over sodium sulfate, and the solvent removed
under vacuum. The product was purified by separation on a silica
gel preparatory plate eluting with 10% methanol in dichloromethane
to give P-029 (108 mg, 53% yield) as a yellow gum.
[0699] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.40 (t, J=2.2 Hz, 1H),
8.20-8.17 (m, 1H), 7.82 (dt, J=7.6 Hz, 1.2 Hz, 1H), 7.56 (t, J=8.0
Hz, 1H), 7.28 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H),
6.97 (d, J=8.8 Hz, 1H), 4.45 (s, 2H), 3.83 (s, 3H), 3.30 (t, J=7.0
Hz, 2H), 2.44 (t, J=8.2 Hz, 2H), 2.03-1.99 (m, 2H) ppm.
[0700] LCMS=93.9% purity. MS (ESI+)=327.7 (M+1).
Example 202
Preparation of P-034
##STR00258##
[0702] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-imidazolidin-2-one
(P-034). A suspension of potassium carbonate (160 mg, 1.16 mmol),
2-imidazolidone (104 mg, 1.21 mmol), and I-70 (150 mg, 0.466 mmol)
in DMF (10 mL) was heated to 80.degree. C. overnight. The reaction
was cooled to room temperature, ethyl acetate (30 mL) and saturated
aqueous ammonium chloride (30 mL) were added, and the layers
separated. The extract was washed with saturated aqueous ammonium
chloride (2.times.30 mL), water (2.times.30 mL), brine (30 mL),
dried over sodium sulfate, and the solvent removed under vacuum.
The crude product was purified by silica gel preparatory TLC to
give P-034 (30.2 mg, 20% yield) as a white powder. .sup.1H NMR (400
MHz, CDCl.sub.3): 8.41 (t, J=2.0 Hz, 1H), 8.19-8.16 (m, 1H), 7.84
(dt, J=7.9 Hz, 1.5 Hz, H), 7.56 (t, J=8.0 Hz, 1H), 7.32 (dd, J=8.2
Hz, 2.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),
4.37 (s, 2H), 4.32 (brs, 1H), 3.84 (s, 3H), 3.41-3.33 (m, 4H)
ppm.
[0703] LCMS=86.3% purity. MS (ESI+)=328.3 (M+1).
Example 203
Preparation of P-035
##STR00259##
[0705] Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-[1,2]thiazinane
1,1-dioxide (P-035). A suspension of sodium hydride (11.7 mg, 0.489
mmol) in DMF (8 mL) was stirred under nitrogen for 5 min. To the
suspension was added 1,4-butanesultam (66.1 mg, 0.489 mmol) under
nitrogen, and the reaction was stirred at room temperature for 30
min. To the reaction was added I-70 (150 mg, 0.466 mmol), and the
reaction stirred overnight at room temperature under nitrogen. The
reaction was diluted with ethyl acetate (40 mL), washed with
saturated aqueous ammonium chloride (2.times.50 mL), water
(2.times.50 mL), brine (40 mL), dried over sodium sulfate, and the
solvent removed under vacuum. The residue was purified by silica
gel preparatory TLC eluting with dichloromethane to give P-035
(99.4 mg; 57% yield) as an off white powder. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.41 (t, J=1.8 Hz, 1H), 8.20-8.17 (m, 1H), 7.85-7.83
(m, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.37 (dd, J=8.4 Hz, 2.4 Hz, 1H),
7.30 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.30 (s, 2H), 3.84
(s, 3H), 3.27-3.24 (m, 2H), 2.11-3.08 (m, 2H), 2.24-2.21 (m, 2H),
1.66-1.570 (m, 2H) ppm.
[0706] LCMS=98.9% purity. MS (APCI-)=376.1 (M).
Example 204
Preparation of P-036
##STR00260##
[0708] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidine-2,5-dione
(P-036). To a solution of pyrrolidine-2,5-dione (67.2 mg, 0.679
mmol) in DMF (10 mL) was added sodium hydride (16.3 mg, 0.679 mmol)
and the reaction was stirred under nitrogen for 15 min until gas
evolution ceased. To the reaction was added I-70 (100 mg, 0.310
mmol) and the reaction was stirred under nitrogen at room
temperature for 16 h. The reaction was diluted with ethyl acetate,
the organic layer washed with water (2.times.50 mL) and saturated
aqueous ammonium chloride (2.times.50 mL), and the aqueous washes
were combined. The aqueous washes were extracted with ethyl acetate
(50 mL) and the organic extracts combined. The combined extracts
were washed with brine (50 mL), dried over sodium sulfate, filtered
and the solvent removed under vacuum. The resulting yellow oil was
purified by silica preparatory TLC eluting with dichloromethane to
give P-036 (68.6 mg; 65% yield) as a yellow oil. .sup.1H NMR (400
MHz, CDCl.sub.3): 8.39 (t, J=2.0 Hz, 1H), 8.18 (ddd, J=8.2, 2.2,
2.0 Hz, 1H), 7.80 (dt, J=8.0, 1.3 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H)
7.45 (dd, J=7.2, 2.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 6.95 (d,
J=8.4 Hz, 1H), 4.66 (s, 2H), 3.82 (s, 3H), 2.71 (s, 4H) ppm. MS
(ESI+)=341.4 (M+1). LCMS=97.5% purity.
Example 205
Preparation of P-045
##STR00261##
[0710] Synthesis of 1-(3-Bromo-4-methoxy-benzyl)-pyrrolidin-2-one
(I-181). A suspension of sodium hydride (28.8 mg, 1.20 mmol) in
anhydrous DMF (15 mL) was stirred at room temperature under
nitrogen for 5 min. To the reaction was added 2-pyrollidone (102
mg, 1.20 mmol) under nitrogen and the reaction stirred for 10 min.
Subsequently I-42 (320 mg, 1.14 mmol) was added and the reaction
was stirred at room temperature overnight. The reaction was diluted
with ethyl acetate (50 mL). The organic material was washed with
saturated aqueous ammonium chloride (2.times.30 mL), water
(2.times.30 mL), brine (2.times.30 mL), dried over sodium sulfate
and the solvent removed under vacuum to give I-42 (243 mg) which
was taken on without purification.
[0711] Synthesis of
1-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-pyrrolidin-2-one
(P-045). A solution of I-42 (230 mg, 0.809 mmol) and
benzo[1,3]dioxol-5-yl-boronic acid (201 mg, 1.21 mmol) in
1,4-dioxane (15 mL) was degassed with a nitrogen stream for 30 min,
and subsequently bis(triphenylphosphine)palladium(II) dichloride
(28.4 mg, 0.0405 mmol) was added under nitrogen. Degassing was
continued for 5 min, followed by the addition of 1 M aqueous sodium
carbonate (2.5 mL). The reaction was heated to 80.degree. C. with
stirring overnight under nitrogen. The reaction did not go to
completion, so additional benzo[1,3]dioxol-5-yl-boronic acid (201
mg, 1.21 mmol) and bis(triphenylphosphine)palladium(II) dichloride
(28.4 mg, 0.0405 mmol) were added and the reaction stirred for 5 h
at 80.degree. C. The reaction was diluted with ethyl acetate (40
mL), washed with brine (2.times.40 mL), water (4.times.40 mL), and
brine (40 mL). The solution was dried over sodium sulfate, filtered
and the solvent removed under vacuum to give a residue. This
material was purified by multiple development silica gel
preparatory plate thin layer chromatography eluting with 10%
methanol in dichloromethane, followed by 10% acetone in
dichloromethane to give P-045 (21.3 mg, 8.1% yield) as a yellow
syrup.
[0712] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.19-7.17 (m, 2H), 7.04
(d, J=1.6 Hz, 1H), 6.96-6.85 (m, 3H), 5.99 (s, 2H), 4.42 (s, 2H),
3.81 (s, 3H), 2.43 (t, J=8.0 Hz, 1H), 2.00-1.97 (m, 2H) ppm. MS
(ESI+)=326.7 (M+1).
##STR00262##
Example 206
Preparation of P-053
[0713] Synthesis of
1-(3-Bromo-4-methoxy-benzyl)-pyrrolidine-2,5-dione (I-182): A
suspension of sodium hydride (56.2 mg, 2.34 mmol) in anhydrous DMF
(20 mL) was stirred under nitrogen for 5 min. To the suspension was
added pyrrolidine-2,5-dione (231 mg, 2.34 mmol), and the resulting
slurry was stirred for 5 min. After stirring, I-109 (500 mg, 2.13
mmol) was added under nitrogen, and the reaction was allowed to
stir at ambient temperature under nitrogen for 17.5 h, and diluted
with ethyl acetate (50 mL). The organic solution was washed with
water (4.times.50 mL), brine (2.times.50 mL), dried over anhydrous
sodium sulfate, and the solvent removed under vacuum to afford
532.8 mg, I-182 as a yellow powder in 84% yield. .sup.1H NMR (400
MHz CDCl.sub.3) d: 7.59 (d, J=2.4 Hz, 1H), 7.34 (dd, J=8.4 Hz, 2.0
Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.569 (s, 2H), 3.870 (s, 3H),
2.710 (s, 4H).
[0714] Synthesis of
1-(3-Benzo[1,3]dioxol-5-yl-4-methoxy-benzyl)-pyrrolidine-2,5-dione
(P-053). A solution of I-182 (300 mg, 1.01 mmol) and
benzo[1,3]dioxol-5-yl-boronic acid (183 mg, 1.10 mmol) in
1,4-dioxane (5 mL) were degassed with a nitrogen stream for 10 min.
Subsequently triphenylphosphine (52.7 mg, 0.201 mmol), solid
potassium carbonate (417 mg, 3.02 mmol) and an ethanol in water
mixture (1:1, 1 mL) were added under nitrogen. The reaction was
stirred under nitrogen for 5 min, palladium(II) acetate (22.6 mg,
0.101 mmol) was added, and the reaction was heated under nitrogen
to 80.degree. C. for 19 h. The solvent was removed under vacuum and
the mixture was diluted with saturated aqueous ammonium chloride
(50 mL) and ethyl acetate (50 mL), the layers separated, and the
aqueous layer extracted with ethyl acetate (50 mL). The combined
organic extracts were washed with water (3.times.30 mL), brine (30
mL), dried over sodium sulfate, and the solvent removed under. The
residue was chromatographed on flash silica gel eluting with 10%
acetone in dichloromethane to afford 153.7 mg of P-053 as a yellow
powder in 45% yield.
[0715] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.35 (m, 2H),
7.02 (d, J=1.6 Hz, 1H), 6.94 (ddd, J=8.0 Hz, J=1.6 Hz, J=0.8 Hz,
1H), 6.87 (m, 2H), 4.63 (s, 2H), 3.79 (s, 3H), 2.70 (s, 4H).
[0716] LCMS=91.2%. MS (ESI+)=340.3 (M+1).
##STR00263##
Example 207
Preparation of I-186
[0717] Synthesis of 4-Fluoro-4'-methoxydiphenylmethane (I-184). A
suspension of 4-fluorophenylboronic acid (6.70 g, 47.9 mmol),
ground solid potassium phosphate (13.6 g, 63.9 mmol),
triphenylphosphine (168 mg, 0.639 mmol), and palladium(II)acetate
(72 mg, 0.319 mmol) was stirred under nitrogen in toluene (100 mL).
Nitrogen was streamed through with stirring for 15 min, and
subsequently 4-(chloromethyl)anisol (5.00 g, 31.9 mmol) was added
under nitrogen, and the reaction was heated to 80.degree. C.
overnight. Additional palladium(II) acetate (72 mg, 0.319 mmol) was
added and the reaction stirred at 80.degree. C. for an additional 6
h. The reaction was not complete so a third portion of
palladium(II)acetate (144 mg, 0.639 mmol) and more
triphenylphosphine (336 mg, 1.28 mmol) was added and the reaction
stirred at 80.degree. C. overnight. The reaction was diluted with
ethyl acetate (300 mL), washed with 1 N aqueous sodium hydroxide
(2.times.300 mL), water (3.times.300 mL), and brine (2.times.300
mL). The organic extract was dried over sodium sulfate and
decolorized over activated carbon, filtered and the solvent removed
under. The residue was purified by flash silica gel column
chromatography (10% ethyl acetate in hexanes Rf=0.31) to afford
2.50 g of I-184 as a clear oil in 36% yield, which was taken on
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
7.13-7.06 (m, 4H), 6.976-6.93 (m, 2H), 6.84-6.82 (m, 2H), 3.89 (s,
2H), 3.78 (s, 3H) ppm.
[0718] Synthesis of 2-Bromo-4-(4-fluoro-benzyl)-1-methoxy-benzene
(I-185). A biphasic solution potassium bromide (1.65 g, 13.9 mmol)
in 21% (w/v) aqueous nitric acid (8.32 g, 27.7 mmol) and
4-fluoro-4-methoxydiphenylmethane (I-184, 1.50 g, 6.94 mmol) and
tetrabutylammonium chloride (57.7 mg, 0.208 mmol) in
1,2-dichloroethane (16 mL) was stirred at room temperature
overnight, and the red suspension diluted with dichloromethane (30
mL). The aqueous layer was removed and the organic layer washed
with aqueous potassium carbonate (2% w/v, 3.times.50 mL), water
(2.times.50 mL), and brine (50 mL). The reaction was dried over
magnesium sulfate, filtered, and the solvent removed under vacuum.
The crude product was purified by flash silica gel column
chromatography (10% ethyl acetate in hexanes Rf=0.39) to 1.24 g of
I-185 as a yellow oil in 60% yield.
[0719] .sup.1H NMR (400 MHz, CDCl.sub.3) d: 7.34 (d, J=1.6 Hz, 1H),
7.12-7.10 (m, 2H), 7.05 (dd, J=6.6 Hz, 1.80 Hz, 1H), 6.99-6.96 (m,
2H), 6.82 (d, J=6.80 Hz, 1H), 3.867 (s, 5H) ppm.
[0720] Synthesis of
2-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolane (I-186). A stream of nitrogen was blown through a solution
of 2-bromo-4-(4-fluoro-benzyl)-1-methoxy-benzene (I-185, 500 mg,
1.69 mmol) in DMF (5 mL) for 15 min. Subsequently solid potassium
acetate (499 mg, 5.08 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (138
mg, 0.169 mmol), and bis(pinocolate)diboron (516 mg, 2.03 mmol)
were added under nitrogen. The reaction was heated to 85.degree. C.
16 h. The reaction was cooled to room temperature, diluted with
ethyl acetate (50 mL) and water (50 mL). The biphasic suspension
was filtered twice to removed spent catalyst and separated. The
organic extract was washed with water (3.times.50 mL) and brine (50
mL), decolorized over activated carbon, dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The residue was
purified by flash silica gel column chromatography (10% acetone in
hexanes, Rf=0.10) to afford 419.8 mg of I-186 as a colorless oil in
72% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) d: 7.50 (d, J=2.4 Hz,
1H), 7.14-7.09 (m, 3H), 6.97-6.92 (m, 2H), 6.78 (d, J=8.4 Hz, 1H),
3.88 (s, 2H), 3.80 (s, 3H), 1.35 (s, 12H) ppm. MS (ESI+)=341.3
(M-1), 500.7 (M+159).
Example 208
Preparation of I-187
##STR00264##
[0722] Synthesis of 2,2-Difluoro-benzo[1,3]dioxol-5-yl-boranic acid
(I-187): A solution of tert-butyl lithium (1.15 mL, 1.95 mmol) in
anhydrous diethyl ether (5 mL) was cooled to -78.degree. C. under
nitrogen. 5-bromo-2,2-difluoro-benzo[1,3]dioxole (180 mg, 0.760
mmol) in diethyl ether (0.80 mL) was added, and the reaction was
stirred for 1 h at -78.degree. C., followed by the addition of
triisopropylborate (0.37 mL, 1.60 mmol) under nitrogen. The
reaction allowed to stir for 1.5 h while allowing to warm to
ambient temperature. The reaction was poured into 4 N aqueous
sodium hydroxide (5 mL), stirred, and adjusted to pH .about.1 by
the dropwise addition of concentrated aqueous hydrochloric acid,
and the product extracted with ethyl acetate (10 mL). The organic
extract was dried over anhydrous sodium sulfate, filtered, and the
solvent removed under vacuum to afford 140.2 mg of I-187 as a brown
solid, which was taken on without further purification.
[0723] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.77-7.74 (m, 1H),
7.67-7.65 (m, 1H), 7.51 (s, 1H).
##STR00265##
Example 209
Preparation of P-131 and P-132
##STR00266##
[0725] Synthesis of
(S)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one
(I-188). A solution of (S)-5-hydroxymethyl-pyrrolidin-2-one (1.0 g,
8.69 mmol), DMF (10 mL), t-butyldimethylsilyl chloride (1.57 g,
10.42 mmol), and imidazole (0.89 g, 13.03 mmol) was stirred at
ambient temperature for 4 hours after which time 4 mL of water were
added. The layers were separated and the aqueous was extracted with
dichloromethane (10 mL). The combined organics were washed with
water (15 mL) and brine (15 mL), dried with sodium sulfate,
filtered and concentrated to afford 1.91 g of I-188 as a colorless
oil in 96% yield.
##STR00267##
[0726] Synthesis of
(R)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one
(I-189).
[0727] I-189 was prepared in an analogous manner as that for I-188,
starting from (R)-5-Hydroxymethyl-pyrrolidin-2-one. 1.91 g of I-189
was obtained as a colorless oil in 96%.
##STR00268##
[0728] Synthesis of
(S)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(6-methoxy-3'-nitro-biphen-
yl-3-ylmethyl)-pyrrolidin-2-one (I-190). Into a 20 mL vial with
stir bar was added I-188 (0.28 g, 1.24 mmol), dry THF (4 mL), and
the solution cooled to 0.degree. C. sodium hydride (65 mg, 1.61
mmol) was added and the suspension stirred for 30 minutes at
ambient temperature. After cooling to 0.degree. C., I-70 (0.40 g,
1.24 mmol) was added the reaction stirred at ambient temperature
for 18 hours after which 5 mL water was added. The product was
extracted with ethyl acetate (4.times.15 mL). The organics were
combined and dried with sodium sulfate, filtered, and concentrated.
Flash column chromatography purification using 30% ethyl
acetate/Hexanes afforded 476 mg of I-190 as a colorless oil in 83%
yield.
##STR00269##
[0729]
(R)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(6-methoxy-3'-nitro--
biphenyl-3-ylmethyl)-pyrrolidin-2-one (I-191). I-191 was prepared
in an analagous manner as that for I-190, starting from I-189. 462
mg of I-191 was obtained as a colorless oil in 80% yield.
##STR00270##
[0730] Synthesis of
(S)-5-Hydroxymethyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-
-2-one (P-131). Into a 50 mL round bottom flask equipped with a
stir bar was added I-190 (0.45 g, 0.96 mmol), dry THF (5 mL), and
the solution was cooled to 0.degree. C. TBAF (1.4 mL, 1.43 mmol,
1.0 M in THF) was added and the reaction was stirred at 0.degree.
C. for 30 minutes. 2 mL of saturated aqueous NH.sub.4Cl and 2 mL of
water were added and the product was extracted with ethyl acetate
(3.times.10 mL). The combined organics were washed with brine,
dried over sodium sulfate, filtered, and concentrated. The residue
was purified by flash column chromatography using 10-25%
acetone/dichloromethane to afford 307 mg (90%) of P-131 as a
colorless semi-solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.39 (s,
1H), 8.18 (dd, J=1.3, 8.3 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.56 (t,
J=7.9 Hz, 1H), 7.32 (dd, J=1.9, 8.4 Hz, 1H), 7.25 (d, J=2.0 Hz,
1H), 6.97 (d, J=8.3 Hz, 1H), 4.81 (d, J=15.0 Hz, 1H), 4.29 (d,
J=14.9 Hz, 1H), 3.83 (s, 3H), 3.78 (d, J=2.5 Hz, 1H), 3.68-3.50 (m,
2H), 2.65-2.48 (m, 1H), 2.46-2.31 (m, 1H), 2.16-2.03 (m, 1H),
2.02-1.91 (m, 1H).
[0731] LC/MS=100.0%, 357.1 (APCI+).
##STR00271##
[0732] Synthesis of
(R)-5-Hydroxymethyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-
-2-one (P-132). P-132 was prepared in a similar manner as that for
P-131, except beginning with I-191. 310 mg (91%) of P-132 was
obtained as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.39
(t, J=1.7 Hz, 1H), 8.18 (dd, J=1.3, 8.3 Hz, 1H), 7.82 (d, J=7.8 Hz,
1H), 7.56 (t, J=8.0 Hz, 1H), 7.32 (dd, J=2.1, 8.5 Hz, 1H), 7.25 (d,
J=2.1 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.80 (d, J=14.9 Hz, 1H),
4.30 (d, J=15.0 Hz, 1H), 3.83 (s, 3H), 3.79 (dd, J=2.8, 11.4 Hz,
1H), 3.68-3.53 (m, 2H), 2.64-2.50 (m, 1H), 2.46-2.32 (m, 1H),
2.15-2.03 (m, 1H), 2.02-1.90 (m, 1H). LC/MS=100.0%, 357.1
(APCI+).
Example 210
Preparation of P-155 and P-156
##STR00272##
[0734] Synthesis of Toluene-4-sulfonic acid
(S)-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-5-oxo-pyrrolidin-2-ylmethy-
l ester (I-192). Into a 20 mL vial with stir bar and
dichloromethane (5 mL) at 0.degree. C. was added P-131 (0.25 g,
0.70 mmol), TsCl (0.16 g, 0.84 mmol), triethylamine (0.15 mL, 1.05
mmol), and DMAP (9 mg, 0.07 mmol). The reaction was stirred at room
temperature for 18 hours and then concentrated. The residue was
purified by flash column chromatography using 10%
acetone/dichloromethane to afford 340 mg (95%) of I-192 as a
colorless oil.
##STR00273##
[0735] Synthesis of Toluene-4-sulfonic acid
(R)-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-5-oxo-pyrrolidin-2-ylmethy-
l ester (I-193). I-193 was prepared in a similar manner as that for
I-192, except beginning with P-132. 290 mg (92%) of I-193 was
obtained as a colorless oil.
##STR00274##
[0736] Synthesis of
(S)-5-Azidomethyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-
-one (I-194). Into a 20 mL vial with stir bar was added I-192 (0.33
g, 0.65 mmol), DMF (4 mL), and NaN.sub.3 (63 mg, 0.97 mmol). The
reaction was stirred for 1 hour at 60.degree. C., and then cooled
to room temperature. 5 mL of water was added and the product was
extracted with dichloromethane (2.times.5 mL). The combined
organics were washed with water (4.times.5 mL), dried over sodium
sulfate, filtered, and concentrated to obtain 0.24 g (97%) of I-194
as a colorless oil.
##STR00275##
[0737] Synthesis of (R)-5-Azido
methyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(I-195). I-195 was prepared in a similar manner as that for I-194
except beginning with I-193. 1-195 (0.20 g, 96%) was obtained as a
colorless oil.
##STR00276##
[0738] Synthesis of
(S)-5-Aminomethyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-
-one (P-155). Into a 50 mL round bottom flask with stir bar was
added I-194 (0.24 g, 0.63 mmol), THF (4 mL), and PPh.sub.3 (0.50 g,
1.89 mmol). The reaction was stirred at room temperature for 18
hours after which 1 mL of water was added. After stirring at room
temperature for 2 more days, the THF was removed under reduced
pressure. 1 N HCl was added to until the aqueous material was pH=1
and the solution was washed with dichloromethane (3.times.3 mL).
The aqueous phase was basified with 1 N NaOH to pH=11 and the
product was extracted with dichloromethane (3.times.3 mL) and
concentrated. The residue was purified by flash column
chromatography using 5% methanol/dichloromethane and afforded 164
mg (73%) of P-155 as a light-yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) 8.39 (s, 1H), 8.18 (dd, J=1.3, 8.2 Hz, 1H), 7.81 (d,
J=7.8 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.30 (dd, J=1.9, 8.4 Hz,
1H), 7.23 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 4.85 (d,
J=14.9 Hz, 1H), 4.15 (d, J=14.9 Hz, 1H), 3.83 (s, 3H), 3.61-3.50
(m, 1H), 2.93-2.84 (m, J=4.8 Hz, 1H), 2.80 (br. s., 1H), 2.61-2.49
(m, 1H), 2.47-2.35 (m, 1H), 2.19-2.03 (m, 1H), 1.95-1.83 (m, 1H).
LC/MS=100.0%, 356.1 (APCI+).
##STR00277##
[0739] Synthesis of
(R)-5-Aminomethyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-
-one (P-156). P-156 was prepared in a similar manner as that for
P-155, except beginning with I-195. P-156 (80 mg, 43%) was obtained
as a light-yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.39 (s,
1H), 8.18 (dd, J=1.1, 8.3 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.56 (t,
J=8.0 Hz, 1H), 7.30 (dd, J=1.8, 8.4 Hz, 1H), 7.23 (d, J=1.9 Hz,
1H), 6.96 (d, J=8.5 Hz, 1H), 4.85 (d, J=14.9 Hz, 1H), 4.15 (d,
J=14.9 Hz, 1H), 3.83 (s, 3H), 3.61-3.49 (m, 1H), 2.93-2.84 (m, 1H),
2.83-2.74 (m, 1H), 2.61-2.49 (m, 1H), 2.46-2.35 (m, 1H), 2.15-2.03
(m, 1H), 1.95-1.83 (m, 1H). LC/MS=100.0%, 356.1 (APCI+).
Example 211
Preparation of P-135
##STR00278##
[0741] Synthesis of
2-Fluoro-5-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzoic acid
methyl ester (I-196). Into a 20 mL vial with stir bar was added
I-70 (0.30 g, 0.93 mmol), 4-Fluoro-3-methoxycarbonylphenylboronic
acid (203 mg, 1.02 mmol), triphenylphosphine (49 mg, 0.19 mmol),
K.sub.3PO.sub.4 (0.40 g, 1.86 mmol), DME (5 mL), water (0.5 mL),
and ethanol (0.5 mL). N.sub.2 gas was bubbled through the stirred
reaction for 10 minutes. Pd(OAc).sub.2 (21 mg, 0.09 mmol) was added
and N.sub.2 was bubbled through for an additional 5 minutes. The
vial was capped and the reaction was stirred at 80.degree. C. for
18 hours. The reaction was cooled to room temperature and 5 mL of
water and 5 mL of ethyl acetate were added. The layers were
separated and the aqueous was extracted with ethyl acetate
(3.times.10 mL). The organics were combined, dried with sodium
sulfate, and concentrated. The residue was purified by flash column
chromatography using 10% acetone/Hexanes to obtain 207 mg (56%) of
I-196 as a colorless oil.
##STR00279##
[0742] Synthesis of
Fluoro-5-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenyl]-methanol
(P-135). Into a 20 mL vial with stir bar was added I-196 (112.3 mg,
0.28 mmol) and 4 mL of dry THF. The solution was cooled to
0.degree. C. and DIBAL-H (0.71 mL, 0.71 mmol, 1.0 M sol. in hexane)
was added. The reaction was stirred at 0.degree. C. for 1 hour.
Aqueous 1 N HCl (1 mL) was added followed by water (5 mL). The
aqueous solution was extracted with ethyl acetate (3.times.10 mL).
The organics were combined, dried over sodium sulfate, and
concentrated. The product was purified by flash column
chromatography using 10% acetone/hexanes to obtain 53 mg (51%) of
P-135 as colorless oil .sup.1H NMR (400 MHz, CDCl.sub.3) 1.72 (t,
J=6.2 Hz, 1H) 3.81 (s, 3H) 3.95 (s, 2H) 4.73 (d, J=6.2 Hz, 2H)
6.91-7.02 (m, 2H) 7.06-7.21 (m, 3H) 7.23-7.28 (m, 1H) 7.54 (t,
J=8.0 Hz, 1H) 7.82 (d, J=7.7 Hz, 1H) 8.16 (dd, J=8.3, 1.3 Hz, 1H)
8.38 (s, 1H) ppm. LC/MS=100.0%, 367.1 (APCI-).
Example 212
Preparation of P-153 and P-154
##STR00280##
[0744] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-imidazole-4-carboxylic
acid methyl ester (I-197) and
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-imidazole-5-carboxylic
acid methyl ester (I-198). Into a 20 mL vial with stir bar was
added I-70 (0.30 g, 0.92 mmol), 1H-imidazole-4-carboxylic acid
methyl ester (0.12 g, 0.93 mmol), K.sub.2CO.sub.3 (0.15 g, 1.12
mmol), and DMF (3 mL). The reaction was stirred at room temperature
for 20 hours. To the reaction was added 10 mL of dichloromethane
and 10 mL of water and the layers were separated. The aqueous was
extracted with 10 mL of dichloromethane and the combined organics
were washed with water (3.times.10 mL). The dichloromethane portion
was concentrated and purified first by flash column chromatography
using 0-5% methanol/dichloromethane followed by preparative TLC
using 10% acetone/dichloromethane. 72.4 mg (21%) of I-197 and 91.1
mg (27%) of I-198 were obtained as light-yellow oils.
##STR00281##
[0745] Synthesis of
[3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3H-imidazol-4-yl]-methanol
(P-153). Into a 20 mL vial with stir bar was added I-198 (85.5 mg,
0.23 mmol) and 5 mL of dry THF. The solution was cooled to
0.degree. C. and DIBAL-H (0.70 mL, 0.70 mmol, 1.0 M sol. in hexane)
was added. The reaction was stirred at room temperature for 16
hours and then cooled to 0.degree. C. Aqueous 1 N HCl (1 mL) was
added followed by 3 mL of 1 N NaOH and 5 mL of ethyl acetate. The
layers were separated and the aqueous was extracted with ethyl
acetate (3.times.10 mL). The organic were combined, dried over
sodium sulfate, and concentrated. The residue was purified by flash
column chromatography using 50% acetone/dichloromethane, followed
by flash column chromatography using 5% methanol/dichloromethane to
obtain 52.2 mg (66%) of P-153 as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 3.79 (s, 3H) 4.38 (d, J=5.2 Hz, 2H) 5.13 (t, J=5.3
Hz, 1H) 5.21 (s, 2H) 6.80 (br. s., 1H) 7.16 (d, J=8.5 Hz, 1H) 7.27
(dd, J=0.5, 1.9 Hz, 1H) 7.34 (d, J=1.9 Hz, 1H) 7.65-7.77 (m, 2H)
7.92 (d, J=7.8 Hz, 1H) 8.20 (dd, J=8.1, 1.7 Hz, 1H) 8.28 (s, 1H)
ppm. LC/MS=99.9%, 340.1 (APCI+)
##STR00282##
[0746] Synthesis of
[1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-imidazol-4-yl]-methanol
(P-154). P-154 was prepared in a similar manner as that for P-153
except beginning with I-197. P-154 (45.0 mg, 71%) was obtained as a
tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 3.79 (s, 3H) 4.28
(d, J=5.5 Hz, 2H) 4.75 (t, J=5.6 Hz, 1H) 5.12 (s, 2H) 7.03 (s, 1H)
7.16 (d, J=8.5 Hz, 1H) 7.38 (dd, J=8.5, 2.1 Hz, 1H) 7.44 (d, J=2.2
Hz, 1H) 7.68 (d, J=0.8 Hz, 1H) 7.72 (t, J=8.0 Hz, 1H) 7.94 (d,
J=7.9 Hz, 1H) 8.20 (dd, J=8.2, 1.5 Hz, 1H) 8.29 (t, J=1.7 Hz, 1H).
LC/MS=99.9%, 340.1 (APCI+).
##STR00283##
Example 213
Preparation of P-140
##STR00284##
[0748] Synthesis of
1-[5'-(4-Fluoro-benzyl)-2'-methoxy-biphenyl-3-yl]-ethanone (P-140).
A nitrogen stream was bubbled through a solution of I-185 (150 mg,
0.508 mmol) and 3-acetylphenylboronic acid (91.7 mg, 0.559 mmol) in
1,2-dimethoxyethane (4 mL) for 15 min, followed by the addition of
ethanol:water (1:1, 1 mL). The nitrogen stream was continued for 10
min, and solid potassium carbonate (210 mg, 1.52 mmol),
triphenylphosphine (26.8 mg, 0.102 mmol), and palladium(II) acetate
(11.4 mg, 0.0508 mmol) were added. The reaction was heated to
80.degree. C. and heated with stirring overnight. The reaction was
diluted with ethyl acetate (50 mL) and saturated aqueous ammonium
chloride (50 mL), filtered twice, and separated. The organic
extract was washed with water (3.times.50 mL), brine (50 mL), dried
over anhydrous sodium sulfate, filtered, and the solvent removed
under vacuum. The reaction was purified by flash silica gel column
chromatography (5% ethyl acetate in hexanes, Rf=0.10 in 10% ethyl
acetate in hexanes) to give P-140 (88.0 mg, 52% yield) as a
colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) d: 7.98 (t,
J=1.6 Hz, 1H), 7.91 (dt, J=7.9 Hz, 1.4 Hz, 1H), 7.70 (dt, J=8.0 Hz,
1.5 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.30-7.30 (m, 2H), 7.23-7.21
(m, 2H), 7.12-7.05 (m, 3H), 3.93 (s, 2H), 3.74 (s, 3H), 2.60 (s,
3H) ppm. LCMS=98.5% purity. MS (APCI+)=335.1 (M+1).
Example 214
Preparation of P-141
##STR00285##
[0750] Synthesis of
2,2-Difluoro-5-[5-(4-fluoro-benzyl)-2-methoxy-phenyl]-benzo[1,3]dioxole
(P-141). A nitrogen stream was bubbled through a solution of I-185
(114 mg, 0.385 mmol) and I-187 (140 mg, 0.693 mmol) in
1,2-dimethoxy ethane (3 mL) for 20 min, followed by addition of
ethanol and water solution (1:1, 0.75 mL) and the nitrogen stream
was continued for 5 min. To the reaction was added solid potassium
carbonate (160 mg, 1.16 mmol), triphenyl phospine (20.2 mg, 0.0770
mmol), and palladium(II) acetate (8.6 mg, 0.0385 mmol) under
nitrogen, the reaction was heated to 80.degree. C., and stirred at
this temperature overnight. The solvent was removed under vacuum,
the residue dissolved in ethyl acetate (20 mL) and water (20 mL),
the biphasic solution was filtered, and the two layers separated.
The aqueous wash was extracted into ethyl acetate (20 mL), and the
combined extracts were washed with water (3.times.50 mL), saturated
aqueous ammonium chloride (50 mL), dried over sodium sulfate,
decolorized with activated carbon, filtered, and the solvent
removed under vacuum. The residue was purified by flash silica gel
column chromatography (5% acetone in dichloromethane, Rf=0.40 in
10% acetone in dichloromethane) followed by preparatory silica TLC
(2.5% acetone in dichloromethane) to give P-141 (96.8 mg, 68%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.48 (d, J=1.6 Hz, 1H),
7.42 (d, J=8.4 Hz, 1H), 7.30-7.179 (m, 5H), 7.11-7.03 (m, 3H), 3.90
(s, 2H), 3.74 (s, 3H) ppm. MS (ESI+)=371.8 (M-1), 353.0 (M-19).
Example 215
Preparation of P-151
##STR00286##
[0752] Synthesis of
5-(4-Fluoro-benzyl)-2-methoxy-3'-methylsulfanyl-biphenyl (P-151).
P-151 was synthesized from I-185 (160 mg, 0.542 mmol) and
3-methylsulfanylphenylboronic acid (100 mg, 0.596 mmol) using the
same condition as described for P-141. To the reaction vial was
added ethyl acetate (50 mL) and water (50 mL), the biphasic
solution filtered, and the layers separated. The organic extract
was washed with water (3.times.50 mL), aqueous saturated ammonium
chloride (50 mL), brine (50 mL), dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The product was
purified by flash silica gel column chromatography (5% acetone in
hexanes) followed by preparatory silica gel TLC (2.5% acetone in
hexanes) to give P-151 (47.6 mg, 26% yield).
[0753] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.35-7.27 (m, 4H),
7.22-7.16 (m, 4H), 7.11-7.07 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 3.909
(s, 2H), 3.73 (s, 2H). LCMS=99.4% purity. MS (APCI+)=338.1 (M).
Example 216
Preparation of P-170
##STR00287##
[0755] Synthesis of
1-[5'-(4-Fluoro-benzyl)-4,2'-dimethoxy-biphenyl-3-yl]-ethanone
(P-170). A nitrogen steam was bubbled through a solution of I-186
(150 mg, 0.438 mmol) and 1-(5-bromo-2-methoxy-phenyl)-ethanone (110
mg, 0.482 mmol) in 1,2-dimethoxy ethane (4 mL) for 10 min, followed
by the addition of an ethanol and water solution (1:1, 1 mL).
Nitrogen bubbling was continued for 5 min, palladium(II) acetate
(9.8 mg, 0.044 mmol), triphenylphosphine (23.0 mg, 0.0877 mmol),
and solid potassium carbonate (181 mg, 1.32 mmol) were added under
nitrogen, and the reaction was heated at 80.degree. C. under
nitrogen for 16 h. The solvent was removed under vacuum and ethyl
acetate (50 mL) was added. The organic solution was washed with
water (3.times.50 mL) and brine (50 mL). The organic extract was
removed under vacuum. The residue was purified by two silica gel
preparatory TLC plates (10% ethyl acetate in hexane with 2
developments followed by 5% acetone in hexanes with 6 developments)
to give P-170 (43.0 mg, 27% yield) as an orange oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.63-7.60 (m, 2H), 7.29-7.25 (m, 2H),
7.21-7.07 (m, 5H), 7.02 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.91 (s,
2H), 3.32 (s, 3H), 2.55 (s, 3H). LCMS=100.0% purity.
[0756] MS (APCI+)=365.1 (M+1).
##STR00288##
Example 217
Preparation of P-162
[0757] Synthesis of 2-Bromo-4-bromomethyl-1-methoxy-benzene (I-42).
Into a 1 L round bottom flask was added 4-methoxybenzyl chloride
(19.7 g, 125.8 mmol), glacial acetic acid (400 mL), and Br.sub.2
(9.1 mL, 177.5 mmol, dropwise over 5 minutes). The brown solution
was stirred at room temperature for 20 hours and then poured into a
10% (w/v) aqueous NaHSO.sub.3 solution (2000 mL). After stirring at
room temperature for 30 minutes, the white solid was filtered
through a coarse glass-frit and the solids were washed with water
(4.times.500 mL). The solid was dried in a vacuum dessicator for 16
hours. I-42 (24.5 g, 74%) was obtained as a white solid.
##STR00289##
[0758] Synthesis of 1-(3-Bromo-4-methoxy-benzyl)-pyrrolidin-2-one
(I-181). Into a dry 100 mL round bottom flask was added
pyrrolidin-2-one (0.20 g, 2.34 mmol), dry DMF (20 mL), and the
solution was cooled to 0.degree. C. NaH (110 mg, 2.76 mmol) was
added and the suspension was stirred at room temperature for 30
minutes. I-42 (0.50 g, 2.12 mmol) was added and the reaction was
stirred at 80.degree. C. for 30 minutes and then cooled to room
temperature. After extraction with dichloromethane (2.times.20 mL),
the combined organics were washed with water (4.times.20 mL), dried
over sodium sulfate, filtered, and concentrated. The residue was
purified by flash column chromatography using 10%
acetone/dichloromethane to obtain 482 mg (80%) of I-181 as a
light-yellow oil.
##STR00290##
[0759] Synthesis of
1-(6-Methoxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one (P-162). Into a
20 mL vial with stir bar was added I-181 (95.5 mg, 0.34 mmol),
phenylboronic acid (45 mg, 0.37 mmol), triphenylphosphine (18 mg,
0.07 mmol), K.sub.2 CO.sub.3 (139 mg, 1.01 mmol), DME (5 mL), water
(0.5 mL), and ethanol (0.5 mL). N.sub.2 gas was bubbled through the
stirred reaction for 10 minutes. Palladium(II) acetate (8 mg, 0.03
mmol) was added and N.sub.2 was bubbled through for an additional 5
minutes. The vial was capped and the reaction was stirred at
80.degree. C. for 18 hours. The reaction was cooled to room
temperature and 5 mL of water and 5 mL of ethyl acetate were added.
The layers were separated and the aqueous was extracted with ethyl
acetate (3.times.10 mL). The organics were combined, dried with
sodium sulfate, concentrated, and the residue was purified by prep
TLC using 10% acetone/dichloromethane to obtain 38.9 mg (41%) of
P-162 as a light-yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 1.98
(quin, J=7.6 Hz, 2H) 2.43 (t, J=8.1 Hz, 2H) 3.29 (t, J=7.1 Hz, 2H)
3.80 (s, 3H) 4.43 (s, 2H) 6.94 (d, J=8.2 Hz, 1H) 7.17-7.24 (m, 2H)
7.29-7.36 (m, 1H) 7.40 (t, J=7.5 Hz, 2H) 7.51 (d, J=7.3 Hz, 2H)
ppm. LC/MS=100.0%, 282.1 (APCI+).
Example 218
Preparation of P-184
##STR00291##
[0761] Synthesis of
1-(6,3'-Dimethoxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one (P-184).
Into a 20 mL vial with stir bar was added I-181 (0.21 g, 0.73
mmol), 3-methoxyphenylboronic acid (0.11 g, 0.73 mmol),
triphenylphosphine (39 mg, 0.15 mmol), K.sub.2CO.sub.3 (0.31 g,
2.22 mmol), DME (5 mL), water (0.5 mL), and ethanol (0.5 mL).
N.sub.2 gas was bubbled through the stirred reaction for 10
minutes. Palladium(II) acetate (17 mg, 0.07 mmol) was added and
N.sub.2 was bubbled through the reaction for an additional 5
minutes. The reaction was stirred at 80.degree. C. for 18 hours
under N.sub.2. The reaction was cooled to room temperature and 5 mL
of water and 5 mL of ethyl acetate were added. The layers were
separated and the aqueous was extracted with ethyl acetate
(3.times.10 mL). The organics were combined, dried with sodium
sulfate, and concentrated. The residue was purified by flash column
chromatography using 10% acetone/dichloromethane to obtain 40.2 mg
(17%) of P-184 as a brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
1.98 (quin, J=7.6 Hz, 2H) 2.43 (t, J=8.1 Hz, 2H) 3.28 (t, J=7.1 Hz,
2H) 3.80 (s, 3H) 3.84 (s, 3H) 4.43 (s, 2H) 6.88 (dd, J=8.3, 2.0 Hz,
1H) 6.93 (d, J=8.2 Hz, 1H) 7.04-7.11 (m, 2H) 7.17-7.23 (m, 2H) 7.32
(t, J=7.9 Hz, 1H) ppm. LC/MS=100.0%, 312.1 (APCI+).
Example 219
Preparation of P-503
##STR00292##
[0763] Synthesis of
1-(6-Hydroxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-503). Into a 50 mL round bottom flask with stir bar was added
P-029 (324.5 mg, 0.99 mmol) and dichloromethane (10 mL). The
solution was cooled to 0.degree. C. and BBr.sub.3 (3.0 mL, 2.98
mmol, 1.0 M in dichloromethane) was added. The reaction was stirred
at room temperature for 18 hours and then water was added. The
layers were separated and the aqueous was extracted with
dichloromethane (4.times.15 mL). The organics were combined, dried
with sodium sulfate, and concentrated. The solid was triturated
with ether and 284.4 mg (92%) of P-503 was obtained as a
tan-colored solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.90 (quin,
J=7.5 Hz, 2H) 2.26 (t, J=8.1 Hz, 2H) 3.24 (t, J=7.0 Hz, 2H) 4.32
(s, 2H) 6.97 (d, J=8.3 Hz, 1H) 7.11 (dd, J=8.3, 2.0 Hz, 1H) 7.25
(d, J=2.0 Hz, 1H) 7.71 (t, J=8.0 Hz, 1H) 8.00 (d, J=7.8 Hz, 1H)
8.17 (dd, J=8.2, 1.6 Hz, 1H) 8.40 (t, J=1.7 Hz, 1H) 9.91 (br. s.,
1H) ppm. LC/MS=98.4%, 313.1 (APCI+).
Example 220
Preparation of P-188
##STR00293##
[0765] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-piperidin-2-one (P-188).
Into a 50 mL round bottom flask with stir bar was added
2-Piperidone (88 mg, 0.89 mmol), dry THF (5 mL), NaH (42 mg, 1.05
mmol), and the suspension was stirred for 10 minutes at room
temperature. I-70 (261 mg, 0.81 mmol) was added and the reaction
was stirred for 18 hours at room temperature. To the reaction was
added 10 mL of H.sub.2O and the THF was removed by rotary
evaporation. The product was extracted with ethyl acetate
(3.times.10 mL) and the combined organics were washed with 20 mL of
brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue
was purified by flash column chromatography using 5-10%
acetone/dichloromethane to obtain 201 mg (73%) of P-188 as a
light-yellow semi-solid. .sup.1H NMR (500 MHz, CDCl.sub.3)
8.40-8.39 (m, 1H), 8.18-8.15 (m, 1H), 7.84-7.82 (m, 1H), 7.56 (t,
J=8.0 Hz), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.24-7.23 (m, 1H), 6.97
(d, J=8.0 Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 3.26-3.24 (m, 2H),
2.47-2.44 (m, 2H), 1.80-1.79 (m, 4H) ppm. .sup.13C-NMR (100 MHz,
CDCl.sub.3) .delta. 170.0, 155.9, 148.2, 140.1, 135.8, 130.7,
130.3, 129.9, 129.0, 128.3, 124.7, 122.0, 111.7, 55.9, 49.6, 47.4,
32.6, 23.4, 21.5 ppm. LC/MS=100.0%, 341.1 (APCI+).
Example 221
Preparation of P-192
##STR00294##
[0767] Synthesis of
2-Bromo-4-(4-fluoro-phenylsulfanylmethyl)-1-methoxy-benzene
(I-199). Into a 20 mL vial with stir bar was added I-42 (0.50 g,
1.90 mmol), 4-fluorothiophenol (0.27 g, 2.09 mmol), dichloromethane
(5 mL), and TEA (0.43 mL, 3.14 mmol). The solution was stirred at
room temperature for 16 hours and then concentrated. The residue
was purified by flash column chromatography using 15%
acetone/hexane to obtain I-199 which was used without further
purification in the next step.
##STR00295##
[0768] Synthesis of
5-(4-Fluoro-phenylsulfanylmethyl)-2-methoxy-3'-nitro-biphenyl
(I-200). Into a 20 mL vial with stir bar was added I-199 (0.40 g,
1.22 mmol), 3-nitrophenylboronic acid (0.20 g, 1.22 mmol), K.sub.2
CO.sub.3 (0.51 g, 3.67 mmol), triphenylphosphine (64 mg, 0.24
mmol), DME (5 mL), EtOH (0.5 mL), and H.sub.2O (0.5 mL). The
mixture was degassed with N.sub.2 for 10 minutes and then
palladium(II) acetate (27 mg, 0.12 mmol) was added. The reaction
was stirred at 80.degree. C. for 18 hours and then filtered through
Celite and concentrated. The residue was purified by flash column
chromatography using 10% acetone/dichloromethane, then by flash
column chromatography using 12% acetone/hexane, followed by
preparative layer chromatography using 15% ethyl acetate/hexane to
give 102 mg (23%) of I-200 as a light-yellow oil. .sup.1H NMR (400
MHz, CDCl.sub.3) 8.33 (s, 1H), 8.17 (dd, J=1.3, 8.3 Hz, 1H), 7.78
(d, J=7.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.23
(dd, J=2.1, 8.5 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 6.98 (t, J=8.7 Hz,
2H), 6.91 (d, J=8.5 Hz, 1H), 4.04 (s, 2H), 3.82 (s, 3H) ppm.
LC/MS=369.0 (APCI-).
##STR00296##
[0769] Synthesis of
5-(4-Fluoro-benzenesulfonylmethyl)-2-methoxy-3'-nitro-biphenyl
(I-201). Into a 20 mL vial with stir bar was added I-200 (38.4 mg,
0.10 mmol), dichloromethane (2 mL), and mCPBA (45 mg, 0.26 mmol).
The reaction was stirred at room temperature for 30 minutes and
then 5 mL of saturated NaHCO.sub.3 (aq.) was added. The product was
extracted with dichloromethane (2.times.5 mL) and then
concentrated. Purification by preparative layer chromatography
using 35% acetone/hexane gave 18.3 mg (44%) of I-201 as a colorless
semi-solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.22 (d, J=1.6 Hz,
1H), 8.21-8.14 (m, 1H), 7.76-7.67 (m, 3H), 7.55 (t, J=8.1 Hz, 1H),
7.23-7.15 (m, 3H), 7.01 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H),
4.30 (s, 2H), 3.84 (s, 3H) ppm. LC/MS=100.0%, 401.0 (APCI-)
##STR00297##
[0770] Synthesis of
5-(4-Fluoro-benzenesulfinylmethyl)-2-methoxy-3'-nitro-biphenyl
(P-192). Into a 20 mL vial with stir bar was added I-200 (35.5 mg,
0.096 mmol), glacial AcOH (0.5 mL), and H.sub.2O.sub.2 (1.1 mL,
0.096 mmol, 0.088M solution in AcOH)). The reaction was stirred at
room temperature for 1 hour and then 10 mL of saturated NaHCO.sub.3
(aq.) and 1 mL of 1N NaOH were added until pH=10. The product was
extracted with dichloromethane (3.times.5 mL) and then
concentrated. Purification by preparative layer chromatography
using 35% acetone/hexane gave 21.0 mg (57%) of P-192 as a colorless
semi-solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.24 (t, J=1.8 Hz,
1H), 8.17 (dd, J=1.3, 8.3 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (t,
J=8.0 Hz, 1H), 7.45-7.36 (m, 2H), 7.17 (t, J=8.5 Hz, 2H), 7.07 (dd,
J=2.1, 8.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H),
4.03 (d, J=2.7 Hz, 2H), 3.83 (s, 3H) ppm. LC/MS=100.0%, 386.0
(APCI+).
Example 222
Preparation of P-195
##STR00298##
[0772] Synthesis of
1-(3-Bromo-4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carbonitrile
(I-202). Into a 100 mL round-bottomed flask with a stir bar was
added I-42 (2.59 g, 9.84 mmol), 6-hydroxy-nicotinonitrile (985 mg,
8.20 mmol), K.sub.2CO.sub.3 (2.49 g, 18.0 mmol), and DME (30 mL).
The reaction was stirred at 80.degree. C. for 20 hours and then
cooled to room temperature and filtered. The filtrate was
concentrated and the resulting light-pink solid was triturated with
40 mL of ether to obtain 529 mg (20%) of I-202 as a white
solid.
##STR00299##
[0773] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridine-3-c-
arbonitrile (P-195). Into a 50 mL round bottom flask with a stir
bar was added I-202 (510 mg, 1.60 mmol), 3-nitrophenylboronic acid
(0.40 g, 2.40 mmol), triphenylphosphine (84 mg, 0.32 mmol),
K.sub.2CO.sub.3 (0.66 g, 4.79 mmol), DME (10 mL), H.sub.2O (1 mL),
EtOH (1 mL), and the suspension was degassed with N.sub.2 for 5
minutes. To this was added palladium(II) acetate (36 mg, 0.16 mmol)
and the reaction was stirred at 80.degree. C. for 18 hours. The
reaction was cooled to rt and 50 mL of H.sub.2O was added and the
product was extracted with ethyl acetate (3.times.20 mL). The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The resulting solid
was triturated with ether (2.times.25 mL) to afford 391 mg (68%) of
P-195 as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.84 (d,
J=2.1 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.6
Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.67 (dd, J=2.4, 9.5 Hz, 1H), 7.52
(d, J=1.9 Hz, 1H), 7.47 (dd, J=1.9, 8.5 Hz, 1H), 7.16 (d, J=8.6 Hz,
1H), 6.51 (d, J=9.5 Hz, 1H), 5.09 (s, 2H), 3.80 (s, 3H) ppm.
LC/MS=93.4%, 362.6 (ESI+).
Example 223
Preparation of P-196
##STR00300##
[0775] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2-oxo-1,2-dihydro-pyridine-4-c-
arbonitrile (P-196). Into a 100 mL round bottom flask with a stir
bar was added I-70 (2.76 g, 8.55 mmol),
2-hydroxy-isonicotinonitrile (934 mg, 7.78 mmol), K.sub.2CO.sub.3
(2.36 g, 17.11 mmol), and DME (30 mL). The suspension was stirred
for 18 hours at 80.degree. C. and then at rt for 2 days. The
reaction was filtered, the filtrate was concentrated, and the
resulting solid was triturated with ether to give 2.12 g (75%) of
P-196 as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.29
(s, 1H), 8.20 (dd, J=1.3, 8.3 Hz, 1H), 8.12 (d, J=7.1 Hz, 1H), 7.93
(d, J=7.8 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H),
7.43 (dd, J=1.9, 8.5 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.04 (d,
J=1.3 Hz, 1H), 6.56 (dd, J=1.7, 7.0 Hz, 1H), 5.12 (s, 2H), 3.79 (s,
3H) ppm. LC/MS=96.1%, 361.0 (APCI-).
Example 224
Preparation of P-207
##STR00301##
[0777] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2-oxo-1,2-dihydro-pyridine-4-c-
arboxylic acid amide (P-207). Into a 20 mL vial with a stir bar was
added P-196 (132 mg, 0.37 mmol) and concentrated HCl (2 mL). The
reaction was stirred at rt for 18 hours, basified with 4N aqueous
NaOH, and the product was extracted with ethyl acetate (3.times.5
mL). The combined organics were concentrated to half their original
volume and 5 mL of hexane was added. The resulting solids were
filtered, washed with hexane, and triturated with ether to afford
29.8 mg (22%) of P-207 as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.28 (s, 1H), 8.20 (dd, J=1.4, 8.3 Hz, 1H), 8.05 (br.
s., 1H), 7.93 (t, J=7.4 Hz, 2H), 7.72 (t, J=8.0 Hz, 1H), 7.61 (br
s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.42 (dd, J=2.1, 8.5 Hz, 1H), 7.15
(d, J=8.5 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 6.54 (dd, J=1.8, 7.0 Hz,
1H), 5.10 (s, 2H), 3.79 (s, 3H) ppm. MS: 380.1 (APCI+).
Example 225
Preparation of P-208
##STR00302##
[0779] Synthesis of
1-(3-Bromo-4-methoxy-benzyl)-5-nitro-1H-pyridin-2-one (I-135). Into
a 100 mL round-bottomed flask with a stir bar was added I-42 (3.0
g, 11.41 mmol), 5-nitro-pyridin-2-ol (1.60 g, 11.41 mmol),
K.sub.2CO.sub.3 (3.47 g, 25.10 mmol), and 30 mL of DME. The
reaction was stirred at 80.degree. C. for 18 hours and then cooled
to rt and filtered. The filtrate was concentrated and the resulting
solid was triturated with 50 mL of ether to give 3.01 g (78%) of
I-135 as a yellow solid.
##STR00303##
[0780] Synthesis of
5-Amino-1-(3-bromo-4-methoxy-benzyl)-1H-pyridin-2-one (I-203). Into
a 250 mL round bottom flask with a stir bar was added I-135 (1.93
g, 5.69 mmol), 75 mL of MeOH, and 400 mg of 10% Pd/C. The
suspension was stirred under a H.sub.2 atmosphere for 1 hour, and
then filtered through Celite and concentrated. To the residue was
added 30 mL of 1N HCl and the reaction was washed with
dichloromethane (3.times.20 mL). The aqueous portion was basified
with 1N NaOH until pH=10, then extracted with dichloromethane
(3.times.15 mL). The organics were dried with Na.sub.2SO.sub.4 and
concentrated to give 825 mg of I-203 as a light-green solid which
used without further purification.
##STR00304##
[0781] Synthesis of
5-Amino-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(I-204). Into a 100 mL round bottom flask with a stir bar was added
I-203 (802 mg, 2.59 mmol), 3-nitrophenylboronic acid (433 mg, 2.59
mmol), triphenylphosphine (136 mg, 0.52 mmol), K.sub.2CO.sub.3
(1.07 g, 7.77 mmol), DME (15 mL), H.sub.2O (1.5 mL), EtOH (1.5 mL),
and the suspension was degassed with N.sub.2 for 10 minutes. To
this was added palladium(II) acetate (58 mg, 0.26 mmol) and the
reaction was stirred at 80.degree. C. for 18 hours. After cooling
to rt 5 mL of aqueous 1N NaOH was added and the product was
extracted with ethyl acetate (3.times.15 mL). The combined organics
were filtered through Celite and concentrated. The residue was
purified by flash column chromatography using 5%
MeOH/dichloromethane to give 185 mg (21%) of I-204 as a brown
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.28 (s, 1H), 8.20 (dd,
J=1.3, 8.2 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H),
7.40 (d, J=1.9 Hz, 1H), 7.35 (dd, J=1.9, 8.5 Hz, 1H), 7.15 (d,
J=8.6 Hz, 1H), 7.05 (dd, J=2.9, 9.5 Hz, 1H), 6.91 (d, J=2.8 Hz,
1H), 6.29 (d, J=9.5 Hz, 1H), 4.99 (s, 2H), 4.29 (br. s., 2H), 3.79
(s, 3H) ppm. LC/MS=100.0%, 352.1 (APCI+).
##STR00305##
[0782] Synthesis of
[1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridin-3-y-
l]-urea (P-208). Into a 20 mL vial with a stir bar was added I-204
(36.5 mg, 0.10 mmol), NaOCN (13.5 mg, 0.21 mmol), H.sub.2O (2 mL),
and 1 mL glacial acetic acid. The reaction was stirred as
40.degree. C. for 2 hours, then cooled to r.t. and 10 mL of
H.sub.2O was added. The suspension was filtered to obtain 19.8 mg
(48%) of P-208 as a gray solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
8.29 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J=7.6
Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.44 (s,
1H), 7.40-7.35 (m, 1H), 7.31 (dd, J=2.5, 9.5 Hz, 1H), 7.15 (d,
J=8.5 Hz, 1H), 6.37 (d, J=9.7 Hz, 1H), 5.79 (s, 2H), 5.07 (s, 2H),
3.79 (s, 3H) ppm. LC/MS=90.5%, 395.1 (APCI+).
Example 226
Preparation of P-212
##STR00306##
[0784] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridine-3-c-
arboxylic acid amide (P-212). Into an 8 mL vial with a stir bar was
added P-195 (44 mg, 0.12 mmol) and concentrated HCl (2 mL). The
reaction was stirred at r.t. for 24 hours. To the reaction was
added 5 mL of ethyl acetate and the solution was basified with
aqueous 4N NaOH. The ethyl acetate layer was removed and
concentrated. The resulting solid was triturated with ether to
obtain 15.6 mg (34%) of P-212 as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.52 (d, J=2.4 Hz, 1H), 8.32-8.26 (m, 1H), 8.20 (dd,
J=1.3, 8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.85 (dd, J=2.5, 9.5
Hz, 1H), 7.76 (br. s., 1H), 7.73 (t, J=8.1 Hz, 1H), 7.49 (d, J=2.0
Hz, 1H), 7.44 (dd, J=2.0, 8.6 Hz, 1H), 7.28 (br. s., 1H), 7.16 (d,
J=8.6 Hz, 1H), 6.42 (d, J=9.5 Hz, 1H), 5.14 (s, 2H), 3.79 (s, 3H)
ppm. LC/MS=96.4%, 380.1 (APCI+).
Example 227
Preparation of P-213
##STR00307##
[0786] Synthesis of
4-Aminomethyl-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(P-213). Into a 20 mL vial with a stir bar with P-196 (144 mg, 0.40
mmol) and 3 mL of THF was added BH.sub.3-THF (2.0 mL, 2.0 mmol,
1.0M solution in THF). The solution was stirred at 60.degree. C.
for 4 hours, then cooled to 0.degree. C. and a solution of 2.0 M
HCl in ether was added slowly, followed by 5 mL of methanol. The
solution was stirred at room temperature for 16 hours and then
concentrated. To the residue was added aqueous 1N HCl and it was
washed with dichloromethane, then basified with aqueous 4N NaOH and
extracted with dichloromethane and concentrated. The residue was
purified by flash column chromatography eluting with 10-17%
methanol/dichloromethane and afforded 7.2 mg (5%) of P-213 as a tan
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.27 (s, 1H), 8.23-8.17
(m, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.79-7.67 (m, 2H), 7.45 (d, J=1.9
Hz, 1H), 7.39 (dd, J=1.8, 8.4 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.35
(s, 1H), 6.19 (dd, J=1.5, 7.0 Hz, 1H), 5.05 (s, 2H), 3.78 (s, 2H),
3.51 (s, 2H) ppm. LC/MS=98.4%, 366.1 (APCI+).
Example 228
Preparation of P-215
##STR00308##
[0788] Synthesis of
[1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2-oxo-1,2-dihydro-pyridin-4-y-
l]-carbamic acid tert-butyl ester (I-206). Into a 25 mL round
bottom flask was placed I-289 (97.5 mg, 0.26 mmol),
diphenylphosphoryl azide (71 mg, 0.26 mmol), triethylamine (26 mg,
0.26 mmol), and t-BuOH (5 mL). The solution was refluxed for 16
hours, then cooled to room temperature. The reaction was diluted
with ethyl acetate, washed with saturated aqueous NaHCO.sub.3, and
brine. After concentration of the organics, the residue was
purified by flash column chromatography eluting with 40%
acetone/hexane to afford 61 mg (53%) of I-206 as a colorless oil.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.60 (s, 1H), 8.27 (s, 1H),
8.20 (dd, J=1.6, 8.2 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.78-7.65 (m,
2H), 7.40 (d, J=2.0 Hz, 1H), 7.36 (dd, J=2.0, 8.5 Hz, 1H), 7.14 (d,
J=8.5 Hz, 1H), 6.53 (d, J=2.1 Hz, 1H), 6.34 (dd, J=2.3, 7.5 Hz,
1H), 4.99 (s, 2H), 3.78 (s, 3H), 1.45 (s, 9H) ppm.
[0789] LC/MS=93.0%, 452.1 (APCI+).
##STR00309##
[0790] Synthesis of
4-Amino-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(P-215). Into a 20 mL vial with a stir bar was added I-206 (50 mg,
0.11 mmol), dichloromethane (2 mL), and 1 mL of TFA. The reaction
was stirred at room temperature for 4 hours and then concentrated.
The residue was diluted with aqueous 1N HCl and washed with
dichloromethane. The aqueous portion was basified with aqueous 4N
NaOH, extracted with dichloromethane, and concentrated to afford 22
mg (56%) of P-215 as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.27 (s, 1H), 8.23-8.16 (m, 1H), 7.91 (d, J=7.6 Hz,
1H), 7.72 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.38-7.30 (m,
2H), 7.13 (d, J=8.5 Hz, 1H), 5.99 (s, 2H), 5.66 (dd, J=2.3, 7.4 Hz,
1H), 5.24 (d, J=2.3 Hz, 1H), 4.90 (s, 2H), 3.78 (s, 3H) ppm.
LC/MS=97.8%, 352.1 (APCI+).
Example 229
Preparation of P-209
##STR00310##
[0792] Synthesis of 1-(3-Bromo-4-methoxy-benzyl)-1H-pyridin-2-one
(I-205). Into a 100 mL round bottom flask with a stir bar was added
I-45 (2.56 g, 9.73 mmol), 2-hydroxypyridine (926 mg, 9.73 mmol),
K.sub.2CO.sub.3 (2.96 g, 21.41 mmol), and 30 mL of DME. The
suspension was stirred at 80.degree. C. for 18 hours and then r.t.
for 2 days after which it was filtered and concentrated. The solid
was triturated with ether to afford 2.20 g (77%) of I-205 as a
white solid.
##STR00311##
[0793] Synthesis of
1-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(P-209). Into a 40 mL vial with a stir bar was added I-205 (250 mg,
0.81 mmol), 3-chlorophenylboronic acid (126 mg, 0.81 mmol),
triphenylphosphine (42 mg, 0.16 mmol), K.sub.2CO.sub.3 (335 mg,
2.43 mmol), DME (10 mL), H.sub.2O (1 mL), EtOH (1 mL), and the
suspension was degassed with N.sub.2 for 10 minutes. To this was
added palladium(II) acetate (18 mg, 0.08 mmol) and the reaction was
stirred at 80.degree. C. for 18 hours. After cooling to r.t., 10 mL
of H.sub.2O was added and the product was extracted with ethyl
acetate (3.times.15 mL). The combined organics were concentrated.
The residue was purified by flash column chromatography using
20%-35% acetone/hexanes to give 241 mg (91%) of P-209 as a
light-yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.84 (dd,
J=1.3, 6.6 Hz, 1H), 7.66-7.52 (m, 1H), 7.51-7.31 (m, 6H), 7.10 (d,
J=9.1 Hz, 1H), 6.39 (d, J=9.1 Hz, 1H), 6.22 (t, J=6.5 Hz, 1H), 5.06
(s, 2H), 3.76 (s, 3H) ppm. LC/MS=97.6%, 326.2 (APCI+).
##STR00312##
Example 230
Preparation of P-193
[0794] Synthesis of 5-Bromo-2-methoxy-3'-nitro-biphenyl (I-207). A
suspension of 5-bromo-2-methoxyphenylboronic acid (500 mg, 2.17
mmol), 3-iodonitrobenzene (647 mg, 2.60 mmol), and potassium
carbonate (599 mg, 4.33 mmol) in methanol (10 mL) and water (2 mL)
was degassed for 30 min under a nitrogen stream followed by the
addition of palladium(II) acetate (9.72 mg, 0.0433 mmol). The
reaction was stirred at room temperature for 4 h. The methanol was
removed under reduced pressure, ethyl acetate (50 mL) and water (50
mL) were added, and the biphasic suspension was filtered. The
layers were separated and the organic was washed with water (50
mL). The aqueous washes were combined and extracted with ethyl
acetate (2.times.50 mL), and the organic extracts combined. The
organic solution was washed with water (3.times.50 mL), saturated
aqueous sodium bicarbonate (50 mL), brine, dried over sodium
sulfate, filtered, and the solvent removed under vacuum to give a
crude brown gum. The product was purified by flash silica gel
column chromatography (5% ethyl acetate in hexanes), and
crystallized by dissolving in diethyl ether (20 mL) and hexanes (50
mL), removing one half of the solvent under vacuum, filtering and
washing with hexanes (2.times.10 mL) to give I-207 (417.8 mg, 63%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.38 (t, J=1.8 Hz, 1H),
8.21-8.19 (m, 1H), 7.81 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.58 (t, J=8.0
Hz, 1H), 7.50-7.45 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 3.82 (s, 3H)
ppm.
[0795] Synthesis of 5-(4-Fluoro-phenoxy)-2-methoxy-3'-nitrobiphenyl
(P-193). To a suspension of I-207 (200 mg, 0.649 mmol),
4-fluorophenol (109 mg, 0.974 mmol), cesium carbonate (423 mg, 1.30
mmol), and N,N-dimethylglycine (20.1 mg, 0.195 mmol) in 1,4-dioxane
(2 mL) was added copper(I) iodide (12.4 mg, 0.0649 mmol) under
argon, and the reaction was heated to 105.degree. C. The reaction
was left to stir overnight under argon at 105.degree. C. The blue
solution was diluted with ethyl acetate (50 mL), washed with water
(2.times.50 mL), brine (50 mL), dried over sodium sulfate,
filtered, and the solvent removed under vacuum. The residue was
purified by flash silica gel column chromatography (10% ethyl
acetate in hexanes), and was crystallized from diethyl ether (5 mL)
to give P-193 (61.4 mg, 28% yield) as a white powder. 1H NMR (400
MHz, CDCl.sub.3) 8.40 (t, J=2.0 Hz, 1H), 8.19-8.16 (m, 1H), 7.82
(dt, J=7.6 Hz, 1.2 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.04-6.95 (m,
7H), 3.83 (s, 3H) ppm. LCMS=98.3% purity. MS (APCI-)=339.2 (M).
Example 231
Preparation of P-230
[0796] Synthesis of 5-Bromo-3'-chloro-2-methoxy-biphenyl (I-208).
I-208 was synthesized from 5-bromo-2-methoxyphenylboronic acid
(2.00 g, 8.66 mmol) and 3-chloroiodobenzene (2.48 g, 10.4 mmol)
using the same conditions as for I-207. The reaction time was
extended to 16 h. The methanol was removed under vacuum, and the
residue dissolved in ethyl acetate (100 mL), washed with water (100
mL), and the aqueous wash extracted with ethyl acetate (100 mL).
The combined organic extracts were washed with saturated aqueous
sodium bicarbonate (2.times.200 mL), water (2.times.200 mL) and
brine (150 mL), dried over sodium sulfate, filtered and the solvent
removed under vacuum to give I-208 (2.56 g, 99% yield). 1H NMR (400
MHz, CDCl.sub.3) 7.49-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.36-7.31
(m, 3H), 6.85 (d, J=8.4 Hz, 1H), 3.80 (s, 3H) ppm.
[0797] Synthesis of
3'-Chloro-2-fluoro-3-(4-fluoro-phenoxy)-6-methoxy-biphenyl (P-230).
To a suspension of I-208 (200 mg, 0.672 mmol), 4-fluorophenol (113
mg, 1.01 mmol), cesium carbonate (438 mg, 1.34 mmol), and
N,N-dimethylglycine hydrochloride salt (28.2 mg, 0.202 mmol) in
1,4-dioxane (2 mL) was added copper(I) iodide (12.8 mg, 0.0672
mmol) under argon. The reaction was heated to 105.degree. C. under
argon, and stirred at 105.degree. C. overnight. The reaction was
diluted with ethyl acetate (20 mL), washed with water (20 mL), and
the aqueous wash extracted into ethyl acetate (20 mL). The combined
organic extracts were washed with 1 N aqueous sodium hydroxide (20
mL), 1 N aqueous hydrochloric acid (20 mL), water (2.times.20 mL),
brine (20 mL), dried over sodium sulfate, filtered, and the solvent
removed under vacuum. The product was purified by preparatory TLC
eluting with 5% acetone in hexanes with 3 developments to give
P-230 (140.6 mg, 64% yield) as a yellow gummy solid. 1H NMR (400
MHz, CDCl.sub.3) 7.51-7.51 (m, 1H), 7.38-7.30 (m, 3H), 7.023-6.93
(m, 7H), 3.81 (s, 3H) ppm. MS (ESI+)=389.6 (M+61), 328.2 (M), 279.5
(M-49).
Example 232
Preparation of P-236
##STR00313##
[0799] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridine-2-c-
arboxylic acid methyl ester (I-290). Into a 20 mL vial with stir
bar was added I-70 (268 mg, 0.83 mmol),
6-hydroxy-pyridine-2-carboxylic acid methyl ester (98 mg, 0.64
mmol), K.sub.2CO.sub.3 (195 mg, 1.41 mmol), and DME (4 mL). The
reaction was stirred at 80.degree. C. for 4 hours and then cooled
to room temperature and filtered. The filtrate was concentrated and
purified by flash column chromatography using 15-50%
acetone/hexanes to afford 98 mg (39%) of I-290 as a tan solid.
##STR00314##
[0800] Synthesis of
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridine-2-c-
arboxylic acid (I-209). Into a 20 mL vial with a stir bar was added
I-290 (92 mg, 0.23 mmol), 1N aqueous NaOH (2 mL), and methanol (2
mL). The reaction was stirred at 60.degree. C. for 18 hours and
then cooled to room temperature and washed with dichloromethane.
The aqueous portion was acidified with 6N aqueous HCl and extracted
with ethyl acetate. The organics were dried over Na.sub.2SO.sub.4
and concentrated to give I-209 (61 mg, 69%) as a tan solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) 8.25 (s, 1H), 8.19 (dd, J=1.4, 8.3 Hz,
1H), 7.88 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.48 (dd,
J=6.8, 9.1 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.21-7.15 (m, 1H),
7.14-7.08 (m, 1H), 6.71 (d, J=6.6 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H),
5.50 (s, 2H), 3.77 (s, 3H) ppm. LC/MS=99.9%, 381.0 (APCI+)
##STR00315##
[0801] Synthesis of
[1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridin-2-y-
l]-carbamic acid tert-butyl ester (I-210). Into a 20 mL vial was
placed I-209 (48 mg, 0.13 mmol), diphenylphosphoryl azide (35 mg,
0.13 mmol), triethylamine (13 mg, 0.13 mmol), and t-BuOH (4 mL).
The solution was stirred at 80.degree. C. for 24 hours and then
cooled to room temperature. The solvent was evaporated, the residue
diluted with saturated aqueous NaHCO.sub.3 and extracted with ethyl
acetate. The organics were concentrated and purified by flash
column chromatography eluting with 15% acetone/dichloromethane to
give I-210 (43 mg, 75%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.42 (br s, 1H), 8.27 (s, 1H), 8.20 (d, J=8.2 Hz,
1H), 7.90 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.40 (dd,
J=7.4, 9.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.31
(d, J=9.0 Hz, 1H), 6.14 (d, J=7.0 Hz, 1H), 5.28 (br s, 2H), 3.76
(s, 3H), 1.27 (s, 9H) ppm. LC/MS=94.2%, 452.1 (APCI+).
##STR00316##
[0802] Synthesis of
6-Amino-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(P-236). Into a 20 mL vial with a stir bar was added I-210 (22 mg,
0.049 mmol), dichloromethane (2 mL), and TFA (2 mL). After 6 hours
at room temperature the solution was concentrated. The residue was
purified by flash column chromatography using 2-5%
methanol/dichloromethane to give 12.5 mg (74%) of P-236 as a brown
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.27 (s, 1H), 8.20 (d,
J=8.2 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.39 (d,
J=1.7 Hz, 1H), 7.25 (dd, J=1.7, 8.5 Hz, 1H), 7.15-7.08 (m, 2H),
6.44 (s, 1H), 5.76 (s, 2H), 5.53 (d, J=8.7 Hz, 1H), 5.40 (d, J=7.6
Hz, 1H), 5.19 (br s, 1H), 3.77 (s, 3H) ppm. LC/MS=100.0%, 352.1
(APCI+).
##STR00317##
Example 233
Preparation of P-218
[0803] Synthesis of 3'-chloro-2-methoxy-5-methyl-biphenyl (I-211).
To 2-methoxy-5-methylboronic acid (4.0 g, 24.1 mmol),
1-chloro-3-iodo-benzene (6.32 g, 26.51 mmol), K.sub.2CO.sub.3 (8.33
g, 60.25 mmol), and palladium(II) acetate (0.27 g, 1.2 mmol) was
added methanol (150 mL), and H.sub.2O (30 mL). Argon gas was
bubbled through the stirred reaction for 5 min. The reaction was
stirred at room temperature under argon for 20 h. The reaction
mixture was concentrated, and H.sub.2O and dichloromethane (60 mL
each) were added. The organic layer was separated and the aqueous
layer was extracted with dichloromethane (2.times.60 mL). The
combined organic extracts were dried with Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography using 1:1 dichloromethane-hexanes then
dichloromethane to afford 5.6 g (98%) of I-211 as a viscous
liquid.
[0804] Synthesis of 5-bromomethyl-3'-chloro-2-methoxy-biphenyl
(I-154). To I-211 (2.0 g, 8.59 mmol) and NBS (1.68 g, 9.45 mmol) in
CCl.sub.4 (30 mL) was added benzoylperoxide (0.1 g, 0.43 mmol). The
reaction was stirred at 85.degree. C. under N.sub.2 for 5 h. The
reaction was cooled to room temperature and concentrated. The
residue was dissolved in mixture of 5% ethyl acetate in hexanes (20
mL) and purified by silica gel column chromatography using 5% ethyl
acetate in hexanes to afford 2.81 g (98%) of I-154 as light yellow
viscous liquid.
[0805] Synthesis of
1-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-218). To a solution of 2-pyrrolidone (0.2 g, 2.41 mmol) in DMF
(1 mL) was added to a cooled (0.degree. C.) slurry of NaH (0.1 g,
2.41 mmol) in DMF (3 mL) under Ar. The reaction mixture was slowly
warmed to room temperature, stirred for 45 min, then cooled to
0.degree. C. To this I-154 (0.5 g, 1.6 mmol) in DMF (2 mL) was
added over 5 min. The reaction mixture was slowly warmed to room
temperature, stirred for 20 h, poured on to crushed-ice water, and
extracted with ethyl acetate (2.times.60 mL). The combined organic
extracts were dried with Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was dissolved in dichloromethane (20 mL)
and purified by silica gel column chromatography using 5% ethyl
acetate in hexanes to afford 0.22 g (43%) of P-218 as a viscous
liquid. 1H NMR (CDCl.sub.3, 400 MHz): 7.49-7.51 (m, 1H), 7.27-7.4
(m, 4H), 7.23 (dd, J=8.4, 2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.93
(d, J=8.4 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.28 (t, J=7.2 Hz,
2H), 2.44 (t, J=8.0 Hz, 2H), 1.95-2.05 (m, 2H) ppm; MS (APCI+):
316.1 (M+1), LC-MS: 100%.
Example 234
Preparation of P-211
##STR00318##
[0807] Synthesis of
N-[1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-6-oxo-1,6-dihydro-pyridin-3-
-yl]-acetamide (P-211). Into a 20 mL vial with a stir bar was added
I-204 (113 mg, 0.32 mmol), dichloromethane (2 mL), Ac.sub.2O (46
uL, 0.48 mmol), and TEA (90 uL, 0.64 mmol). The reaction was
stirred at room temperature for 4 hours, 1N aqueous HCl was added,
the product was extracted with dichloromethane, and the organics
were concentrated. The residue was purified by flash column
chromatography using 25%-35% acetone/dichloromethane to afford 12.5
mg (10%) of P-211 as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.66 (s, 1H), 8.28 (s, 1H), 8.23-8.12 (m, 2H), 7.92
(d, J=7.8 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H),
7.41-7.32 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 6.42 (d, J=9.5 Hz, 1H),
5.09 (s, 2H), 3.79 (s, 3H), 1.95 (s, 3H) ppm. LC/MS=95.5%.
Example 235
Preparation of P-223
##STR00319##
[0809] Synthesis of
1-(3',4'-difluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-223). To I-181 (0.15 g, 0.53 mmol), 3,4-difluorophenylboronic
acid (0.13 g, 0.79 mmol), triphenylphosphine (0.07 g, 0.26 mmol),
K.sub.2CO.sub.3 (0.03 g, 0.21 mmol) and palladium(II) acetate
(0.014 g, 0.06 mmol) were added dioxane (6 mL) and EtOH-H.sub.2O
(1:1, 3 mL). Argon gas was bubbled through the stirred reaction for
5 min. The reaction was stirred at 85.degree. C. under argon for 20
h. The reaction was cooled to room temperature and concentrated.
The residue was purified by silica gel column chromatography using
30-50% ethyl acetate in hexanes to afford 0.15 g (89%) of P-223 as
a light brown viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz):
7.33-7.38 (m 1H), 7.14-7.24 (m, 4H), 6.93 (d, J=8.4 Hz, 1H), 4.43
(s, 2H), 3.81 (s, 3H), 3.29 (t, J=7.2 Hz, 2H), 2.44 (t, J=8.4 Hz,
2H), 1.95-2.05 (m, 2H) ppm;
[0810] MS (APCI+): 318.1 (M+1), LC-MS: 100%.
Example 236
Preparation of P-240
##STR00320##
[0812] Synthesis of
4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-benzamide (P-240). A
suspension of I-154 (300 mg, 0.963 mmol),
4-aminocarboxyphenylboronic acid (238 mg, 1.44 mmol),
triphenylphosphine (50.4 mg, 0.193 mmol), and water (1 mL) was
degassed with a nitrogen stream for 30 minutes. To the reaction was
added palladium(II) acetate (22 mg, 0.0963 mmol) under nitrogen and
the reaction was heated to 90.degree. C. under nitrogen with
stirring overnight. The solvent was removed under vacuum and the
product crystallized in hexanes (50 mL). The product was purified
by flash silica gel column chromatography (5% methanol in
dichloromethane) to give P-240 (112 mg, 33% yield) as a grey solid.
1H NMR (400 MHz, CDCl.sub.3) 7.75-7.73 (m, 2H), 7.49 (t, J=1.6 Hz,
1H), 7.38-7.27 (m, 5H), 7.14-7.10 (m, 2H), 6.91 (d, J=8.0 Hz, 1H),
6.0 (br s, 1H), 5.75 (br s, 1H), 4.01 (s, 2H), 3.79 (s, 3H) ppm.
LCMS=92.3% purity. MS (APCI+)=352.1 (M+1).
Example 237
Preparation of P-245
##STR00321##
[0814] Synthesis of
1-(6-methoxy-3'-methylsulfanyl-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-245). To I-181 (0.15 g, 0.53 mmol),
3-methylsulfanyl-benzeneboronic acid (0.11 g, 0.639 mmol),
triphenylphosphine (0.07 g, 0.26 mmol), K.sub.2CO.sub.3 (0.03 g,
0.21 mmol) and palladium(II) acetate (0.014 g, 0.06 mmol) were
added dioxane (6 mL) and EtOH-H.sub.2O (1:1, 3 mL). Argon gas was
bubbled through the stirred reaction for 5 min. The reaction was
stirred at 85.degree. C. under argon for 20 h. The reaction was
cooled to room temperature and concentrated. The residue was
purified by silica gel column chromatography using 15% acetone in
dichloromethane then reverse phase (C.sub.18) prep TLC using 40%
acetonitrile in water then by silica gel column chromatography
using 5% methanol in dichloromethane to afford 0.013 g (8%) of
P-245 as a viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz): 7.39-7.45
(m 1H), 7.2-7.34 (m, 4H), 7.17 (d, J=6.4 Hz, 1H), 6.93 (d, J=8.4
Hz, 1H), 4.43 (s, 2H), 3.8 (s, 3H), 3.28 (t, J=7.2 Hz, 2H), 2.43
(t, J=8.0 Hz, 2H), 1.95-2.05 (m, 2H) ppm;
[0815] MS (APCI+): 328.1 (M+1), LC-MS: 93.2%.
Example 238
Preparation of P-248
##STR00322##
[0817] Synthesis of
(S)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidin-2-one (I-212).
Into a 100 mL round-bottomed flask with a stir bar was added
(S)-4-hydroxy-pyrrolidin-2-one (3.04 g, 30.07 mmol), TBSCl (4.99 g,
33.07 mmol), imidazole (3.07 g, 45.10 mmol), and DMF (30 mL). After
stirring at room temperature for 18 hours, the reaction was added
to 100 mL of water and stirred for 30 minutes. The solids were
filtered and washed with water. After drying the solids in a vacuum
dessicator for 3 days, 5.97 g (92%) of I-212 was obtained.
##STR00323##
[0818] Synthesis of
((S)-4-(tert-Butyl-dimethyl-silanyloxy)-1-(6-methoxy-3'-nitro-biphenyl-3--
ylmethyl)-pyrrolidin-2-one (I-213). Into a 250 mL round-bottomed
flask with a stir bar was added I-212 (2.57 g, 11.95 mmol), THF
(150 mL), and the solution was cooled to 0.degree. C. NaH (0.56 g,
14.12 mmol) was added and the suspension was stirred at room
temperature for 30 minutes. To this, I-70 (3.50 g, 10.86 mmol) was
added and the reaction was stirred for 20 hours at room temperature
after which time 50 mL of water was added and the product was
extracted with ethyl acetate. The organics were concentrated to
yield 8.9 g of I-213, which was used as is in the next
reaction.
##STR00324##
[0819] Synthesis of
(S)-4-Hydroxy-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-248). Compound I-213 (8.9 g, 19.5 mmol) from the step described
above was added to a 100 mL round-bottomed flask, followed by 10 mL
of THF and TBAF (29 mL, 29 mmol, 1.0M in THF). The solution was
stirred at room temperature for 30 minutes after which time
NH.sub.4Cl and brine were added. The product was extracted with
ethyl acetate, dried over Na.sub.2SO.sub.4, filtered and
concentrated. Flash column chromatography purification eluting with
25-50% acetone/dichloromethane followed by flash column
chromatography eluting with 5% methanol/dichloromethane gave 143 mg
(4%, 2 steps) of P-248. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.40 (d,
J=1.6 Hz, 1H), 8.21-8.14 (m, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.56 (t,
J=8.0 Hz, 1H), 7.31-7.20 (m, 2H), 6.98 (d, J=8.5 Hz, 1H), 4.63-4.48
(m, 2H), 4.46-4.34 (m, 1H), 3.83 (s, 3H), 3.56 (dd, J=5.6, 10.8 Hz,
1H), 3.24 (dd, J=1.6, 10.9 Hz, 1H), 2.76 (dd, J=6.5, 17.4 Hz, 1H),
2.45 (dd, J=2.1, 17.3 Hz, 1H), 1.83 (d, J=4.0 Hz, 1H) ppm.
LC/MS=97.4%, 343.1 (APCI+).
Example 239
Preparation of P-253
##STR00325##
[0821] Synthesis of Carbamic acid
(S)-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-5-oxo-pyrrolidin-3-yl
ester (P-253). Into a 20 mL vial with a stir bar was added
chlorosulfonyl isocyanate (42 mg, 0.30 mmol), 1 mL dichloromethane,
then P-248 (51.3 mg, 0.15 mmol) in 2 mL of dichloromethane. The
reaction was stirred at room temperature for 18 hours after which 2
mL of water was added and the mixture was stirred at room
temperature for 30 minutes. The layers were separated and the
aqueous was extracted with dichloromethane. The combined organics
were concentrated and then purified by preparative layer TLC using
50% acetone/dichloromethane to obtain P-253 (12.4 mg, 21%) as an
off-white semi-solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.30 (s,
1H), 8.20 (dd, J=2.1, 8.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.72 (t,
J=8.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (d, J=9.0 Hz, 1H), 6.59 (br.
s., 2H), 5.04 (t, J=5.8 Hz, 1H), 4.49-4.30 (m, 2H), 3.80 (s, 3H),
3.46-3.38 (m, 1H), 3.21 (d, J=11.4 Hz, 1H), 2.78 (dd, J=6.9, 17.5
Hz, 1H), 2.23 (d, J=18.1 Hz, 1H) ppm. LC/MS=100.0%, 386.1
(APCI+).
Example 240
Preparation of P-506
##STR00326##
[0823] Synthesis of
(R)-4-Hydroxy-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-506). P-506 was prepared in a similar manner as that described
above for P-248 except starting with
(R)-4-Hydroxy-pyrrolidin-2-one. .sup.1H NMR (400 MHz, CDCl.sub.3)
8.40 (t, J=1.9 Hz, 1H), 8.17 (dd, J=1.7, 8.2 Hz, 1H), 7.84 (d,
J=7.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.30-7.27 (m, 1H), 7.22 (d,
J=2.1 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.61-4.48 (m, 2H), 4.41 (d,
J=14.8 Hz, 1H), 3.85-3.81 (m, 3H), 3.56 (dd, J=5.6, 10.9 Hz, 1H),
3.24 (dd, J=1.8, 10.8 Hz, 1H), 2.75 (dd, J=6.5, 17.3 Hz, 1H), 2.44
(dd, J=2.1, 17.4 Hz, 1H), 2.12 (br s, 1H) ppm. LC/MS=95.6%, 343.1
(APCI+).
Example 241
Preparation of P-266
##STR00327##
[0825] Synthesis of
4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-benzenesulfonamide
(P-266). P-266 was synthesized from I-154 (300 mg, 0.963 mmol) and
4-aminosulfonylphenylboronic acid pinocolate ester (409 mg, 1.44
mmol) using the same conditions as for the synthesis of P-240. The
solvent was removed under vacuum and the residue suspended in ethyl
acetate (20 mL) and water (20 mL). The layers were separated and
the organic solution was washed with water (40 mL), saturated
aqueous sodium bicarbonate (40 mL), water (2.times.40 mL), and
brine (40 mL), dried over sodium sulfate, filtered, and the solvent
removed under vacuum. The residue was purified by flash silica gel
column chromatography (2.5% acetone in dichloromethane) to give a
material which was then purified by preparatory silica gel TLC
(eluting with 2.5% acetone in dichloromethane with 3 developments)
to give P-266 (52.2 mg, 14% yield) as a clear gum. 1H NMR (400 MHz,
CDCl.sub.3) 7.86-7.83 (m, 2H), 7.49-7.48 (m, 1H), 7.38-7.29 (m,
5H), 7.14-7.09 (m, 2H), 6.92 (d, J=8.4 Hz, H), 4.71 (s, 2H), 4.03
(s, 2H), 3.80 (s, 3H) ppm. LCMS=100.0% purity. MS (APCI-)=386.0
(M-1), 217.0 (M-171).
Example 242
Preparation of I-216
##STR00328##
[0827] Synthesis of 3-Bromo-2-fluoro-4-methoxy-benzaldehyde (I-30).
A solution of 2-bromo-3-fluoroanisol (5.00 g, 24.4 mmol) in
trifluoroacetic acid (25 mL) was heated to 80.degree. C. and then a
solution of hexamethylenetetramine (6.83 g, 48.8 mmol) in
trifluoroacetic acid (25 mL) was added dropwise over 1.5 h. Upon
completion of the addition, the reaction was stirred at 80.degree.
C. for 1 h under nitrogen. The excess trifluoroacetic acid was
removed under vacuum, and the pH was adjusted to 7.5-8.0 by
addition of saturated aqueous potassium carbonate (.about.100 mL).
The white solid that formed was filtered to give I-30 which was
used without additional purification.
[0828] Synthesis of Formic acid 3-bromo-2-fluoro-4-methoxy-phenyl
ester (I-215). To a solution of I-30 (4.84 g) in dichloromethane
(60 mL) was added meta-chloroperbenzoic acid (16.09 g) and the
reaction was stirred at room temperature overnight. The reaction
was diluted with dichloromethane (200 mL), washed with saturated
aqueous sodium thiosulfate (300 mL), and extracted into
dichloromethane (2.times.100 mL). The combined organic extracts
were washed with saturated aqueous sodium bicarbonate (3.times.400
mL), water (2.times.400 mL), and brine (400 mL), dried over sodium
sulfate, decanted, and the solvent removed under vacuum to give
I-215 (12:5, 4.05 g) which was used as is without additional
purification.
[0829] .sup.1H NMR (400 MHz, CDCl.sub.3) d: 8.27 (t, J=0.8 Hz, 1H),
7.10-7.06 (m, 1H), 6.70 (dd, J=8.2 Hz, 1.0 Hz, 1H), 3.92 (s, 3H)
ppm.
[0830] Synthesis of 3-Bromo-2-fluoro-4-methoxy-phenol (I-216). To a
solution of I-215 (4.05 g) in ethyl alcohol (75 mL) was added solid
potassium hydroxide pellets (1.71 g) and the brown solution was
stirred at room temperature overnight. The reaction was acidified
to pH 2 using concentrated hydrochloric acid and the ethanol was
removed under vacuum. The material was diluted with water (300 mL)
and extracted with dichloromethane (300 mL, 2.times.100 mL). The
combined extracts were washed with brine (500 mL), dried over
sodium sulfate, decanted, and the solvent removed under vacuum. The
residue was then dissolved in diethyl ether (500 mL) and extracted
with 1 M aqueous sodium hydroxide (300 mL, 2.times.250 mL). The
combined aqueous layers were acidified to pH 2 with concentrated
hydrochloric acid and extracted into diethyl ether (2.times.300
mL). The combined diethyl ether extracts were washed with water
(500 mL) and brine (300 mL), dried over sodium sulfate, decanted,
and the solvent removed under vacuum to give an orange solid. The
solid was purified by flash silica gel column chromatography
eluting with dichloromethane to give I-216 (1.45 g) as a yellow
powder. 1H NMR (400 MHz, CDCl.sub.3) 6.96-6.91 (m, 1H), 6.62 (dd,
J=9.2 Hz, 2.0 Hz, 1H), 4.78 (d, J=3.6 Hz, 1H), 3.86 (s, 3H)
ppm.
##STR00329## ##STR00330##
Example 243
Preparation of P-254
[0831] Synthesis of 3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ol
(I-217). A solution of I-216 (390 mg, 1.76 mmol) in toluene (6 mL)
was degassed with a nitrogen stream for 10 min. To this solution
was added ethanol (1 mL), 3-chlorophenylboronic acid (331 mg, 2.12
mmol), 2 M aqueous sodium carbonate (1.76 mL, 3.53 mmol), and the
nitrogen stream was continued for 15 min. To this suspension was
added tetrakis(triphenylphosphine) palladium(0) (102 mg, 0.0882
mmol) under nitrogen and the reaction was heated to 90.degree. C.
overnight. Additional tetrakis(triphenylphosphine)palladium(0) (102
mg, 0.0882 mmol) was added under nitrogen and the reaction reacted
at 90.degree. C. for 24 h, and a third portion of
tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.0882 mmol) was
added and the reaction heated to 90.degree. C. for 24 hours.
Approximately one half of the solvent was removed under vacuum and
the residual material was diluted with ethyl acetate (100 mL) and
saturated aqueous ammonium chloride (100 mL). The layers were
filtered, separated, and the organic solution was washed with
saturated aqueous sodium bicarbonate (2.times.100 mL), water (100
mL), and brine (50 mL). The solvent was dried over sodium sulfate,
filtered, and the solvent removed under reduced pressure. The
product was purified by flash silica gel column chromatography
(eluting with 2.5% acetone in dichloromethane) to give I-217 (398
mg, 89% yield). 1H NMR (400 MHz, CDCl.sub.3) 7.41 (s, 1H),
7.39-7.28 (m, 3H), 6.97 (t, J=9.4 Hz, 1H), 6.67 (dd, J=9.2 Hz, 2.0
Hz, 1H), 4.79 (s, 1H), 3.72 (s, 3H) ppm.
[0832] Synthesis of
3'-Chloro-2-fluoro-6-methoxy-3-(4-nitro-phenoxy)-biphenyl (I-219).
A suspension of I-217 (200 mg, 0.792 mmol), 4-iodonitrobenzene (179
mg, 0.720 mmol), cesium carbonate (469 mg, 1.44 mmol), and
2,2,6,6-tetramethylheptane-3,5-dione (37 uL, 0.180 mmol) in
N-methylpyrrolidone (4 mL) was stirred under nitrogen. To this
reaction was added copper(I) chloride (35.6 mg, 0.360 mmol) and the
reaction was heated to 100.degree. C. under nitrogen overnight. The
reaction was diluted with ethyl acetate (20 mL) and washed with
water (20 mL). The aqueous wash was extracted with ethyl acetate
(20 mL) and the organic extracts were combined. The organic
extracts were washed with water (2.times.20 mL), 1 N aqueous sodium
hydroxide (2.times.20 mL), 1 N aqueous hydrochloric acid
(2.times.20 mL), brine (20 mL), dried over sodium sulfate,
filtered, and the solvent removed under vacuum to give crude I-219
(181.0 mg, 61% yield) which was used as is in the next
reaction.
[0833] Synthesis of
4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yloxy)-phenyl-amine
hydrochloride salt (I-221). To a suspension of I-219 (180 mg, 0.645
mmol) and iron powder (126 mg, 2.26 mmol) in ethanol (2.6 mL) and
water (0.8 mL) was added solid ammonium chloride (193 mg, 3.60
mmol). The reaction was purged with nitrogen, and heated to
85.degree. C. with stirring for 3 h. The solvent was removed under
vacuum and the material was diluted in ethyl acetate (50 mL) and
water (50 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (50 mL). The combined organic extracts
were washed with water (2.times.50 mL) and brine (50 mL), dried
over sodium sulfate, filtered, and the solvent removed under
reduced pressure. The product was purified by flash silica gel
column chromatography (5% acetone in dichloromethane) to give the
free base of I-221 (136 mg). The free base was dissolved in diethyl
ether (2.5 mL) and 2 N hydrogen chloride in diethyl ether (0.8 mL)
was added drop wise. The salt began to precipitate out after 15 min
and the suspension was allowed to stir for an additional 1.5 h. The
solid was filtered and washed with diethyl ether (3 mL) and hexanes
(4.times.5 mL) to give I-221 (104 mg, 47% yield) as a beige powder.
1H NMR (400 MHz, DMSO-d.sub.6) 9.6 (br s, 2H), 7.51-7.45 (m, 3H),
7.36-7.25 (m, 4H), 7.08-7.01 (m, 3H), 3.77 (s, 3H) ppm. MS
(ESI+)=345.5 (M+1).
[0834] Synthesis of
N-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yloxy)-phenyl]-methanesulfo-
namide (P-254). A suspension of I-221 (50.0 mg, 0.138 mmol) and
pyridine (21.8 mg, 0.276 mmol) in chloroform (1 mL) was stirred for
10 min. To the suspension was added methanesulfonylchloride (15.8
mg, 0.138 mmol) and the reaction was stirred at room temperature
overnight. The solvent was removed under vacuum and the residue was
purified by preparatory silica gel TLC (5% acetone in
dichloromethane, 2 developments, 0.5% acetone in dichloromethane, 5
developments, and 5% acetone in dichloromethane) to give P-254
(26.1 mg, 47% yield) as a orange gum. 1H NMR (400 MHz, CDCl.sub.3)
7.42-7.42 (m, 1H), 7.35-7.29 (m, 3H), 7.25-7.18 (m, 2H), 7.18 (t,
J=2.8 Hz, 1H), 7.00-6.95 (m, 2H), 6.75 (dd, J=7.4 Hz, 0.2 Hz, 1H),
6.20 (s, 1H), 3.80 (s, 3H), 2.98 (s 3H) ppm. MS (ESI+)=421.6 (M),
343.0 (M-79.0).
Example 244
Preparation of P-283
[0835] Synthesis of
1-(2'-Fluoro-3'-hydroxy-6'-methoxy-biphenyl-3-yl)-ethanone (I-218).
A solution of I-216 (500 mg, 2.26 mmol) and 3-acetylphenylboronic
acid (446 mg, 2.72 mmol) in toluene (8 mL) was degassed with a
nitrogen stream. To this solution was added ethanol (1.5 mL) and 2
M aqueous sodium carbonate (2.25 mL, 4.52 mmol), followed by the
addition of tetrakis(triphenylphosphine)palladium(0) (130 mg, 0.113
mmol). The reaction was heated to 100.degree. C. for 24 h. An
additional portion of tetrakis(triphenylphosphine)palladium(0) (130
mg, 0.113 mmol) was added under nitrogen and the reaction was
heated to 100.degree. C. overnight. An additional portion of
3-aceteylphenyl boronic acid (223 mg, 1.36 mmol) was added and the
reaction heated to 100.degree. C. an additional 24 hours. The
reaction was diluted with ethyl acetate (50 mL) and water (50 mL),
filtered, and the layers separated. The aqueous layer was extracted
with ethyl acetate (50 mL) and the organic extracts combined. The
organic solution was washed with water (2.times.100 mL), saturated
aqueous sodium bicarbonate (100 mL), brine (50 mL), dried over
sodium sulfate, filtered and the solvent removed under vacuum. The
product was purified by flash silica gel column chromatography
(0-5% acetone in dichloromethane) to give I-218 (280 mg, 48% yield)
as a brown solid.
[0836] 1H NMR (400 MHz, CDCl.sub.3) 8.01 (m, 1H), 7.97 (dt, J=7.9
Hz, 1.5 Hz, 1H), 7.62 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.54 (t, J=7.0
Hz, 1H), 6.99 (t, J=9.2 Hz, 1H), 6.69 (dd, J=9.2 Hz, 2.0 Hz, 1H),
4.81 (d, J=4.4 Hz, 1H), 3.73 (s, 3H), 2.63 (s, 3H) ppm.
[0837] Synthesis of
1-[2'-Fluoro-6'-methoxy-3'-(4-nitro-phenoxy)-biphenyl-3-yl]-ethanone
(I-220). A solution of I-218 (275 mg, 1.06 mmol) and
4-iodonitrobenzene (264 mg, 1.06 mmol) in N-methylpyrrolidone (5.5
mL) was degassed with a nitrogen stream for 1 min. To the solution
was added cesium carbonate (689 mg, 2.11 mmol), copper(I) chloride
(52.3 mg, 0.528 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (48.6
mg, 0.264 mmol), and the reaction was heated to 90.degree. C. for
18 h. The reaction was cooled to room temperature and the solvent
was removed under vacuum. The residue was taken up in ethyl acetate
(20 mL), washed with water (20 mL), the aqueous wash extracted with
ethyl acetate (20 mL), and the organic extracts combined. The
organic extracts were washed with water (2.times.40 mL), 1 N
aqueous sodium hydroxide (40 mL), 1 N aqueous hydrochloric acid
(2.times.40 mL), and brine (50 mL). The solvent was dried over
sodium sulfate, filtered, and removed under vacuum to give a brown
solid. The residue was purified by flash silica gel column
chromatography (I-5% acetone in dichloromethane) followed by flash
silica gel column chromatography (30% ethyl acetate in hexanes) to
give I-220 (78.4 mg, 19% yield). 1H NMR (400 MHz, CDCl.sub.3)
8.23-8.20 (m, 2H), 8.02 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.60 (m,
1H), 7.55 (t, J=7.8 Hz, 1H), 7.20 (t, J=9.0 Hz, 1H), 7.05-7.02 (m,
2H), 6.84 (dd, J=9.2 Hz, 1.6 Hz, 1H), 3.83 (s, 3H), 2.63 (s, 3H)
ppm.
[0838] Synthesis of
4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-yloxy)-phenyl-amine
hydrochloride salt (P-283). A suspension of I-220 (75.0 mg, 0.197
mmol), ammonium chloride (53.5 mg, 1.00 mmol), and iron powder
(38.5 mg, 0.690 mmol) in ethanol (0.8 mL) and water (0.25 mL) was
purged with nitrogen and stirred under nitrogen for 4 h at
85.degree. C. The solvent was removed under vacuum and the residual
material was suspended in ethyl acetate (50 mL). The organic
suspension was washed with water (50 mL), the aqueous layer was
extracted with ethyl acetate (50 mL), and the organic solutions
combined. The combined extracts were washed with water (2.times.50
mL) and brine (50 mL), dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The residue was dissolved in diethyl
ether (2 mL), and 2 N hydrogen chloride in diethyl ether (400 uL)
was added. The reaction was stirred for 1 h and filtered to give
P-283 (57.0 mg, 75% yield) as a white powder.
[0839] 1H NMR (400 MHz, DMSO-d.sub.6) d: 7.98 (dt, J=7.3 Hz, 1.5
Hz, 1H), 7.93 (s, 1H), 7.66-7.59 (m, 2H), 7.34-7.29 (m, 3H),
7.09-7.03 (m, 3H), 3.77 (s, 3H), 2.60 (s, 3H) ppm. MS (ESI+)=352.9
(M+1)
##STR00331##
Example 245
Preparation of I-223
[0840] Synthesis of 3-Bromo-2-fluoro-4-methoxy-benzaldehyde using
titanium(IV) chloride (I-30). A solution of 2-bromo-3-fluoroanisol
(5.00 g, 24.3 mmol) in dichloromethane (120 mL) was cooled to
0.degree. C. in a salt-ice bath and purged with nitrogen. The
reaction was allowed to stir 15 min under nitrogen. To the reaction
was added titanium(IV) chloride (23.1 g, 122 mmol), followed by
.alpha.,.alpha.-dichloromethyl-methyl ether (4.21 g, 36.6 mmol) at
0.degree. C. under nitrogen. The reaction was allowed to warm to
room temperature and stirred for 22 h. The red solution was poured
into ice water (600 mL), and extracted into dichloromethane
(3.times.200 mL). The organic extracts were combined, washed with
saturated aqueous sodium bicarbonate (2.times.400 mL), water
(2.times.400 mL), and brine (400 mL), dried over sodium sulfate,
filtered, and the solvent was removed under vacuum. The product was
dried in a vacuum oven at 80.degree. C. overnight to give I-30
(5.75 g, quantitative yield). 1H NMR (400 MHz, CDCl.sub.3) 10.22
(s, 1H), 7.86 (dd, J=8.8 Hz, 7.6 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H),
4.01 (s, 3H) ppm.
[0841] Synthesis of (3-Bromo-2-fluoro-4-methoxy-phenyl)-methanol
(I-31). A suspension of I-30 (5.20 g, 22.3 mmol) in tetrahydrofuran
(40 mL) and water (40 mL) was cooled to 0.degree. C. and sodium
borohydride (2.53 g, 66.9 mmol) was added portionwise. The reaction
was stirred for 3.5 h allowing the reaction to warm to room
temperature. The tetrahydrofuran was removed under vacuum, water
was added (100 mL) and the resultant solid was extracted into ethyl
acetate (2.times.200 mL). The combined extracts were washed with
water (2.times.200 mL), brine (200 mL), dried over sodium sulfate,
filtered, and the solvent removed under vacuum to give I-31 (4.82
g, 92% yield) as a white powder. 1H NMR (400 MHz, CDCl.sub.3) 7.32
(t, J=8.4 Hz, 1H), 6.71 (dd, J=8.4 Hz, 1.6 Hz, 1H), 4.72 (d, J=6.0
Hz, 2H), 3.92 (s, 3H), 1.70 (t, J=6.0 Hz, 1H) ppm.
[0842] Synthesis of
1-(2'-Fluoro-3'-hydroxymethyl-6'-methoxy-biphenyl-3-yl)-ethanone
[0843] (I-222). A solution of I-31 (4.00 g, 17.0 mmol),
3-acetylphenylboronic acid (3.07 g, 18.7 mmol) in ethanol (17.5
mL), water (17.5 mL) and 1,4-dioxane (35 mL) was degassed with a
nitrogen stream for 30 min. To the solution was added potassium
carbonate (7.06 g, 51.1 mmol), triphenylphosphine (1.34 g, 5.11
mmol), and palladium(II) acetate (382 mg, 1.70 mmol), and the
reaction was stirred under nitrogen for 10 min. The reaction was
heated to 85.degree. C. for 4 h under nitrogen, and additional
palladium(II) acetate (191 mg, 0.851 mmol) and triphenylphosphine
(700 mg, 2.55 mmol) were added. Heating with stirring was continued
for 4 h, the reaction was cooled to room temperature, and ethyl
acetate (300 mL) was added. The reaction was washed with water (300
mL), sodium chloride was added (.about.1 g) and the aqueous wash
was extracted with ethyl acetate (300 mL). The organic extracts
were combined, washed with water (500 mL) and brine (500 mL), dried
over sodium sulfate, decolorized with activated charcoal, filtered,
and the solvent was removed under reduced pressure. The crude
product was purified by flash silica gel column chromatography (50%
ethyl acetate in hexanes) to give pure I-222 (700 mg, 15% yield).
1H NMR (400 MHz, CDCl.sub.3) 8.00-8.00 (m, 1H), 7.97 (dt, J=7.9 Hz,
1.6 Hz, 1H), 7.61 (dd, J=6.2 Hz, 1.4 Hz, 1H), 7.53 (t, J=7.6 Hz,
1H), 7.38 (t, J=8.6 Hz, 1H), 6.80 (dd, J=8.8 Hz, 1.2 Hz, 1H), 4.74
(d, J=6.0 Hz, 2H), 3.79 (s, 3H), 2.63 (s, 3H), 1.74 (t, J=6.0 Hz,
1H) ppm. H)
[0844] Synthesis of Carbonic acid
3'-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester
(I-223). A solution of I-222 (700 mg, 2.55 mmol) and pyridine (429
uL, 6.64 mmol) in tetrahydrofuran (10 mL) was cooled to 0.degree.
C. in an ice water bath. To the solution was added
methylchloroformate (542 uL, 5.61 mmol) under nitrogen. The white
suspension that formed was stirred at room temperature overnight.
The pH was adjusted to 1 by the addition of concentrated aqueous
hydrochloric acid, and the solution was extracted with
dichloromethane (2.times.30 mL). The combined organic extracts were
washed with brine (30 mL), dried over magnesium sulfate, filtered,
and the solvent was removed under vacuum to give I-223 (661.3 mg,
78% yield) as an orange syrup. .sup.1H NMR. (400 MHz, CDCl.sub.3)
7.98-7.95 (m, 2H), 7.61-7.58 (m, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.41
(t, J=8.4 Hz, 1H), 6.79 (dd, J=8.6 Hz, 1.0 Hz, 1H), 5.22 (s, 2H),
3.81 (s, 3H), 3.79 (s, 3H) ppm.
Example 246
Preparation of P-304
##STR00332##
[0846] Synthesis of
4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-benzenesulfinic
acid amide (P-304). A suspension of I-223 (300 mg, 0.928 mmol),
4-amino sulfonylbenzylboronic pinocolate ester (289 mg, 1.02 mmol),
and potassium carbonate (385 mg, 2.78 mmol) in dimethylformamide (2
mL) was purged with nitrogen and allylpalladium chloride dimer
(50.9 mg, 0.139 mmol) and bis(diphenylphosphino) pentane (123 mg,
0.278 mmol) were added. The reaction was heated to 65.degree. C.
overnight. To this reaction was added ethyl acetate (25 mL) and
water (25 mL) and the layers separated. The aqueous layer was
extracted with ethyl acetate (2.times.25 mL), and the organic
extracts were combined and washed with brine (50 mL). The organic
solution was dried over magnesium sulfate, filtered, and the
solvent removed under vacuum. The product was purified by flash
silica gel column chromatography (5% acetone in dichloromethane)
followed by trituration with diethyl ether (25 mL) to give P-304
(117 mg, 30% yield) as a faint yellow powder. .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.99-7.98 (m, 1H), 7.95 (dt, J=7.6 Hz, 1.4 Hz, 1H),
7.86-7.84 (m, 2H), 7.60-7.58 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.38
(d, J=8.4 Hz, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H),
4.74 (s, 2H), 4.04 (s, 2H), 3.77 (s, 3H), 2.62 (s, 3H) ppm.
[0847] LCMS=100.0% purity. MS (APCI+)=414.0 (M+1).
Example 247
Preparation of P-305
##STR00333##
[0849] Synthesis of
4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-benzamide
(P-305). A suspension of I-223 (300 mg, 0.928 mmol),
4-aminocarbonylbenzylboronic acid (190 mg, 1.02 mmol), and
potassium carbonate (385 mg, 2.78 mmol) in dimethylformamide (2 mL)
was purged with nitrogen and allylpalladium chloride dimer (50.9
mg, 0.139 mmol) and bis(diphenylphosphino)pentane (123 mg, 0.278
mmol) were added. The reaction was heated to 65.degree. C.
overnight. To this reaction was added ethyl acetate (25 mL) and
water (25 mL) and the layers separated. The aqueous layer was
extracted with ethyl acetate (2.times.25 mL), and the organic
extracts combined and washed with brine (50 mL). The organic
solution was dried over magnesium sulfate, filtered, and the
solvent removed under vacuum to give crude product. The product was
purified by flash silica gel column chromatography (5-10% acetone
in dichloromethane) followed by trituration with diethyl ether (25
mL) to give P-305 (160 mg, 46% yield) as a white powder. .sup.1H
NMR (400 MHz, CDCl.sub.3) 7.99 (m, 1H), 7.95 (dt, J=7.7 Hz, 1.3 Hz,
1H), 7.75-7.73 (m, 2H), 7.61-7.58 (m, 1H), 7.52 (t, J=7.6 Hz, 1H),
7.32 (d, J=8.4 Hz, 2H), 7.11 (t, J=8.6 Hz, 1H), 6.73 (d, J=8.8 Hz,
1H), 5.97 (br s, 1H), 5.54 (br s, 1H), 4.03 (s, 2H), 3.76 (s, 3H),
2.62 (s, 3H) ppm. LCMS=96.5% purity. MS (APCI+)=378.1 (M+1).
Example 248
Preparation of P-276
##STR00334##
[0851] Synthesis of
4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-benzoic acid
methyl ester (P-276). A suspension of I-223 (300 mg, 0.928 mmol),
4-methoxycarbonyl-benzylboronic acid (184 mg, 1.02 mmol), and
potassium carbonate (385 mg, 2.78 mmol) in dimethylformamide (2 mL)
was purged with nitrogen and allylpalladium chloride dimer (50.9
mg, 0.139 mmol) and bis(diphenylphosphino)pentane (123 mg, 0.278
mmol) were added. The reaction was heated to 65.degree. C.
overnight. To this reaction was added ethyl acetate (5 mL) and
water (5 mL), the layers were filtered through celite, the celite
washed with ethyl acetate (15 mL) and water (15 mL), and the layers
separated. The aqueous layer was extracted with ethyl acetate
(2.times.50 mL), and the organic extracts combined and washed with
brine (100 mL). The organic solution was dried over magnesium
sulfate, filtered, and the solvent removed under vacuum to give
crude product. The product was purified by flash silica gel column
chromatography (25% ethyl acetate in hexanes), followed by a
preparatory silica gel TLC plate (eluting with 25% ethyl acetate in
hexnaes), and trituration with diethyl ether (5 mL) to give P-276
(72.4 mg, 20% yield) as a white powder. .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.99-7.94 (m, 4H), 7.59-7.58 (m, 1H), 7.52 (t, J=7.8
Hz, 1H), 7.30 (d, J=8.80\ Hz, 2H), 7.11 (t, J=8.6 Hz, 1H),
6.74-6.72 (m, 1H), 4.03 (s, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 2.62
(s, 3H) ppm. LCMS=96.6% purity. MS (APCI+)=394.1 (M+2).
Example 249
Preparation of I-226
##STR00335##
[0853] Synthesis of
5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid methyl ester (I-226). A suspension of I-223 (500 mg, 1.50
mmol), 2-methylcarboxypyridine-5-boronic acid pinocol ester (435
mg, 1.65 mmol), and potassium carbonate (624 mg, 4.51 mmol) in
dimethylformamide (3.5 mL) was degassed under a nitrogen stream for
15 min. To this solution was added bis(diphenylphosphino)pentate
(199 mg, 0.451 mmol) and allylpalladium chloride dimer (82.7 mg,
0.226 mmol). The reaction was heated to 65.degree. C. for 50 h. The
reaction was diluted with ethyl acetate (50 mL) and filtered
through celite. To the filtrate was added water (50 mL), and the
layers were separated. The aqueous wash was extracted with ethyl
acetate (2.times.50 mL), and all three organic extracts were
combined and washed with brine (100 mL). The organic solution was
dried over magnesium sulfate, filtered, and the solvent removed
under vacuum. The residue was purified by flash silica gel column
chromatography (5% acetone in dichloromethane) followed by
trituration with diethyl ether (15 mL), filtered, and washed with
diethyl ether (5 mL) to give I-226 (190.6 mg, 32% yield) as a white
powder. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.66 (d, J=2.0 Hz, 1H),
8.06 (d, J=8.0 Hz, 1H), 7.97-7.94 (m, 2H), 7.67 (dd, J=8.2 Hz, 2.2
Hz, 1H), 7.57 (dd, J=7.6 Hz, 1.6 Hz, H), 7.52 (t, J=7.6 Hz, 1H),
7.13 (t, J=8.6 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 4.05 (s, 2H), 4.00
(s, 3H), 3.77 (s, 3H), 2.62 (s, 3H) ppm.
[0854] LCMS=100.0% purity. MS (APCI+)=394.1 (M+1).
Example 250
Preparation of I-224
##STR00336##
[0856] Synthesis of
[4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methyl-carb-
amic acid tert-butyl ester (I-224). To a suspension of I-223 (500
mg, 1.50 mmol) and 4-(tert-butoxycarbonyl-N-methylamino)phenyl
boronic acid (415 mg, 1.65 mmol), and potassium carbonate (624 mg,
4.51 mmol) in dimethylformamide (3.5 mL) was added
bis(diphenylphosphino)pentate (199 mg, 0.451 mmol) and
allylpalladium chloride dimer (82.7 mg, 0.226 mmol) under nitrogen.
The reaction was heated to 85.degree. C. for 29 h. The reaction was
diluted with ethyl acetate (30 mL) and water (30 mL) and filtered
through a Celite plug. The Celite was washed with ethyl acetate
(2.times.20 mL) and water (20 mL), and the layers separated. The
aqueous wash was extracted with ethyl acetate (2.times.50 mL), and
all three organic extracts were combined and washed with water
(2.times.100 mL) and brine (100 mL). The organic solution was dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The residue was purified by flash silica gel column
chromatography (dichloromethane) to give I-224 (624.3 mg, 90%
yield) as a yellow oil which was used as is without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (d, J=1.0 Hz,
1H), 7.95 (dt, J=7.7 Hz, 1.3 Hz, 1H), 7.60 (dd, J=7.6 Hz, 1.2 Hz,
1H), 7.52 (t, J=7.6 Hz, 1H), 7.19-7.09 (m, 5H), 6.72 (d, J=8.4 Hz,
1H), 3.95 (s, 2H), 3.75 (s, 3H), 2.62 (s, 3H), 1.45 (s, 9H) ppm.
LCMS=94.1% purity. MS (APCI+)=364.1 (M-100).
Example 251
Preparation of P-328
##STR00337##
[0858] Synthesis of
5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid (I-228). A solution of I-226 (150 mg, 0.381 mmol) in
tetrahydrofuran (1 mL), methanol (1 mL), water (1 mL) and 1 N
aqueous sodium hydroxide (0.763 mL) was stirred at room temperature
for 18 h. Approximately one half of the solvent was removed under
vacuum. The remaining solution was adjusted to pH 3 by addition of
glacial acetic acid. The suspension was extracted with
dichloromethane (10 mL), water (5 mL) was added to the wash, and
the aqueous wash was extracted with additional dichloromethane
(2.times.10 mL). All three organic extracts were combined, dried
over magnesium sulfate, filtered, and the solvent was removed under
vacuum, and the residue was dried under high vacuum for 24 h. The
resultant beige syrup crystallized in diethyl ether (5 mL), stirred
for 30 min, filtered, and washed with hexanes (2.times.2 mL) to
give I-226 (90.6 mg, 63% yield) as a white powder.
[0859] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.62 (d, J=2.0 Hz, 1H),
7.99-7.94 (m, 2H), 7.87 (s, 1H), 7.78 (dd, J=7.8 Hz, 2.2 Hz, 1H),
7.58 (d, J=5.2 Hz, 2H), 7.39 (t, J=8.8 Hz, 1H), 6.98 (d, J=8.4 Hz,
1H), 4.08 (s, 2H), 3.73 (s, 3H), 2.588 (s, 3H) ppm. LCMS=100.0%
purity (APCI+). MS (APCI+)=424.1 (M+45), 380.0 (M+1).
[0860] Synthesis of
5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid amide (P-328). A solution of I-228 (50.0 mg, 0.184 mmol) in
toluene (2 mL) was stirred under nitrogen. To this reaction was
added thionyl chloride (65.7 mg, 0.552 mmol) and the reaction was
heated to 100.degree. C. for 2 h over which time it turned from
colorless to a deep red. The solvent and excess thionyl chloride
was removed under reduced pressure and the residue was dissolved in
tetrahydrofuran (2 mL). To the solution was then added aqueous
ammonium hydroxide (40 uL). The reaction was stirred at room
temperature for 1 h. The reaction was diluted with ethyl acetate
(30 mL) and washed with saturated aqueous sodium bicarbonate (30
mL). The aqueous wash was extracted with ethyl acetate (30 mL) and
the organic extracts were combined. The combined extracts were
washed with saturated aqueous sodium bicarbonate (25 mL), dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The residue was purified by preparatory silica gel TLC
(eluting with 12.5% acetone in dichlormethane, 3 developments) to
give P-328 (12.6 mg, 18% yield) as a white powder. .sup.1H NMR.
(400 MHz, CDCl.sub.3) 8.47 (d, J=2.0 Hz, 1H), 8.13 (d, J=8.0 Hz,
1H), 7.98-7.94 (m, 2H), 7.78 (s, 1H), 7.69 (dd, J=8.0 Hz, 2.0 Hz,
1H), 7.96-7.58 (m, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.14 (t, J=8.6 Hz,
1H), 6.76 (d, J=8.4 Hz, 1H), 5.48 (s, 1H), 4.05 (s, 3H), 3.77 (s,
3H), 2.62 (s, 3H) ppm. LCMS=95.9% purity.
[0861] MS (APCI+)=379.1 (M+1).
Example 252
Preparation of P-324
##STR00338##
[0863] Synthesis of 2-Bromo-6-methoxy-4-nitro-phenylamine (I-229).
Into a 2 L round bottom flask with a stir bar was added
2-methoxy-4-nitro-phenylamine (50.0 g, 297.4 mmol), CH.sub.3CN (1
L), and NBS (53.5 g, 297.4 mmol). The reaction was stirred at room
temperature for 2 hours while protected from light. The reaction
was concentrated and then 500 mL water was added. The product was
extracted with ethyl acetate and concentrated. The solid which
precipitated from the aqueous washes was combined with the solid
which resulted from the organic concentration to give I-229 (59.6
g) which was used without further purification.
##STR00339##
[0864] Synthesis of 1-Bromo-3-methoxy-5-nitro-benzene (I-230). Into
a 2 L round-bottomed flask equipped with a mechanical stirrer was
added I-229 (59.8, 249.2 mmol), ethanol (167 mL), water (83 mL),
and the mixture was cooled to 0.degree. C. H.sub.2SO.sub.4 (750 mL)
was added followed by NaNO.sub.2 (25.8 g, 373.8 mmol) in 75 mL
water. The reaction was stirred at 0.degree. C. for 15 minutes,
room temperature for 30 minutes, and 60.degree. C. for 15 minutes,
after which it was cooled to room temperature and filtered. The
solids were washed with water, dried in a 40.degree. C. vacuum oven
for 1 hour, then a vacuum dessicator for 5 days. After drying for
an additional 6 hours in a 60.degree. C. vacuum oven, 47.3 g (84%)
of I-230 was obtained as a rust-colored solid.
##STR00340##
[0865] Synthesis of
3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol
(I-232). Into a 250 mL round bottom flask was placed I-231 (2.03 g,
9.31 mmol), bis(piniacolato)diboron (2.60 g, 10.24 mmol), KOAc
(2.74 g, 27.93 mmol), and 50 mL dioxane. After degassing with
N.sub.2 for 10 minutes, PdCl.sub.2dppf-CH.sub.2Cl.sub.2 (0.38 g,
0.47 mmol) was added and the reaction was stirred at 90.degree. C.
for 20 hours. Most of the solvent was removed by rotary evaporation
and brine was added. The product was extracted with ethyl acetate
and the organics were filtered through Celite and concentrated. The
residue was purified by flash column chromatography eluting with
20% ethyl acetate/hexanes to afford 1.44 g (58%) of I-232.
##STR00341##
[0866] Synthesis of
3-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-5-nitro-phenol
(I-233). Into a 40 mL vial with a stir bar was added I-33 (597 mg,
1.81 mmol), I-232 (480 mg, 1.81 mmol), NaHCO.sub.3 (456 mg, 5.43
mmol), DME (10 mL), ethanol (1 mL), and water (1 mL). After
degassing for 10 minutes, tetrakis(triphenylphosphine)palladium(0)
(208 mg, 0.18 mmol) was added and the reaction was stirred at
65.degree. C. for 18 hours. The reaction was cooled to room
temperature and diluted with 10 mL water. The product was extracted
with ethyl acetate, dried over Na.sub.2SO.sub.4, and concentrated.
Flash column chromatography purification of the residue with 15-20%
ethyl acetate/hexanes afforded 175 mg (25%) of I-233 as a yellow
oil.
##STR00342##
[0867] Synthesis of
3-Amino-5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenol
(P-324). Into a 40 mL vial was added I-233 (175 mg, 0.39 mmol), Fe
powder (89 mg, 1.35 mmol), NH.sub.4Cl (120 mg, 1.93 mmol), water (1
mL), and ethanol (3 mL). The suspension was stirred at 80.degree.
C. for 2 hours, then filtered through Celite. The filtrate was
diluted with ethyl acetate and washed with water and brine. After
concentrating the organics, the residue was purified by flash
column chromatography eluting with 20-50% ethyl acetate/hexanes to
give 104 mg (65%) of P-324 as a colorless oil. .sup.1H NMR (400
MHz, CDCl.sub.3) 7.40 (s, 1H), 7.38-7.27 (m, 3H), 7.11 (t, J=8.6
Hz, 1H), 6.74-6.61 (m, 2H), 6.12 (d, J=17.4 Hz, 2H), 6.04 (t, J=1.9
Hz, 1H), 3.80 (s, 2H), 3.75 (s, 3H), 3.63 (br s, 2H) ppm.
LC/MS=97.7%, 358.2 (APCI+).
Example 253
Preparation of P-331 and P-338
##STR00343##
[0869] Synthesis of
[4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methyl-amin-
e hydrochloride (P-331). To a solution of I-224 (485 mg, 1.05 mmol)
in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL)
dropwise and the reaction was allowed to stir at room temperature
for 4 h. The solvent was removed under vacuum, and the residue was
dissolved in ethyl acetate (20 mL) and water (10 mL). The pH of the
aqueous layer was adjusted to 8 using solid sodium bicarbonate. The
layers were separated and the organic solution was washed with
brine. The organic extract was dried over sodium sulfate and the
solvent was removed under vacuum. The residue was dried under high
vacuum overnight to give the free base. A portion of the free base
(44.5 mg) was dissolved in diethyl ether (2 mL). To the solution
was added 2 N hydrogen chloride in diethyl ether (184 uL, 0.367
mmol) dropwise, and the reaction was stirred at room temperature
for 3 h. The resultant solid was filtered and dried under vacuum in
an abderhaulden apparatus under acetone at reflux to give P-331
(28.8 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (m, 1H), 7.86
(s, 1H), 7.58 (d, J=5.2 Hz, 1H), 7.26 (t, J=8.8 Hz, 1H), 7.09 (d,
J=8.4 Hz, 2H), 6.93 (d, J=9.2 Hz, 1H), 6.77 (br m, 2H), 3.84 (s,
2H), 3.71 (s, 3H), 2.72 (s, 3H), 2.59 (s, 3H) ppm.
[0870] LCMS=94.4% purity. MS (APCI+)=364.1 (M+1).
[0871] Synthesis of
1-[4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-1-methyl--
urea (P-338). A suspension of P-331 free base (180 mg, 0.495 mmol)
in glacial acetic acid (1 mL) and water (1 mL) was stirred until a
solution formed. To the solution was added a solution of potassium
cyanate (120 mg, 1.49 mmol) in water (250 uL), and the solution
became cloudy. The reaction was stirred at room temperature for 2.5
h. The reaction was diluted with diethyl ether (10 mL) and water (5
mL) and the layers separated. The organic extract was washed with
saturated aqueous sodium bicarbonate (10 mL), dried over sodium
sulfate, filtered, and the solvent removed under vacuum. The
residue was dissolved in diethyl ether (30 mL), washed with
saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL),
dried over sodium sulfate, filtered, and the solvent was removed
under vacuum. The residue was purified by preparatory silica TLC
(10% acetone in dichloromethane, 2 developments), and dried
overnight in a vacuum oven at 40.degree. C. to give P-338 (96.1 mg,
48% yield) as a white powder. 1H NMR (400 MHz CDCl.sub.3) d: 8.00
(d, J=1.2 Hz, 1H), 7.95 (dt, J=7.7 Hz, 1.4 Hz, 1H). 7.61 (dd, J=7.6
Hz, 1.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H),
7.22-7.14 (m, 3H), 6.75 (d, J=8.4 Hz, 1H), 4.34 (brs, 2H), 3.98 (s,
2H), 3.76 (s, 3H), 3.24 (s, 3H), 2.62 (s, 3H). LCMS=96.1%
purity.
[0872] MS (APCI+)=407.1 (M+1).
##STR00344## ##STR00345##
Example 254
Preparation of P-277
[0873] Synthesis of
1-[3'-(6-Amino-pyridin-3-ylmethyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]-et-
hanone (P-277). A solution of I-223 (1.00 g, 3.01 mmol) and
2-aminopyridine-5-boronic acid pinacol ester (728 mg, 3.31 mmol) in
N,N-dimethylformamide (8 mL) was degassed using a nitrogen stream
for 10 min. To the solution was added potassium carbonate (1.25 g,
9.03 mmol), allylpalladium(II) chloride dimer (165 mg, 0.451 mmol),
and bis(diphenylphosphino)pentane (398 mg, 0.903 mmol) under
nitrogen and the suspension was stirred at 65.degree. C. under
nitrogen for 15 h. To the reaction was added ethyl acetate (50 mL)
and water (50 mL) and the biphasic suspension was filtered through
celite (.about.15 g). The celite was washed with ethyl acetate
(2.times.20 mL), and water (2.times.20 mL) and the filtrate was
separated. The aqueous layer was extracted with ethyl acetate (100
mL) and the organic extracts were combined. The organic solution
was washed with water (200 mL) and brine (200 mL), dried over
sodium sulfate, filtered, and the solvent removed under vacuum. The
residue was purified by flash silica gel column chromatography
(impurities eluted with 50% ethyl acetate in hexanes, product
eluted with 12.5% acetone in dichloromethane) to give P-277 (653
mg, 62% yield) as an orange oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
7.99 (m, 1H), 7.95 (dt, J=7.73 Hz, 1.6 Hz, 1H), 7.61-7.59 (m, 1H),
7.52 (t, J=7.6 Hz, 1H), 7.30 (dd, J=8.2 Hz, 2.2 Hz, 1H), 7.09 (t,
J=8.6 Hz, 1H), 6.71 (dd, J=8.4 Hz, 0.8 Hz, 1H), 6.46 (d, J=8.8 Hz,
1H), 4.33 (s, 2H), 3.83 (s, 2H), 3.75 (s, 3H), 2.62 (s, 3H).
LCMS=100.0% purity.
[0874] MS (APCI+)=351.1 (M+1).
Example 255
Preparation of P-361
[0875] Synthesis of
1-[5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-3-(-
2-chloro-ethyl)-urea (I-237). A solution of P-277 (300 mg, 0.856
mmol) in chloroform (7.4 mL) was purged with nitrogen for 5 min at
room temperature. To this solution was added
2-chloroethylisocyanate (90.3 mg, 0.856 mmol), and the reaction was
stirred at reflux for 24 h. Additional 2-chloroethylisocyanate (220
uL, 2.57 mmol) was added and the reaction was heated at reflux for
an additional 16 h. The solvent was removed under vacuum and the
resultant red syrup was purified by flash silica gel column
chromatography (0-25% acetone in dichoromethane) followed by
preparatory thin layer chromatography to give I-237 (41.7 mg, 11%
yield) as a yellow oil.
[0876] Synthesis of
1-[5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-imi-
dazolidin-2-one (P-361). A suspension of I-237 (40.0 mg, 0.0877
mmol) and sodium carbonate (27.9 mg, 0.263 mmol) in acetonitrile (1
mL) was stirred at reflux overnight. The reaction was cooled to
room temperature and filtered. The solvent was removed under vacuum
and the resultant yellow oil was crystallized in diethyl ether (2
mL), filtered, washed with hexanes (2.times.1 mL) and dried in a
vacuum oven overnight at 40.degree. C. to give P-361 (17.1 mg, 46%
yield) as an off white powder. .sup.1H NMR (400 MHz, CDCl.sub.3)
8.10 (d, J=1.6 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J=7.8 Hz, 1H),
7.63-7.48 (m, 3H), 7.46-7.39 (m, 1H), 7.14-7.05 (m, 1H), 6.97 (d,
J=8.3 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 4.42 (t, J=7.9 Hz, 2H), 3.89
(s, 2H), 3.82 (t, J=7.9 Hz, 2H), 3.75 (s, 3H), 2.62 (s, 3H)
ppm.
[0877] LCMS=91.4% purity. MS (APCI+)=420.1 (M+1).
Example 256
Preparation of P-355
##STR00346##
[0879] Synthesis of
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
(I-238). Into a 250 mL round-bottomed flask was added 3.0 g of
5-bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol),
bis(piniacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74
mmol), and DMSO (100 mL). After degassing for 20 minutes,
PdCl.sub.2dppf-CH.sub.2Cl.sub.2 (1.39 g, 1.64 mmol) was added and
the solution was stirred for 24 hours at 80.degree. C., and then at
room temperature for 3 days. 50 mL water was added and the product
was extracted with ethyl acetate. The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated. The
dark-colored residue was purified by flash column chromatography
eluting with 20% acetone/hexanes to give a red solid. The solid was
triturated with hexane to give 1.72 g (46%) of I-238 as a
light-pink solid.
##STR00347##
[0880] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-carbamic acid tert-butyl ester (P-355). Into a 20 mL vial was
added I-33 (401 mg, 1.22 mmol), I-238 (336 mg, 1.46 mmol),
K.sub.2CO.sub.3 (504 mg, 3.65 mmol), DME (5 mL), water (0.5 mL),
ethanol (0.5 mL), and the suspension was degasses for 15 minutes.
Tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.12 mmol) was
added and the reaction stirred at 80.degree. C. for 16 hours. The
reaction was diluted with water and extracted with ethyl acetate.
The organics were concentrated and purified by flash column
chromatography eluting with 15-20% ethyl acetate/hexanes to afford
P-355 (64 mg, 15%) as a light-yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.62 (br s, 1H), 7.68-7.56 (m, 2H), 7.40-7.30
(m, 3H), 7.26-7.21 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 6.75 (d, J=8.3
Hz, 1H), 4.03 (br s, 2H), 3.78 (s, 3H) ppm. LC/MS=98.5%, 353.0
(APCI+).
Example 257
Preparation of P-344
##STR00348##
[0882] Synthesis of
C-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-met-
hylamine (P-344). Into a 100 mL round bottom flask was added P-355
(0.55 g, 1.56 mmol), methanol (20 mL), concentrated HCl (0.65 mL,
7.79 mmol), and 10% Pd/C (100 mg). The suspension was stirred under
a H.sub.2 balloon for 18 hours, then filtered through Celite. The
filtrate was concentrated. To the solid was added 1N aqueous NaOH
and the product was extracted with dichloromethane. The
dichloromethane was concentrated and purified by flash column
chromatography eluting with 5-10% methanol/dichloromethane to give
P-344 (89 mg, 16%) as a colorless oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.55 (d, J=1.2 Hz, 1H), 8.32 (br s, 3H), 7.71 (dd,
J=1.9, 7.9 Hz, 1H), 7.50-7.37 (m, 3H), 7.36 (d, J=5.4 Hz, 2H), 7.27
(d, J=6.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.75 (br s, 2H), 4.14
(q, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.73 (s, 3H) ppm. LC/MS=95.1%,
357.1 (APCI+).
Example 258
Preparation of P-367
##STR00349##
[0884] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-carbamic acid ethyl ester (P-367). Into an 8 mL vial was added
P-344 (43 mg, 0.12 mmol), dichloromethane (2 mL), triethylamine (33
uL, 0.24 mmol). The solution was cooled to 0.degree. C. and ethyl
chloroformate (20 mg, 0.18 mmol) was added. After 15 minutes at
room temperature the solution was concentrated. The residue was
purified by flash column chromatography eluting with 40-60% ethyl
acetate to give 23 mg (54%) of P-367 as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) 8.39 (d, J=1.5 Hz, 1H), 7.63 (t, J=6.0 Hz,
1H), 7.59 (dd, J=1.7, 8.1 Hz, 1H), 7.50-7.40 (m, 2H), 7.37 (s, 1H),
7.33 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.6 Hz, 1H), 7.20 (d, J=7.9 Hz,
1H), 6.94 (d, J=8.6 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 4.03-3.96 (m,
2H), 3.94 (s, 2H), 3.72 (s, 3H), 1.16 (t, J=7.1 Hz, 3H) ppm.
[0885] LC/MS=100.0%, 429.1 (APCI+).
Example 259
Preparation of P-368
##STR00350##
[0887] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-urea (P-368). Into an 8 mL vial was added P-344 (43 mg, 0.12
mmol), dichloromethane (2 mL), and trimethylsilyl isocyanate (49
uL, 0.36 mmol). After 1 hour at 35.degree. C., the solution was
concentrated. The resulting solid was triturated with ether to
afford P-368 (25 mg, 52%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.44 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.48-7.40 (m,
2H), 7.37 (s, 1H), 7.34 (t, J=8.9 Hz, 1H), 7.28 (d, J=7.6 Hz, 2H),
6.94 (d, J=8.6 Hz, 1H), 6.51 (br s, 1H), 5.64 (br s, 2H), 4.25 (d,
J=5.0 Hz, 2H), 3.97 (s, 2H), 3.72 (s, 3H). LC/MS=96.4%, 400.1
(APCI+).
Example 260
Preparation of P-371
##STR00351##
[0889] Synthesis of
3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-1,1-dimethyl-urea hydrochloride (P-371). Into an 8 mL vial was
added P-344 (23 mg, 0.064 mmol), dichloromethane (1.5 mL),
triethylamine (18 uL, 0.13 mmol) and the solution was cooled to
0.degree. C. Dimethylcarbamyl chloride (9 uL, 0.097) was added and
the reaction stirred for 18 hours at room temperature. The
dichloromethane solution was washed with water and brine, and then
concentrated. The residue was purified by flash column
chromatography eluting with 5% methanol/dichloromethane. The
colorless oil obtained was triturated with ether to obtain a white
solid. The resulting solid was dissolved in 2 mL of 4.0 M
HCl/dioxane and stirred for 2 hours at room temperature. The oil
was treated with ether to form a solid, which was filtered to
obtain P-371 (6.1 mg, 20%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
8.60 (s, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H),
7.50-7.35 (m, 4H), 7.28 (d, J=6.4 Hz, 1H), 7.11 (br s, 1H), 6.97
(d, J=8.6 Hz, 1H), 4.41 (br s, 2H), 4.08 (s, 2H), 3.73 (s, 3H),
2.82 (s, 6H) ppm. LC/MS=100.0%, 428.1 (APCI+).
Example 261
Preparation of P-372
##STR00352##
[0891] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-3-ethyl-urea (P-372). Into an 8 mL vial was added P-344 (23 mg,
0.064 mmol), dichloromethane (1.5 mL), and the solution was cooled
to room temperature. Ethyl isocyanate (8 uL, 0.097 mmol) was added
and the reaction was stirred for 18 hours at room temperature and
then concentrated. To the resulting solid was added 4.0 M
HCl/dioxane and the solution was stirred for 18 hours at room
temperature and then concentrated. The oil which was obtained was
treated with ether to form a solid, which was filtered to afford
P-372 (15.1 mg, 50%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.63 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.63 (d, J=8.2
Hz, 1H), 7.51-7.33 (m, 4H), 7.28 (d, J=6.3 Hz, 1H), 6.98 (d, J=8.6
Hz, 1H), 6.62 (br s, 1H), 6.31 (br s, 1H), 4.42 (s, 2H), 4.10 (s,
2H), 3.74 (s, 3H), 3.01 (q, J=7.1 Hz, 2H), 0.99 (t, J=7.1 Hz, 3H)
ppm. MS: 428.1 (APCI+).
Example 262
Preparation of P-373
##STR00353##
[0893] Synthesis of 4-Methyl-piperazine-1-carboxylic acid
[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-amide (P-373). Into an 8 mL vial was added P-344 (23 mg, 0.064
mmol), dichloromethane (1.5 mL), triethylamine (18 uL, 0.13 mmol).
The solution was cooled to 0.degree. C. and
4-methyl-piperazine-1-carbonyl chloride (10 mg, 0.097 mmol) was
added. After 18 hours at room temperature the reaction was washed
with water, followed by brine. The organics were concentrated and
purified by flash column chromatography eluting with 5-10%
methanol/dichloromethane to afford 28 mg of semi-solid. The
semi-solid was dissolved in 2 mL of 4.0M HCl/dioxane and stirred at
room temperature for 18 hours, and then concentrated. Ether was
added and a solid formed, which was filtered. To the solid was
added 5N aqueous NaOH and the product was extracted with
dichloromethane and then concentrated. Purification of the residue
by flash column chromatography eluting with 10%
methanol/dichloromethane afforded P-373 (9.6 mg, 31%) as a
colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.38 (d, J=1.5
Hz, 1H), 7.57 (dd, J=2.0, 8.1 Hz, 1H), 7.48-7.39 (m, 2H), 7.37 (s,
1H), 7.32 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 7.17 (d, J=8.1
Hz, 1H), 7.09 (t, J=5.8 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.26 (d,
J=5.6 Hz, 2H), 3.93 (s, 2H), 3.72 (s, 3H), 3.17 (d, J=5.2 Hz, 4H),
2.29-2.20 (m, 4H), 2.16 (s, 3H) ppm. LC/MS=100.0%, 483.1
(APCI+).
Example 263
Preparation of P-374
##STR00354##
[0895] Synthesis of
1-(2-Chloro-ethyl)-3-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl-
)-pyridin-2-ylmethyl]-urea (I-239). Into an 8 mL vial was added
P-344 (63 mg, 0.177 mmol), dichloromethane (2 mL), and the reaction
was cooled to 0.degree. C. Chloroethyl isocyanate (19 mg, 0.177
mmol) was added and the reaction was stirred at room temperature
for 1 hour and then concentrated to yield I-239 which was used as
is.
##STR00355##
[0896] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-imidazolidin-2-one (P-374). Into an 8 mL vial was added I-239
(82 mg, 0.177 mmol), THF (2 mL), and the suspension was cooled to
0.degree. C. Sodium hydride (8 mg, 0.212 mmol) was added and the
reaction was stirred at room temperature for 3 days. An additional
4 mg of sodium hydride was added and the reaction was stirred at
50.degree. C. for 1 hour. Water was added and the product was
extracted with ethyl acetate. The organics were concentrated and
purified by flash column chromatography eluting with 25-50%
acetone/dichloromethane to give P-374 (35 mg, 47%, 2 steps) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.42 (d, J=1.5 Hz,
1H), 7.60 (dd, J=1.9, 7.9 Hz, 1H), 7.49-7.39 (m, 2H), 7.37 (s, 1H),
7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.7 Hz, 1H), 7.19 (d, J=7.9 Hz,
1H), 6.94 (d, J=8.6 Hz, 1H), 6.41 (s, 1H), 4.28 (s, 2H), 3.95 (s,
2H), 3.72 (s, 3H), 3.31-3.19 (m, 4H) ppm. LC/MS=100.0%, 426.1
(APCI+).
Example 264
Preparation of P-375
##STR00356##
[0898] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-3-methyl-imidazolidin-2-one (P-375). Into an 8 mL vial was added
P-374 (21 mg, 0.05 mmol), THF (1 mL) and the solution was cooled to
0.degree. C. Sodium hydride (3 mg, 0.076 mmol) was added and after
15 minutes at room temperature, methyl iodide (6 uL, 0.101 mmoL)
was added. The reaction was stirred for 30 minutes at room
temperature and then 1 mL of water was added. The THF was
evaporated and the product was extracted with ethyl acetate and
concentrated. The residue was passed through a silica gel plug
eluting with methanol, which afforded P-375 (18.1 mg, 82%) as a
colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.42 (d, J=1.6
Hz, 1H), 7.60 (dd, J=2.0, 7.9 Hz, 1H), 7.50-7.39 (m, 2H), 7.37 (s,
1H), 7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 7.19 (d, J=8.1
Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.31 (s, 2H), 3.95 (s, 2H), 3.72
(s, 3H), 3.24 (s, 4H), 2.67 (s, 3H) ppm. LC/MS=97.8%, 440.1
(APCI+).
Example 265
Preparation of P-520
##STR00357##
[0900] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-carbamic acid phenyl ester (P-520). Into an 18 mL vial was added
P-344 (128 mg, 0.36 mmol), TEA (0.10 mL, 0.72 mmol), and
dichloromethane (3 mL). The solution was cooled to 0.degree. C. and
phenylchloroformate (68 uL, 0.54 mmol) was added. After stirring at
room temperature for 15 minutes the reaction was concentrated.
Purification by flash column chromatography (25%-75% EtOAc/hexanes)
afforded P-520 (102 mg, 59%) as an off-white solid. (400 MHz,
DMSO-d.sub.6) 8.44 (s, 1H), 8.30 (t, J=5.9 Hz, 1H), 7.63 (dd,
J=1.5, 7.9 Hz, 1H), 7.49-7.26 (m, 8H), 7.24-7.17 (m, 1H), 7.12 (d,
J=7.9 Hz, 2H), 6.95 (d, J=8.6 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 3.96
(s, 2H), 3.73 (s, 3H) ppm. LC/MS=100.0%, 477.1 (APCI+).
Example 266
Preparation of P-460
##STR00358##
[0902]
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
lmethyl]-3-methyl-urea hydrochloride (P-460). Into an 8 mL vial was
added P-520 (84 mg, 0.18 mmol), DMSO (2 mL), and 40% aq. MeNH.sub.2
(0.14 mL). After stirring for 30 minutes at room temperature, 5 mL
of water was added. The product was extracted with EtOAc (4.times.2
mL) and the organics were concentrated. The white solid was
triturated with ether to afford the free base compound. To the free
base was added 4N HCl/dioxane (2 mL) and after stirring for 5
minutes at room temperature the solution was concentrated. The
residue was triturated with ether to provide P-460 (42 mg, 53%) as
a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.64 (s, 1H), 8.16
(d, J=7.9 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.51-7.34 (m, 4H), 7.28
(d, J=6.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.80 (br s, 1H), 6.30
(br s, 1H), 4.44 (s, 2H), 4.10 (s, 2H), 3.74 (s, 3H), 2.55 (s, 3H)
ppm. LC/MS=97.5%, 414.0 (APCI+).
Example 267
Preparation of P-461
##STR00359##
[0904]
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
lmethyl]-3-ethyl-imidazolidin-2-one hydrochloride (P-461). Into an
18 mL vial was added P-374 (65 mg, 0.16 mmol), THF (3 mL), and the
solution was cooled to 0.degree. C. NaH (9 mg, 0.23 mmol) was added
and the suspension was stirred at room temperature for 15 minutes.
EtI (25 uL, 0.31 mmol) was added and the reaction was stirred for 1
hour at room temperature. Water was added and the product was
extracted with EtOAc (3.times.3 mL). The organics were washed with
water, brine, and concentrated. To the residue was added 2 mL of 4N
HCl/dioxane. After stirring to dissolve, the solution was
concentrated. The resulting residue was triturated with ether,
filtered, washed with ether, and dried to give P-461 (51 mg, 65%)
as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.63 (br s,
2H), 8.07 (br s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.50-7.33 (m, 4H),
7.29 (d, J=5.8 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 4.51 (s, 2H), 4.09
(br s, 2H), 3.74 (s, 3H), 3.57 (s, 2H), 3.31 (s, 2H), 3.19-3.10 (m,
2H), 1.10-0.97 (m, 3H) ppm. LC/MS=84.2%, 454.2 (APCI+).
Example 268
Preparation of P-462
##STR00360##
[0906]
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1-oxy-pyrid-
in-2-ylmethyl]-3-ethyl-urea (P-462). Into an 18 mL vial was added
P-372 (66 mg, 0.15 mmol), dichloromethane (4 mL), and the solution
was cooled to 0.degree. C. mCPBA (69 mg, 0.31 mmol) was added and
the reaction was stirred at room temperature for 1 hour after which
5 mL of saturated aqueous NaHCO.sub.3 was added. The layers were
separated and the organic layer was washed sequentially with 5 mL
each of saturated aqueous NaHCO.sub.3, H.sub.2O, and brine. The
residue was then washed with 1N NaOH (2.times.5 mL), water (5 mL),
and brine (5 mL). The product was dried over Na.sub.2SO.sub.4,
filtered and concentrated to obtain P-462 (14.8 mg, 22%) as a white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.19 (s, 1H), 7.53-7.34
(m, 4H), 7.29 (d, J=6.6 Hz, 1H), 7.25-7.16 (m, 2H), 6.96 (d, J=8.6
Hz, 1H), 6.38 (t, J=6.0 Hz, 1H), 6.17 (t, J=5.4 Hz, 1H), 4.22 (d,
J=6.2 Hz, 2H), 3.91 (s, 2H), 3.73 (s, 3H), 3.09-2.91 (m, 2H), 0.97
(t, J=7.2 Hz, 3H) ppm. LC/MS=100.0%, 444.1 (APCI+).
Example 269
Preparation of P-463
##STR00361##
[0908]
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1-oxy-pyrid-
in-2-ylmethyl]-imidazolidin-2-one (P-463). Into an 18 mL vial was
added P-374 (62 mg, 0.15 mmol), dichloromethane (4 mL), and the
solution was cooled to 0.degree. C. mCPBA (82 mg, 0.36 mmol) was
added and the reaction was stirred at room temperature for 1 hour
after which 5 mL of aqueous 1N NaOH was added. The layers were
separated and the aqueous layer was extracted with dichloromethane
(2.times.3 mL). The organics were combined and washed with water (5
mL) and brine (5 mL) and then concentrated. The residue was taken
up in 5 mL of EtOAc and it was washed with 5 mL of brine, dried
over Na.sub.2SO.sub.4, and concentrated to a solid. The residue was
triturated with ether to afford P-463 (23.5 mg, 35%) as a white
solid.
[0909] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (s, 1H), 7.49-7.34
(m, 4H), 7.32-7.16 (m, 3H), 6.96 (d, J=8.6 Hz, 1H), 6.56 (s, 1H),
4.31 (s, 2H), 3.93 (s, 2H), 3.73 (s, 3H), 3.45-3.36 (m, 2H),
3.32-3.25 (m, 2H) ppm. LC/MS=93.4%, 442.0 (APCI+).
Example 270
Preparation of P-465
##STR00362##
[0911]
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylm-
ethyl]-carbamic acid 2-chloro-ethyl ester (I-240). Into an 18 mL
vial was added P-344 (100 mg, 0.28 mmol), dichloromethane (4 mL),
TEA (78 uL, 0.56 mmol), and after the solution was cooled to
0.degree. C. 2-Chloroethyl chloroformate (43 uL, 0.42 mmol) was
added. The reaction was stirred at room temperature for 18 hours
and then 5 mL of water was added. The layers were separated and the
aqueous was extracted with 5 mL more dichloromethane. The organics
were combined, washed with 5 mL of water and 5 mL of brine, dried
over Na.sub.2SO.sub.4, and then concentrated. The residue which was
obtained was used as is in the next reaction.
##STR00363##
[0912]
3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
lmethyl]-oxazolidin-2-one hydrochloride (P-465). Into an 18 mL vial
was added I-240 (0.28 mmol), THF (3 mL), and NaH (28 mg, 0.70
mmol). The reaction was stirred at room temperature for 18 hours,
50.degree. C. for 4 hours, and then room temperature for 3 days. To
the reaction was added 5 mL of water and the product was extracted
with EtOAc. The organics were washed with brine and then dried over
Na.sub.2SO.sub.4. The residue was purified by flash column
chromatography eluting with 20%-50% acetone/hexanes. The free base
which was obtained was dissolved in 1 mL of 4N HCl/dioxane and then
concentrated. Compound P-465 was obtained as a tan solid (24.1 mg,
19% for 2 steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.52 (s, 1H),
7.77 (br. s., 1H), 7.49-7.32 (m, 6H), 7.27 (br s, 1H), 6.96 (d,
J=8.6 Hz, 1 H), 4.47 (s, 2H), 4.35-4.24 (m, 2H), 4.01 (s, 2H), 3.73
(s, 3H), 3.57-3.50 (m, 2H) ppm.
[0913] LC/MS=100.0%, 427.1 (APCI+).
Example 271
Preparation of P-521
##STR00364##
[0915]
N-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
lmethyl]-oxalamic acid ethyl ester (I-241). Into an 18 mL vial was
added P-344 (152 mg, 0.43 mmol), TEA (0.11 mL, 0.85 mmol), and
dichloromethane (4 mL). The solution was cooled to 0.degree. C. and
ethyl chlorooxoacetate (71 uL, 0.64 mmoL) was added. After 20
minutes at room temperature the reaction was washed with brine and
the organics were concentrated. The semi-solid was triturated with
1:1 ether:EtOAc, filtered, and washed with EtOAc to provide I-241
(69 mg, 35%) as a gray-blue solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.38 (t, J=6.0 Hz, 1H), 8.41 (s, 1H), 7.59 (dd,
J=4.0, 8.0 Hz, 2H), 7.48-7.25 (m, 8H), 7.22 (d, J=8.1 Hz, 2H), 6.94
(d, J=8.6 Hz, 2H), 4.39 (d, J=6.0 Hz, 2H), 4.32-4.18 (m, 2H), 3.94
(s, 2H), 3.72 (s, 3H), 1.27 (t, J=7.1 Hz, 3H) ppm. LC/MS=97.9%,
457.0 (APCI+).
##STR00365##
[0916]
N-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
lmethyl]-oxalamide (P-521). Into an 8 mL vial was added I-241 (14.8
mg, 0.032 mmol) and 2 mL of 7N NH.sub.3/MeOH. After stirring for 1
hour at room temperature, the solution was concentrated to afford
P-521 (11.9 mg, 87%) as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.15 (t, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.08 (br s,
1H), 7.82 (br s, 1H), 7.59 (dd, J=1.9, 8.1 Hz, 1H), 7.48-7.25 (m,
5H), 7.19 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 4.39 (d, J=6.2
Hz, 2H), 3.94 (s, 2H), 3.72 (s, 3H) ppm. LC/MS=98.9%, 428.0
(APCI+).
Example 272
Preparation of I-145
##STR00366##
[0918] Synthesis of Carbonic acid
3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester
(I-145). A solution of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 3.00
g, 11.3 mmol) in pyridine (2.31 g, 29.3 mmol) and tetrahydrofuran
(40 mL) was cooled to 0.degree. C. in an ice water bath. The
reaction vessel was purged with nitrogen and methyl chloroformate
(2.34 g, 24.8 mmol) was added. The ice bath was removed and the
reaction was stirred at room temperature overnight. The white
suspension was adjusted to pH 2 by addition of 1 N aqueous
hydrochloric acid (.about.25 mL) and the yellow biphasic solution
was diluted with dichloromethane (200 mL) and water (150 mL). The
layers were separated, and the aqueous layer was extracted with
dichloromethane (2.times.100 mL). The dichloromethane extracts were
combined, washed with water (2.times.200 mL) and brine (200 mL),
dried over sodium sulfate, filtered, and the solvent removed under
vacuum to give I-145 (3.84 g, quantitative yield).
[0919] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.41-7.32 (m, 4H),
7.29-7.26 (m, 1H), 6.76 (dd, J=8.40 Hz, 0.80 Hz, 1H), 5.204 (s,
2H), 3.800 (s, 3H), 3.795 (s, 3H) ppm.
[0920] LCMS=98.2% purity. MS (APCI+)=249.0 (M-78), MS (APCI-)=249.0
(M-78).
Example 273
Preparation of P-376
##STR00367##
[0922] Synthesis of 2-(3-chloro-phenyl)-3-methoxy-6-methyl-pyridine
(I-243): To 2-bromo-3-methoxy-6-methylpyridine (0.2 g, 1.0 mmol),
3-chlorophenylboronic acid (1) (0.19 g, 1.2 mmol), PPh.sub.3 (0.13
g, 0.5 mmol), K.sub.2CO.sub.3 (0.06 g, 0.4 mmol) and Pd(OAc).sub.2
(0.03 g, 0.12 mmol) was added dioxane (3 mL), and EtOH-H.sub.2O
(1:1, 1.5 mL). Ar gas was bubbled through the stirred reaction for
5 min. The reaction was stirred at 180.degree. C. for 15 m using
microwave oven (Biotage Intiator II). The reaction was cooled to
room temperature, concentrated, and H.sub.2O and dichloromethane
(40 mL each) were added. The organic layer was separated and the
aqueous layer was extracted with dichloromethane (2.times.25 mL).
The combined organic extracts were dried with Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography using 1:1 dichloromethane-hexanes then
dichloromethane to afford 0.19 g (81%) of I-243 as a viscous
liquid.
[0923] Synthesis of
6-bromomethyl-2-(3-chloro-phenyl)-3-methoxy-pyridine (I-244). To
I-243 (1.02 g, 4.36 mmol) and NBS (0.78 g, 4.36 mmol) in CCl.sub.4
(20 mL) was added benzoylperoxide (0.03 g, 0.12 mmol). The reaction
was stirred at 80.degree. C. under N.sub.2 for 20 h. The reaction
was cooled to room temperature and concentrated. The residue was
dissolved in mixture of dichloromethane and hexanes (1:1, 8 mL) and
purified by silica gel column chromatography using 1:1
dichloromethane-hexanes to afford 0.83 g (61%) of I-244 as a
viscous liquid.
[0924] Synthesis of
{4-[6-(3-chloro-phenyl)-5-methoxy-pyridin-2-ylmethyl]-phenyl}-urea
(P-376). To I-244 (0.31 g, 1.0 mmol),
[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea
(0.39 g, 1.5 mmol), (PPh.sub.3).sub.4Pd (0.12 g, 0.1 mmol) and
K.sub.3PO.sub.4 (0.42 g, 2.0 mmol) was added DME (8 mL), and
EtOH-H.sub.2O (1:1, 4 mL). Ar gas was bubbled through the stirred
reaction for 5 min. The reaction was stirred at 160.degree. C. for
20 m using microwave oven (Biotage Intiator II). The reaction was
cooled to room temperature, concentrated and H.sub.2O and
dichloromethane (50 mL each) were added. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.25 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 3-5% methanol in
dichloromethane than triturated with 1:1 ethyl acetate in hexanes
to afford 0.023 g (6%) of P-376 as off-white solid. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): 8.42 (s, 1H), 7.84-7.93 (m, 2H), 7.4-7.54
(m, 3H), 7.3 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.14 (d,
J=8.0 Hz, 2H), 5.77 (s, 2H), 3.99 (s, 2H), 3.83 (s, 3H) ppm; MS
(APCI+): 368.0 (M+1), LC-MS: 92.5%.
Example 274
Preparation of P-379
##STR00368##
[0926] Synthesis of
5-[6-(3-chloro-phenyl)-5-methoxy-pyridin-2-ylmethyl]-pyridin-2-ylamine
(P-379) To I-244 (0.1 g, 0.32 mmol), 5-(4,4,5,5-tetramethyl
[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.08 g, 0.38 mmol),
(PPh.sub.3).sub.4Pd (0.04 g, 0.03 mmol) and K.sub.3PO.sub.4 (0.14
g, 0.64 mmol) was added DME (3 mL), and EtOH-H.sub.2O (1:1, 1.54
mL). Ar gas was bubbled through the stirred reaction for 5 min. The
reaction was stirred at 150.degree. C. for 20 m using microwave
oven (Biotage Intiator II). The reaction was cooled to room
temperature, concentrated. The residue was purified by prep TLC
using 70% ethyl acetate in hexanes to afford 0.06 g (55%) of P-379
as a viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz): 8.03 (d, J=1.6
Hz, 1H), 7.93-4-7.96 (m, 1H), 7.82-7.86 (m, 1H), 7.34-7.58 (m, 3H),
7.2 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.47 (dd, J=8.4, 0.8
Hz, 1H), 4.35 (s, 2H), 4.01 (s, 2H), 3.84 (s, 3H) ppm; MS (APCI+):
326.1 (M+1), LC-MS: 100%.
Example 275
Preparation of P-386
##STR00369##
[0928] Synthesis of
1-{5-[6-(3-chloro-phenyl)-5-methoxy-pyridin-2-ylmethyl]-pyridin-2-yl}-3-e-
thyl-urea hydrochloride (P-386). To P-379 (0.05 g, 0.15 mmol) in
pyridine (1.5 mL) was added ethylisocyanate (0.033 g, 0.46 mmol).
The reaction was stirred at room temperature for 20 h. Water and
ethyl acetate (20 mL each) were added. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate
(2.times.10 mL). The combined organic extracts were washed with
water (2.times.30 mL), brine (20 mL), dried with Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was dissolved in ether (2
mL), then 2M HCl in ether (0.5 ml) was added, stirred for 1 h. The
ether layer was decanted, triturated with ether (2.times.2 mL),
dried to afford 0.045 g (68%) of P-386 as light yellow solid.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): 10.03 (br s, 1H), 7.84-7.9 (m,
3H), 7.76 (br s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.44-7.5 (m, 2H),
7.34 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 4.08 (s, 2H), 3.85
(s, 3H), 3.15-3.23 (m, 2H), 1.08 (t, J=7.2 Hz, 3H) ppm; MS (APCI+):
397.1 (M+1), LC-MS: 99%, HPLC 97.9% pure.
Example 276
Preparation of P-099
##STR00370##
[0930] Synthesis of
(4-Fluoro-phenyl)-(2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-methanone
(I-246). In an 8 mL vial equipped with a stir bar was placed
nitrobenzene (1.0 mL) and AlCl.sub.3 (92.7 mg, 0.695 mmol). After
stirring for 5 minutes, 4-fluorobenzoyl chloride (83.2 .mu.L, 0.695
mmol) was added and the mixture was allowed to stir for 1 hour at
room temperature. Then, I-81 (150 mg, 0.579 mmol) was added and the
reaction mixture was stirred at room temperature for 19 hours. The
reaction mixture as quenched with water (25 mL) and extracted with
EtOAc (2.times.30 mL). The extractions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated to a yellow
solid. The crude material was triturated with Et.sub.2O (5 mL) and
the solid was collected by suction filtration. After the solid was
washed with Et.sub.2O, 64.5 mg of I-246 was isolated as a light
yellow solid in 30% yield. MS (APCI-): 366.0 (M-1)
##STR00371##
[0931] Synthesis of
3-(4-Fluoro-benzyl)-6-methoxy-3'-nitro-biphenyl-2-ol (P-099) In an
8 mL vial equipped with a stir bar was placed I-246 (60 mg, 0.163
mmol) and triethylsilane (350 .mu.L). The mixture was cooled in an
ice-water bath and then TFA (350 .mu.L) was added. The reaction
mixture was warmed to room temperature and reacted for 17 hours.
After this time period, additional triethylsilane (1.1 mL) and TFA
(1.1 mL) was introduced and the reaction mixture was heated to
60.degree. C. in an oil bath for 24 hours. The reaction mixture was
concentrated by a stream of N.sub.2, quenched with water (20 mL)
and extracted with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by
SiO.sub.2 column chromatography utilizing 15% EtOAc/hexanes as the
eluent to produce 18.9 mg of P-099 as a viscous, tan oil in 33%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.72 (s, 3H), 3.94
(s, 2H), 4.73 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.96-7.00 (m, 2H),
7.01 (d, J=8 Hz, 1H), 7.19-7.22 (m, 2H), 7.63 (t, J=7 Hz, 1H), 7.69
(dt, J=8, 2 Hz, 1H), 8.22-8.26 (m, 2H) ppm.
[0932] MS (APCI-): 352.1 (M-1); LC-MS: 98%.
Example 277
Preparation of P-137
##STR00372##
[0934] Synthesis of
4-(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-carbonyl)-benzonitrile
[0935] (I-247). In an 8 mL vial equipped with a stir bar was placed
nitrobenzene (2.0 mL) and
[0936] AlCl.sub.3 (515 mg, 3.86 mmol). After stirring for 5
minutes, 4-cyanobenzoyl chloride (83.2 .mu.L, 0.695 mmol) was added
and the mixture was allowed to stir for 30 minutes at room
temperature. Then, I-81 (200 mg, 0.771 mmol) was added and the
reaction mixture was stirred at 60.degree. C. for 17 hours. The
reaction was quenched with 1M HCl (4 mL), water was added (20 mL)
and then extracted with dichloromethane (2.times.30 mL). The
organic portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The material began to solidify which
was increased by the addition of hexanes (4 mL). The solid was
collected by suction filtration, washed with hexanes (3.times.1 mL)
to produce 147 mg of I-247 as a light yellow solid in 51% yield. MS
(APCI-): 373.1 (M-1); [0937] LC-MS: 91%.
##STR00373##
[0938] Synthesis of
4-[Hydroxy-(2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-methyl]-benzonitr-
ile (P-137). In an 8 mL vial equipped with a stir bar was placed
I-247 (20 mg, 0.0534 mmol), absolute EtOH (300 .mu.L), anhydrous
THF (400 .mu.L) followed by NaBH.sub.4 (40.5 mg, 1.07 mmol). The
reaction mixture was stirred at room temperature for 17 hours. The
reaction was quenched with water (20 mL) and extracted with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated to produce 12.0 mg of P-137 as an off-white solid in
63% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.01 (d, J=3
Hz, 1H), 3.74 (s, 3H), 6.08 (m, 1H), 6.55 (d, J=8 Hz, 1H), 6.99 (d,
J=9 Hz, 1H), 7.13 (s, 1H), 7.54 (d, J=8 Hz, 2H), 7.59 (t, J=8 Hz,
1H), 7.67 (d, J=8 Hz, 2H), 7.69-7.72 (m, 1H), 8.19-8.22 (m, 1H),
8.26-8.27 (m, 1H) ppm. MS (APCI-) .delta. 375.1 (M-1).
Example 278
Preparation of P-138
##STR00374##
[0940] Synthesis of
4-(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzonitrile
(P-138). In an 8 mL vial equipped with a stir bar was placed I-247
(60 mg, 0.160 mmol) and triethylsilane (600 .mu.L). The reaction
mixture was cooled in an ice-water bath and then TFA (600 .mu.L)
was added. The mixture was heated to 70.degree. C. for 23 hours.
The reaction mixture was concentrated by a stream of N.sub.2
followed by the addition of water (20 mL) and extraction with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by SiO.sub.2 column
chromatography utilizing 25% EtOAc/hexanes as the eluent to produce
21.9 mg of P-138 as a pale yellow solid in 38% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 3.72 (s, 3H), 4.02 (s, 2H), 4.77 (s,
1H), 6.56 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 7.35 (d, J=9 Hz,
2H), 7.57 (d, J=8 Hz, 2H), 7.64-7.70 (m, 2H), 8.24-8.27 (m, 2H)
ppm.
[0941] MS (APCI-): 359.1 (M-1), LC-MS: >99%.
Example 279
Preparation of P-157
##STR00375##
[0943] Synthesis of
(4-Dimethylamino-phenyl)-(2-hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-met-
hanone (I-248). In an 8 mL vial equipped with a stir bar was placed
nitrobenzene (2.5 mL) and AlCl.sub.3 (773 mg, 5.80 mmol). After
stirring for 5 minutes, 4-dimethylamino-benzoyl chloride (533 mg,
2.90 mmol) was added and the mixture was allowed to stir for 30
minutes at room temperature. Then, I-81 (300 mg, 1.16 mmol) was
added and the reaction mixture was stirred at 60.degree. C. for 23
hours. The reaction was quenched with 1M HCl (4 mL), water was
added (20 mL) and then extracted with dichloromethane (2.times.30
mL). The organic portions were combined, washed with brine (30 mL),
dried (MgSO.sub.4) and concentrated. The residue was purified by
SiO.sub.2 column chromatography utilizing 10% EtOAc/hexanes as the
eluent to produce 167 mg of I-248 as a yellow solid in 37%
yield.
##STR00376##
[0944] Synthesis of
3-(4-Dimethylamino-benzyl)-6-methoxy-3'-nitro-biphenyl-2-ol
(P-157). In an 8 mL vial equipped with a stir bar was placed I-248
(165 mg, 0.420 mmol) and triethylsilane (1.6 mL). The reaction
mixture was cooled in an ice-water bath and then TFA (1.6 mL) was
added. The mixture was heated to 65.degree. C. for 17 hours. The
reaction mixture was concentrated by a stream of N.sub.2 followed
by the addition of water (25 mL) and extraction with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by SiO.sub.2 column
chromatography utilizing 50% EtOAc/hexanes as the eluent to produce
52.4 mg of P-157 as a orange-red viscous oil in 33% yield. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 2.91 (s, 6H), 3.73 (s, 3H), 3.90
(s, 2H), 4.86 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.69 (2, J=9 Hz, 2H),
7.11-7.15 (m, 3H), 7.57 (t, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H),
8.17-8.20 (m, 1H), 8.25 (s, 1H) ppm. MS (APCI+): 379.1 (M+1);
LC-MS: >99%.
Example 280
Preparation of P-173
##STR00377##
[0946] Synthesis of
(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-(4-pyrazol-1-yl-phenyl)-meth-
anone (I-249). In an 8 mL vial equipped with a stir bar was placed
nitrobenzene (2.4 mL) and AlCl.sub.3 (515 mg, 3.86 mmol). After
stirring for 5 minutes, 4-pyrazol-1-yl-benzoyl chloride (318 mg,
1.54 mmol) was added and the mixture was allowed to stir for 45
minutes at room temperature. Then, I-81 (250 mg, 0.964 mmol) was
added and the reaction mixture was stirred at 60.degree. C. for 17
hours. The reaction was quenched with 1M HCl (10 mL), water was
added (15 mL) and then extracted with dichloromethane (2.times.30
mL). The organic portions were combined, washed with brine (30 mL),
dried (MgSO.sub.4) and concentrated. The residue was purified by
SiO.sub.2 column chromatography utilizing 50% EtOAc/hexanes as the
eluent to produce 257 mg of I-249 as a yellow solid in 64%
yield.
##STR00378##
[0947] Synthesis of
6-Methoxy-3'-nitro-3-(4-pyrazol-1-yl-benzyl)-biphenyl-2-ol (P-173).
In an 8 mL vial equipped with a stir bar was placed I-249 (150 mg,
0.361 mmol) and triethylsilane (1.3 mL, 8.14). The reaction mixture
was cooled in an ice-water bath and then TFA (1.3 mL, 17.5 mmol)
was added. The mixture was heated to 70.degree. C. for 16 hours.
The reaction mixture was concentrated by a stream of N.sub.2
followed by the addition of water (20 mL) and extraction with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by SiO.sub.2 column
chromatography utilizing 20% EtOAc/hexanes as the eluent to produce
105 mg of P-173 as a yellow viscous oil in 33% yield. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 3.73 (s, 3H), 4.01 (s, 2H), 4.79 (s,
1H), 6.44-6.45 (m, 1H), 6.56 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H),
7.33 (d, J=8 Hz, 2H), 7.60-7.65 (m, 3H), 7.69-7.71 (m, 2H), 7.88
(d, J=3 Hz, 1H), 8.22-8.23 (m, 1H), 8.24-8.26 (m, 1H) ppm.
[0948] MS (APCI+): 402.1 (M+1); LC-MS: >99%.
Example 281
Preparation of P-174
##STR00379##
[0950] Synthesis of
[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-(2-hydroxy-6-methoxy-3'-nitro-bip-
henyl-3-yl)-methanone (I-250) In an 8 mL vial equipped with a stir
bar was placed nitrobenzene (2.4 mL) and AlCl.sub.3 (515 mg, 3.86
mmol). After stirring for 5 minutes,
3,5-dimethyl-isoxazole-4-carbonyl chloride (246 mg, 1.54 mmol) was
added and the mixture was allowed to stir for 45 minutes at room
temperature. Then, I-81 (250 mg, 0.964 mmol) was added and the
reaction mixture was stirred at 60.degree. C. for 17 hours. The
reaction was quenched with 1M HCl (10 mL), water was added (15 mL)
and then extracted with dichloromethane (2.times.30 mL). The
organic portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by
SiO.sub.2 column chromatography utilizing 50% EtOAc/hexanes as the
eluent to produce 194 mg of I-250 as a light brown solid in 55%
yield.
##STR00380##
[0951] Synthesis of
3-[4-(3,5-Dimethyl-isoxazol-4-yl)-benzyl]-6-methoxy-3'-nitro-biphenyl-2-o-
l (P-174). In an 8 mL vial equipped with a stir bar was placed TFA
(114 .mu.L, 1.22 mmol) and anhydrous dichloromethane (450 .mu.L).
The solution was cooled to about -40 to -50.degree. C. in an
acetone-dry ice bath. Then NaBH.sub.4 (46.2 mg, 1.22 mmol) was
added portion wise over 5 minutes. The reaction mixture was warmed
to 0.degree. C. in an ice-water bath and then a solution of I-250
(45 mg, 0.122 mmol) in anhydrous dichloromethane (450 .mu.L) was
added drop wise over 5 minutes. The reaction mixture was warmed to
room temperature and reacted for 18 hours. The reaction mixture was
slowly quenched with water (20 mL) and extracted with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by SiO.sub.2 column
chromatography utilizing 30% EtOAc/hexanes as the eluent to produce
16.9 mg of P-174 as a pale yellow viscous oil in 39% yield.
[0952] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.16 (s, 3H), 2.32
(s, 3H), 3.62 (s, 2H), 3.71 (s, 3H), 4.84 (s, 1H), 6.51 (d, J=7 Hz,
1H), 6.95 (d, J=7 Hz, 1H), 7.66-7.70 (m, 2H), 8.24-8.28 (m, 2H)
ppm. MS (APCI+): 355.1 (M+1); LC-MS: >99%.
Example 282
Preparation of P-180
##STR00381##
[0954] Synthesis of
4-(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzaldehyde
(P-180). In an 8 mL vial equipped with a stir bar was placed P-138
(105 mg, 0.291 mmol) and anhydrous THF (950 .mu.L). The solution
was cooled in an ice-water bath for 10 minutes and then DIBAL-H
(1.0M in hexanes, 1.46 mL, 1.46 mmol) was added. The reaction
mixture was warmed to room temperature and reacted for 17 hours.
The reaction was cooled in an ice-water bath, quenched slowly with
1M HCl (4 mL) followed by the addition of water (20 mL) and
extraction with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by
SiO.sub.2 column chromatography utilizing 25% EtOAc/hexanes as the
eluent to produce 32.4 mg of P-180 as an off-white solid in 31%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.72 (s, 3H), 4.05
(s, 2H), 4.76 (s, 1H), 6.57 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H),
7.42 (d, J=8 Hz, 2H), 7.63-7.70 (m, 2H), 7.81 (d, J=8 Hz, 2H),
8.24-8.26 (m, 2H), 9.97 (s, 1H) ppm. MS (APCI-): 362.1 (M-1);
LC-MS: 99%.
Example 283
Preparation of P-183
##STR00382##
[0956] Synthesis of
3-(4-Hydroxymethyl-benzyl)-6-methoxy-3'-nitro-biphenyl-2-ol
(P-183). In an 8 mL vial equipped with a stir bar was placed P-180
(23 mg, 0.0630 mmol) and anhydrous MeOH (250 .mu.L). The mixture
was cooled in an ice-water bath and then NaBH.sub.4 (11.9 mg, 0.315
mmol) was added upon which the reaction mixture became a solution.
The reaction was stirred for 22 hours at room temperature, quenched
with 1M aqueous HCl (4 mL) and water (20 mL) and extracted with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by SiO.sub.2 column
chromatography utilizing 50% EtOAc/hexanes as the eluent to produce
15.1 mg of P-183 as an orange viscous oil in 65% yield. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 3.72 (s, 3H), 3.98 (s, 2H), 4.67 (s,
2H), 4.74 (s, 1H), 6.55 (d, J=9 Hz, 1H), 7.13 (d, J=9 Hz, 1H),
7.24-7.32 (m, 4H), 7.62 (t, J=8 Hz, 1H), 7.68-7.71 (m, 1H),
8.21-8.25 (m, 2H) ppm. MS (APCI+): 348.1 (M-17); LC-MS:
>99%.
Example 284
Preparation of P-190
##STR00383##
[0958] Synthesis of
N-[4-(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-carbonyl)-phenyl]-acetamide
(I-251). In an 18 mL vial equipped with a stir bar was placed
nitrobenzene (4.6 mL) and AlCl.sub.3 (1.23 g, 9.24 mmol). After
stirring for 5 minutes, 4-acetylamino-benzoyl chloride (913 mg,
4.62 mmol) was added and the mixture was allowed to stir for 30
minutes at room temperature. Then, I-81 (600 mg, 2.31 mmol) was
added and the reaction mixture was stirred at 70.degree. C. for 21
hours. The reaction was quenched with 1M aqueous HCl (10 mL), water
was added (100 mL) and then extracted with dichloromethane
(2.times.50 mL). The organic portions were combined, washed with
brine (200 mL), dried (MgSO.sub.4) and concentrated. The residue
was triturated with Et.sub.2O (35 mL), collected by suction
filtration and washed with Et.sub.2O (5.times.2 mL) to produce 333
mg of I-251 as a pale orange solid in 35% yield. MS (APCI+): 407.0
(M+1)
##STR00384##
[0959] Synthesis of
N-[4-(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-phenyl]-acetamide
(P-190). In an 8 mL vial equipped with a stir bar was placed I-251
(200 mg, 0.492 mmol) and triethylsilane (1.80 mL, 11.3). The
reaction mixture was cooled in an ice-water bath and then TFA (1.80
mL, 24.6 mmol) was added. The mixture was heated to 70.degree. C.
for 18 hours. The reaction mixture was concentrated by a stream of
N.sub.2 followed by the addition of water (30 mL) and extraction
with dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by SiO.sub.2 column
chromatography utilizing 5% 1M NH.sub.3 in MeOH/dichloromethane as
the eluent to produce 36.6 mg of P-190 as a light yellow solid in
19% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.16 (s, 3H),
3.72 (s, 3H), 3.94 (s, 2H), 4.74 (s, 1H), 6.55 (d, J=9 Hz, 1H),
7.09 (bs, 1H), 7.7.11 (d, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 2H), 7.42
(d, J=8 Hz, 2H), 7.62 (t, J=8 Hz, 1H), 7.68-7.70 (m, 1H), 8.21-8.25
(m, 2H) ppm. MS (APCI+): 393.1 (M+1); LC-MS: 93%.
##STR00385## ##STR00386##
Example 285
Preparation of P-260
[0960] Synthesis of 3-Iodo-4-methoxy-phenylamine (I-252). In a
3-neck 250 mL round-bottomed flask equipped with a stir bar,
condenser and N.sub.2 lines was placed iron powder (3.50 g, 62.7
mmol), ammonium chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and
water (23 mL). The mixture was heated to 85.degree. C. and then
2-iodo-1-methoxy-4-nitro-benzene (5.0 g, 17.9 mmol) was added
portion wise over a period of about 2 minutes. The mixture was
allowed to stir at 85.degree. C. for 2 hours and then filtered
through Celite. The Celite was washed with EtOH (100 mL) and the
filtrate was concentrated. To the concentrated material was added
water (100 mL) and ethyl acetate (150 mL). The organic portion was
removed and the aqueous portion was re-extracted with ethyl acetate
(150 mL). The organic portions were combined, washed with brine
(150 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by column chromatography utilizing 50% EtOAc/hexanes as
the eluent to produce 3.92 g of I-252 as a brown semi-solid in 88%
yield. MS (ESI+): 250.1 (M+1).
[0961] Synthesis of 1-(5'-Amino-2'-methoxy-biphenyl-3-yl)-ethanone
(I-253). In a 3-neck 100 mL round-bottomed flask equipped with a
condenser, stir bar and N2 lines was placed I-252 (2.92 g, 11.7
mmol), 3-acetylylphenylboronic acid (2.11 g, 12.9 mmol), potassium
carbonate (4.85 g, 35.1 mmol), triphenylphosphine (921 mg, 3.51
mmol), 1,4-dioxane (23 mL), 50% aqueous ethanol (23 mL) followed by
palladium (II) acetate (263 mg, 1.17 mmol). The mixture was heated
to 90.degree. C. for 16 hours and then cooled to room temperature.
The palladium catalyst was removed via filtration and to the
filtrate was added 1M aqueous HCl (50 mL) and water (50 mL). The
aqueous portion was extracted with ethyl acetate (2.times.75 mL),
the organic portions were combined, washed with brine (75 mL),
dried (MgSO.sub.4) and concentrated. The residue was purified by
column chromatography utilizing 50% EtOAc/hexanes as the eluent to
produce 1.18 g of I-253 as a pale orange oil in 42% yield. MS
(APCI+): 242.0 (M+1).
[0962] Synthesis of
1-[2'-Methoxy-5'-(4-nitro-phenylamino)-biphenyl-3-yl]-ethanone
(I-254). To a 40 mL vial equipped with a stir bar was placed
1-iodo-4-nitrobenzene (1.26 g, 5.07 mmol), cesium carbonate (2.20
g, 6.76 mmol),
(.+-.)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (316 mg,
0.507 mmol), and a solution of I-253 (816 mg, 3.38 mmol) in toluene
(13.5 mL). The mixture was stirred for 10 minutes and then
tris(dibenzylideneacetone)dipalladium(0) (310 mg, 0.338 mmol) and
the mixture was heated to 110.degree. C. for 16 hours. The reaction
was cooled to room temperature and then filtered through Celite.
The filtrate was treated with water (40 mL), 1M HCl (40 mL) and
then extracted with ethyl acetate (2.times.75 mL). The organic
portions were combined, washed with brine (75 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
chromatography utilizing 35% EtOAc/hexanes as the eluent to produce
277 mg of I-254 as a dark orange solid in 23% yield.
[0963] Synthesis of
1-[5'-(4-Amino-phenylamino)-2'-methoxy-biphenyl-3-yl]-ethanone
hydrochloride (P-260). In an 18 mL vial equipped with a stir bar
was placed iron powder (148 mg, 2.66 mmol), ammonium chloride (207
mg, 3.87 mmol), absolute EtOH (3.1 mL) and water (1.0 mL). The
mixture was heated to 85.degree. C. and then I-254 (275 mg, 0.759
mmol) was added and the mixture was heated for 2 hours. The
reaction was cooled to room temperature, filtered through Celite
and extracted with ethyl acetate (2.times.40 mL). The organic
portions were combined, washed with brine (40 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
chromatography utilizing 75% EtOAc/hexanes as the eluent to produce
207 mg of the free base as a dark orange oil in 82% yield. The free
base was treated with 4.0 M HCl in 1,4-dioxane (1.0 mL) and stirred
for 3 hours at room temperature. The reaction mixture was treated
with diethyl ether (4 mL) and the solid was collected via suction
filtration. After washing the solid with diethyl ether (3.times.2
mL), 20 mg of P-260 was isolated as a brown solid in 44% yield.
[0964] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.61 (s, 3H),
3.75 (s, 3H), 4.63 (br s, 1H), 7.02-7.20 (m, 7H), 7.57 (t, J=8.0
Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 8.02 (t, J=2
Hz, 1H), 9.42 (br s, 3H) ppm. MS (APCI-): 366.9 (M-2)
Example 286
Preparation of P-267
[0965] Synthesis of
N-[4-(3'-Acetyl-6-methoxy-biphenyl-3-ylamino)-phenyl]-methanesulfonamide
(P-267). In an 8 mL vial equipped with a stir bar was placed P-260
(free base) (60.0 mg, 0.180 mmol), anhydrous dichloromethane (600
.mu.L), pyridine (14.6 .mu.L, 0.180 mmol), methanesulfonyl chloride
(13.9 .mu.L, 0.180 mmol). The reaction mixture was stirred at room
temperature for 17 hours and then quenched with 1M aqueous HCl to
pH 1-2. After adding water (20 mL), an extraction was performed
with dichloromethane (2.times.30 mL), the organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column utilizing 10%
acetone/dichloromethane as the eluent to produce 25 mg of P-267 as
an off-white solid in 34% yield after drying in a high vacuum oven
for 2 hours at 40.degree. C.
[0966] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.2.63 (s, 3H),
2.96 (s, 3H), 3.81 (s, 3H), 6.08 (br s, 1H), 6.91-6.98 (m, 3H),
7.11-7.14 (m, 4H), 7.51 (t, J=8 Hz, 1H), 7.72 (dt, J=8, 1 Hz, 1H),
7.92 (d, J=8 Hz, 1H), 8.10 (t, J=2 Hz, 1H) ppm. MS (APCI+): 411.1
(M+1)
[0967] LC-MS: 97%.
Example 287
Preparation of P-261
##STR00387##
[0969] Synthesis of
[4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-carbamic
acid tert-butyl ester (I-255). In an 8 mL vial equipped with a stir
bar was placed I-223 (295 mg, 0.888 mmol),
4-[(tert-butoxycarbonyl)amino]-phenylboronic acid (232 mg, 0.977
mmol), potassium carbonate (270 mg, 1.95 mmol),
1,5-bis(diphenylphosphino)pentane (39.1 mg, 0.0888 mmol),
allylpalladium(II) chloride dimer (16.2 mg, 0.0444 mmol) and
dimethylformamide (1.5 mL). The reaction mixture was heated to
80.degree. C. for 17 hours. In order to consume residual I-223,
additional allylpalladium(II) chloride dimer (32.5 mg, 0.0888 mmol)
and 1,5-bis(diphenylphosphino)pentane (78.2 mg, 0.178 mmol) were
added and the reaction mixture was allowed to stir at 80.degree. C.
for 17 hours. The reaction mixture was filtered through Celite and
to the filtrate was added water (40 mL) and a saturated ammonium
chloride solution (40 mL). After an extraction with ethyl acetate
(2.times.50 mL), the organic portions were combined, washed with
brine (50 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by column chromatography utilizing 30% EtOAc/hexanes as
the eluent to produce 365 mg of I-255 as a pale yellow solid in 91%
yield.
##STR00388##
[0970] Synthesis of
1-[3'-(4-Amino-benzyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]-ethanone;
hydrochloride (P-261). In an 8 mL vial equipped with a stir bar was
placed I-255 (265 mg, 0.590 mmol), dichloromethane (2.0 ml) and
trifluoroacetic acid (438 .mu.L, 5.90 mmol). The reaction mixture
was stirred at room temperature for 4 hours and then quenched to pH
7 with a saturated sodium bicarbonate solution. After the addition
of water (30 mL) and extraction with dichloromethane (2.times.30
mL), the organic portions were combined, washed with brine (30 mL),
dried (MgSO.sub.4) and concentrated. The crude material was treated
with diethyl ether (3 mL) and 2.0 M HCl in diethyl ether (1 mL) and
allowed to stir at room temperature for 2 hours. The solid was
collected an washed with diethyl ether (3.times.2 mL) to produce
139 mg of P-261 as a pale orange powder in 61% yield. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 2.59 (s, 3H), 3.72 (s, 3H), 3.96
(s, 2H), 6.96 (d, J=8 Hz, 1H), 7.20-7.34 (m, 5H), 7.57 (d, J=5 Hz,
2H), 7.85 (bs, 1H), 7.94-7.97 (m, 1H) ppm. MS (APCI+): 350.1
(M+1-HCl).
Example 288
Preparation of P-269
##STR00389##
[0972] Synthesis of
[4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-269). In an 8 mL vial equipped with a stir bar was placed P-261
(31 mg, 0.0803 mmol), water (400 .mu.L), acetic acid (200 .mu.L)
and sodium cyanate (20.9 mg, 0.321 mmol). The mixture was stirred
at room temperature for 4 hours and then water (20 mL) was added
followed by an extraction with dichloromethane (2.times.30 mL). The
organic portions were combined, washed with a saturated sodium
bicarbonate solution (30 mL) and brine (30 mL), dried (MgSO.sub.4)
and concentrated. The residue was purified by column chromatography
utilizing 75% acetone/dichloromethane as the eluent to produce 18
mg of P-269 as an off-white solid in 56% yield. .sup.\1H NMR (400
MHz, CDCl.sub.3) .delta. 2.62 (s, 3H), 3.75 (s, 3H), 3.95 (s, 2H),
4.59 (br s, 2H), 6.27 (br s, 1H), 6.72 (d, J=8 Hz, 1H), 7.11 (t,
J=9 Hz, 1H), 7.21 (s, 4H), 7.52 (t, J=8 Hz, 1H), 7.60 (dd, J=9, 1
Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.99 (br s, 1H) ppm. MS (APCI+):
393.1 (M+1); LC-MS: 95%.
##STR00390## ##STR00391##
Example 289
Preparation of P-280
[0973] Synthesis of 3'-Chloro-2-methoxy-5-nitro-biphenyl (I-256).
In a 3-neck 500 mL round bottomed flask equipped with a stir bar,
condenser and nitrogen lines was placed was placed
2-iodo-1-methoxy-4-nitrobenzene (7.0 g, 25.1 mmol),
3-chlorophenylboronic acid (4.32 g, 27.6 mmol), potassium carbonate
(10.4 g, 75.3 mmol), triphenylphosphine (1.98 g, 7.53 mmol),
1,4-dioxane (50 mL), 50% aqueous EtOH followed by palladium acetate
(564 mg, 2.51 mmol). The mixture was heated to 90.degree. C. in an
oil bath for 16 hours and then quenched with 1M aqueous HCl (80
mL). After the reaction mixture was filtered through Celite, water
(100 mL) and 1M aqueous HCl (100 mL) were added followed by
extractions with ethyl acetate (3.times.150 mL). The organic
portions were combined, washed with brine (250 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 20% EtOAc/Hexanes as the eluent to produce 4.26 g of
I-256 as an orange solid in 64% yield. MS (ESI+): 263.3 (M+).
[0974] Synthesis of 3'-Chloro-6-methoxy-biphenyl-3-ylamine (I-257).
In a 3-neck 250 mL round bottomed flask equipped with a stir bar,
condenser and nitrogen lines was placed iron powder (3.17 g, 56.7
mmol), ethanol (66 mL) and water (21 mL). The mixture was heated to
85.degree. C. in an oil bath and then I-256 (4.26 g, 16.2 mmol) was
added and the reaction was continued at 85.degree. C. for 2 hours.
The reaction mixture was cooled to room temperature and filtered
through Celite. To the filtrate was added water (150 mL) and
extractions were performed with ethyl acetate (3.times.100 mL). The
organic portions were combined, washed with brine (100 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
column utilizing 65% EtOAc/Hexanes as the eluent to produce 2.87 g
of I-257 as an orange viscous oil in 76% yield. MS (APCI+): 234.0
(M+1)
[0975] Synthesis of
(3'-Chloro-6-methoxy-biphenyl-3-yl)-(4-nitro-phenyl)-amine (I-258).
In a 3-neck 100 mL round-bottomed flask equipped with a stir bar,
condenser and nitrogen lines was placed I-257 (1.2 g, 5.13 mmol),
4-iodo-nitrobenzene (1.92 g, 7.70 mmol),
(.+-.)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene (480 mg,
0.770 mmol), cesium carbonate (3.34 g, 10.3 mmol), toluene (21 mL)
followed by tris(dibenzylideneacetone)dipalladium(0) (470 mg, 0.513
mmol). The mixture was heated to 100.degree. C. in an oil bath for
17 hours and then cooled to room temperature and quenched with 1M
aqueous HCl (50 mL). The reaction mixture was filtered through
Celite and to the filtrate was added water (50 mL) followed by
extractions with ethyl acetate (2.times.75 mL). The organic
portions were combined, washed with brine (100 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 25% EtOAc/Hexanes as the eluent to produce 1.36 g of
I-258 as a red-orange solid in 75% yield. MS (APCI+): 355.1
(M+1)
[0976] Synthesis of
N-(3'-Chloro-6-methoxy-biphenyl-3-yl)-benzene-1,4-diamine;
hydrochloride (P-280). In a 40 mL vial equipped with a stir bar was
placed iron powder (330 mg, 5.92 mmol), ethanol (6.9 mL) and water
(2.2 mL). The mixture was heated to 85.degree. C. in an oil bath
and then I-258 (600 mg, 1.69 mmol) was added and the reaction was
continued at 85.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and filtered through Celite. To the
filtrate was added water (50 mL) and extractions were performed
with ethyl acetate (2.times.50 mL). The organic portions were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column utilizing 75%
EtOAc/Hexanes as the eluent to produce 480 mg of the free base of
P-280. To the free base was added Et.sub.2O (4 mL) and 2.0 M HCl in
Et.sub.2O (2 mL) and the mixture was stirred at room temperature
for 1 hour. The solid was collected, washed with Et.sub.2O (10 mL)
and dichloromethane (8 mL) and then dried in a high vacuum oven set
at 35.degree. C. for 2 hours to produce 355 mg of P-280 as a pale
blue solid in 58% yield.
[0977] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H),
7.02-7.21 (m, 7H), 7.38-7.45 (m, 3H), 7.51-7.53 (m, 1H), 9.97 (br
s, 3H) ppm. MS (ESI+): 326.4 [(M+1)-HCl].
[0978] LC/MS: 92%.
Example 290
Preparation of P-294
[0979] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylamino)-phenyl]-urea (P-294).
In an 8 mL vial equipped with a stir bar was placed P-280 (150 mg,
0.415 mmol), water (2.4 mL), acetic acid (1.2 mL) and sodium
cyanate (108 mg, 1.66 mmol). The mixture was stirred at room
temperature for 72 hours and then water (20 mL) was added followed
by an extraction with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 40% acetone/dichloromethane as the eluent to produce 46
mg of P-294 as a light purple solid in 30% yield. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 3.71 (s, 3H), 5.67 (br s, 2H), 6.90-6.92
(m, 3H), 7.01 (s, 2H), 7.23 (d, J=9 Hz, 2H), 7.37-7.49 (m, 4H),
7.68 (s, 1H), 8.23 (br s, 1H) ppm. MS (APCI+): 368.1 (M+1); LC-MS:
95%.
Example 291
Preparation of P-281
##STR00392##
[0981] Synthesis of
1-[3'-(2-Amino-pyrimidin-5-ylmethyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]--
ethanone hydrochloride (P-281). In an 18 mL vial equipped with a
stir bar was placed I-223 (704 mg, 2.12 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine
(515 mg, 2.33 mmol), potassium carbonate (879 mg, 6.36 mmol),
1,5-bis(diphenylphosphino)pentane (280 mg, 0.636 mmol),
allylpalladium(II) chloride dimer (116 mg, 0.318 mmol) and
dimethylformamide (4.2 mL). The reaction mixture was heated to
70.degree. C. for 65 hours. The reaction mixture was filtered
through Celite and to the filtrate were added water (40 mL) and a
saturated ammonium chloride solution (40 mL). After an extraction
with ethyl acetate (2.times.50 mL), the organic portions were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column chromatography
utilizing 20% acetone/dichloromethane (gradient elution increased
to 30%, then 40% acetone/dichloromethane) as the eluent to produce
341 mg of P-281 an off-white solid in 46% yield. Then P-281 (20 mg,
0.0569 mmol) was treated with 1,4-dioxane (1 mL) and the mixture
was heated to form a solution. To this solution was added 4.0M HCl
in 1,4-dioxane (1 mL) and the mixture was stirred at room
temperature for 3 hours. The solvent was removed via nitrogen
stream and the resulting solid was triturated with diethyl ether (1
mL), collected via suction filtration and washed with diethyl ether
(3.times.1 mL) to produce 12 mg of P-281 HCl salt as a pale yellow
solid in 55% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
2.59 (s, 3H), 3.73 (s, 3H), 3.83 (s, 2H), 6.97 (d, J=8 Hz, 1H),
7.35 (t, J=9 Hz, 1H), 7.59 (d, J=6 Hz, 2H), 7.88 (bs, 1H),
7.95-7.97 (m, 1H), 8.36 (bs, 2H). MS (APCI+): 352.1 [(M+1)-HCl];
LC-MS: 98%.
Example 292
Preparation of P-284
##STR00393##
[0983] Synthesis of
N-[5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-m-
ethanesulfonamide (P-284). In an 8 mL vial equipped with a stir bar
was placed P-281 (free base) (70.0 mg, 0.199 mmol), pyridine (800
.mu.L) and methane sulfonyl chloride (15.4 .mu.L, 0.199 mmol). The
reaction mixture was stirred at room temperature for 2 hours and
then heated to 50.degree. C. for 2 hours and then quenched with
aqueous 1M HCl to pH I-2. After adding water (20 mL), an extraction
was performed with ethyl acetate (2.times.30 mL), the organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 20% acetone/dichloromethane as the eluent to produce 29
mg of P-284 as a light yellow solid in 34% yield after drying in a
high vacuum oven for 2 hours at 35.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 2.62 (s, 3H), 3.44 (s, 3H), 3.77 (s, 3H), 3.91
(s, 2H), 6.76 (d, J=8 Hz, 1H), 7.158 (t, J=8 Hz, 1H), 7.53 (t, J=8
Hz, 1H), 7.59 (dd, J=8, 1 Hz, 1H), 7.95 (t, J=1 Hz, 1H), 7.97 (m,
1H), 8.51 (s, 2H), 9.85 (br s, 1H) ppm. MS (APCI+): 430.0 (M+1);
LC-MS: 92%. HPLC: 97%.
Example 293
Preparation of P-315
##STR00394##
[0985] Synthesis of
1-[5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-3-
-ethyl-urea (P-315), In an 8 mL vial equipped with a stir bar was
placed P-281 (free base) (80 mg, 0.228 mmol), pyridine (1.0 mL) and
ethyl isocyanate (36.1 .mu.L, 0.456 mmol). The reaction mixture was
stirred at room temperature for 18 hours. TLC analysis indicated
that the reaction mixture consisted of mostly starting materials.
To the reaction mixture was added ethyl isocyanate (180 .mu.L, 2.28
mmol) and the mixture was heated to 55.degree. C. for 65 hours. The
reaction mixture was quenched with water (3 mL) and the resulting
solid was collected, washed with water (3.times.2 mL), ethyl
acetate (3.times.1 mL) and dried in a high vacuum oven set at
40.degree. C. for 4 hours to produce 59 mg of P-315 as a white
solid in 61% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.09 (t, J=7 Hz, 3H), 2.59 (s, 3H), 3.18-3.26 (m, 2H), 3.73 (s,
3H), 3.90 (s, 2H), 6.97 (d, J=9 Hz, 1H), 7.36 (t, J=9 Hz, 1H),
7.57-7.59 (m, 2H), 7.88 (s, 1H), 7.94-7.97 (m, 1H), 8.46 (s, 2H),
8.91 (t, J=4 Hz, 1H), 9.61 (s, 1H) ppm. MS (APCI+): 423.1 (M+1);
LC-MS: 94%, HPLC: 93%.
Example 294
Preparation of P-325
##STR00395##
[0987] Synthesis of
1-[3'-(2-Dimethylamino-pyrimidin-5-ylmethyl)-2'-fluoro-6'-methoxy-bipheny-
l-3-yl]-ethanone (P-325). In an 8 mL vial equipped with a stir bar
was placed I-223 (200 mg, 0.602 mmol),
dimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl-
]-amine (165 mg, 0.662 mmol), potassium carbonate (250 mg, 1.81
mmol), 1,5-bis(diphenylphosphino)pentane (79.6 mg, 0.181 mmol),
allylpalladium(II) chloride dimer (33.0 mg, 0.0903 mmol) and
dimethylformamide (1.2 mL). The reaction mixture was heated to
65.degree. C. for 18 hours. The reaction mixture was filtered
through Celite and to the filtrate were added water (40 mL) and a
saturated ammonium chloride solution (40 mL). After an extraction
with ethyl acetate (2.times.50 mL), the organic portions were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column chromatography
utilizing 50% ethyl acetate/hexanes as the eluent to produce 90 mg
of P-325 as a yellow solid in 39% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 2.59 (s, 3H), 3.07 (s, 6H), 3.72 (s, 3H),
3.77 (s, 2H), 6.94 (d, J=9 Hz, 1H), 7.30 (t, J=9 Hz, 1H), 7.58 (d,
J=5 Hz, 2H), 7.87 (s, 1H), 7.94-7.96 (m, 1H), 8.24 (s, 2H) ppm.
[0988] MS (APCI+): 380.1 (M+1); LC-MS: >99%.
Example 295
Preparation of P-362
##STR00396##
[0990] Synthesis of
[5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-ure-
a (P-362). In an 8 mL vial equipped with a stir bar was placed
P-281 (free base) (30 mg, 0.0854 mmol), 1,4-dioxane (800 .mu.L)
pyridine (34.5 .mu.L, 0.427 mmol) and trimethylsilyl isocyanate
(57.8 .mu.L, 0.427 mmol). The reaction mixture was heated to
90.degree. C. for 18 hours and then water (15 mL) and 1M HCl (15
mL) were added followed by an extraction with dichloromethane
(2.times.30 mL). The organic portions were combined and dried
(MgSO.sub.4) and concentrated. To the residue was added hexanes
until cloudy and the resulting solid was collected, washed with
hexanes (3.times.1 mL) and dried in a high vacuum oven set at
40.degree. C. for 4 hours to produce 8 mg of P-362 as a pale yellow
solid in 23% yield.
[0991] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.59 (s, 3H),
3.73 (s, 3H), 3.80 (s, 2H), 6.96 (d, J=9 Hz, 1H), 7.34 (t, J=9 Hz,
1H), 7.58-7.59 (m, 2H), 7.87 (s, 1H), 7.94-7.97 (m, 1H), 8.29 (s,
2H) ppm. LC-MS: >99%.
Example 296
Preparation of P-366
##STR00397##
[0993] Synthesis of
1-[5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-3-
-(2-chloro-ethyl)-urea (P-366). In an 8 mL vial equipped with a
stir bar was placed P-281 (free base) (70 mg, 0.199 mmol),
chloroform (1.5 mL) and chloroethylisocyanate (17.0 .mu.L, 0.199
mmol). The reaction mixture was heated to 65.degree. C. for 18
hours. TLC analysis indicated a small amount of starting material
was present. To the reaction mixture was added
chloroethylisocyanate (50.90 .mu.L, 0.597 mmol) and the mixture was
stirred at 75.degree. C. for 22 hours. The reaction was quenched
with water (30 mL) and extracted with dichloromethane (2.times.30
mL). The organic portions were combined, washed with brine (30 mL),
dried (MgSO.sub.4) and concentrated. The residue was purified by
column chromatography utilizing 15% acetone/dichlormethane and then
recrystallized by dissolving the solid with dichloromethane (1 mL)
and adding hexanes until cloudy. The solid was collected, washed
with hexanes (3.times.1 mL) to produce 9 mg of P-366 as a white
solid in 10% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.62
(s, 3H), 3.69-3.72 (m, 4H), 3.77 (s, 3H), 3.89 (s, 2H), 6.76 (d,
J=8 Hz, 1H), 7.15 (t, J=9 Hz, 1H), 7.45 (s, 1H), 7.51-7.59 (m, 2H),
7.94-7.98 (m, 2H), 8.38 (s, 2H), 9.36 (br s, 1H) ppm. MS (APCI+):
457.1 (M+1).
Example 297
Preparation of P-288
##STR00398##
[0995] Synthesis of
(3'-Chloro-6-methoxy-biphenyl-3-yl)-methyl-(4-nitro-phenyl)-amine
(I-259), In a 40 mL vial equipped with a stir bar was placed I-258
(600 mg, 1.69 mmol), anhydrous DMF (6.8 mL), NaH (60%)(94.6 mg,
2.37 mmol) and methyl iodide (579 .mu.L, 9.30 mmol). The reaction
mixture was stirred at 50.degree. C. for 17 hours and then quenched
with water (30 mL) and a saturated ammonium chloride solution (30
mL). After extracting with EtOAc (2.times.50 mL), the extracts were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column utilizing 20%
EtOAc/hexanes as the eluent to produce 490 mg of I-259 as a
yellow-orange solid in 79% yield.
[0996] Synthesis of
N-(3'-Chloro-6-methoxy-biphenyl-3-yl)-N-methyl-benzene-1,4-diamine;
hydrochloride (P-288). In a 40 mL vial equipped with a stir bar was
placed iron powder (260 mg, 4.66 mmol), ethanol (5.3 mL) and water
(1.7 mL). The mixture was heated to 85.degree. C. in an oil bath
and then I-259 (490 mg, 1.33 mmol) was added and the reaction was
continued at 85.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and filtered through Celite. To the
filtrate was added water (50 mL) and extractions were performed
with ethyl acetate (2.times.50 mL). The organic portions were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column utilizing 50%
EtOAc/hexanes as the eluent to produce 376 mg of the free base of
P-288 as an orange, viscous oil. To the free base was added
Et.sub.2O (5 mL) and 2.0 M HCl in Et.sub.2O (3 mL) and the mixture
was stirred at room temperature for 2 hours. The solid was
collected, washed with Et.sub.2O (6 mL) and dried in a high vacuum
oven set at 40.degree. C. for 3 hours to produce 225 mg of P-288 as
a light brown solid in 54% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 3.25 (s, 3H), 3.79 (s, 3H), 6.85 (d, J=9 Hz,
2H), 7.12 (d, J=2 Hz, 1H), 7.15-7.21 (m, 4H), 7.38-7.44 (m, 3H),
7.52-7.54 (m, 1H), 9.84 (br s, 3H) ppm.
[0997] MS (APCI+): 339.1 (M+1-HCl); LC-MS: 99%.
Example 298
Preparation of P-293
##STR00399##
[0999] Synthesis of
{4-[(3'-Chloro-6-methoxy-biphenyl-3-yl)-methyl-amino]-phenyl}-urea
(P-293). In an 8 mL vial equipped with a stir bar was placed P-288
(100 mg, 0.266 mmol), water (1.6 mL), acetic acid (800 .mu.L) and
sodium cyanate (69.2 mg, 1.06 mmol). The mixture was stirred at
room temperature for 72 hours and then water (30 mL) was added
followed by an extraction with dichloromethane (2.times.30 mL). The
organic portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was triturated with
diethyl ether (2 mL) to produce 49 mg of P-293 as an off-white
solid in 48% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
3.19 (s, 3H), 3.73 (s, 3H), 5.72 (br s, 2H), 6.87-6.89 (m, 3H),
6.94 (dd, J=9, 3 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 7.28 (d, J=9 Hz,
2H), 7.36-7.43 (m, 3H), 7.48 (br s, 1H), 8.34 (br s, 1H) ppm. MS
(APCI+): 382.1 (M+1); LC-MS: 98%.
##STR00400##
Example 299
Preparation of P-334
[1000] Synthesis of
1-[2'-Fluoro-6'-methoxy-3'-(4-nitro-benzyl)-biphenyl-3-yl]-ethanone
(I-261) In an 18 mL vial equipped with a stir bar was placed I-223
(600 mg, 1.81 mmol), 4-nitrophenylboronic acid (332 mg, 1.99 mmol),
potassium carbonate (750 mg, 5.43 mmol),
1,5-bis(diphenylphosphino)pentane (239 mg, 0.543 mmol),
allylpalladium(II) chloride dimer (99.3 mg, 0.272 mmol) and
dimethylformamide (3.6 mL). The reaction mixture was heated to
80.degree. C. for 18 hours. The reaction mixture was filtered
through Celite and to the filtrate were added water (40 mL) and a
saturated ammonium chloride solution (40 mL). After an extraction
with ethyl acetate (2.times.50 mL), the organic portions were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column chromatography
utilizing 30% ethyl acetate/hexanes as the eluent to produce 410 mg
of I-261 as a red-orange, wet solid in 60% yield.
[1001] MS (ESI-): 378.5 (M-1).
[1002] Synthesis of
1-[2'-Fluoro-6'-hydroxy-3'-(4-nitro-benzyl)-biphenyl-3-yl]-ethanone
(I-262). In an 18 mL vial equipped with a stir bar was placed I-261
(351 mg, 0.925 mmol) and dichloromethane (3.0 mL). The solution was
cooled to -78.degree. C. in a dry-ice/acetone bath over 15 minutes
and then boron tribromide (1.0M in dichloromethane) (2.78 mL, 2.78
mmol) was added and the vial was allowed to gradually warm to room
temperature over a period of 2 hours. The reaction was poured into
ice-water (40 mL) and then extracted with dichloromethane
(2.times.30 mL). The organic portions were combined, washed with
brine (50 mL), dried (MgSO.sub.4) and concentrated to produce 274
mg of I-262 as a brown solid in 81% yield.
[1003] Synthesis of
1-[6'-Ethoxy-2'-fluoro-3'-(4-nitro-benzyl)-biphenyl-3-yl]-ethanone
(I-263). In an 18 mL vial equipped with a stir bar was added I-262
(200 mg, 0.547 mmol), dimethylformamide (3.6 mL) and iodoethane
(131 .mu.L, 1.64 mmol). The mixture was stirred for 5 minutes and
then potassium carbonate (227 mg, 1.64 mmol) was added and the
reaction mixture was stirred at room temperature for 18 hours. The
reaction mixture was quenched with water (30 mL) and acidified to
pH 1 with 1M HCl. An extraction was performed with dichloromethane
(2.times.30 mL) and the organic portions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated to produce 185
mg of I-263 as a red-orange oil in 86% yield.
[1004] Synthesis of
1-[3'-(4-Amino-benzyl)-6'-ethoxy-2'-fluoro-biphenyl-3-yl]-ethanone;
hydrochloride (P-334). In an 18 mL vial equipped with a stir bar
was placed iron powder (129 mg, 2.31 mmol), ethanol (5.6 mL) and
water (850 .mu.L). The mixture was heated to 85.degree. C. in an
oil bath and then I-263 (260 mg, 0.661 mmol) was added and the
reaction was continued at 85.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature and filtered through Celite.
To the filtrate was added water (50 mL) and extractions were
performed with ethyl acetate (2.times.50 mL). The organic portions
were combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column utilizing 40%
EtOAc/hexanes as the eluent. To this purified material (free base)
was added Et.sub.2O (3 mL) and 2.0 M HCl in Et.sub.2O (1.5 mL) and
the mixture was stirred at room temperature for 1 hour. The solid
was collected and dried in a high vacuum oven set at 40.degree. C.
for 3 hours to produce 46 mg of P-334 as an orange solid in 17%
yield.
[1005] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.18 (t, J=7 Hz,
3H), 2.59 (s, 3H), 3.47 (br s, 2H), 3.96 (s, 2H), 4.03 (q, J=7 Hz,
2H), 6.94 (d, J=9 Hz, 1H), 7.20-7.32 (m, 5H), 7.55-7.62 (m, 2H),
7.91 (s, 1H), 7.94 (dt, J=7, 2 Hz, 1H) ppm.
[1006] MS (APCI+): 364.1 (M+1-HCl); LC-MS: 98%.
Example 300
Preparation of P-335
[1007] Synthesis of
[4-(3'-Acetyl-6-ethoxy-2-fluoro-biphenyl-3-ylmethyl)-phenyl]-urea
(P-335). In an 8 mL vial equipped with a stir bar was placed P-334
(38 mg, 0.0950 mmol), water (500 .mu.L), acetic acid (250 .mu.L)
and sodium cyanate (24.7 mg, 0.380 mmol). The mixture was stirred
at room temperature for 18 hours and then water (3 mL) was added
and then the pH was adjusted to 6 with a saturated sodium
bicarbonate solution. The resulting solid was collected and dried
in a high vacuum oven set at 40.degree. C. for 4 hours to produce
20 mg of P-335 as a pale orange solid in 53% yield. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.27 (t, J=7 Hz, 3H), 2.62 (s, 3H),
3.94 (s, 2H), 3.99 (q, J=7 Hz, 2H), 4.65 (s, 2H), 6.40 (s, 1H),
6.70 (d, J=8 Hz, 1H), 7.078 (t, J=8 Hz, 1H), 7.21 (s, 4H), 7.50 (t,
J=8 Hz, 1H), 7.62 (dd, J=8, 1 Hz, 1H), 7.94 (dt, J=8, 2 Hz, 1H),
8.03 (br s, 1H) ppm.
[1008] MS (APCI+): 407.1 (M+1); LC-MS: 94%.
Example 301
Preparation of P-340
##STR00401##
[1010] Synthesis of
{4-[2-Fluoro-3'-(1-hydroxy-ethyl)-6-methoxy-biphenyl-3-ylmethyl]-phenyl}--
urea (P-340). In an 8 mL vial equipped with a stir bar was placed
P-269 (21 mg, 0.0535 mmol), methanol (200 .mu.L) and sodium
borohydride (6.1 mg, 0.161 mmol). The mixture was stirred at room
temperature for 1 hour and then quenched with water (2 mL) and 1M
aqueous HCl (4 mL). After stirring for 20 minutes, a saturated
sodium bicarbonate solution was used to adjust the mixture to pH
7-8. After extracting with dichloromethane (2.times.30 mL), the
organic portions were combined, dried (MgSO.sub.4) and
concentrated. The residue was purified via column chromatography
utilizing 40% acetone/dichloromethane as the eluent produce 10 mg
of P-340 as a white solid in 49% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.33 (d, J=6 Hz, 3H), 3.69 (s, 3H), 3.83 (s,
2H), 4.70-4.78 (m, 1H), 5.15 (d, J=4 Hz, 1H), 5.76 (s, 2H), 6.89
(d, J=9 Hz, 1H), 7.06 (d, J=8 Hz, 2H), 7.13 (d, J=7 Hz, 1H), 7.21
(t, J=9 Hz, 1H), 7.25-7.36 (m, 4H), 8.42 (s, 1H) ppm. MS (APCI+):
377.1 [(M+1)-18]; LC-MS: >99%.
Example 302
Preparation of P-381
##STR00402##
[1012] Synthesis of
N-[4-(2-Fluoro-6-methoxy-3'-pyrrolidin-1-yl-biphenyl-3-ylmethyl)-phenyl]--
acetamide (P-381). In an 8 mL vial equipped with a stir bar was
placed P-168 (100 mg, 0.233 mmol), 1,4-dioxane (800 .mu.L) and
pyrrolidine (117 .mu.L, 1.40 mmol). The mixture was degassed with
nitrogen for 20 minutes and then dichlorobis(chloro tert-butyl
phosphine) palladium (50.2 mg, 0.0932 mmol) was added. The mixture
was heated to 85.degree. C. for 20 hours and then filtered through
Celite. The filtrate was treated with water (20 mL) and a saturated
ammonium chloride solution (20 mL). After an extraction with ethyl
acetate (2.times.30 mL), the organic portions were combined, washed
with brine (30 mL), dried (MgSO.sub.4) and concentrated. The
residue was purified by column chromatography utilizing 20%
acetone/dichloromethane as the eluent and to produce 31 mg of P-381
as a pale orange solid in 32% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.38 (d, J=14 Hz, 4H), 2.01 (s, 3H), 3.24 (m,
4H), 3.65 (s, 3H), 3.84 (s, 2H), 6.76 (d, 1H), 6.84 (d, J=8 Hz,
1H), 6.93 (t, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 2H), 7.17 (t, J=8 Hz,
1H), 7.23 (br s, 1H), 7.30-7.32 (m, 1H), 7.48 (d, J=8 Hz, 2H), 9.83
(s, 1H) ppm. LC-MS: 92%.
Example 303
Preparation of P-390
##STR00403##
[1014] Synthesis of
N-[4-(2-Fluoro-6-methoxy-3'-morpholin-4-yl-biphenyl-3-ylmethyl)-phenyl]-a-
cetamide (P-390). In an 8 mL vial equipped with a stir bar was
placed P-168 (80 mg, 0.187 mmol), sodium tert-butoxide (27.0 mg,
0.281 mmol), toluene (700 .mu.L), morpholine (19.6 .mu.L, 0.224
mmol) and
2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane
(13.3 .mu.L, 0.0374 mmol). The mixture was degassed with nitrogen
for 15 minutes and then tris(dibenzylideneacetone)-dipalladium(0)
(8.56 mg, 0.00935 mmol) was added. The mixture was heated to
90.degree. C. for 18 hours and then filtered through Celite. The
filtrate was treated with water (20 mL) and a saturated ammonium
chloride solution (20 mL). After an extraction with ethyl acetate
(2.times.30 mL), the organic portions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by column chromatography utilizing 10%
acetone/dichloromethane as the eluent and to produce 21 mg of P-390
as an off white solid in 26% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 2.01 (s, 3H), 3.09 (t, J=5 Hz, 4H), 3.69 (s,
3H), 3.72 (t, J=5 Hz, 4H), 3.85 (s, 2H), 6.72 (d, J=7 Hz, 1H), 6.83
(br s, 1H), 6.87 (d, J=9 Hz, 1H), 6.92 (dd, J=8, 2 Hz, 1H), 7.13
(d, J=8 Hz, 2H), 7.18-7.27 (m, 2H), 7.47 (d, J=8 Hz, 2H), 7.69-7.80
(m, 1H) ppm. MS (APCI+): 435.1 (M+1); LC-MS: 95%.
Example 304
Preparation of P-385
##STR00404##
[1016] Synthesis of
4-[5'-(4-Fluoro-benzyl)-2'-methoxy-biphenyl-3-yl]-morpholine
(P-385). In an 8 mL vial equipped with a stir bar was placed I-185
(200 mg, 0.678 mmol),
4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-morpho-
line (216 mg, 0.746 mmol), potassium carbonate (281 mg, 2.03 mmol),
triphenylphosphine (53.3 mg, 0.203 mmol), 1,4-dioxane (1.1 mL), 50%
aqueous ethanol (1.1 mL) followed by palladium (II) acetate (15.2
mg, 0.0678 mmol). The mixture was heated to 90.degree. C. for 18
hours and then cooled to room temperature. The palladium catalyst
was removed via filtration through Celite. To the filtrate were
added water (30 mL) and a saturated ammonium chloride solution (30
mL). After the aqueous portion was extracted with ethyl acetate
(2.times.30 mL), the organic portions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by column chromatography utilizing 20% EtOAc/hexanes as
the eluent and dried in a high vacuum oven set at 40.degree. C. for
9 hours to produce 137 mg of P-385 as a yellow viscous oil in 54%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.18 (t, J=5 Hz,
4H), 3.78 (s, 3H), 3.87 (t, J=5 Hz, 4H), 3.92 (s, 2H), 6.87-7.01
(m, 5H), 7.04 (t, J=2 Hz, 1H), 7.09 (dd, J=8, 3 Hz, 1H), 7.12-7.17
(m, 3H), 7.30 (t, J=8 Hz, 1H) ppm. MS (APCI+): 378.1 (M+1); LC-MS:
>99%
Example 305
Preparation of P-391
##STR00405##
[1018] Synthesis of
2-Chloro-6-[5-(4-fluoro-benzyl)-2-methoxy-phenyl]-pyridine (P-391).
In an 8 mL vial equipped with a stir bar was placed I-185 (250 mg,
0.847 mmol),
2-chloro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
(243 mg, 1.02 mmol), sodium tert-butoxide (122 mg, 1.27 mmol) and
1,4-dioxane. The mixture was degassed with nitrogen for 20 minutes
and then dichlorobis(chloro tert-butyl phosphine) palladium (122
mg, 0.127 mmol) was added. The mixture was heated to 90.degree. C.
for 18 hours and then filtered through Celite. The filtrate was
treated with water (20 mL) and a saturated ammonium chloride
solution (20 mL). After an extraction with ethyl acetate
(2.times.30 mL), the organic portions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by column chromatography utilizing 10% ethyl
acetate/hexanes as the eluent. The material was then recrystallized
with diethyl ether and hexanes to produce 29 mg of P-391 as a white
solid in 10% yield.
[1019] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.84 (s, 3H), 3.96
(s, 2H), 6.91 (d, J=8 Hz, 1H), 6.94-6.98 (m, 2H), 7.12-7.17 (m,
2H), 7.23 (dd, J=8, 1 Hz, 1H), 7.64 (t, J=8 Hz, 1H), 7.69 (d, J=2
Hz, 1H), 7.79 (dd, J=8, 1 Hz, 1H) ppm. MS (APCI+): 328.0 (M+1);
[1020] LC-MS: 97%.
##STR00406##
[1020] Example 306
Preparation of P-395
[1021] Synthesis of Carbonic acid
3'-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester
(I-266). In an 18 mL vial equipped with a stir bar was placed I-265
(465 mg, 1.81 mmol), anhydrous tetrahydrofuran (6.0 mL) and
pyridine (381 .mu.L, 4.71 mmol). The resulting clear solution was
cooled in an ice water bath for 10 minutes and then methyl
chloroformate (308 .mu.L, 3.98 mmol) was added and reaction mixture
was slowly warmed to room temperature and reacted for 17 hours. The
reaction was acidified to pH 1 with 1M HCl, water (30 mL) was added
followed by an extraction with dichlormethane (2.times.60 mL). The
organic portions were combined, washed with brine (40 mL), dried
(MgSO.sub.4) and concentrated. After drying in a high vacuum oven
for 2 hours at 45.degree. C., 378 mg of I-266 was isolated as a
light yellow in 66% yield.
[1022] Synthesis of
3'-(2-Amino-pyrimidin-5-ylmethyl)-2'-fluoro-6'-methoxy-biphenyl-3-carboni-
trile (P-395). In an 8 mL vial equipped with a stir bar was placed
I-266 (120 mg, 0.381 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine
(92.7 mg, 0.419 mmol), potassium carbonate (158 mg, 1.14 mmol),
1,5-bis(diphenylphosphino)pentane (50.3 mg, 0.114 mmol),
allylpalladium(II) chloride dimer (20.9 mg, 0.0572 mmol) and
dimethylformamide (1.3 mL). The reaction mixture was heated to
85.degree. C. for 18 hours. The reaction mixture was filtered
through Celite and to the filtrate were added water (30 mL) and a
saturated ammonium chloride solution (30 mL). After an extraction
with ethyl acetate (2.times.30 mL), the organic portions were
combined, washed with brine (40 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by column chromatography
utilizing 10% acetone/dichloromethane and then 30%
acetone/dichloromethane as the eluent to produce 62 mg of P-395 as
a pale yellow solid in 49% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 3.73 (s, 5H), 6.47 (s, 2H), 6.96 (d, J=8 Hz,
1H), 7.33 (t, J=9 Hz, 1H), 7.61-7.69 (m, 2H), 7.82-7.84 (m, 2H),
8.12 (s, 2H) ppm.
[1023] MS (APCI+): 335.1 (M+1); LC-MS: 94%.
Example 307
Preparation of P-399
[1024] Synthesis of
1-[5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-3--
ethyl-urea (P-399). In an 8 mL vial equipped with a stir bar was
placed P-395 (60 mg, 0.180 mmol), pyridine (600 .mu.L) and ethyl
isocyanate (71.2 .mu.L, 0.900 mmol). The reaction mixture was
stirred at room temperature for 18 hours. TLC analysis indicated
that the reaction mixture consisted of about 50% starting
materials. To the reaction mixture was added ethyl isocyanate (71.2
.mu.L, 0.900 mmol) and the mixture was heated to 55.degree. C. for
5 hours. The reaction mixture was quenched with water (4 mL) and
the resulting solid was collected, washed with water (3.times.2
mL), ethyl acetate (3.times.2 mL) and dried in a high vacuum oven
set at 40.degree. C. for 18 hours to produce 36 mg of P-399 as a
white solid in 49% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.09 (t, J=7 Hz, 3H), 3.19-3.25 (m, 2H), 3.74 (s, 3H), 3.89
(s, 2H), 6.98 (d, J=9 Hz, 1H), 7.39 (t, J=9 Hz, 1H), 7.61-7.70 (m,
2H), 7.83-7.85 (m, 2H), 8.46 (s, 2H), 8.91 (t, J=6 Hz, 1H), 9.611
(s, 1H) ppm. MS (APCI+): 406.1 (M+1); LC-MS: 92%.
##STR00407##
Example 308
Preparation of P-400
[1025] Synthesis of 5-(3-Bromo-4-methoxy-benzyl)-pyridin-2-ylamine
(I-267) In a 40 mL vial equipped with a stir bar was placed I-42
(1.0 g, 3.57 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine
(865 mg, 3.93 mmol), potassium phosphate (tribasic) (1.52 g, 7.14
mmol), dimethoxyethane (6.0 mL) and 50% aqueous ethanol (6.0 mL).
The mixture was degassed with nitrogen for 20 minutes and then add
tetrakis(triphenylphosphine)palladium(0) (619 mg, 0.536 mmol). The
mixture was heated to 60.degree. C. for 4 hours and then the
palladium catalyst was filtered off. To the filtrate were added
water (50 mL) and a saturated ammonium chloride solution (50 mL).
After extracting with ethyl acetate (2.times.60 mL), the organic
portions were combined, washed with brine (50 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 10% acetone/dichloromethane, 30% acetone/dichloromethane,
40% acetone/dichloromethane as the eluent to produce 308 mg of
I-267 as a yellow viscous oil in 29% yield. MS (APCI+): 295.0
(M+1); LC-MS: >99%.
[1026] Synthesis of
1-[5-(3-Bromo-4-methoxy-benzyl)-pyridin-2-yl]-3-ethyl-urea (I-268).
In an 8 mL vial equipped with a stir bar was placed I-267 (300 mg,
1.02 mmol), pyridine (3.5 mL) and ethyl isocyanate (646 .mu.L, 8.16
mmol). The reaction mixture was stirred at room temperature for 18
hours. The reaction mixture was quenched with water (30 mL) and 1M
aqueous HCl (30 mL). After extracting with dichloromethane
(2.times.60 mL), the organic portions were washed with 1M aqueous
HCl (40 mL), brine (40 mL), dried (MgSO.sub.4) and concentrated.
The crude sticky material was recrystallized with diethyl ether (2
mL), ethyl acetate (1 mL) and hexanes (700 .mu.L). The resulting
solid was collected by suction filtration and washed with diethyl
ether (2.times.1 mL) to produce 49 mg of I-268 as an off-white
solid in 13% yield. MS (APCI+): 366.0 (M+1); LC-MS: 98%.
[1027] Synthesis of
1-[5-(3'-Cyano-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-3-ethyl-urea
(P-400). In an 8 mL vial equipped with a stir bar was placed I-268
(47 mg, 0.129 mmol), 3-cyanophenylboronic acid (22.7 mg, 0.155
mmol), potassium phosphate (tribasic) (54.8 mg, 0.258 mmol),
dimethoxyethane (250 .mu.L) and 50% aqueous ethanol (250 .mu.L).
The mixture was degassed with nitrogen for 15 minutes and then add
tetrakis(triphenylphosphine)palladium(0) (14.9 mg, 0.0129 mmol).
The mixture was heated to 85.degree. C. for 18 hours and then the
palladium catalyst was filtered off. To the filtrate were added
water (20 mL) and a saturated ammonium chloride solution (20 mL).
After extracting with ethyl acetate (2.times.30 mL), the organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 15% acetone/dichloromethane as the eluent to produce 27
mg of P-400 as a white solid in 55% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.07 (t, J=7 Hz, 3H), 3.13-3.20 (m, 2H), 3.75
(s, 3H), 3.84 (s, 2H), 7.07 (d, J=8 Hz, 1H), 7.23 (s, 1H), 7.25 (s,
1H), 7.55-7.62 (m, 3H), 7.77-7.82 (m, 1H), 7.90 (m, 1H), 8.10 (br
s, 1H), 9.06 (s, 1H) ppm. MS (APCI+): 387.1 (M+1); LC-MS: 98%.
Example 309
Preparation of P-433
##STR00408##
[1029] Synthesis of 4-Tributylstannanyl-pyridine-2-carbonitrile
(I-214). In a 40 mL vial equipped with a stir bar was placed
4-iodo-pyridine-2-carbonitrile (1.26 g, 5.48 mmol), 1,4-dioxane (18
mL), and bis(tributyl) tin (3.32 mL, 6.58 mmol). After the reaction
mixture was degassed with nitrogen for 15 minutes,
bis(triphenylphosphine)-palladium(II) dichloride (192 mg, 0.274
mmol) was added. The reaction mixture was heated to 90.degree. C.
for 18 hours and then quenched with 2.2 M aqueous potassium
fluoride (100 ml) in order to consume excess tin reagent. After
stirring at room temperature for 2 hours, the mixture was filtered
through Celite. To the filtrated was added water (50 mL), followed
by extractions with ethyl acetate (5.times.100 mL). The organic
portions were combined, washed with 2.2 M aqueous potassium
fluoride (150 mL), water (150 mL) and brine (150 mL). After drying
the organic portion with magnesium sulfate, the material was
concentrated and purified by column chromatography utilizing 5%
ethyl acetate/hexanes as the eluent to produce 1.24 g of I-214 as a
colorless oil in 58% yield.
[1030] MS (APCI+): 394.0 (M+1)
##STR00409##
[1031] Synthesis of
4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitr-
ile (P-433). In an 18 mL vial equipped with a stir bar was placed
I-33 (162 mg, 0.492 mmol), 1,4-dioxane (2.3 mL), and I-214 (232 mg,
0.590 mmol). After the reaction mixture was degassed with nitrogen
for 20 minutes, bis(triphenylphosphine)-palladium(II) dichloride
(17.3 mg, 0.0246 mmol) was added. The reaction mixture was heated
to 80.degree. C. for 18 hours. To the reaction mixture was added
water (40 mL) followed by extractions with ethyl acetate
(2.times.60 mL). The organic portions were combined, washed with
brine (40 mL), dried (magnesium sulfate) and concentrated. The
residue was purified by column chromatography utilizing 30% ethyl
acetate/hexanes as the eluent to produce 102 mg of P-433 as an
orange oil in 59% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 3.74 (s, 3H), 4.06 (s, 2H), 6.98 (d, J=9 Hz, 1H), 7.28-7.30
(m, 1H), 7.38-7.47 (m, 4H), 7.56 (d, J=5 Hz, 1H), 7.93 (s, 1H),
8.65 (d, J=5 Hz, 1H) ppm.
[1032] MS (APCI+): 354.0 (M+1); LC-MS: 97%.
Example 310
Preparation of P-437
##STR00410##
[1034] Synthesis of
C-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-met-
hylamine (P-437). In an 8 mL vial equipped with a stir bar was
placed P-433 (95 mg, 0.269 mmol), methanol (2.8 mL), concentrated
HCl (113 .mu.L, 1.35 mmol), 10% palladium on activated carbon (19.0
mg), followed by attachment of a balloon of hydrogen. The mixture
was allowed to stir at room temperature for 2 hours and then
filtered through Celite. To the filtrate was added water (20 mL),
the pH was adjusted to 10-11 with 1M NaOH, and extractions were
done with ethyl acetate (2.times.60 mL). The organic portions were
combined, washed with brine (50 mL), dried (magnesium sulfate) and
concentrated. The residue was purified by column chromatography
utilizing 10% methanol/dichloromethane to produce 14 mg of P-437 as
a black, semi-solid in 14% yield.
[1035] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.17 (s, 2H),
3.74 (s, 3H), 3.78 (s, 2H), 3.95 (s, 2H), 6.96 (d, J=8 Hz, 1H),
7.06-7.07 (m, 1H), 7.28-7.47 (m, 6H), 8.37 (d, J=5 Hz, 1H) ppm. MS
(APCI+): 358.0 (M+1); LC-MS: 96%.
##STR00411##
Example 311
Preparation of P-454
[1036] Synthesis of 2-Bromo-1-methoxy-4-(4-nitro-benzyl)-benzene
(I-269). In a 100 mL round bottomed flask equipped with a stir bar
was placed I-42 (2.0 g, 7.14 mmol), 4-nitrophenylboronic acid (2.27
g, 7.85 mmol), potassium phosphate (tribasic) (3.03 g, 14.3 mmol),
dimethoxyethane (12 mL) and 50% aqueous ethanol (12 mL). The
mixture was degassed with nitrogen for 20 minutes and then added
tetrakis(triphenylphosphine)palladium(0) (825 mg, 0.714 mmol). The
mixture was heated to 60.degree. C. for 4 hours and then the
palladium catalyst was filtered off. To the filtrate were added
water (50 mL) and a saturated ammonium chloride solution (100 mL).
After extracting with ethyl acetate (3.times.100 mL), the organic
portions were combined, washed with brine (150 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 15% ethyl acetate/hexanes as the eluent to produce 1.06 g
of I-269 as a pale yellow solid in 46% yield. MS (APCI-): 321.2
(M-1).
[1037] Synthesis of 3'-Chloro-2-methoxy-5-(4-nitro-benzyl)-biphenyl
(I-270). In a 40 mL vial equipped with a stir bar was placed I-269
(960 mg, 2.98 mmol), 3-chlorophenylboronic acid (559 mg, 3.58
mmol),), potassium phosphate (tribasic) (1.27 g, 5.96 mmol),
dimethoxyethane (5 mL) and 50% aqueous ethanol (5 mL) and
tetrakis(triphenylphosphine)palladium(0) (344 mg, 0.298 mmol). The
mixture was heated to 67.degree. C. for 65 hours and then the
palladium catalyst was filtered off. To the filtrate were added
water (50 mL) and a saturated ammonium chloride solution (70 mL).
After extracting with ethyl acetate (3.times.75 mL), the organic
portions were combined, washed with brine (80 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 10% ethyl acetate/hexanes as the eluent to produce 1.05 g
of I-270 as a yellow viscous oil in quantitative yield. MS (APCI-):
351.8 (M-2).
[1038] Synthesis of
4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-271). In
a 40 mL vial equipped with a stir bar was placed iron powder (586
mg, 10.5 mmol), ethanol (12 mL) and water (3.8 mL). The mixture was
heated to 85.degree. C. in an oil bath and then I-270 (1.05 g, 3.00
mmol) was added and the reaction was continued at 85.degree. C. for
2 hours. The reaction mixture was cooled to room temperature and
filtered through Celite. To the filtrate was added water (60 mL)
and extractions were performed with ethyl acetate (2.times.60 mL).
The organic portions were combined, washed with brine (60 mL),
dried (MgSO.sub.4) and concentrated to produce 862 mg of I-271 as a
pale orange viscous oil in 89% yield.
[1039] MS (APCI+): 324.1 (M+1); LC-MS: 97%.
[1040] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-thiazol-2-yl-amine
(P-454). In an 8 mL vial equipped with a stir bar was placed I-271
(70 mg, 0.216 mmol), 2-bromothiazole (38.5 .mu.L, 0.432 mmol), 10%
aqueous ethanol (1.1 mL) and concentrated hydrochloric acid (36.0
.mu.L, 0.432 mmol). The mixture was heated to 95.degree. C. for 18
hours and then combined with the reaction mixture from a 50 mg
scale reaction of the exact same type. After water (30 mL) and 5%
aqueous potassium carbonate (30 mL) were added, the aqueous portion
was extracted with ethyl acetate (2.times.30 mL) and the organic
portions were combined, washed with water (40 mL), brine (40 mL),
dried (magnesium sulfate) and concentrated. The crude material was
purified by column chromatography utilizing 3%
acetone/dichloromethane as the eluent to produce 70 mg of P-454 as
viscous, light yellow oil in 47% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.79 (s, 3H), 3.94 (s, 2H), 6.61 (d, J=4 Hz,
1H), 6.91 (d, J=8 Hz, 1H), 7.12-7.19 (m, 5H), 7.27-7.33 (m, 4H),
7.38 (dt, J=7, 2 Hz, 1H), 7.50 (t, J=2 Hz, 1H). MS (APCI+): 407.0
(M+1); LC-MS: 99%.
Example 312
Preparation of P-458
##STR00412##
[1042] Synthesis of
2-{[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]--
methyl-amino}-ethanol (P-458). In an 8 mL vial equipped with a stir
bar was placed I-177 (40 mg, 0.110 mmol), 2-(methylamino)-ethanol
(13.2 .mu.L, 0.165 mmol), isopropanol (600 .mu.L) and
diisopropylethylamine (57.5 .mu.L, 0.330 mmol). The mixture was
heated to 80.degree. C. for 18 hours, combined with an identical 20
mg scale reaction and then treated with water (30 mL), 1M HCl (20
mL) and extracted with dichloromethane (2.times.50 mL). The organic
portions were combined, washed with brine (50 mL), dried (magnesium
sulfate) and concentrated. The residue was purified by silica gel
column chromatography utilizing 10% acetone/dichloromethane as the
eluent to produce 35 mg of P-458 as a colorless, viscous oil in 52%
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.10 (s, 3H),
3.52-3.53 (m, 4H), 3.72 (s, 3H), 3.75 (s, 2H), 4.64 (t, J=5 Hz,
1H), 6.93 (d, J=8 Hz, 1H), 7.27-7.32 (m, 2H), 7.38 (s, 1H),
7.43-7.47 (m, 2H), 8.22 (s, 2H) ppm.
[1043] MS (APCI+): 402.0 (M+1); LC-MS: 99%.
Example 313
Preparation of P-467
##STR00413##
[1045] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-(1-methyl-1H-imidazo-
l-2-yl)-amine (P-467). In an 8 mL vial equipped with a stir bar was
placed I-271 (150 mg, 0.463 mmol), 2-bromo-1-methyl-1H-imidazole
(67.8 .mu.L, 0.695 mmol), p-toluenesulfonic acid (106 mg, 0.556
mmol) and toluene (2.0 mL). The mixture was heated to 115.degree.
C. for 18 hours and then treated with water (30 mL) followed by
adjustment to pH 10 with 5% aqueous potassium carbonate. After
extracting with ethyl acetate (2.times.35 mL), the organic portions
were combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel column
chromatography utilizing 5% then 50% acetone/dichloromethane as the
eluent to produce 89 mg of P-467 as a pale orange solid in 47%
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.45 (s, 3H),
3.74 (s, 3H), 3.82 (s, 2H), 6.61 (d, J=2 Hz, 1H), 6.81 (d, J=2 Hz,
1H), 7.02-7.07 (m, 3H), 7.15 (d, J=2 Hz, 1H), 7.19 (dd, J=8, 2 Hz,
1H), 7.24 (d, J=8, 2H), 7.35-7.44 (m, 3H), 7.48 (bs, 1H), 8.09 (s,
1H) ppm; MS (APCI+): 404.1 (M+1).
[1046] LC-MS: >99%.
##STR00414##
Example 314
Preparation of P-515
[1047] Synthesis of
4-[4-(3-Bromo-2-fluoro-4-methoxy-benzyl)-pyridin-2-yl]-piperazine-1-carbo-
xylic acid tert-butyl ester (I-273). In a 40 mL vial equipped with
a stir bar was placed I-31 (642 mg, 2.15 mmol),
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperaz-
ine-1-carboxylic acid tert-butyl ester (922 mg, 2.37 mmol),
potassium phosphate (tribasic) (913 mg, 4.30 mmol), dimethoxyethane
(3.6 mL) and 50% aqueous ethanol (3.6 mL). After degassing with
nitrogen for 15 minutes, tetrakis(triphenylphosphine)palladium(0)
(248 mg, 0.215 mmol) was added. The mixture was heated to
60.degree. C. for 5 hours and then the palladium catalyst was
removed by filtering through Celite. To the filtrate were added
water (50 mL) and a saturated ammonium chloride solution (50 mL).
After extracting with ethyl acetate (3.times.75 mL), the organic
portions were combined, washed with brine (75 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 35% ethyl acetate/hexanes as the eluent to produce 495 mg
of I-273 as a yellow, viscous oil in 48% yield.
[1048] MS (APCI+): 480.0 (M+1);
[1049] Synthesis of
4-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pip-
erazine-1-carboxylic acid tert-butyl ester (I-274). In a 18 mL vial
equipped with a stir bar was placed I-273 (490 mg, 1.02 mmol),
3-chlorophenyl boronic acid (191 mg, 1.22 mmol), potassium
phosphate (tribasic) (433 mg, 2.04 mmol), dimethoxyethane (2.0 mL)
and 50% aqueous ethanol (2.0 mL). After degassing with nitrogen for
15 minutes, tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.102
mmol) was added. The mixture was heated to 90.degree. C. for 22
hours and then the palladium catalyst was removed by filtering
through Celite. To the filtrate was added water (150 mL) followed
by extractions with ethyl acetate (3.times.75 mL). The organic
portions were combined, washed with brine (75 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 25% then 35% ethyl acetate/hexanes as the eluent to
produce 360 mg of I-274 as a pale yellow solid in 69% yield. MS
(APCI+): 512.1 (M+)
[1050] Synthesis of
1-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pip-
erazine (P-515) In a 40 mL vial equipped with a stir bar was placed
I-274 (360 mg, 0.703 mmol) and dichlormethane (2.3 mL). The
solution was cooled in an ice-water bath for 10 minutes and then
trifluoroacetic acid (522 .mu.L, 7.03 mmol) was added. The solution
was stirred at room temperature for 3 hours and then concentrated
by a stream of nitrogen. To the oil was added water (50 mL), a
saturated sodium bicarbonate solution (till pH 8) followed by
extractions with dichloromethane (2.times.75 mL). The organic
portions were combined, washed with brine (50 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by column
utilizing 10%, 15% and then 20% methanol/dichloromethane as the
eluent to produce 120 mg of P-515 as an off-white solid in 41%
yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.80 (t, J=5 Hz,
4H), 3.39 (t, J=5 Hz, 4H), 3.73 (s, 3H), 3.84 (s, 2H), 6.46 (d, J=5
Hz, 1H), 6.69 (s, 1H), 6.94 (d, J=8 Hz, 1H), 7.28 (bd, J=7 Hz, 1H),
7.32 (t, J=9 Hz, 1H), 7.36 (s, 1H), 7.41-7.47 (m, 2H), 7.98 (d, J=5
Hz, 1H) ppm. MS (APCI+): 412.1 (M+1); LC-MS: >99%.
Example 315
Preparation of P-518
##STR00415##
[1052] Synthesis of
4-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pip-
erazine-1-carboxylic acid amide (P-518). In an 8 mL vial equipped
with a stir bar was placed P-515 (50 mg, 0.121 mmol), water (800
.mu.L), acetic acid (400 .mu.L) and sodium cyanate (31.5 mg, 0.484
mmol). The mixture was stirred at room temperature for 18 hours and
then water (30 mL) was added. After adjusting to pH 8 with a
saturated sodium bicarbonate solution, the aqueous portion was
extracted with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated to produce an off-white solid. The
residue was triturated with diethyl ether (1 mL), collected and
dried in a high vacuum oven for 18 hours to produce 17 mg of P-518
as an off-white solid in 30% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 3.36-3.44 (m, 8H), 3.73 (s, 3H), 3.85 (s,
2H), 6.03 (s, 2H), 6.48 (d, J=5 Hz, 1H), 6.76 (s, 1H), 6.94 (d, J=9
Hz, 1H), 7.28 (d, J=7 Hz, 1H), 7.33 (t, J=9 Hz, 1H), 7.37 (s, 1H),
7.41-7.47 (m, 2H), 8.00 (d, J=5 Hz, 1H) ppm. MS (APCI+): 455.1
(M+1).
Example 316
Preparation of P-519
##STR00416##
[1054] Synthesis of
4-[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pip-
erazine-1-carboxylic acid ethylamide (P-519). In an 8 mL vial
equipped with a stir bar was placed P-515 (60 mg, 0.146 mmol),
pyridine (500 .mu.L) and ethyl isocyanate (92.5 .mu.L, 1.17 mmol).
The mixture was stirred at room temperature for 18 hours and then
treated with water (20 mL) and a saturated sodium bicarbonate
solution (20 mL). After extractions with dichloromethane
(3.times.30 mL), the organic portions were combined, washed with 1M
HCl (2.times.30 mL), brine (40 mL), dried (MgSO.sub.4) and
concentrated to produce an off-white solid. The crude material was
triturated with diethyl ether (1 mL), collected and dried in a high
vacuum oven for 18 hours to produce 22 mg of P-519 in 31% yield.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.02 (t, J=4 Hz, 3H),
3.05-3.18 (m, 2H), 3.42 (br s, 4H), 3.53 (br s, 4H), 3.74 (s, 3H),
3.93 (s, 2H), 6.57 (m, 2H), 6.96 (d, J=8 Hz, 2H), 7.28 (d, J=7 Hz,
1H), 7.35-7.48 (m, 3H), 7.96 (d, J=5 Hz, 1H) ppm.
[1055] MS (APCI+): 483.1 (M+1); LC-MS: 98%.
Example 317
Preparation of P-527
##STR00417##
[1057] Synthesis of
2-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]--
pyridine (P-527). In an 8 mL vial equipped with a stir bar was
placed 2-(1H-pyrazol-4-yl)-pyridine (31.4 mg, 0.216 mmol), DMF (600
.mu.L) and sodium hydride
[1058] (60%)(11.9 mg, 0.296 mmol). The mixture was stirred at room
temperature for 25 minutes and then a solution of I-33 (75 mg,
0.228 mmol) and DMF (600 .mu.L) was added and the reaction mixture
was stirred at room temperature for 18 hours. The reaction was
quenched with water (40 mL) and extracted with dichloromethane
(2.times.35 mL). The organic portions were combined, washed with
brine (40 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by silica gel column chromatography utilizing 30%
acetone/dichloromethane to produce 58 mg (65%) of P-527 as a
colorless viscous oil.
[1059] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H),
5.39 (s, 2H), 7.00 (d, J=9 Hz, 1H), 7.15-7.18 (m, 1H), 7.29-7.31
(m, 1H), 7.36 (d, J=9 Hz, 1H), 7.39 (s, 1H), 7.42-7.49 (m, 2H),
7.65 (dt, J=8, 1 Hz, 1H), 7.74 (td, J=8, 2 Hz, 1H), 8.03 (s, 1H),
8.36 (s, 1H), 8.48-8.50 (m, 1H) ppm. MS (APCI+): 394.1 (M+1);
LC-MS: 92%.
Example 318
Preparation of P-528
##STR00418##
[1061] Synthesis of
4-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]--
pyridine (P-528). In an 8 mL vial equipped with a stir bar was
placed 4-(1H-pyrazol-4-yl)-pyridine (31.4 mg, 0.216 mmol), DMF (600
.mu.L) and sodium hydride (60%)(11.9 mg, 0.296 mmol). The mixture
was stirred at room temperature for 25 minutes and then a solution
of I-33 (75 mg, 0.228 mmol) and DMF (600 .mu.L) was added and the
reaction mixture was stirred at room temperature for 18 hours. The
reaction was quenched with water (40 mL) and extracted with
dichloromethane (2.times.35 mL). The organic portions were
combined, washed with brine (40 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel column
chromatography utilizing 40% acetone/dichloromethane to produce 41
mg of P-528 as a white solid in 46% yield.
[1062] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H),
5.38 (s, 2H), 7.00 (d, J=8 Hz, 1H), 7.30 (br d, J=7 Hz, 1H), 7.36
(d, J=9 Hz, 1H), 7.39 (s, 1H), 7.42-7.48 (m, 2H), 7.57-7.58 (m,
2H), 8.09 (s, 1H), 8.49 (m, 3H) ppm.
[1063] MS (APCI+): 394.1 (M+1); LC-MS: 90%.
Example 319
Preparation of P-544
##STR00419##
[1065] Synthesis of
2-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]--
pyridine hydrochloride salt (P-544). In an 8 mL vial equipped with
a stir bar was placed 2-(1H-pyrazol-3-yl)-pyridine (41.8 mg, 0.288
mmol), DMF (800 uL) and sodium hydride (15.8 mg, 0.394 mmol). The
reaction mixture was stirred at room temperature for 25 minutes and
then a solution of I-33 (100 mg, 0.303 mmol) in DMF (800 uL) was
added and the reaction mixture was stirred at room temperature for
18 hours. The reaction was quenched with water (20 mL) and
extracted with ethyl acetate (2.times.30 mL). The organic portions
were combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by silica gel column
chromatography utilizing 15% acetone/dicholormethane as the eluent
to produce 79 mg as a colorless, viscous oil. The hydrochloride
salt was formed by treated the purified product with 1,4-dioxane
(500 uL) and 4.0M HCl in 1,4-dioxane (500 uL). After stirring for 1
hour at room temperature the reaction mixture was concentrated and
dried in a high vacuum oven set at 35.degree. C. for 18 hours to
provide 80 mg of P-544 as a white solid in 62% yield. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H), 5.49 (s, 2H), 7.01
(d, J=8 Hz, 1H), 7.09 (s, 1H), 7.30 (br d, J=7 Hz, 1H), 7.36-7.40
(m, 2H), 7.43-7.49 (m, 2H), 7.59 (br s, 1H), 8.01 (d, J=2 Hz, 1H),
8.16 (bs, 2H), 8.65 (d, J=5 Hz, 1H) ppm. MS (APCI+): 394.1
(M+1-HCl); LC-MS: >99%.
Example 320
Preparation of P-545
##STR00420##
[1067] Synthesis of
2-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]--
pyrazine (P-545). Same as procedure for P-544. Target compound
crashed out of DMF with addition of water (6 mL), collect solid,
wash with water (3.times.2 mL), dry in vacuum oven to afford 46 mg
(35%) of P-545 as an off-white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 3.75 (s, 3H), 5.42 (s, 2H), 7.01 (d, J=8 Hz,
1H), 7.30 (br d, J=7 Hz, 1H), 7.39 (t, J=8 Hz, 2H), 7.43-7.48 (m,
2H), 8.14 (s, 1H), 8.41 (d, J=2 Hz, 1H), 8.50 (s, 1H), 8.54-8.55
(m, 1H), 8.99 (d, J=2 Hz, 1H) ppm. MS (APCI+): 395.1 (M+1); LC-MS:
99%.
Example 321
Preparation of P-546
##STR00421##
[1069] Synthesis of
4-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]--
pyrimidine hydrochloride salt (P-546). Same as procedure for P-544.
Purification was performed using 30% acetone/dichloromethane as the
eluent. HCl salt formation provided 73 mg of P-546 HCl salt as a
white solid in 56% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 3.75 (s, 3H), 5.43 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.30 (br
d, J=7 Hz, 1H), 7.39 (br s, 1H), 7.40-7.49 (m, 3H), 7.79 (dd, J=6,
1 Hz, 1H), 8.21 (s, 1H), 8.61 (s, 1H), 8.71 (br d, J=5 Hz, 1H),
9.07 (s, 1H) ppm. MS (APCI+): 395.1 (M+1-HCl); [1070] LC-MS:
>99%.
Example 322
Preparation of P-549
##STR00422##
[1072] Synthesis of
3-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazol-2-yl]-
-pyridine hydrochloride salt (P-549). Same as procedure for P-544.
Purification was performed using 5% methanol/dichloromethane as the
eluent. HCl salt formation provided 14 mg of P-549 as a pale yellow
solid in 11% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
3.74 (s, 3H), 5.47 (s, 2H), 6.96 (d, J=9 Hz, 1H), 7.21-7.23 (m,
1H), 7.28-7.31 (m, 2H), 7.44-7.46 (m, 2H), 7.67-7.70 (m, 1H), 7.88
(s, 2H), 8.23 (dt, J=8, 2 Hz, 1H), 8.85 (dd, J=5, 2 Hz, 1H), 8.94
(d, J=2 Hz, 1H) ppm.
[1073] MS (APCI+): 394.1 (M+1-HCl); LC-MS: >99%.
Example 323
Preparation of P-559
##STR00423##
[1075] Synthesis of
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-thiophen-2-yl-1H-i-
midazole hydrochloride salt (P-559). Same as procedure for P-544.
Purification performed using 5% methanol/dichloromethane as the
eluent. HCl salt formation provided 61 mg of P-559 in 46% yield.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H), 5.52 (s,
2H), 6.84 (d, J=9 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 7.27-7.28 (m, 1H),
7.31-7.34 (m, 1H), 7.37 (bs, 1H), 7.44-7.49 (m, 2H), 7.70-7.75 (m,
3H), 8.00 (br d, J=4 Hz, 1H) ppm.
[1076] MS (APCI+): 399.1 (M+1-HCl); LC-MS: >99%.
Example 324
Preparation of P-551
##STR00424##
[1078] Synthesis of
2-[1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-5-trifluoromethyl-
-1H-pyrazol-3-yl]-pyridine hydrochloride salt (P-551). Same as
procedure for P-544. Purification performed using 3%
methanol/dichloromethane as the eluent. HCl salt formation provided
49 mg of P-551 as a white solid in 32% yield.
[1079] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H),
5.58 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 7.28-7.30
(m, 1H), 7.38 (s, 1H), 7.44-7.48 (m, 3H), 7.50 (s, 1H), 7.94-8.06
(m, 2H), 8.64-8.66 (m, 1H) ppm. MS (APCI+): 462.1 (M+1-HCl); [1080]
LC-MS: >99%.
Example 325
Preparation of P-552
##STR00425##
[1082] Synthesis of
3-[2-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-5-trifluoromethyl-
-2H-pyrazol-3-yl]-pyridine hydrochloride salt (P-552). Same as
procedure for P-544. Purification performed using 20%
acetone/dichloromethane as the eluent. HCl salt formation provided
53 mg of P-552 as an off-white solid in 35% yield.
[1083] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.75 (s, 3H),
5.58 (s, 2H), 7.01 (d, J=9 Hz, 1H), 7.27-7.31 (m, 2H), 7.37 (s,
1H), 7.43-7.49 (m, 2H), 7.72 (t, J=8 Hz, 2H), 8.48 (br d, J=8 Hz,
1H), 8.70 (dd, J=5, 1 Hz, 1H), 9.17 (d, J=2 Hz, 1H) ppm. MS
(APCI+): 462.1 (M+1-HCl); LC-MS: 98%.
Example 326
Preparation of P-388
##STR00426##
[1085] Synthesis of
1-(2-Chloro-ethyl)-3-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl-
)-pyridin-2-yl]-urea (I-272). To a solution of P-252 (180 mg, 0.525
mol) in chloroform (4 mL) was added 2-chloroethylisocyanate (66.4
mg, 0.630 mmmol) under nitrogen. The solution was stirred at room
temperature for 48 h. Additional 2-chloroethylisocyanate (33.2 mg,
315 mmol) was added, and the reaction was stirred at 80.degree. C.
overnight. The solvent was removed under vacuum and the crude
residue was purified by flash silica gel column chromatography
(0-5% acetone in dichloromethane) to give I-272 (86.9 mg, 37%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.75 (s, 1H), 8.10 (m,
1H), 7.47-7.38 (m, 1H), 7.38-7.26 (m, 4H), 7.10 (t, J=8.4 Hz, 1H),
6.90 (s, 1H), 6.72 (d, J=9.2 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 3.89
(s, 2H), 3.76 (s, 3H), 3.72-3.67 (m, 4H) ppm.
[1086] LCMS=55.1% purity. MS (APCI+)=448.0 (M).
[1087] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-imi-
dazolidin-2-one (P-388). A suspension of I-272 (85.0 mg, 0.190
mmol) and sodium carbonate (60.3 mg, 0.569 mmol) in acetonitrile (2
mL) was stirred at reflux 21 h. The reaction was cooled to room
temperature and the sodium carbonate removed by filtration. The
solid was washed with ethyl acetate (3.times.5 mL) and the filtrate
removed under vacuum. The residue was purified by silica gel
preparatory thin layer chromatography eluting with 15% acetone in
dichloromethane and using two developments, triturated in diethyl
ether (2 mL), and filtered to give P-388 (11.8 mg, 15% yield) as a
red pink powder. .sup.1H NMR (400 MHz, CDCl.sub.3) d: 8.09 (s, 1H),
7.43-7.28 (m, 5H), 7.08 (t, J=8.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H),
6.69 (d, J=8.8 Hz, 1H), 4.42 (t, J=8.0 Hz, 2H), 3.88 (s, 2H), 3.82
(t, J=7.8 Hz, 2H), 3.75 (s, 3H) ppm. LCMS=95.9% purity. MS
(APCI+)=412.1 (M+1).
Example 327
Preparation of I-275
##STR00427##
[1089] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid methyl ester (I-275). I-275 was synthesized from I-145 (516
mg, 1.59 mmol) and 2-methylcarboxypyridine-5-boronic acid pinocol
ester (460 mg, 1.75 mmol) using the a similar procedure to P-252.
The crude material was purified by flash silica gel column
chromatography (0-5% acetone in dichloromethane) to give I-275 (381
mg, 62% yield) as an orange syrup. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.65 (d, J=2.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.66
(dd, J=8.0 Hz, 2.0 Hz, 1H), 7.37-7.33 (m, 3H), 7.26-7.24 (m, 1H),
7.11 (t, J=8.6 Hz, 1H), 6.73 (dd, J=8.6 Hz, 1.0 Hz, 1H), 4.04 (s,
2H), 4.00 (s, 3H), 3.77 (s, 3H) ppm.
[1090] LCMS=96.8% purity. MS (APCI+)=386.0 (M+1).
Example 328
Preparation of I-276
##STR00428##
[1092] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid (I-276). To a solution of I-275 (317 mg, 0.822 mmol) in
tetrahydrofuran (2.2 mL), methanol (2.2 mL), and water (2.2 mL) was
added 1 N aqueous sodium hydroxide (1.64 mL, 1.64 mmol). The
resultant solution was stirred at room temperature for 23 h. The pH
was adjusted with glacial acetic acid to pH 4. Approximately
three-fourths of the solvent was removed under vacuum, and the
remaining suspension was diluted with water (10 mL). The suspension
was extracted with dichloromethane (3.times.10 mL), and the
combined extracts were dried over magnesium sulfate, filtered, and
the solvent removed under vacuum to give I-276 (250.8 mg, 82%
yield) as a beige solid.
[1093] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.50 (m, 1H), 8.13 (d,
J=7.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.37-7.32 (m, 3H), 7.26-7.24 (m,
1H), 7.13 (t, J=8.6 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.05 (s, 2H),
3.77 (s, 3H) ppm. MS (APCI+)=327.2 (M-44), MS (APCI-)=327.9
(M-44).
Example 329
Preparation of P-382
##STR00429##
[1095] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid dimethylamide (P-382). A solution of I-276 (50.0 mg, 0.134
mmol), dimethyl amine (33% by weight in ethanol, 26.6 uL, 0.148
mmol), EDCI (28.4 mg, 0.148 mmol), and HOBt (20.0 mg, 0.148 mmol)
was stirred at room temperature for 36 h. The solvent was removed
under vacuum and the residue dissolved in ethyl acetate (5 mL). The
organic solution was washed with water (5 mL), and the aqueous wash
extracted with ethyl acteate (5 mL). The organic extracts were
combined, washed with aqueous saturated sodium bicarbonate (10 mL),
water (5 mL) and brine (5 mL), dried over sodium sulfate, filtered,
and the solvent removed under vacuum. The crude yellow oil was
purified by silica gel preparatory thin layer chromatography
(dichloromethane) and dried under high vacuum at room temperature
for 4 h to give P-382 (28.6 mg, 54% yield) as a clear syrup.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.48 (s, 1H), 7.63-7.58 (m, 2H),
7.39-7.28 (m, 4H), 7.12 (t, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H),
4.00 (s, 2H), 3.770 (s, 3H), 3.13 (s, 3H), 3.10 (s, 3H) ppm.
LCMS=97.4% purity. MS (APCI+)=399.1 (M+1).
Example 330
Preparation of P-401
##STR00430##
[1097] Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid amide (P-401). To a suspension of I-276 (100 mg, 0.269 mmol)
in toluene (3 mL) was added thionyl chloride (70.5 uL, 0.807 mmol).
The reaction was sealed with nitrogen and stirred at 115.degree. C.
for 4 h over which it turned to a deep brown solution. The solvent
and excess thionyl chloride were removed under reduced pressure,
and the residue was dissolved in anhydrous tetrahydrofuran (3 mL).
To the yellow solution was added aqueous concentrated ammonium
hydroxide (5.8 uL, 0.807 mmoL) and the brown suspension was stirred
at room temperature over night. The brown suspension was dissolved
in ethyl acetate (50 mL) and water (50 mL). The two layers were
separated, and the aqueous layer extracted with ethyl acetate (50
mL). The two organic extractions were combined, washed with water
(50 mL), brine (50 mL), dried over sodium sulfate, filtered, and
the solvent removed under vacuum to give crude product. The product
was purified by silica gel silica gel preparatory thin layer
chromatography (eluting with 10% acetone in dichoromethane) to give
P-401 (42.0 mg, 42% yield) as an off-white solid. .sup.1HNMR (400
MHz, DMSO-d.sub.6) 8.54 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8.0 Hz,
1H), 7.78 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.57 (s, 1H), 7.45-7.35 (m,
4H), 7.28 (d, J=6.8 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 4.06 (s, 2H),
3.73 (s, 3H) ppm. LCMS=100.0% purity. MS (APCI+)=371.0 (M+1).
##STR00431##
Example 331
Preparation of I-280
[1098] Synthesis of Carbonic acid
3'-cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester
(I-278). I-278 was synthesized from
2'-fluoro-3'-hydroxymethyl-6'-methoxy-biphenyl-3-carbonitrile (500
mg, 1.94 mmol) using the same conditions as I-145 to give I-278
(466 mg, 75% yield) as a tacky white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.71 (m, 1H), 7.65-7.63 (m, 2H), 7.54-7.52 (m, 1H),
7.45-7.41 (m, 1H), 6.79 (d, J=9.2 Hz, 1H), 5.21 (s, 2H), 3.80 (s,
3H), 3.80 (s, 3H) ppm. LCMS=95.9% purity. MS (APCI-)=240.1 (M-75).
MS (APCI+)=279.1 (M-32).
[1099] Synthesis of
5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid methyl ester (I-279). I-279 was synthesized from I-278 (440.0
mg, 1.40 mmol) and 2-methylcarboxypyridine-5-boronic acid pinocol
ester (405 mg, 1.54 mmol) using the similar conditions to the
preparation of P-252. The crude product was purified by trituration
with diethyl ether (25 mL), filtered, and washed with diethyl ether
(2.times.5 mL) to give I-279 (354 mg, 67% yield) as a yellow
powder. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.65 (d, J=2.0 Hz, 1H),
8.07 (d, J=8.0 Hz, 1H), 7.69-7.60 (m, 4H), 7.51 (t, J=7.8 Hz, 1H),
7.15 (t, J=8.6 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 4.05 (s, 2H), 4.00
(s, 3H), 3.78 (s, 3H) ppm.
[1100] LCMS=96.3% purity. MS (APCI+)=377.1 (M+1).
[1101] Synthesis of
5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid (I-280). A solution of I-279 (150 mg, 0.399 mmol) and 1 N
aqueous sodium hydroxide (797 uL, 0.797 mmol) in methanol (1.5 mL),
water (1.5 mL) and tetrahydrofuran (1.5 mL) was stirred at room
temperature 11.5 h. Approximately one-half of the solvent was
removed under vacuum and the remaining suspension was acidified
with glacial acetic acid (2 mL). The suspension was diluted with
water (50 mL), and extracted into dichloromethane (2.times.30 mL).
The combined extracts were washed with brine (50 mL), dried over
sodium sulfate, filtered, and the solvent removed under vacuum to
give I-280 (109 mg, 76% yield) as a yellow foam.
Example 332
Preparation of P-415
##STR00432##
[1103] Synthesis of
5-(3'-Cyano-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid amide (P-415). P-415 was synthesized from I-280 (100 mg, 0.276
mmol) using the same conditions as for the preparation of P-401.
The crude product was purified by silica gel preparatory thin layer
chromatography (eluting with 25% acetone in dichloromethane),
triturated with diethyl ether (5 mL), filtered, and washed with
hexanes (2 mL) to give P-415 (10.0 mg, 10% yield) as a beige
powder. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.46 (m, 1H), 8.13 (d,
J=8.00 Hz, 1H), 7.78 (s, 1H), 7.70-7.61 (m, 4H), 7.51 (t, J=7.8 Hz,
1H), 7.16 (t, J=8.6 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 5.55 (s, 1H),
4.04 (s, 2H), 3.78 (s, 3H) ppm. LCMS purity=94.6%. MS (APCI+)=362.1
(M+1).
[1104] HPLC (254 nm); 92.23%. [Mobile Phase A and Mobile Phase
B=Water and Acetonitrile, Symmetry C18, (250.times.4.6 mm, 5 um),
Flow=1.0 mL/min, Inj. Wash=ACN, Inj. Vol.=10 uL. Retention
time=24.17 min]
Example 333
Preparation of P-504
##STR00433##
[1106] Synthesis
1-(2,6-Dimethoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(I-281). To a stirred solution of starting I-81 (1.93 mmol, 1.0
eq.) and 1-hydroxymethyl-pyrrolidin-2-one (1.93 mmol, 1.0 eq) in
nitrobenzene at room temperature was added aluminum chloride (1.93
mmol, 1.0 eq). The resulting mixture was stirred at room
temperature for 16 h. The reaction was diluted with water, and
extracted with 2 portions of dichloromethane. The combined organics
were washed with brine, dried over magnesium sulfate, and the
filtrate concentrated in vacuo. The residue was purified via silica
gel plug filtration, using a methanol/dichloromethane gradient as
eluent to afford I-281 as a glassy solid in 72% yield. .sup.1H NMR
(400 MHz, CDCl.sub.3) 2.03 (quintet, J=8.0, 7.6 Hz, 2H), 2.46 (dd,
J=8.4, 8.0 Hz, 2H), 3.28 (s, 3H), 3.34 (dd, J=8.8, 6.8 Hz, 2H),
3.75 (s, 3H), 4.51 (s, 2H), 6.76 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4
Hz, 1H), 7.58 (dd, J=8.4, 7.6 Hz, 1H), 7.77 (dt, J=7.6, 1.2 Hz,
1H), 8.21 (ddd, J=8.0, 1.2, 0.8 Hz, 1H), 8.32 (dd, J=2.0, 1.6 Hz,
1H) ppm. LC/MS (100%): APCI(+) found: 357.1 (M+1); calc'd: 356.4
m/z.
[1107] Synthesis
1-(2,6-Dihydroxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P-504). To a stirred solution I-281 in dichloromethane at
-70.degree. C. was added 1 eq. of boron tribromide as a 1.0 M
solution in dichloromethane. The resultant mixture was allowed to
warm to room temperature. After 3 h, the reaction was again cooled
to -70.degree. C. and an additional 1 eq. of boron tribromide
solution was added, and the reaction was allowed to warm to room
temperature, and stir for 16 h. The reaction was cooled to
-70.degree. C., and excess (3.6 eq.) boron tribromide solution was
added, and the reaction warmed to room temperature with stirring
over 18 h. The reaction was quenched with water, and extracted with
ethyl acetate. The combined extracts were washed successively with
water and brine, and the dried (MgSO.sub.4) solution was
concentrated to afford P-504 as a tan solid in 59% yield.
[1108] .sup.1H NMR, (400 MHz, DMSO-d.sub.6): 1.96 (quintet, J=7.6
Hz, 2H), 2.33 (dd, J=8.4, 8.0 Hz, 2H), 3.43 (t, J=7.2 Hz, 2H), 4.27
(s, 2H), 6.48 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.65 (dd,
J=8.8, 8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 8.12-8.14 (m, 2H), 9.45
(s, 1H), 9.55 (s, 1H) ppm. LC/MS (90.9%): APCI.sup.- found: 327.1
(M-1); calc'd: 328.3 m/z.
Example 334
Preparation of P-504, 1-282 and P-229
##STR00434##
[1110] (Demethylation of I-281: To a stirred solution of I-281 in
dichloromethane at -70.degree. C. was added a 1.0 M solution of
boron tribromide in dichloromethane over 1 minute. The resultant
solution was allowed to warm to room temperature and stirred
overnight, at which point TLC analysis indicated no progress. The
reaction was again cooled to -70.degree. C., and additional boron
tribromide solution (1 eq.) was added over 1 min. The resultant
solution was allowed to warm to room temperature, and stirred for 1
min, at which point, The reaction mixture was poured into ice
water, and extracted with 3 portions of ethyl acetate. The combined
extracts were washed with 3 portions of water, and brine. The
solution was dried over magnesium sulfate, concentrated in vacuo,
and the residue purified via preparatory thin layer chromatography
using 30% acetone in hexanes to afford the above compounds; P-504,
1-282, P-229.
[1111] I-282: .sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.93 (quintet,
J=7.6 Hz, 2H), 2.28 (dd, J=8.0, 7.6 Hz, 2H), 3.20 (s, 3H),
3.24-3.30 (M, 2H), 4.34 (s, 2H), 6.77 (d, J=8.4 Hz, 1H), 7.04 (d,
J=8.4 Hz, 1H), 7.71 (dd, J=9.2, 7.6 Hz, 1H), 7.85 (dd, J=8.0, 1.6
Hz, 1H), 8.19-8.21 (M, 2H), 9.76 (s, 1H) ppm.
[1112] LC/MS (97%) APCI.sup.+ found: 343.1 (M+1); calc'd: 342.4
m/z
[1113] P-229: .sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.96 (quintet,
J=7.6 Hz, 2H), 2.33 (t, J=8.0 Hz, 2H), 3.44 (t, J=7.2 Hz, 2H), 3.68
(s, 3H), 4.32 (s, 2H), 6.65 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz,
1H), 7.67 (t, J=8.0 Hz, 1H), 7.73 (dt, J=7.6, 1.6, 1.2 Hz, 1H),
8.07 (m, 1H), 8.15 (ddd, J=8.4, 1.6, 1.2 Hz, 1H) 9.53 (s, 1H)
ppm.
[1114] LC/MS (100%) APCI.sup.+ found: 343.1 (M+1); calc'd: 342.4
m/z
Example 335
Preparation of P-394
##STR00435##
[1116] Synthesis of
[4-(3'-Cyano-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea (P-384). A
suspension of I-285 (0.60 mmol, 1.0 eq), 3-cyanophenylboronic acid
(1.2 mmol, 2 eq), potassium phosphate (1.2 mmol, 2 eq), and
tetrakis(triphenylphosphine)palladium (0.06 mmol, 0.1 eq) in 5 mL
of dimethoxyethane and 1.6 mL of 50% aqueous ethanol was degassed
with nitrogen for 10 minutes. The resultant mixture was heated at
80.degree. C. for 18 h and cooled to ambient temperature. The
solids were removed by filtration and the cake washed with ethyl
acetate. The filtrate washed with successive portions of water and
brine, dried over magnesium sulfate, and filtered. The filtrate was
concentrated under a stream of nitrogen to a volume of 5 mL, and
the solids collected by filtration, washed with 2 portions of ethyl
acetate, and dried in vacuo over ethyl acetate vapors for 3 h to
afford the title compound, P-394, as a solid in 62% yield. .sup.1H
NMR, (400 MHz, DMSO-d.sub.6): 3.75 (s, 3H), 3.83 (s, 2H), 5.76 (s,
2H), 7.04-7.10 (m, 3H), 7.20-7.22 (m, 2H), 7.27-7.29 (m, 2H), 7.60
(dd, J=8.0, 7.6 Hz, 1H), 7.77-7.80 (m, 2H), 7.89 (dd, J=1.6, 1.2
Hz, 1H), 8.40 (s, 1H) ppm. LC/MS=98.5% purity: APCI.sup.+ found:
358.1 calc'd: 357.4 m/z
Example 336
Preparation of P-421
##STR00436##
[1118] Synthesis of
[4-(3'-Chloro-6-hydroxy-biphenyl-3-ylmethyl)-phenyl]-urea (P-421).
To a suspension of P-378 (2.2 mmol, 1.0 eq.) in dichloromethane at
-70.degree. C. was added a 1.0 M solution of boron tribromide in
dichloromethane (6.6 mmol, 3 eq) over 5 min. The resultant mixture
was allowed to stir and warm to ambient temperature, and stirred
for 20 min. The reaction was poured into ice water (100 mL),
stirred for 30 min, filtered, and the cake washed with successive
portions of water and hexanes. The solids were dried in vacuo over
ethyl acetate vapors for 4 h to afford the title compound P-421,
which was taken into further reactions as is. A portion of P-421
was further purified via chromatography on silica gel using acetone
in dichloromethane as eluent, followed by trituration with
dichloromethane to afford pure P-421 compound as a white solid.
[1119] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.78 (s, 2H), 5.75 (s,
2H), 6.86 (d, J=8.0 Hz, 1H), 7.00 (dd, J=8.4, 2.4 Hz, 1H), 7.07 (d,
J=8.4 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.4
(m, 1H), 7.41 (dd, J=8.0, 7.6 Hz, 1H), 4.47 (m, 1H), 7.56 (m, 1H),
8.40 (s, 1H), 9.50 (s, 1H) ppm.
[1120] LC/MS=100% purity. APCI.sup.+ found: 353.0 calc'd: 352.8
m/z
Example 337
Preparation of P-420
##STR00437##
[1122] Synthesis of
[4-(3'-Chloro-6-difluoromethoxy-2-fluoro-biphenyl-3-ylmethyl)-phenyl]-ure-
a (P-420). To a solution of P-421 (0.992 mmol, 1.0 eq) in 10 mL of
dimethylformamide was added sodium hydroxide (2.98 mmol, 3 eq), and
the resultant suspension stirred 5 min. Sodium
chlorodifluoroacetate (4.96 mmol, 5 eq) was added, and the mixture
stirred at 50.degree. C. for 18 h, and cooled to ambient
temperature. Additional sodium hydroxide (2 mmol, 2 eq) and sodium
chlorodifluoroacetate (3 mmol, 3 eq) were added, and the reaction
stirred at 50.degree. C. for an additional 5 h. The reaction was
poured into 50 mL of water, and extracted with 3 portions of ethyl
acetate. The combined organics were washed with successive portions
of water and brine, dried over magnesium sulfate, filtered and
concentrated. The residue was purified 3 times with flash column
chromatography on silica gel, followed by prep TLC to afford the
title compound, P-420, as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 3.89 (s, 2H), 5.76 (s, 2H), 7.10 (t, J=74.4 Hz, 1H),
7.12 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.27-7.31 (m, 3H), 7.33 (d,
J=2.0 Hz, 1H), 7.39-7.50 (m, 4H), 8.41 (s, 1H) ppm.
[1123] LC/MS=98.1% purity. APCI.sup.+ found: 403.0 calc'd: 402.8
m/z
Example 338
Preparation of P-468
##STR00438##
[1125] Synthesis of
[4-(3'-Chloro-2-fluoro-6-hydroxy-biphenyl-3-ylmethyl)-phenyl]-urea
(P-468). To a suspension of P-243 (3.9 mmol, 1.0 eq.) in
dichloromethane at -70.degree. C. was added a 1.0 M solution of
boron tribromide in dichloromethane (12 mmol, 3 eq) over 30 sec.
The resultant mixture was allowed to stir and warm to ambient
temperature, and stirred for 1 h. The reaction was poured into ice
water (75 mL), filtered, and the cake washed with successive
portions of water and hexanes. The solids were dried in vacuo at
40-45.degree. C. for 16 h to afford the title compound P-468, which
was taken into further reactions as is. A portion of the title
compound P-468 was further purified via chromatography on a silica
gel using acetone in dichloromethane as eluent to afford pure P-468
title compound as a white solid.
[1126] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.78 (s, 2H), 5.76 (s,
2H), 6.73 (d, J=8.4 Hz, 1H), 7.04-7.08 (m, 3H), 7.28-7.33 (m, 3H),
7.38-7.46 (m, 3H), 8.41 (s, 1H), 9.82 (s, 1H) ppm. HPLC purity:
99.5%
##STR00439##
Example 339
Preparation of I-286, I-287, I-150, I-147 and I-288
[1127] Synthesis of 3-Bromo-4-difluoromethoxy-benzaldehyde (I-286).
A suspension of 3-bromo-4-hydroxy-benzaldehyde (4.97 mmol; 1.0
eq.), cesium carbonate (7.46 mmol; 1.5 eq.) and sodium
chlorodifluoroacetate was stirred at 65.degree. C. for 5.5 h. The
mixture was partitioned with ethyl acetate and water, and the
aqueous portion extracted with diethyl ether. The combined extracts
were washed with successive portions of water and brine, dried over
magnesium sulfate, filtered and concentrated to afford the title
compound, I-286, as a yellow oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 7.49 (t, J=72.4 Hz, 3H), 7.54 (d, J=8.4 Hz, 1H),
8.00 (dd, J=8.4, 2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 9.96 (s, 1H)
ppm.
[1128] Synthesis of
3'-Chloro-6-difluoromethoxy-biphenyl-3-carbaldehyde (I-287). A
mixture of I-286 (7.98 mmol, 1.0 eq), 3-chlorophenylboronic acid
(8.76 mmol, 1.1 eq), cesium carbonate (15.9 mmol, 2.0 eq) and
palladium(II)acetate (0.40 mmol, 0.05 eq) in 20 mL of DMF was
degassed with nitrogen for 5 min. The resulting suspension was
heated to 50.degree. C. for 2 h, cooled to ambient for 16 h, and
additional palladium(II) acetate (0.40 mmol, 0.05 eq) added, and
the reaction heated again to 50.degree. C. for 2 h. The reaction
was cooled to <30.degree. C., and the solids removed by
filtration. The filtrate was partitioned with ethyl acetate and
water, and the aqueous portion extracted with ethyl acetate. The
combined extracts were washed with successive portions of 5%
lithium chloride, 0.5 N HCl, water and brine, dried over magnesium
sulfate, filtered and concentrated to afford the title compound,
I-287, as an oil in 98% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6):
7.40 (t, J=72.8 Hz, 1H), 7.49-7.62 (m, 5H), 8.02-8.04 (m, 2H),
10.04 (s, 1H) ppm.
[1129] Synthesis of
(3'-Chloro-6-difluoromethoxy-biphenyl-3-yl)-methanol (I-150). To a
solution of I-287 (6.8 mmol, 1.0 eq) in a mixture of 18 mL of THF
and 6 mL of water at 0-5.degree. C. was added sodium borohydride
(10 mmol, 1.5 eq), and the resultant mixture stirred for 10
minutes. The reaction was diluted with 10 mL of water, and the pH
adjusted to 8 with 15% ammonium chloride, and extracted with two
portions of ethyl acetate. The combined organics were washed with
successive portions of water and brine, dried over magnesium
sulfate, filtered and concentrated to afford the title compound,
I-150, in quantitative yield.
[1130] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 4.54 (d, J=5.6 Hz, 2H),
5.28 (t, J=5.2 Hz, 1H), 7.14 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.8 Hz,
1H), 7.40 (s, 1H), 7.42-7.52 (m, 6H) ppm.
[1131] Synthesis of
5-Bromomethyl-3'-chloro-2-difluoromethoxy-biphenyl (I-147). To a
solution of I-150 (3.5 mmol, 1.0 eq) in dichloromethane at
0-5.degree. C. was added phosphorous tribromide (1.8 mmol, 0.5 eq),
and the resulting solution was allowed to stir and warm naturally
to ambient temperature over 2 h. To the reaction was added 15 mL of
ice water, and the aqueous portion was extracted with 2 portions of
ethyl acetate. The combined organics were washed with successive
portions of saturated sodium bicarbonate, water and brine, dried
over sodium sulfate, filtered and concentrated to afford the title
compound, I-147 as an oil in 53% yield. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 4.77 (s, 2H), 7.21 (t, J=74.0 Hz, 1H), 7.31 (d,
J=8.4 Hz, 1H), 7.41-7.60 (m, 6H) ppm.
[1132] Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(I-288). A suspension of I-147 (1.7 mmol, 1.0 eq),
2-fluoropyridine-5-boronic acid (1.9 mmol, 1.1 eq), and potassium
phosphate (3.4 mmol, 2.0 eq) in a mixture of dimethoxyethane (11
mL), and of 50% ethanol (5.4 mL) was degassed with nitrogen for 5
min. To the reaction was added
tetrakis(triphenylphosphine)palladium (0.09 mmol, 0.05 eq), and the
mixture was degassed further for 2 min. The suspension was heated
to 65.degree. C. for 1.5 h, cooled to ambient temperature, thiol
functionalized silica gel (0.344 mmol) was added and stirred for 3
h. The solids were removed by filtration, the filtrate partition
with ethyl acetate and water, and the aqueous extracted with ethyl
acetate. The combined organics were washed with successive portions
of water and brine, dried over magnesium sulfate, filtered and
concentrated. The residue was purified via flash column
chromatography on silica gel using acetone in hexanes as eluent to
afford the title compound as an oil in 55% yield.
[1133] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 4.03 (s, 2H), 7.12 (t,
J=70.0 Hz, 1H), 7.11 (dd, J=8.4, 3.2 Hz, 1H), 7.25 (s, 1H), 7.31
(s, 1H), 7.36 (dd, J=6.4, 2.4 Hz, 1H), 7.41-7.52 (m, 6H), 7.90 (td,
J=8.4, 2.4 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H) ppm.
Example 340
Preparation of P-614
##STR00440##
[1135] Synthesis of
2-Azetidin-1-yl-5-(3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyrid-
ine (P-614). A mixture of I-288 (0.404 mmol, 1.0 eq.) and azetidine
(0.445 mmol; 1.1 eq.) in excess DBU was heated to 160.degree. C.
for 2.5 h, and allowed to cool to room temperature. The resultant
mixture was partitioned with dichloromethane and 0.5N HCl, and the
aqueous portion extracted with dichloromethane. The organics were
washed with 0.5 N HCl and water, dried over magnesium sulfate,
filtered and concentrated. The residue was purified by flash column
chromatography on silica gel using acetone in dichloromethane as
eluent to afford the title compound, P-614, as an oil in 32%
yield.
[1136] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.83-3.88 (m, 6H), 6.29
(d, J=8.0 Hz, 1H), 7.10 (t, J=74.0 Hz, 1H), 7.22 (s, 1H), 7.27-7.50
(m, 8H), 8.01 (d, J=2.0 Hz, 1H) ppm.
[1137] LC/MS (99%)--found: 402.4 calc'd: 400.9 m/z.
Example 341
Preparation of P-422
##STR00441##
[1139] Synthesis of
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-tetrazol-1-yl-pyri-
dine (P-422). A suspension of P-252 (0.18 g, 0.53 mmol) and sodium
azide (0.1 g, 1.58 mmol) in glacial acetic acid (5 mL) was added
trimethylorthoformate (0.17 g, 1.58 mmol) was stirred at room
temperature for 18. The reaction was diluted with cold water (60
mL), and basified with sat. NaHCO.sub.3 solution. The suspension
was extracted with dichloromethane (2.times.5 mL), washed with
brine (10 ml), dried over Na.sub.2SO.sub.4, filtered, and
concentrated under vacuum. The residue was purified by silica gel
column chromatography using dichloromethane, than preparatory thin
layer chromatography 40% ethyl acetate in hexanes to afford the
free base of P-422 (0.13 g, 62% yield) as white solid. A portion of
the free base of P-422 (0.04 g, 0.1 mmol) in ether (2 mL), then 2M
HCl in ether (0.3 ml) was added, stirred for 4 h. The ether layer
was decanted, triturated with ether (2.times.2 mL), dried to afford
P-422 (0.03 g, 64% yield) as white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 10.13 (s, 1H), 8.58 (s, 1H), 8.0 (d, J=1.6 Hz, 1H),
7.36-7.48 (m, 4H), 7.26-7.34 (m, 1H), 6.98 (d, J=9.2 Hz, 1H), 4.11
(s, 2H), 3.74 (s, 3H) ppm; MS (APCI+): 368.0 (M+1), LC-MS:
100%.
Example 342
Preparation of P-434
##STR00442##
[1141] Synthesis of
[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-urea
(P-434). To I-134 (0.14 g, 0.36 mmol) in THF (2.0 mL) was added
pyridine (0.5 mL) and trimethylsilylisocyanate (0.06 g, 0.54 mmol).
The reaction was stirred at room temperature for 90 h, and
concentrated under vacuum. The residue was then triturated with 1:1
dichloromethane-hexanes (5 mL), and dried to afford P-434 (0.16 g,
98% yield) as off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
9.08 (br s, 1H), 7.34-7.78 (m, 8H), 7.14 (d, J=8.4 Hz, 2H), 6.09
(s, 2H), 3.85 (s, 3H) ppm. MS (APCI+): 399 (M+1), LC-MS: 100%
Example 343
Preparation of P-441
##STR00443##
[1143] Synthesis of
{4-[1-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-1-hydroxy-ethyl]-pheny-
l}-urea (P-441). To I-135 (0.06 g, 0.15 mmol) in THF (10.0 mL) was
added methylmagnesium bromide (3M solution in diethyl ether, 0.2
mL, 0.6 mmol). The reaction was stirred at room temperature for 4
h, cooled to 0.degree. C., and quenched with saturated ammonium
chloride solution (3 mL). The reaction was extracted with ethyl
acetate (2.times.60 mL), washed with brine (40 ml), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by preparatory thin layer chromatography using 6%
methanol-in dichloromethane to afford P-441 (0.04 g, 61% yield) as
white solid.
[1144] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.42 (s, 1H), 7.70 (t,
J=8.8 Hz, 1H), 7.14-7.42 (m, 7H), 6.96 (d, J=8.4 Hz, 2H), 5.76 (s,
2H), 5.60 (s, 1H), 3.74 (s, 3H), 1.82 (s, 3H) ppm. MS (APCI+): 397
(M-16), LC-MS: 99.0%.
Example 344
Preparation of P-532
##STR00444##
[1146] Synthesis of
3'-Chloro-3-[bisdeutero-(4-nitro-phenyl)-methyl]-2-fluoro-6-methoxy-biphe-
nyl (I-291). A solution of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-nitro-phenyl)-methanone
(500 mg, 1.30 mmol) in dichloromethane (10 mL) was purged with
nitrogen. Trifluoroacetic acid (2.49 mL, 32.40 mmol) was added and
the reaction cooled to 0.degree. C. in an ice water bath. To the
solution was added sodium borodeuteride (543 mg, 12.96 mmol)
portion wise over 45 min. The reaction was stirred for 20 h,
allowing to warm to room temperature. The reaction was neutralized
with saturated aqueous sodium bicarbonate (25 mL) to pH 7.5, and
extracted with ethyl acetate (50 mL). The extract was washed with
water (2.times.25 mL) and brine (25 mL), dried over sodium sulfate,
and the solvent removed under reduced pressure to give crude I-291.
The product was purified by flash silica gel column chromatography
eluting with 20% ethyl acetate in hexanes to give I-291 (157 mg,
32% yield) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
8.18-8.15 (m, 2H), 7.52-7.37 (m, 5H), 7.29-7.27 (m, 1H), 6.97 (d,
J=8.8 Hz, 1H), 3.74 (s, 3H) ppm.
[1147] Synthesis of
4-[(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-bisduetero-methyl]-phenyl-
amine (I-292). A suspension of I-291 (140 mg, 0.375 mmol), iron
powder (73.2 mg, 1.31 mmol) and solid ammonium chloride (102 mg,
1.91 mmol) in ethanol (1.5 mL) and water (500 uL) was heated to
105.degree. C. for 1 h. The solvent was removed under vacuum, the
residue suspended in water (20 mL), and extracted with ethyl
acetate (2.times.20 mL). The combined organic extracts were washed
with water (2.times.20 mL) and brine (20 mL), dried over magnesium
sulfate, and the solvent removed under vacuum to give crude I-292.
The product was purified by flash silica gel column chromatography
to give I-292 (103 mg, 30.0% yield) as an orange oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.39 (m, 1H), 7.36-7.26 (m, 3H), 7.07 (t,
J=8.6 Hz, 1H), 7.03-7.00 (m, 2H), 6.68 (dd, J=8.4 Hz, 1.2 Hz, 1H),
6.65-6.61 (m, 2H), 3.74 (s, 3H), 3.57 (s, 2H) ppm.
[1148] Synthesis of
{4-[(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-bisduetero-methyl]-pheny-
l}-urea (P-532). A solution of I-292 (80 mg, 0.233 mmol) and sodium
cyanate (30.2 mg, 0.465 mmol) in water (4 mL) and glacial acetic
acid (2 mL) was stirred at room temperature for 2 h. The reaction
basified with saturated aqueous sodium bicarbonate (25 mL), and
extracted with dichloromethane (2.times.30 mL). The extract was
dried over magnesium sulfate and the solvent removed under vacuum
to give crude product. The crude product was purified by silica gel
preparatory thin layer chromatography eluting with 5% acetone in
dichloromethane to give P-532 (35.4 mg, 39% yield) as a white
powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.42 (s, 1H),
7.47-7.41 (m, 2H), 7.36 (s, 1H), 7.30-7.24 (m, 4H), 7.07 (d, J=8.8
Hz, 2H), 6.92 (d, J=9.2 Hz, 1H), 5.76 (s, 2H), 3.72 (s, 3H) ppm.
LCMS=100.0% purity MS (APCI+)=387.1 (M+1); HPLC (254 nm); 98.747%.
[Mobile Phase A and Mobile Phase B=Water and Acetonitrile, Symmetry
C18, (250.times.4.6 mm, 5 um), Flow=1.0 mL/min, Inj. Wash=ACN, Inj.
Vol.=10 uL. Retention time=27.89 min]
Example 345
Preparation of P-402
##STR00445##
[1150] Synthesis of
2-Bromo-5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine
(P-402). A solution of I-33 (400 mg, 1.21 mmol) and
2-bromopyridine-5-boronic acid (282 mg, 1.39 mmol) in
1,2-dimethoxyethane (12 mL) was degassed with a nitrogen stream for
10 minutes. To the solution was added potassium phosphate (770 mg,
3.63 mmol), ethanol (2.5 mL), water (2.5 mL), and
tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol) and
the reaction was stirred under nitrogen for 2 h. The ethanol and
dimethoxyethane were removed under vacuum, and the aqueous solution
extracted with ethyl acetate (3.times.20 mL). The combined organic
extracts were washed with water (10 mL) and brine (10 mL), dried
over sodium sulfate, and the solvent removed under vacuum. The
crude product was purified by flash silica gel column
chromatography eluting with 10% ethyl acetate in hexanes, followed
by silica gel preparatory thin layer chromatography eluting with
15% ethyl acetate in hexanes to give P-402 (243 mg, 49% yield).
.sup.1H NMR (CDCl.sub.3, 400 MHz): 8.27 (s, 1H), 7.24-7.41 (m, 6H),
7.09 (t, J=8.6 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 3.91 (s, 2H), 3.76
(s, 3H) ppm. Calc. 406.68; APCI.sup.+ (M+1): 407.9, 96%.
Example 346
Preparation of P-469
##STR00446##
[1152] Synthesis of
3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-oxa-
zolidin-2-one (P-469). A solution of P-402 (100 mg, 0.246 mmol) and
2-oxazolidinone (21.4 mg, 0.246 mmol) in dioxane (1 mL) and water
(7 uL) was degassed with a nitrogen stream for 15 min. To the
solution was added sodium tert-butoxide (33.0 mg, 0.344 mmol),
xantphos (8.5 mg, 0.0148 mmol), and palladium(II) acetate (1.65 mg,
0.00737 mmol), and the reaction was heated to 100.degree. C. with
stirring for 20 h. Additional 2-oxazolidinone (21.4 mg, 0246 mmol),
sodium tert-butoxide (33.0 mg, 0.344 mmol), xantphos (8.5 mg,
0.0148 mmol), and palladium(II)acetate (1.65 mg, 0.00737 mmol) were
added, and reacted stirred at reflux overnight. The reaction was
diluted with water (10 mL) and extracted with ethyl acetate (25
mL). The organic extract was washed with water (25 mL), brine (25
mL), dried over sodium sulfate, and the solvent removed under
vacuum. The residue was purified by silica gel preparatory thin
layer chromatography (10% ethyl acetate in hexanes.times.2, 35%
ethyl acetate in hexanes.times.4) to give crude product. To the
crude oil was added diethyl ether (2 mL) and 2 N hydrochloric acid
in diethyl ether. The suspension was stirred for 2 h, and filtered
to give P-469 (22.9 mg, 21% yield) as a yellow powder. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): 8.27 (d, J=2.4 Hz, 1H), 8.00 (d, J=8.8 Hz,
1H), 7.68 (dd, J=8.6 Hz, 2.6 Hz, 1H), 7.48-7.27 (m, 6H), 6.94 (d,
J=8.8 Hz, 1H), 4.44 (t, J=8.0 Hz, 2H), 4.14 (t, J=8.0 Hz, 2H), 3.73
(s, 3H).
[1153] LCMS purity=97.43%. MS (APCI+)=413.0 (M+1).
Example 347
Preparation of P-470
##STR00447##
[1155] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-3-m-
ethyl-imidazolidin-2-one (P-470). A solution of P-402 (115 mg,
0.283 mmol), 1-methyl-imidazolidin-2-one (56.7 mg, 0.566 mmol), and
xantphos (9.0 mg, 0.0170 mmol) in dioxane (1 mL) was degassed under
a nitrogen stream for 15 min. To the solution was added sodium
tert-butoxide (38.0 mg, 0.396 mmol), water (7 uL), and
palladium(II) acetate (1.90 mg, 0.00848 mmol) under nitrogen. The
reaction was stirred at 100.degree. C. for 24 h. The reaction was
diluted with water (30 mL), and extracted with ethyl acetate
(2.times.30 mL). The organic extracts were combined, washed with
water (30 mL) and brine (30 mL), dried over sodium sulfate, and the
solvent removed under vacuum. The crude product was purified by
silica gel thin layer chromatography eluting with 40% ethyl acetate
in hexanes and developed 6 times to give P-470 (76.1 mg, 63%
yield).
[1156] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.21 (d, J=8.8 Hz,
1H), 8.15 (d, J=2.4 Hz, 1H), 7.49-7.27 (m, 5H), 7.08 (t, J=8.6 Hz,
1H), 6.69 (dd, J=9.8 Hz, 1.0 Hz, 1H), 4.02 (t, J=8.0 Hz, 2H), 3.90
(s, 2H), 3.75 (s, 3H), 3.46 (t, J=8.0 Hz, 2H), 2.90 (s, 3H)
ppm.
Example 348
Preparation of P-423
##STR00448##
[1158] Synthesis of
1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pip-
erazine (P-423). To carbonic acid
3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester
(0.2 g, 0.62 mmol),
1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperaz-
ine (0.2 g, 0.68 mmol), bis-diphenylphosphinopentane (0.08 g, 0.18
mmol), potassium carbonate (0.26 g, 1.85 mmol) and allyl palladium
(II) chloride dimer (0.034 g, 0.09 mmol) was added dimethyl
formamide (6 mL). The reaction was degassed with an argon stream
for 10 min. The reaction was stirred at 85.degree. C. for 18 h. The
reaction was cooled to room temperature, poured onto crushed
ice-water (150 mL), filtered, washed with water, dried over sodium
sulfate, filtered, and the solvent removed under vacuum. The
residue was purified by silica gel column chromatography using 10%
methanol in dichloromethane to afford P-423 (0.05 g, 18% yield) as
light brown gummy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.20
(br s, 3H) 3.55-3.99 (m, 10H), 6.95 (d, J=8.59 Hz, 1H), 7.11 (br s,
1H), 7.23-7.39 (m, 3H), 7.39-7.55 (m, 2H), 7.69 (br s, 1H), 8.02
(s, 1H), 9.33 (br s, 2H) ppm. Calc. 411.9; APCI.sup.+ (M+1): 412.1,
97%.
Example 349
Preparation of P-514
##STR00449##
[1160] Synthesis of
4-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pip-
erazine-1-carboxylic acid ethylamide hydrochloride (P-514). To
P-423 (0.05 g, 0.11 mmol) in pyridine (1.5 mL) was added
ethylisocyanate (0.023 g, 0.33 mmol). The reaction was stirred at
room temperature for 20 h, and concentrated under vacuum. The
residue was purified by preparative thin layer chromatography using
5% methanol in dichloromethane to give crude material. The solid
was dissolved in diethyl ether (2 mL), then 2M HCl in diethyl ether
(0.5 ml) was added, the reaction stirred for 1 h, and concentrated
under vacuum to afford P-514 (0.035 g, 58% yield) as light yellow
solid.
[1161] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.20-8.26 (m, 1H), 7.93
(s, 1H), 7.74 (br s, 1H), 7.4-7.48 (m, 2H), 7.26-7.38 (m, 3H), 7.21
(br s, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.59 (br s, 1H), 3.89 (s, 2H),
3.73 (s, 3H), 3.40-3.75 (m, 8H), 3.01-3.16 (m, 2H), 1.00-1.08 (m,
3H) ppm. MS (APCI+): 483.1 (M+1), LC-MS: 99.1%.
##STR00450##
Example 350
Preparation of P-564
[1162] Synthesis of 4-(4-Fluoro-phenyl)-1-methyl-piperidin-4-ol
(I-293). A solution of N-methyl-piperidin-4-one (1.50 g, 13.3 mmol)
in diethyl ether (10 mL) was degassed under a nitrogen stream. The
solution was cooled to 0.degree. C. in an salt ice bath. To the
stirring solution was added 4-fluorophenylmagnesium bromide (1.74
g, 14.6 mmol) dropwise over 5 min. A solid formed partway through
the addition, and additional diethyl ether was added (2 mL).
[1163] The reaction was then stirred at 0.degree. C. for 2 h. To
the suspension was added aqueous ammonium chloride (15 mL). The
biphasic solution was diluted with ethyl acetate (40 mL) and
additional saturated aqueous ammonium chloride (20 mL). The layer
was separated, and the organic extract washed with brine (50 mL),
dried over sodium sulfate, filtered, and the solvent removed under
vacuum to give I-293 (965 mg, 32% yield) as a brown powder. The
product was taken on without further purification. .sup.1H NMR (400
MHz, DMSO-d.sub.6): 7.51-7.48 (m, 2H), 7.13-7.09 (m, 2H), 4.80 (s,
1H), 2.52-2.53 (m, 3H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 1.94-1.87
(m, 2H), 1.57-1.54 (m, 2H) ppm.
[1164] Synthesis of
4-(3'-Chloro-6-methoxy-biphenyl-3-yl)-4-(4-fluoro-phenyl)-1-methyl-piperi-
dine (P564). To nitrobenzene (2 mL) was added a solution of I-293
(286 mg, 1.37 mmol) in dimethylformamide (1.5 mL). The reaction was
stirred under a nitrogen atmosphere, cooled of 0.degree. C. in an
ice-water bath, and aluminum trichloride (304 mg, 2.28 mmol) was
added. The reaction was stirred at 0.degree. C. for 30 min over the
time which the solution turned from orange to purple. To the
solution was added I-294 (250 mg, 1.14 mmol) in dimethyl formamide
(0.5 mL). The solution was stirred for 2 h allowing to warm to room
temperature. The reaction was diluted with ethyl acetate (50 mL),
washed with saturated aqueous ammonium chloride (50 mL), water (50
mL), and brine (50 mL), dried over sodium sulfate, decanted, and
the solvent removed under vacuum. The residue was dissolved in
ethyl acetate (50 mL), and extracted into 4N aqueous hydrochloric
acid (50 mL). The aqueous extract was basified to pH 9 with solid
sodium bicarbonate, and the product extracted with ethyl acetate
(3.times.50 mL), and the solvent removed under vacuum. The product
was purified by flash silica gel column chromatography eluting with
10% ethyl acetate in hexanes. The impure product was diluted with
dichloromethane, dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The residue was suspended in diethyl
ether, filtered, and the mother liquor removed under vacuum to give
P-564 (109 mg, 23% yield) as a yellow orange powder. .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.46-7.46 (s, 1H), 7.32-7.26 (m, 3H),
7.24-7.20 (m, 2H), 7.16-7.15 (m, 2H), 6.99-6.94 (m, 2H), 6.90-6.87
(m, 1H), 3.78 (s, 3H), 2.46 (m, 8H), 2.24 (s, 3H) ppm. LCMS=96.14%
purity MS[APCI+]=410.1 (M+1),
##STR00451## ##STR00452##
Example 351
Preparation of P-516
[1165] Synthesis of 3-Bromo-4-tridueteromethoxy-benzaldehyde
(I-295). A suspension of 3-bromo-4-hydroxy-benzaldehyde (15.0 g,
74.6 mmol) and solid potassium carbonate (10.3 g, 74.6 mmol) in
dimethylformamide (150 mL) was stirred at room temperature for 15
min. To the suspension was added trideuteromethyl iodide (21.6 g,
149.2 mmol) and the reaction was stirred at room temperature for 60
h. The reaction was diluted with water (1000 mL) and extracted with
ethyl acetate (2.times.600 mL). The combined organic extracts were
washed with brine (1000 mL), dried over sodium sulfate, and the
solvent removed under vacuum to give I-295 (16.33 g) as a gummy
beige solid which was taken on without further purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) d: 9.86 (s, 1H), 8.10 (d, J=2.0
Hz, 1H), 7.94 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H)
ppm.
[1166] Synthesis of
3'-Chloro-6-trideuteromethoxy-biphenyl-3-carbaldehyde (I-296). A
suspension of I-296 (10.0 g, 45.9 mmol) and 3-chlorophenylboronic
acid (7.90 g, 50.45 mmol) in dimethyl formamide (225 mL) and 1 N
aqueous cesium carbonate (45 mL) was degassed with a nitrogen
stream for 30 min. To the suspension was added palladium(II)
acetate (1.04 g, 4.59 mmol) and the reaction was stirred at
50.degree. C. overnight. The suspension was filtered through celite
and washed with dimethyl formamide (100 mL). The solution was
diluted with water (1000 mL), and extracted with ethyl acetate
(2.times.600 mL). The combined extracts were washed with brine (500
mL), dried over sodium sulfate, decanted, and the solvent removed
under vacuum. The crude brown product was purified by flash silica
gel column chromatography eluting with 15% acetone in hexanes to
give I-296 (10.29 g, 90% yield) as a clear oil which solidified to
a yellow powder.
[1167] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.94 (s, 1H), 7.96 (dd,
J=8.4 Hz, 1.6 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.58 (s, 1H),
7.49-7.44 (m, 3H), 7.35 (d, J=8.4 Hz, 1H) ppm.
[1168] Synthesis of
(3'-Chloro-6-trideuteromethoxy-biphenyl-3-yl)-methanol (I-297). A
solution of I-296 (9.75 g, 39.05 mmol) in tetrahydrofuran (75 mL)
and water (75 mL) was cooled to 0.degree. C. in an ice water bath.
Over 5 minutes was added solid sodium borohydride (2.22 g, 58.58
mmol). The reaction was stirred, allowing to warm to room
temperature over 3 h. The reaction was diluted with ethyl acetate
(250 mL), washed with water (125 mL), and the aqueous wash
extracted with ethyl acetate (250 mL). The combined extracts were
washed with brine, dried over sodium sulfate, and the solvent
removed under vacuum to give product. The crude material was dried
under high vacuum to give I-297 (9.01 g, 92% yield) as a pale
yellow oil.
[1169] Synthesis of
5-Bromomethyl-3'-chloro-2-trideuteromethoxy-biphenyl (I-298).
[1170] A solution of I-297 (9.00 g, 35.76 mmol) and phosphorus
tribromide (4.84 g, 17.9 mmol) in dichloromethane (50 mL) was
stirred at 0.degree. C. and allowed to warm to room temperature
with stirring for 18.5 h. The reaction was cooled in an ice water
bath and 150 mL water was added. The reaction was extracted with
dichloromethane (2.times.100 mL). The combined extracts were washed
with aqueous saturated sodium bicarbonate (250 mL) and brine (100
mL), dried over magnesium sulfate, filtered, and the solvent
removed under vacuum to give I-298 (10.5 g, 92% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): 7.51-7.40 (m, 6H), 7.12 (d, J=8.8 Hz, 1H),
4.75 (s, 2H) ppm.
[1171] Synthesis of
[5-(3'-Chloro-6-trideuteromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-urea
(P-516). A suspension of I-298 (5.00 g, 15.89 mmol),
1-(uriedo)phenylboronic acid pinacol ester (4.16 g, 15.89 mmol),
and solid potassium phosphate (6.75 g, 31.79 mmol), in
1,2-dimethoxyethane (40 mL), water (10 mL), and ethyl alcohol (10
mL), was degassed with a nitrogen stream for 15 minutes. To the
suspension was added palladium tetrakis(triphenylphosphine) (3.67
g, 3.18 mmol) and the reaction was stirred overnight for 17 h. The
suspension was diluted with ethyl acetate (250 mL), washed with
water (200 mL) and brine (100 mL), dried over sodium sulfate,
filtered, and the solvent was removed under vacuum. The crude dark
red gum was dissolved in 100 mL DCM, and silia-thiol (10 g) was
added. The suspension was stirred at room temperature overnight.
The suspension was filtered and the solvent removed under vacuum.
The crude material was purified by flash silica gel column
chromatography (10% isopropyl alcohol in dichloromethane), and
dried under high vacuum overnight to give P-516 (1.20 g, 20% yield)
as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.48-7.47
(m, 1H), 7.44-7.35 (m, 3H), 7.29-7.27 (m, 2H), 7.20-7.15 (m, 2H),
7.10-7.07 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 3.83 (s, 2H) ppm.
LCMS=94.2% purity. MS (ESI+)=370.4 (M+1).
[1172] HPLC (254 nm); 97.000%. [Mobile Phase A and Mobile Phase
B=Water and Acetonitril, Symmetry C18, (250.times.4.6 mm, 5 um),
Flow=1.0 mL/min, Inj. Wash=ACN, Inj. Vol.=10 uL. Retention
time=26.69 min]
##STR00453##
Example 352
Preparation of I-299 and I-271
[1173]
N-[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-acetamide
(I-299) A solution of I-154 (3.90 g, 12.5 mmol) and
2-acetimidopyridine-5-boronic acid pinocol ester (3.60 g, 13.8
mmol) in 1,2-dimethoxyethane (100 mL) was degassed with a nitrogen
stream for 15 min. To the solution was added ethanol (12.5 mL),
water (12.5 mL), solid potassium phosphate (5.30 g, 25.0 mmol), and
degassing was continued for 20 min. To the resulting suspension,
triphenyl phosphine (985 mg, 3.78 mmol) and palladium(II)acetate
(281 mg, 1.25 mmol) were added under nitrogen. The suspension was
heated to 85.degree. C. with stirring for 4 h. The reaction was
diluted with ethyl acetate (500 mL), washed with water (2.times.250
mL) and brine (250 mL), dried over sodium sulfate, decanted, and
the solvent removed under vacuum. The crude material was purified
by flash silica gel column chromatography eluting with 40% ethyl
acetate in hexanes to give I-299 (2.20 g, 48% yield) as a yellow
oil. .sup.1H NMR. (400 MHz, DMSO-d.sub.6): 7.49 (t, J=1.8 Hz, 1H),
7.42-7.28 (m, 5H), 7.16-7.10 (m, 5H), 6.89 (d, J=8.4 Hz, 1H), 3.92
(s, 2H), 3.79 (s, 3H), 2.16 (s, 3H) ppm.
[1174] 4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
hydrochloride salt
[1175] (I-271). A solution of I-299 (2.20 g, 6.01 mmol) in ethanol
(90 mL) and concentrated aqueous hydrochloric acid (90 mL) was
stirred at room temperature for 1 h, and heated to 80.degree. C.
for an additional 2 h. The reaction was diluted with water (500 m),
basified to pH 9 with solid sodium bicarbonate, and extracted with
ethyl acetate (3.times.250 mL). The combined extracts were washed
with water (250 mL) and brine (250 mL), dried over sodium sulfate,
decanted, and the solvent removed under vacuum. The crude product
was stirred in 2 N hydrogen chloride in ethyl ether (15 mL) for 3 h
at room temperature. The suspension was filtered to give I-271
(1.55 g, 80% yield) as a beige powder.
[1176] .sup.1H NMR (400 MHz, DMSO-d.sub.6) d: 9.95 (br s, 2H),
7.49-7.34 (m, 6H), 7.25-7.20 (m, 4H), 7.05 (d, J=8.4 Hz, 1H), 3.94
(s, 2H), 3.74 (s, 3H) ppm.
[1177] LCMS=94.5% purity. MS (APCI+)=324.1 (M+1)
Example 353
Preparation of P-129
##STR00454##
[1179] Synthesis of
(2-Hydroxy-6-methoxy-3'-nitro-biphenyl-3-yl)-isoxazol-5-yl-methanone
(P-129). Nitrobenzene (1 mL) and AlCl.sub.3 (154 mg, 1.15 mmol)
were placed in an 8 mL vial with a stir bar and stirred at room
temperature for 10 min. Isoxazole-5-carbonyl chloride (151 mg, 1.15
mmol) was added and the solution was allowed to stir at room
temperature for another 30 minutes. Then adding I-81 (250 mg, 0.96
mmol) was added and the resulting solution was stirred at room
temperature for 20 hours and heating for 1 hour. The reaction
mixture was diluted with ethyl acetate (90 mL) washed with water,
brine and dried over Na.sub.2SO.sub.4. After filtration and removal
of solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/hexane to yield 100 mg (32%) of
P-129. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.91 (s, 3H) 6.71-6.78 (m,
1H) 7.10-7.15 (m, 1H) 7.52-7.64 (m, 1H) 7.57-7.64 (m, 1H),
7.72-7.77 (m, 1H) 8.21-8.30 (m, 1H) 8.44-8.47 (m, 1H), 8.48-8.53
(m, 1H), 12.62 (s, 1H) ppm.
Example 354
Preparation of P-130
##STR00455##
[1181] Synthesis of
3-isoxazol-5-ylmethyl-6-methoxy-3'-nitro-biphenyl-2-ol (P-130).
Compound P-129 (80 mg, 0.24 mmol) was diluted with TFA (2 mL) and
cooled to -20.degree. C. NaBH.sub.4 was added slowly and then the
solution was purge with N.sub.2 for 2 minutes. The reaction mixture
was stirred at room temperature for 20 hours under N.sub.2. The
reaction was quenched with ice/water (20 mL) and the pH was
adjusted to .about.6 using saturated aqueous NaHCO.sub.3. The
solution was extracted with ethyl acetate (2.times.30 mL) and the
combined ethyl acetate extracts were washed with brine and dried
over Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by preparative chromatography plate with 30%
ethyl acetate/hexanes to yield 52 mg of compound (P-130). .sup.1H
NMR (400 MHz, CDCl.sub.3) 3.73 (s, 3H), 4.12 (s, 2H), 4.89 (s, 1H),
5.99 (s, 1H), 6.57 (d, J=8.59 Hz, 1H), 7.20 (d, J=8.59 Hz, 1H),
7.63-7.73 (m, 2H), 8.14 (s, 1H), 8.22-8.29 (m, 2H) ppm. LC-MS
(APCI+): 327.1 (M+1).
Example 355
Preparation of P-133
##STR00456##
[1183] Synthesis of
3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzylamine (P-133).
[1184] A reaction mixture of compound I-70 (300 mg, 0.93 mmol),
2-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-isoindole-1,3-
-dione (338 mg, 0.93 mmol), triphenylphosphine (73 mg, 0.28 mmol),
K.sub.3PO.sub.4 (394 mg, 1.86 mmol), Pd(OAc).sub.2 (20.8 mg, 0.09
mmol) in 1,2-dimethoxyethane (8 mL), ethanol (0.8 mL) and water
(0.8 mL) was stirred at 80.degree. C. for 20 hours under Ar. The
reaction mixture was diluted with ethyl acetate (40 mL), washed
with water, brine and dried over Na.sub.2SO.sub.4. After filtration
and removal of solvent, the residue was purified by silica gel
column chromatography with ethyl acetate/hexane to yield 370 mg of
product that was reacted with hydrazine hydrate (0.11 mL, 2.34
mmol) in ethanol (10 mL). The reaction mixture was stirred at
80.degree. C. for 2 hours. The mixture was filtered and the
filtrate was concentrated. The resulting residue was triturated
with diethyl ether to obtain 150 mg (77%) of compound P-133.
.sup.1H NMR (400 MHz, CDCl.sub.3) 1.45 (br s, 2H), 3.80 (s, 3H),
3.86 (s, 2H), 4.07 (s, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.08-7.31 (m,
5H), 7.37 (d, J=7.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.80 (d, J=7.8
Hz, 1H) 8.15 (dd, J=8.2, 1.34 Hz, 1H) 8.38 (s, 1H) ppm. LC-MS
(APCI+): 349.1 (M+1) 100%.
Example 356
Preparation of P-158
##STR00457##
[1186] Synthesis of
N-[2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzyl]-formamide
(P-158). Formic acid (0.18 mL, 4.57 mmol) was added to acetic
anhydride (0.42 mL, 4.57 mmol) at 0.degree. C. Then reaction
mixture was heated at 50.degree. C. for 2 hours. 0.3 mL of the
above mixture was added dropwise into the DCM (1 mL) solution of
P-133 (50 mg, 0.14 mmol) at -30.degree. C. and then stirred at
-10.degree. C. 30 minutes then room temperature 20 hours. The
reaction mixture was diluted with ethyl acetate, washed with water,
brine and dried over Na.sub.2SO.sub.4. After removal of solvent,
the residue was purified by 2 g silica gel column chromatography
with ethyl acetate/hexane as eluent to give 53 mg of product P-158.
Yield: 100%. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.81 (s, 3H)
4.05 (s, 2H) 4.50 (d, J=5.77 Hz, 2H) 5.50 (br. s., 1H) 6.93 (d,
J=8.99 Hz, 1H) 7.03-7.14 (m, 2H) 7.16-7.35 (m, 4H) 7.54 (t, J=7.98
Hz, 1H) 7.80 (d, J=7.51 Hz, 1H) 8.13-8.19 (m, 2H) 8.37 (s, 1H)
LC-MS (APCI+): 349.1 (M+1) 98.2%.
Example 357
Preparation of P-501
##STR00458##
[1188] Synthesis of
N-[2-(6-Hydroxy-3'-nitro-biphenyl-3-ylmethyl)-benzyl]-formamide
((P-501). To a mixture of compound P-158 (30 mg, 0.08 mmol) in
dichloromethane (2 mL), was added BBr.sub.3 (1M in dichloromethane,
0.24 mL, 0.24 mmol) at -78.degree. C. under N.sub.2. The reaction
mixture was stirred at -78.degree. C. to room temperature and room
temperature over night. The reaction mixture was diluted with water
and extracted with ethyl acetate (3.times.6 mL). The ethyl acetate
extracts were washed with water, brine, and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by preparative chromatography plate with 2%
methanol (7M NH.sub.3)/dichloromethane (two developments) to give
20 mg (69%) of compound P-501. .sup.1H NMR (400 MHz, CDCl.sub.3)
4.03 (s, 2H), 4.49 (d, J=5.6 Hz, 2H), 5.52 (br s, 1H), 6.83-6.90
(m, 1H), 6.98-7.10 (m, 2H), 7.19-7.33 (m, 4H), 7.58 (t, J,=,7.9 Hz,
1H), 7.84 (d, J,=,7.5 Hz, 1H), 8.12-8.22 (m, 2H), 8.39 (s, 1H) ppm;
[1189] LC-MS (APCI+): 363.1 (M+1) 100%.
Example 358
Preparation of P-160
##STR00459##
[1191] Synthesis of
[3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzyl]-carbamic acid
tert-butyl ester (11.times.6) (P-160). A reaction mixture of
compound I-70 (400 mg, 1.24 mmol),
3-(n-Boc-aminomethyl)phenylboronic acid (312 mg, 1.24 mmol),
triphenylphosphine (98 mg, 0.37 mmol), K.sub.3PO.sub.4 (526 mg,
2.48 mmol), Pd(OAc).sub.2 (27.8 mg, 0.12 mmol) in
1,2-dimethoxyethane (10 mL), ethanol (1 mL) and water (1 mL) was
stirred at 80.degree. C. 20 hours under Ar. The reaction mixture
was diluted with ethyl acetate (40 mL), washed with water, brine
and dried over Na.sub.2SO.sub.4. After removal of solvent, the
residue was purified by silica gel column chromatography with ethyl
acetate/hexane to yield 200 mg of product P-160.
[1192] Yield: 36% .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.44 (s,
9H) 3.81 (s, 3H) 3.97 (s, 2H) 4.28 (br. s., 2H) 4.80 (br. s., 1H)
6.94 (d, J=8.32 Hz, 1H) 7.05-7.22 (m, 5H) 7.22-7.30 (m, 1H) 7.54
(t, J=7.98 Hz, 1H) 7.83 (d, J=7.65 Hz, 1H) 8.16 (dd, J=8.25, 1.14
Hz, 1H) 8.39 (s, 1H); LC-MS (APCI-): 448.2 (M-1) 100%.
Example 359
Preparation of P-161
##STR00460##
[1194] Synthesis of
3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-benzylamine (P-161).
[1195] To a mixture of compound P-160 (53 mg, 0.12 mmol) in
dichloromethane (2 mL), was added TFA (3 mL). The reaction mixture
was stirred at room temperature for 1 h. After removal of most
solvent, the residue was dissolved in dichloromethane (5 mL) and
washed with saturated aqueous NaHCO.sub.3 (2.times.10 mL), water,
brine and dried over Na.sub.2SO.sub.4. After filtration and removal
of solvent, the residue was purified by preparative chromatography
plate with 2% methanol (7M NH.sub.3)/dichloromethane to yield 30 mg
(73%) of compound P-161. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.81 (s,
3H), 3.84 (s, 2H), 3.98 (s, 2H), 6.94 (d, J=8.3 Hz, 1H), 7.09 (d,
J=7.51 Hz, 1H), 7.13-7.23 (m, 4H), 7.22-7.31 (m, 1H), 7.54 (t,
J=7.98 Hz, 1H), 7.83 (d, J=7.78 Hz, 1H), 8.11-8.20 (m, 1H), 8.39
(s, 1H) ppm; LC-MS (APCI+): 349.1 (M+1) 100%.
Example 360
Preparation of P-179
##STR00461##
[1197] 1-(3-Bromo-4-methoxy-benzyl)-1H-pyridin-2-one (I-205). A
reaction mixture of compound I-42 (550 mg, 1.96 mmol), pyridin-2-ol
(170 mg, 1.78 mmol), K.sub.2CO.sub.3 (538 mg, 3.89 mmol) in
1,2-dimethoxyethane (5 mL) was stirred at 80.degree. C. for 20
hours under Ar. The reaction mixture was diluted with
dichloromethane (15 mL), washed with water, brine and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by silica gel column chromatography with ethyl
acetate/hexanes to yield 230 mg (39%) of I-205.
[1198] Synthesis of
1-(3'-Acetyl-6-methoxy-biphenyl-3-ylmethyl)-1H-pyridin-2-one
(P-179). A reaction mixture of compound I-205 (100 mg, 0.35 mmol),
3-acetylphenyl boronic acid (58 mg, 0.35 mmol), triphenylphosphine
(18 mg, 0.07 mmol), K.sub.2CO.sub.3 (145 mg, 1.05 mmol),
Pd(OAc).sub.2 (9.5 mg, 0.04 mmol) in 1,2-dimethoxyethane (3 mL),
ethanol (0.5 mL) and water (0.5 mL) was stirred at 80.degree. C.
for 20 hours under Ar. The reaction mixture was diluted with ethyl
acetate (15 mL), washed with water, brine and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by preparative chromatography plate with 2%
methanol (7M NH.sub.3)/dichloromethane to give 52 mg (46%) of
compound P-179. .sup.1H NMR (400 MHz, CDCl.sub.3) 2.63 (s, 3H),
3.80 (s, 3H), 5.13 (s, 2H), 6.10-6.18 (m, 1H), 6.55-6.64 (m, 1H),
6.96 (d, J=8.5 Hz, 1H), 7.27-7.37 (m, 4H), 7.45-7.53 (m, 1H), 7.69
(d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.07 (s, 1H) ppm. LC-MS
(APCI+): 334.1 (M+1).
Example 361
Preparation of P-172
##STR00462##
[1200] 1-(3'-Acetyl-6-methoxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one
(P172). A reaction mixture of compound I-181 (120 mg, 0.42 mmol),
3-acetylphenyl boronic acid (69.2 mg, 0.42 mmol),
triphenylphosphine (22 mg, 0.08 mmol), K.sub.2CO.sub.3 (174 mg,
1.26 mmol), Pd(OAc).sub.2 (9.5 mg, 0.04 mmol) in
1,2-dimethoxyethane (4 mL), ethanol (0.5 mL) and water (0.5 mL) was
stirred at 80.degree. C. for 20 hours under Ar. The reaction
mixture was diluted with ethyl acetate (15 mL), washed with water,
brine and dried over Na.sub.2SO.sub.4. After filtration and removal
of solvent, the residue was purified by preparative chromatography
plate with 2% methanol (7M NH.sub.3)/dichloromethane to give 48 mg
(34%) of compound P-172. .sup.1H NMR (400 MHz, CDCl.sub.3)
1.93-2.06 (m, 2H), 2.44 (t, J=8.1 Hz, 2H), 2.64 (s, 3H), 3.30 (t,
J=7.0 Hz, 2H), 3.81 (s, 3H), 4.45 (s, 2H), 6.96 (d, J=8.4 Hz, 1H),
7.20 (d, J=2.1 Hz, 1H), 7.22-7.29 (m, 1H), 7.45-7.56 (m, 1H), 7.71
(d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.09 (s, 1H) ppm. LC-MS
(APCI+): 324.1 (M+1).
Example 362
Preparation of P-241
##STR00463##
[1202] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-dimethyl-amine
(P-241). A reaction mixture of compound I-154 (200 mg, 0.64 mmol),
4-(dimethylamino)phenylboronic acid (138 mg, 0.83 mmol),
triphenylphosphine (34 mg, 0.12 mmol), K.sub.2CO.sub.3 (132 mg,
0.96 mmol), Pd(OAc).sub.2 (14.0 mg, 0.06 mmol) in
1,2-dimethoxyethane (2 mL), ethanol (0.25 mL) and water (0.25 mL)
was stirred at 80.degree. C. for 3.5 hours under Ar. The reaction
mixture was diluted with water (10 mL) and extract with ethyl
acetate (3.times.5 mL), washed with brine and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by silica gel column chromatography with ethyl
acetate/hexane to yield 140 mg of product P-241 as the free base.
This residue was dissolved in ether (3 mL) and stir for 0.5 hour,
followed by adding 2M HCl solution in ether (3 mL) and the solution
was stirred for another 2 hours. Removal of the solvent provided
P-241 HCl salt (120 mg, 77%) as a white solid.
[1203] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.14 (s, 6H), 3.80 (s,
3H), 3.99 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 7.08 (d, J=2.0\ Hz, 1H),
7.09-7.14 (m, 1H), 7.27-7.39 (m, 5H), 7.48 (s, 1H), 7.67 (d, J=8.3
Hz, 2H), 14.64 (br s. 1H) ppm.
Example 363
Preparation of P-246
##STR00464##
[1205] Synthesis of
N-[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methanesulfonamide
(P-246). A reaction mixture of compound I-145 (300 mg, 0.96 mmol),
4-(N-phenyl-methanesulfonamide)boronic acid (228 mg, 0.96 mmol),
triphenylphosphine (75 mg, 0.29 mmol), K.sub.3PO.sub.4 (407 mg,
0.92 mmol), Pd(OAc).sub.2 (22.0 mg, 0.10 mmol) in
1,2-dimethoxyethane (4 mL), ethanol (0.5 mL) and water (0.5 mL) was
stirred at 80.degree. C. for 16 hours under Ar. The reaction
mixture was diluted with water (20 mL) and extract with ethyl
acetate (3.times.5 mL), washed with brine and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by silica gel column chromatography with ethyl
acetate/hexanes as eluent to give 46 mg (16%) of P-246. .sup.1H NMR
(400 MHz, CDCl.sub.3) 2.99 (s, 3H) 3.79 (s, 3H) 3.94 (s, 2H) 6.20
(br. s., 1H) 6.91 (d, J=8.32 Hz, 1H) 7.08-7.17 (m, 4H) 7.16-7.22
(m, 2H) 7.27-7.34 (m, 2H) 7.35-7.41 (m, 1H) 7.48 (s, 1H)
Example 364
Preparation of P-476
##STR00465##
[1207] Synthesis of
[4-(3'-Chloro-6-hydroxy-biphenyl-3-ylmethyl)-phenyl]-methyl-carbamic
acid tert-butyl ester (I-300). A reaction mixture of compound I-33
(300 mg, 0.96 mmol),
methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic
acid tert-butyl ester (417 mg, 1.25 mmol), triphenylphosphine (52
mg, 0.20 mmol), K.sub.3PO.sub.4 (414 mg, 2.0 mmol), Pd(OAc).sub.2
(52.0 mg, 0.20 mmol) in 1,2-dimethoxyethane (4 mL), ethanol (0.5
mL) and water (0.5 mL) was stirred at 80.degree. C. for 3 hours
under Ar. The reaction mixture was diluted with water (10 mL) and
extract with ethyl acetate (3.times.5 mL), washed with brine and
dried over Na.sub.2SO.sub.4. After filtration and removal of
solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/hexane as eluent to give 340 mg
(81%) of product I-300.
[1208] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methyl-amine
hydrochloric acid (P-476). I-300 (90 mg, 0.21 mmol) was dissolved
in dichloromethane (1 mL) and then TFA (1 mL) was added and the
mixture was stirred at room temperature 0.5 hour. followed by
removal TFA in vacuo. The material was acidified with aqueous 1M
HCl to pH=2 and extracted with ether (3.times.3 mL). The aqueous
layer was then basified with aqueous 2M Na.sub.2CO.sub.3 to pH=9
and then extracted with ethyl acetate
[1209] (3.times.3 mL) and the combined extracts were concentrated.
The residue was dissolved in ether (3 mL) and 2M HCl solution in
ether (3 mL) was added and the mixture was allowed to stir for 2
hours. The solid was vacuum filtered to afford 32 mg (41%, two
steps) of P-476 as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
2.98 (s, 3H), 3.79 (s, 3H), 3.95 (s, 2H), 6.90 (d, J=8.3 Hz, 1H),
7.04-7.12 (m, 2H), 7.27-7.39 (m, 5H), 7.45-7.54 (m, 3H), 11.47 (br
s, 2H) ppm.
Example 365
Preparation of P-247
##STR00466##
[1211] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-carbamic acid
tert-butyl ester (I-301). A reaction mixture of compound I-154 (300
mg, 0.96 mmol), 4-(N-Boc-amino)phenylboronic acid (228 mg, 0.96
mmol), triphenylphosphine (75 mg, 0.29 mmol), K.sub.3PO.sub.4 (407
mg, 1.92 mmol), Pd(OAc).sub.2 (22.0 mg, 0.10 mmol) in
1,2-dimethoxyethane (4 mL), ethanol (0.5 mL) and water (0.5 mL) was
stirred at 80.degree. C. for 3 hours under Ar. The reaction mixture
was diluted with water (20 mL) and extract with ethyl acetate
(3.times.5 mL), washed with brine and dried over Na.sub.2SO.sub.4.
After filtration and removal of solvent, the residue was purified
by silica gel column chromatography with ethyl acetate/hexane to
yield 200 mg (50%) of product I-301.
[1212] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ethyl-carbamic
acid tert-butyl ester (I-302) I-301 (140 mg, 0.33 mmol) was
dissolved in 2 mL of DMF and stirred for 10 minutes under N.sub.2;
then NaH was added. Once effervescence had ceased. ethyl iodide was
added and the reaction mixture was stirred at room temperature for
2 hours and quenched with 20 mL of water. The mixture was extracted
with ethyl acetate (3.times.5 mL), and the combined organic
extracts were washed with brine and dried over Na.sub.2SO.sub.4.
After filtration and removal of solvent, 120 mg (81%) of I-302 was
collected.
[1213] Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ethylamine;
HCl salt (P-247). Compound I-302 (120 mg, 0.27 mmol) was dissolved
in dichloromethane (1 mL) and then added TFA (1 mL) was added The
mixture was stirred at room temperature for 0.5 hour. The mixture
was concentrated and the residue was dissolved in ether (2 mL) and
2M HCl solution in ether (2 mL) was added and the mixture was
allowed to stir for another 2 hours. The solid was vacuum filtered
to afford 30 mg (29%, two steps) of P-247 as white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) 1.32-1.43 (m, 3H), 3.32 (br s, 2H), 3.79
(s, 3H), 3.94 (s, 2H), 6.90 (d, J=8.3 Hz, 1H), 7.03-7.14 (m, 2H),
7.23-7.39 (m, 5H), 7.44-7.55 (m, 3H), 11.40 (br. s., 1H) ppm.
Example 366
Preparation of P-477
##STR00467##
[1215] Synthesis of
N-[3-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-acetamide
(P-477). A reaction mixture of compound I-154 (500 mg, 1.60 mmol),
3-(N-Phenyl-acetamide)boronic acid (280 mg, 1.60 mmol),
triphenylphosphine (126 mg, 0.48 mmol), K.sub.3PO.sub.4 (678 mg,
3.20 mmol), Pd(OAc).sub.2 (36.0 mg, 0.16 mmol) in
1,2-dimethoxyethane (5 mL), ethanol (0.5 mL) and water (0.5 mL) was
stirred at 80.degree. C. for 16 hours under Ar. The reaction
mixture was diluted with water (20 mL) and extract with ethyl
acetate (3.times.5 mL), washed with brine and dried over
Na.sub.2SO.sub.4. After removal of solvent, the residue was
purified by silica gel column chromatography with ethyl
acetate/hexane and methanol/dichloromethane to yield 178 mg (30%)
of P-477) .sup.1H NMR (400 MHz, CDCl.sub.3) 2.11-2.23 (m, 3H), 3.79
(s, 3H), 3.94 (s, 2H), 6.90 (d, J=8.32 Hz, 1H), 6.95 (d, J=7.51 Hz,
1H), 7.04-7.09 (m, 1H), 7.09-7.16 (m, 2H), 7.19-7.34 (m, 4H),
7.34-7.42 (m, 2H), 7.50 (s, 1H) ppm.
Example 367
Preparation of P-255
##STR00468##
[1217] Synthesis of
3-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (P-255). To
a 24 mL vial was placed P-477 (80 mg, 0.22 mmol), concentrated HCl
(4 mL) and EtOH (4 mL) and the reaction mixture was stirred at
85.degree. C. over night. White solid was formed upon cooling to
room temperature. To the vial was added H.sub.2O (10 mL) and the
mixture was stirred at room temperature for 20 minutes then
filtered to yield 75 mg (95%) of P-255. .sup.1H NMR (400 MHz,
CDCl.sub.3) 3.77 (s, 3H), 3.96 (s, 2H), 6.84-6.96 (m, 1H),
7.03-7.14 (m, 2H), 7.16-7.44 (m, 7H), 7.50 (s, 1H), 10.50 (br s,
2H) ppm.
Example 368
Preparation of P-270
##STR00469##
[1219] Synthesis of
[3-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea (P-270).
To a 24 mL vial was placed P-255 (60 mg, 0.17 mmol), NaOCN (21.7
mg, 0.33 mmol),
[1220] AcOH (1 mL) and H.sub.2O (2 mL). The reaction mixture was
stirred at room temperature over night. The white solid formed was
filtered to yield 54 mg. (87%) of P-270. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 3.74 (s, 3H), 3.86 (s, 2H), 5.76 (s, 2H), 6.78 (m,
1H), 7.04 (d, J=8 Hz, 1H), 7.11 (t, J=8 Hz, 1H), 7.17-7.20 (m, 3H),
7.23-7.25 (m, 1H), 7.35-7.43 (m, 3H), 7.48 (m, 1H), 8.43 (s, 1H)
ppm.
Example 369
Preparation of P-271
##STR00470##
[1222] Synthesis of
N-[3-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methanesulfonamide
(P-271). To a 4 mL vial was added P-255 (60 mg, 0.17 mmol),
followed by pyridine (2 mL) then methanesulfonyl chloride (13
.mu.L) at 0.degree. C. The resulting solution was allowed to stir
at room temperature overnight. The reaction mixture was diluted
with water (10 mL) and extracted with ethyl acetate (3.times.5 mL).
The combined organics were concentrated under vacuum, and the
residue was purified by silica gel column chromatography with
methanol/dichloromethane to yield 36.7 mg (55%) of P-271). .sup.1H
NMR (400 MHz, CDCl.sub.3) 2.98 (s, 3H), 3.79 (s, 3H), 3.94 (s, 2H),
6.53 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.99-7.17 (m, 5H), 7.22-7.35
(m, 3H), 7.34-7.41 (m, 1H), 7.48 (s, 1H) ppm.
Example 370
Preparation of P-282
##STR00471##
[1224] Synthesis of
3-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-benzamide (P-282).
[1225] A reaction mixture of compound I-154 (200 mg, 0.64 mmol),
3-benzamid boronic acid (129 mg, 0.96 mmol), triphenylphosphine (50
mg, 0.20 mmol), K.sub.3PO.sub.4 (271 mg, 1.28 mmol), Pd(OAc).sub.2
(14.0 mg, 0.06 mmol) in 1,2-dimethoxyethane (2.5 mL), ethanol (0.25
mL) and water (0.25 mL) was stirred at 80.degree. C. overnight
under Ar. The reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3.times.3 mL), and the combined
organic extracts were washed with brine and dried over
Na.sub.2SO.sub.4. After filtration and removal of solvent, the
residue was purified by silica gel column chromatography eluting
with ethyl acetate/hexane and dichloromethane to yield 108 mg (48%)
of P-282).
[1226] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.78 (s, 3H), 3.99 (s,
2H), 6.12 (br s, 2H), 6.89 (d, J=8.32 Hz, 1H), 7.08-7.15 (m, 2H),
7.23-7.39 (m, 5H), 7.48 (s, 1H), 7.57-7.64 (m, 1H), 7.69 (s, 1H)
ppm.
Example 371
Preparation of P-303
##STR00472##
[1228] Synthesis of
[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-dimethyl-am-
ine (P-303). A reaction mixture of compound I-33 (100 mg, 0.30
mmol), 4-N,N-dimethylphenylboronic acid (60 mg, 0.36 mmol),
K.sub.3PO.sub.4 (127 mg, 0.60 mmol) in 1,2-dimethoxyethane (4 mL),
ethanol (0.5 mL) and water (0.5 mL) was purged with argon for 5
minutes before adding palladium tetrakis(triphenylphosphine) (18
mg, 0.02 mmol) and then stirred at 80.degree. C. overnight under
argon. The reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3.times.3 mL). The combined organic
extracts were washed with brine and dried over Na.sub.2SO.sub.4.
After filtration and removal of solvent, the residue was purified
by silica gel column chromatography with ethyl acetate/hexane and
methanol/ethyl acetate as eluent to give free base P-303. P-303 was
dissolved in ether (2 mL) and HCl (2M in ether) was added and the
resulting solution was then stirred for 30 minutes. Filtration of
the mixture afforded 53 mg (43%) of P-303 HCl salt. .sup.1H NMR
(400 MHz, CDCl.sub.3) 2.91 (s, 6H), 3.74 (s, 3H), 3.87 (s, 2H),
6.62-6.74 (m, 3H), 7.01-7.13 (m, 3H), 7.24-7.36 (m, 3H), 7.40 (s,
1H) ppm.
Example 372
Preparation of P-310
##STR00473##
[1230] Synthesis of
2-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-5-ethoxy-thiophene
(P-310). A reaction mixture of compound I-33 (100 mg, 0.30 mmol),
4-ethoxythiophene boronic acid (50 mg, 0.36 mmol), K.sub.3PO.sub.4
(127 mg, 0.60 mmol) in 1,2-dimethoxyethane (4 mL), ethanol (0.5 mL)
and water (0.5 mL) was purged with Ar for 5 minutes before adding
palladium tetrakis(triphenylphosphine) (18 mg, 0.02 mmol) and then
stirred at 80.degree. C. over night under Ar. The reaction mixture
was diluted with water (10 mL) and extract with ethyl acetate
(3.times.3 mL). The combined organic extracts were washed with
brine and dried over Na.sub.2SO.sub.4. After filtration and removal
of solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/hexanes and methanol/ethyl
acetate as eluent to give 40 mg (35%) of P-310. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 1.39 (t, J=8 Hz, 3H), 3.74 (s, 3H), 3.89
(2, 2H), 4.00 (q, 2H), 6.80 (m, 1H), 7.05-7.40 (m, 7H) ppm.
Example 373
Preparation of P-311
##STR00474##
[1232] Synthesis of
[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methyl-carb-
amic acid tert-butyl ester (I-303). A reaction mixture of compound
I-33 (300 mg, 0.91 mmol),
methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic
acid tert-butyl ester (240 mg, 1.09 mmol), palladium
tetrakis(triphenylphosphine) (53 mg, 0.05 mmol), K.sub.3PO.sub.4
(380 mg, 1.82 mmol) in 1,2-dimethoxyethane (10 mL), ethanol (1 mL)
and water (1 mL) was purged with argon for 5 minutes before adding
palladium tetrakis(triphenylphosphine) (53 mg, 0.05 mmol) and then
stirred at 80.degree. C. for 2 hours under argon. The reaction
mixture was diluted with water (10 mL) and extract with ethyl
acetate
[1233] (3.times.5 mL). The combined organic extracts were washed
with brine and dried over Na.sub.2SO.sub.4. After filtration and
removal of solvent, the residue was purified by silica gel column
chromatography with ethyl acetate/hexane as eluent to give 240 mg
(60%) of I-303.
[1234] Synthesis of
[4-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-methyl-amin-
e (P-311). I-303 (240 mg, 0.21 mmol) was dissolved in
dichloromethane (1 mL) and then TFA (1 mL) was added and the
mixture was stirred at room temperature for 0.5 hour. The solvent
was removed and the residue was diluted with ether (3 mL) and HCl
(2M in ether) (2 mL) and the mixture was stirred at room
temperature for 2 hours. The resulting solids were filtered to
provide 130 mg (70%) of P-311 HCl salt. .sup.1H NMR (400 MHz,
CDCl.sub.3) 2.99 (br s, 3H), 3.76 (s, 3H), 3.95 (s, 2H), 6.71 (d,
J=8.5 Hz, 1H), 7.07 (t, J=8.5 Hz, 1H), 7.27-7.40 (m, 6H), 7.47-7.55
(m, 2H), 11.46 (br s, 1H) ppm.
Example 374
Preparation of P-326
##STR00475##
[1236] Synthesis of
1-[3'-(4-Dimethylamino-benzyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]-ethano-
ne (P-326). In an 24 mL vial equipped with a stir bar was placed
I-223 (150 mg, 0.45 mmol), 4-(dimethylamino)phenylboronic acid
(89.1 mg, 0.54 mmol), potassium carbonate (136 mg, 0.99 mmol),
1,5-bis(diphenylphosphino)pentane (60 mg, 0.14 mmol),
allylpalladium(II) chloride dimer (26 mg, 0.07 mmol) and
dimethylformamide (3 mL). The reaction mixture was heated to
80.degree. C. over night under N.sub.2. The reaction mixture was
filtered through celite and to the filtrate was added water (10
mL). After extraction with ethyl acetate (3.times.10 mL), the
organic portions were combined, washed with brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by column chromatography utilizing EtOAc/hexanes as the
eluent to give free base product. Conversion of the free base
product to HCl salt was accomplished by dissolving the free base in
ether (2 mL) and then HCl (2N in ether) was added and the resulting
mixture was stirred for 0.5 hour. The resulting solids were
filtered to provide 66.2 mg (39%) of P-326 HCl salt. .sup.1H NMR
(400 MHz, CDCl.sub.3) 2.62 (s, 3H), 2.91 (s, 6H), 3.74 (s, 3H),
3.88 (s, 2H), 6.70 (d, J=8.6 Hz, 3H), 7.04-7.14 (m, 3H), 7.47-7.55
(m, 1H), 7.54-7.64 (m, 1H), 7.94 (d, J=7.8 Hz, 1H), 8.00 (s, 1H)
ppm.
Example 375
Preparation of P-332
##STR00476##
[1238] Synthesis of
1-[3'-(6-Dimethylamino-pyridin-3-ylmethyl)-2'-fluoro-6'-methoxy-biphenyl--
3-yl]-ethanone (P-332). In an 24 mL vial equipped with a stir bar
was placed I-223 (150 mg, 0.45 mmol),
6-(dimethylamino)pyridin-3-yl-boronic acid (155 mg, 0.54 mmol),
potassium carbonate (136 mg, 0.99 mmol),
1,5-bis(diphenylphosphino)pentane (60 mg, 0.14 mmol),
allylpalladium(II) chloride dimer (26 mg, 0.07 mmol) and
dimethylformamide (3 mL). The reaction mixture was heated to
80.degree. C. overnight under N.sub.2. The reaction mixture was
filtered through Celite and to the filtrate was added water (10
mL). After extraction with ethyl acetate (3.times.10 mL), the
organic portions were combined, washed with brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by column chromatography utilizing EtOAc/hexanes as the
eluent to give free base product. Conversion of the free base
product to HCl salt was accomplished by dissolving it in
dichloromethane (1 mL) and then adding HCl (2N in ether) and stir
0.5 hour. After filtration, 100 mg (59 5) of P-332 HCl salt was
obtained.
[1239] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.40 (br s, 6H),
3.77 (s, 3H), 3.85 (s, 2H); 6.7-8.1 (m, 9H).
TABLE-US-00015 Table of 1H NMR Spectra P-008 1H NMR (CDCl3, 400
MHz): d = 3.87 (3H, s), 3.97 (2H, s), 6.97 (1H, d, J = 8.4 Hz),
7.12-7.15 (3H, m), 7.17 (1H, dd, J = 8.4 and 8.4 Hz), 7.55 (1H, dd,
J = 8 and 8 Hz), 7.82 (1H, m), 8.17 (1H, m), 8.38 (1H, m), 8.51
(2H, m). P-011 1H NMR (CDCl3, 400 MHz): d = 3.84 (3H, s), 3.98 (2H,
s), 6.98 (1H, d, J = 8.8 Hz), 7.13 (2H, m), 7.19 (1H, d, J = 2.8
Hz), 7.22 (1H, dd, J = 8 and 2 Hz), 7.61 (1H, m), 7.80 (1H, m),
7.84 (1H, m), 8.52 (2H, m). P-013 1H NMR (400 MHz, DMSO-d6) d ppm
3.75-3.87 (m, 3 H) 4.11 (s, 2 H) 7.16 (d, J = 8.46 Hz, 1 LCMS =
purity. H) 7.43 (d, J = 8.33 Hz, 1 H) 7.48-7.60 (m, 2 H) 7.76 (d, J
= 9.40 Hz, 1 H) 7.90 (s, 1 H) 7.96 (d, APCI(-) = 372 J = 9.27 Hz, 1
H) 8.00-8.10 (m, 2 H) (M + 14). 94.9% P-028 1H NMR (CDCl3, 400
MHz): d = 3.82 (3H, s), 5.00 (2H, s), 6.91 (1H, m), 6.98 (1H, d, J
= 8.4 Hz), 7.08-7.15 (2H, m), 7.22 (1H, m), 7.34 (1H, m), 7.40 (1H,
dd, J = 8.4 and 2 Hz), 7.56 (1H, dd, J = 8.4 and 8.4 Hz), 7.79 (1H,
m), 8.18 (1H, m), 8.37 (1H, m). P-046 .sup.1H NMR (400 MHz,
CDCl.sub.3): 3.82 (s, 3H), 3.95 (s, 3H), 5.32 (s, 2H), 6.98 (d, J =
8.5 Hz, 1H), APCI.sup.+(M + 1): 7.17 (dd, J = 10.5, 8.7 Hz, 1H),
7.21-7.32 (m, 2H), 7.64 (ddd, J = 8.4, 4.6, 2.4 Hz, 1H), 7.97 (s,
342., 100% 1 H), 8.03 (dd, J = 7.0, 2.3 Hz, 1 H), 8.07 (s, 1 H)
ppm. P-048 1H NMR (CDCl3, 400 MHz): d = 8.06 (s, 1 H), 7.97 (s, 1
H), 7.89-7.96 (m, 1 H), 7.45-7.52 Calc. 341.3; (m, 1 H), 7.32 (dd,
J = 8.5, 2.3 Hz, 1 H), 7.19-7.28 (m, 2 H), 6.99 (d, J = 8.5 Hz, 1
H), 5.31 (s, 2 APCI.sup.+(M + 1): H), 3.93 (s, 3 H), 3.80 (s, 3 H)
342, 100% P-049 1H NMR (CDCl3, 400 MHz): d = 8.31 (Brs, 1 H),
8.21-8.25 (m, 1 H), . 7.85-7.89 (m, 2 H), 7.57- Calc. 369.33; 7.74
(m, 3 H), 7.12-7.17 (m, 2 H), . 6.93 (d, J = 8.8 Hz, 1 H), 3.89 (s,
3 H) APCI.sup.-(M): 369, 100% P-050 1H NMR (CDCl3, 400 MHz): d =
8.30 (s, 1 H), 8.19-8.22 (m, 1 H), 7.73 (dd, J = 7.7, 1.3 Hz, 1
Calc. 355.34; H), 7.57 (t, J = 8.0 Hz, 1 H), 7.10-7.21 (m, 3 H),
6.98 (t, J = 8.7 Hz, 1 H), 6.74 (d, J = 7.6 Hz, 2 H),
APCI.sup.-(M): 355, 3.95 (s, 2 H), 3.77 (s, 3 H) 100% P-051 .sup.1H
NMR (400 MHz, CDCl.sub.3): 3.79 (s, 3H), 6.12 (br. s., 1H), 6.82
(d, J = 8.7 Hz, 1H), 7.04 (t, J = Calc. 371.34; 8.7 Hz, 2H), 7.40
(dd, J = 8.5, 5.5 Hz, 2H), 7.47 (t, J = 8.6 Hz, 1 H), 7.50-7.64 (m,
1H), 7.70 (s, APCI.sup.+(M - OH): 1H), 8.22 (s, 1H), 8.27 (s, 1 H)
ppm. 354, 94% P-054 1H NMR (CDCl3, 400 MHz): d = 3.79 (3H, s), 4.19
(2H, s), 6.90 (1H, d, J = 9.2 Hz), 6.98 (1H, d, J = 8.8 Hz), 7.04
(2H, m), 7.27 (2H, m), 7.64 (1H, dd, J = 8 and 8 Hz), 7.89 (1H, m),
8.28 (1H, m), 8.39 (1H, m). P-057 1H NMR (CDCl3, 400 MHz): d = 4.19
(2H, s), 6.45 (1H, t, J = 72 Hz), 7.02 (2H, m), 7.13 (1H, d, J =
8.4 Hz), 7.27 (2H, m), 7.55 (1H, d, J = 8.4 Hz), 7.62 (1H, dd, J =
8 and 8 Hz), 8.29 (2H, m), 8.79 (1H, m). P-060 1H NMR (CDCl3, 400
MHz): d = 3.82 (3H, s), 5.32 (2H, s), 6.98 (1H, d, J = 8.4 Hz),
7.15- 7.22 (3H, m), 7.28 (1H, m), 7.31-7.36 (1H, m), 7.97 (1H, s),
8.07 (1H, s). P-061 1H NMR (CDCl3, 400 MHz): d = 3.83 (3H, s), 5.32
(2H, s), 6.98 (1H, d, J = 8.8 Hz), 7.13 (2H, m), 7.19 (1H, m), 7.28
(1H, m), 7.97 (1H, s), 8.07 (1H, s). P-063 1H NMR (CDCl3, 400 MHz):
d = 3.82 (3H, s), 5.33 (2H, s), 6.99 (1H, d, J = 8 Hz), 7.25-7.30
(2H, m), 7.46-7.68 (3H, m), 7.74 (1H, m), 7.97 (1H, s), 8.08 (1H,
s). P-078 1H NMR (CDCl3, 400 MHz): d = 1.71-1.77(m, 1H), 2.19-2.23
(m, 1H), 2.33-2.37 (m, 1H), MS(APCI+): 2.54-2.58 (m, 1H), 2.68-2.71
(m, 1H), 2.85-2.91 (m, 1H), 3.63 (s, 2H), 3.82 (s, 3H), 4.33-4.36
352 (M + 1), (m, 1H), 6.95 (d, J = 8 Hz, 1H), 7.268 (d, J = 3.4 Hz,
1H), 7.31 (dd, J = 8, 2 Hz, 1H), 7.5 (t, 1H), LCMS: 97.55% 7.56 (d,
J = 8 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.78 (s, 1H). P-083 1H NMR
(CDCl3, 400 MHz): d = 3.34-3.47(t, 2H), 3.82 (s, 3H), 4.29-4.33 (t,
2H), 4.42 (s, MS(ESI+): 352 2H), 6.98 (d, J = 8.4 Hz, 1H), 7.22 (d,
J = 2.4 Hz, 1H), 7.3 (dd, J = 8.4, 2.4 Hz, 1H), 7.52 (t, 1H), (M +
1), LCMS: 7.59 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.77 (s,
1H). 94% P-095 1H NMR (DMSO-d6, 400 MHz): d = 8.19-8.24 (m, 2 H),
8.00 (br. s., 1 H), 7.82-7.90 (m, 2 H), Calc. 383.38; 7.74 (t, J =
8.0 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.29-7.39 (m, 2H), 7.08
(d, J = 8.4 Hz, 1 H)), APCI.sup.-(M - 1): 3.81 (s. 3 H), 3.16 ppm
(s, 3 H) 382; (M - 2): 381, P-096 1H NMR (DMSO-d6, 400 MHz): d =
8.18-8.25 (m, 2 H), 7.73-7.85 (m, 4 H), 7.65 (d, J = 9.1 Hz, Calc.
369.35; 2 H), 7.40-7.51 (m, 2 H), 6.85 (d, J = J = 9.2 1 H), 3.84
(s, 3 H) APCI.sup.-(M - 2): 367, P-097 1H NMR (CDCl3, 400 MHz): d =
8.33 (br, s, 1 H), 8.17-8.21 (m, 1 H), 7.76-7.79 (m, 1 H), 7.56 (t,
J = 8.0 Hz, 1H), 7.16-7.20 (m, 1 H), 7.11 (d, J = 8.5 Hz, 1 H),
6.95-7.01 (m, 2 H), 6.73 (d, J = 8.8 Hz, 1 H), 3.96 (s, 2 H), 3.73
(s, 3 H), 3.13 (s, 3 H) P-098 1H NMR (CDCl3, 400 MHz): d = 716-7.26
(m, 3 H), 7.03 (t, J = 8.8 Hz, 1 H), 6.96 (t, J = 8.8 Hz, 2 Calc.
325.3; H), 6.78 (d, J = 7.6, 1 H), 6.67-6.71 (m, 3 H), 3.92 (s, 2
H), 3.74 (s, 3 H) ESI+ (M + 1): 326 95%. P-106 1H NMR (400 MHz,
CDCl3) d ppm 8.48 (s, 1 H) 8.11-8.36 (m, 4 H) 7.47-7.73 (m, 4 H)
7.02- 7.23 (m, 2 H) 6.55 (d, J = 8.5 Hz, 1 H) 6.44-6.59 (m, 1 H)
3.96 (s, 2 H) 3.72 (s, 3 H) P-110 1H NMR (DMSO-d6, 400 MHz): d =
1.45 (9H, s), 3.77 (3H, s), 3.90 (2H, s), 7.10 (1H, d, J = 8.4 Hz),
7.28 (2H, m), 7.60 (1H, dd, J = 8.4 and 2 Hz), 7.70 (2H, m), 7.92
(1H, m), 8.18 (2H, m), 8.28 (1H, m), 9.62 (1H, s). P-111 1H NMR
(CDCl3, 450 MHz): d = 3.81 (3H, s), 3.84 (2H, s), 4.32 (2H, br),
6.46 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 2.5 Hz), 7.17 (1H, dd, J
= 8.5 and 2.5 Hz), 7.25 (1H, m), 7.54 (1H, dd, J = 8 and 8 Hz),
7.81 (1H, m), 7.97 (1H, m), 8.16 (1H, m), 8.38 (1H, m). P-112 1H
NMR (CDCl3, 500 MHz): d = 1.50 (9H, s), 3.80 (3H, s), 3.93 (2H, s),
6.40 (1H, br), 6.92 (1H, d, J = 8.5 Hz), 7.12 (3H, m), 7.17 (1H,
dd, J = 8.5 and 2.5 Hz), 7.28 (1H, m), 7.53 (1H, dd, J = 8 and 8
Hz), 7.81 (1H, m), 8.15 (1H, m), 8.38 (1H, m). P-113 1H NMR (CDCl3,
500 MHz): d = 3.80 (3H, s), 3.87 (2H, s), 6.63 (2H, m), 6.92 (1H,
d, J = 8.5 Hz), 6.99 (2H, m), 7.14 (1H, d, J = 2 Hz), 7.18 (1H, dd,
J = 8.5 and 2.5 Hz), 7.53 (1H, dd, J = 8 and 8 Hz), 7.81 (1H, m),
8.15 (1H, m), 8.38 (1H, m). P-114 1H NMR (CDCl3, 500 MHz): d = 2.16
(3H, s), 3.81 (3H, s), 3.94 (2H, s), 6.93 (1H, d, J = 8.5 Hz), 7.07
(1H, br), 7.13-7.18 (4H, m), 7.41 (2H, d, J = 8.5 Hz), 7.53 (1H,
dd, J = 8 and 8 Hz), 7.81 (1H, m), 8.15 (1H, m), 8.38 (1H, m).
P-116 1H NMR (CDCl3, 400 MHz): d = 8.25-8.28 (m, 2 H), 7.72 (d, J =
8.0 Hz, 1 H), 7.62 (t, J = 8.0 Hz, Calc. 391.33; 1 H), 7.7.16-7.21
(m, 3 H), 6.98-7.05 (m, 3 H), 6.36 (t, J = 112 Hz, 1 H), 4.00 (s, 2
H), APCI-(M): 391, P-121 1H NMR (CDCl3, 500 MHz): d = 3.39 (6H, s),
3.82 (3H, s), 4.02 (2H, s), 6.96 (1H, d, J = 8.5 Hz), 7.17 (1H, d,
J = 2 Hz), 7.20 (1H, dd, J = 8.5 and 2 Hz), 7.26-7.30 (4H, m), 7.55
(1H, dd, J = 8 and 8 Hz), 7.83 (1H, m), 8.17 (1H, m), 8.39 (1H, m).
P-122 1H NMR (CDCl3, 400 MHz): d = 2.68 (2H, m), 2.80 (2H, m), 3.80
(3H, s), 3.95 (2H, s), 6.93 (1H, d, J = 8 Hz), 7.12-7.18 (4H, m),
7.35 (1H, br), 7.41 (2H, d, J = 8 Hz), 7.53 (1H, dd, J = 8 and 8
Hz), 7.81 (1H, m), 8.15 (1H, m), 8.37 (1H, m). P-123 1H NMR
(DMSO-d6, 400 MHz): d = 2.93 (3H, s), 3.77 (3H, s), 3.90 (2H, s),
7.08-7.13 (3H, m), 7.21-7.29 (4H, m), 7.70 (1H, dd, J = 8 and 8
Hz), 7.92 (1H, m), 8.17 (1H, m), 8.27 (1H, m), 9.60 (1H, br). P-125
1H NMR (400 MHz, CDCl3) d ppm 8.20-8.27 (m, 2 H) 8.06 (d, J = 1.7
Hz, 1 H) 7.58-7.73 (m, 2 H) 7.46 (dd, J = 8.5, 2.3 Hz, 1 H) 7.10
(d, J = 8.5 Hz, 1 H) 6.68 (d, J = 8.5 Hz, 1 H) 6.54 (d, J = 8.5 Hz,
1 H) 4.79 (s, 1 H) 3.91 (s, 3 H) 3.88 (s, 2 H) 3.71 (s, 3 H) P-126
1H NMR (400 MHz, CDCl3) d ppm 8.30 (d, J = 2.1 Hz, 2 H) 8.19-8.28
(m, 2 H) 7.62-7.70 (m, 2 H) 7.52 (dd, J = 8.2, 2.4 Hz, 1 H) 7.22
(d, J = 8.2 Hz, 1 H) 7.12 (d, J = 8.5 Hz, 1 H) 6.55 (d, J = 8.5 Hz,
1 H) 4.85 (s, 1 H) 3.93 (s, 2 H) 3.72 (s, 3 H) P-127 1H NMR (CDCl3,
400 MHz): d = 8.30 (br, s, 1 H), 8.19-8.21 (m, 1 H), 7.74 (d, J =
8.0 Hz, 1 H), Calc. 347.4; 7.58 (t, J = 8.0 Hz, 1 H), 7.24 (t, J =
8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 3.78 (s, 3 H), 3.62-3.69
APCI.sup.-(M) 347, (m, 1 H), 2.80-3.02 (m, 4 H), 2.03-2.15 (s, 2
H), 1.90-1.99 (m, 1 H), 1.65-1.72 (M, 1 H) 99% P-136 1H NMR
(DMSO-d6, 400 MHz): d = 8.23 (ddd, J = 8.2, 2.3, 1.1 Hz, 4 H), 8.15
(s, 4 H), 7.83 (d, J = 1.2 Hz, 2 H), 7.81 (d, J = 1.2 Hz, 3 H),
7.71-7.77 (m, 4 H), 7.28-7.40 (m, 13 H), 7.19-7.26 (m, 8 H), 7.00
(s, 4 H), 3.97 ppm (s, 8 H) P-139 1H NMR (CDCl3, 400 MHz): d = 7.55
(br, s 1 H), 7.46-7.48 (m, 1 H), 7.25-7.33 (m, 2 H), 7.15- 7.19 (m,
2 H), 7.07 (t, J = 6.8 Hz, 1 H), 6.95-6.99 (m, 2 H), 6.69 (dd, J =
6.8, 0.8 Hz, 1 H), 3.92 (s., 2 H), 3.44 (s, 3 H) P-142 1H NMR
(CDCl3, 400 MHz): d = 3.81 (3H, s), 3.91 (2H, s), 4.63 (1H, s),
6.76 (2H, m), 6.93 (1H, d, J = 8 Hz), 7.07 (2H, m), 7.13-7.19 (2H,
m), 7.53 (1H, dd, J = 8 and 8 Hz), 7.82 (1H, m), 8.15 (1H, m), 8.38
(1H, m). P-143 1H NMR (CDCl3, 400 MHz): d = 1.46 (9H, s), 3.80 (3H,
s), 3.91 (2H, d, J = 6 Hz), 3.93 (2H, s), 6.92 (1H, d, J = 8 Hz),
7.12-7.18 (4H, m), 7.42 (2H, d, J = 8 Hz), 7.53 (1H, dd, J = 8 and
8 Hz), 7.81 (1H, m), 8.15 (1H, m), 8.16 (1H, br), 8.37 (1H, m).
P-144 1H NMR (DMSO-d6, 400 MHz): d = 2.86 (6H, s), 3.77 (3H, s),
3.92 (2H, s), 4.14 (2H, s), 7.09 (1H, d, J = 8 Hz), 7.23-7.28 (4H,
m), 7.54 (2H, d, J = 8 Hz), 7.70 (1H, dd, J = 8 and 8 Hz), 7.92
(1H, d, J = 8 Hz), 8.18 (1H, m), 8.27 (1H, m), 10.0 (1H, br), 10.87
(1H, s). P-145 1H NMR (DMSO-d6, 400 MHz): d = 3.75 (2H, br), 3.77
(3H, s), 3.91 (2H, s), 7.09 (1H, d, J = 8 Hz), 7.23-7.28 (4H, m),
7.50 (2H, d, J = 8 Hz), 7.70 (1H, dd, J = 8 and 8 Hz), 7.92 (1H,
m), 8.16 (3H, br), 8.18 (1H, m), 8.27 (1H, m). P-146 1H NMR
(DMSO-d6, 400 MHz): d = 1.39 (1H, m), 1.65-1.85 (5H, m), 2.82-2.92
(4H, m), 3.28-3.45 (4H, m), 3.77 (3H, s), 3.90 (2H, s), 7.20 (2H,
d, J = 8 Hz), 7.23-7.26 (2H, m), 7.50 (2H, d, J = 8 Hz), 7.70 (1H,
dd, J = 8 and 8 Hz), 7.92 (1H, m), 8.19 (1H, m), 8.26 (1H, m), 9.69
(1H, br), 10.18 (1H, s). P-148 1H NMR (METHANOL-d4, 400 MHz): d =
8.16 (s, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.33 (s, 5 H), 7.36 (s, 6
H), 6.92 (s, 3 H), 4.07 (s, 5 H), 3.78 (s, 7 H), 0.00 ppm (s, 10 H)
P-149 1H NMR (400 MHz, CDCl3) d ppm 8.30 (s, 1 H) 8.19 (dd, J =
8.2, 1.2 Hz, 1 H) 7.75 (d, J = 7.6 Hz, 1 H) 7.52-7.63 (m, 1 H) 7.38
(s, 1 H) 7.07 (d, J = 8.3 Hz, 1 H) 6.52 (d, J = 8.5 Hz, 1 H) 4.87
(d, J = 5.2 Hz, 2 H) 3.75 (s, 3 H) P-150 1H NMR (400 MHz,
METHANOL-d4) d ppm 8.13-8.20 (m, 1 H) 8.12 (s, 1 H) 8.04 (d, J =
2.0 Hz, 1 H) 7.57-7.70 (m, 3 H) 7.11 (d, J = 8.5 Hz, 1 H) 6.80 (d,
J = 8.5 Hz, 1 H) 6.60 (d, J = 8.5 Hz, 1 H) 4.56-4.61 (m, 2 H) 3.91
(s, 1 H) 3.68 (s, 1 H) 3.44-3.50 (m, 5 H) 2.89 (s, 2 H) P-152 1H
NMR (CDCl3, 400 MHz): d = 8.26-8.30 (m, 2 H), 8.19-8.23 (m., 1 H),
7.69-7.73 (m, 1 H), Calc. 372.8; 7.58 (t, J = 8.4 Hz, 1 H), 7.49
(dd, J = 8.2, 2.5 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 7.15 (t, J =
8.6 Hz, 1 APCI.sup.+(M + 1): H), 6.76 (d, J = 8.4 Hz, 1 H), 3.96
(s, 2 H), 3.78 (s, 3 H) 373, 99% P-159 1H NMR (DMSO-d6, 400 MHz): d
= 2.67 (2H, t, J = 7 Hz), 3.06 (2H, m), 3.77 (3H, s), 3.90 (2H, s),
7.09 (1H, d, J = 8.8 Hz), 7.20 (2H, d, J = 8 Hz), 7.23-7.26 (2H,
m), 7.50 (2H, d, J = 8.8 Hz), 7.70 (1H, dd, J = 8 and 8 Hz), 7.76
(3H, br), 7.92 (1H, m), 8.18 (1H, m), 8.26 (1H, m), 10.10 (1H, s).
P-164 1H NMR (CDCl3, 400 MHz): d = 2.91 (6H, s), 3.42 (2H, br),
3.81 (3H, s), 3.93 (2H, s), 4.45 (2H, br), 6.85 (2H, m), 6.93 (1H,
d, J = 8.8 Hz), 7.11-7.19 (4H, m), 7.54 (1H, dd, J = 8 and 8 Hz),
7.82 (1H, d, J = 8 Hz), 8.15 (1H, m), 8.37 (1H, m), 13.0 (1H, br).
P-165 1H NMR (CDCl3, 400 MHz): d = 1.81 (4H, br), 2.65 (4H, br),
2.92 (2H, t, J = 6 Hz), 3.80 (3H, s), 3.91 (2H, s), 4.10 (2H, t, J
= 6 Hz), 6.85 (2H, d, J = 8 Hz), 6.93 (1H, d, J = 8 Hz), 7.20- 7.19
(4H, m), 7.52 (1H, dd, J = 8 and 8 Hz), 7.82 (1H, m), 8.15 (1H, m),
8.38 (1H, m). P-166 1H NMR (CDCl3, 400 MHz): d = 1.45 (2H, m), 1.60
(4H, m), 2.50 (4H, br), 2.76 (2H, t, J = 6 Hz), 3.80 (3H, s), 3.91
(2H, s), 4.08 (2H, t, J = 6 Hz), 6.83 (2H, m), 6.92 (1H, d, J = 8
Hz), 7.10 (2H, d, J = 8 Hz), 7.14-7.19 (2H, m), 7.52 (1H, dd, J = 8
and 8 Hz), 7.82 (1H, m), 8.15 (1H, m), 8.38 (1H, m). P-168 1H NMR
(CDCl3, 400 MHz): d = 7.26 (s, 13 H), 3.92 (s, 3 H), 3.75 (s,
6 H), 2.16 (s, 5 H), 1.54 ppm (s, 11 H) P-171 1H NMR (CDCl3, 400
MHz): d = 2.56 (4H, m), 2.78 (2H, t, J = 6 Hz), 3.72 (2H, t, J = 5
Hz), 3.80 (3H, s), 3.91 (2H, s), 4.08 (2H, t, J = 6 Hz), 6.84 (2H,
d, J = 8 Hz), 6.92 (1H, d, J = 8 Hz), 7.08- 7.19 (4H, m), 7.52 (1H,
dd, J = 8 and 8 Hz), 7.82 (1H, m), 8.15 (1H, m), 8.38 (1H, m).
P-175 1H NMR (METHANOL-d4, 400 MHz): d = 7.23 (s, 9 H), 4.40 (s, 4
H), 3.94 (s, 7 H), 3.78 (s, 5 H), 2.92 ppm (s, 10 H) P-177 1H NMR
(400 MHz, METHANOL-d4) d ppm 8.26 (d, J = 1.9 Hz, 1 H) 8.18 (dd, J
= 8.0, 1.3 Hz, 1 H) 8.12 (s, 1 H) 7.54-7.76 (m, 4 H) 7.37 (d, J =
8.2 Hz, 1 H) 7.17 (d, J = 8.5 Hz, 1 H) 6.63 (d, J = 8.6 Hz, 1 H)
4.00 (s, 3 H) 3.98 (s, 2 H) 3.69 (s, 2 H) P-178 1H NMR (400 MHz,
METHANOL-d4) d ppm 8.18-8.26 (m, 2 H) 8.00 (d, J = 4.3 Hz, 1 H)
7.78 (dd, J = 9.3, 8.2 Hz, 2 H) 7.61-7.71 (m, 1 H) 7.32 (d, J = 8.6
Hz, 1 H) 7.17 (dd, J = 7.4, 5.0 Hz, 1 H) 6.94 (d, J = 8.6 Hz, 1 H)
4.16 (s, 2 H) 3.78 (s, 3 H) P-181 1H NMR (DMSO-d6, 400 MHz): d =
8.43 (s, 3 H), 8.16 (s, 3 H), 7.74 (d, J = 7.9 Hz, 3 H), 7.30 (d, J
= 8.6 Hz, 8 H), 7.08 (d, J = 8.3 Hz, 6 H), 5.77 (s, 5 H), 3.86 (s,
6 H), 3.32 (s, 4 H), 2.54 (s, 1 H), 1.06 ppm (t, J = 7.0 Hz, 2 H)
P-185 1H NMR (400 MHz, METHANOL-d4) d ppm 8.03-8.19 (m, 1 H)
7.56-7.67 (m, 1 H) 7.49- 7.58 (m, 1 H) 7.29-7.48 (m, 5 H) 7.00 (d,
J = 8.6 Hz, 1 H) 4.24 (s, 2 H) 3.78 (s, 3 H) P-186 1H NMR (CDCl3,
400 MHz): d = 1.98-2.04 (m, 2H), 2.42-2.46 (t, 2H), 3.28-3.32 (t,
2H), 3.82 (s, 3H), 4.45 (s, 2H), 6.96 (d, J = 8.4 Hz, 1H), 7.22 (d,
J = 2.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.4 Hz, 1H), 7.56 (t, 1H), 7.69
(d, J = 8 Hz, 1H), 8.04 (d, J = 8 Hz, 1H), 8.24 (s, 1H), 8.47 (s,
1H) P-187 1H NMR (CDCl3, 400 MHz): d = 7.25-7.41 (m, 4 H),
7.16-7.19 (m, 2 H), 7.07 (t, J = 8.4 Hz, 1 H), 6.97 (t, J = 8.4 Hz,
2 H), 6.71 (d, J = 8.4 Hz, 1 H), 3.93 (s, 2 H), 3.75 (s, 3 H) P-194
1H NMR (DMSO-d6, 400 MHz): d = 2.00 (3H, s), 3.76 (3H, s), 5.04
(2H, s), 6.95 (2H, m), 7.01 (1H, d, J = 8.8 Hz), 7.35 (1H, m), 7.41
(1H, dd, J = 8 and 8 Hz), 7.48 (2H, m), 7.51-7.54 (2H, m),
7.57-7.60 (1H, m), 9.78 (1H, s). P-197 1H NMR (CDCl3, 400 MHz): d =
2.32 (s, 3H), 3.81 (s, 3H), 5.26 (s, 2H), 6.85(d, J = 9.2 Hz,
MS(APCI+): 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H),
7.44 (d, J = 2.4 Hz, 1H), 7.5 (dd, J = 8.4, 352 (M + 1), 2.4 Hz,
1H), 7.52-7.56 (t, 1H), 7.81-7.84 (m, 1H), 8.15-8.18 (m, 1H), 8.39
(s, 1H) LCMS: 100% P-199 1H NMR (CDCl3, 400 MHz): d = 3.43 (2H,
br), 3.78 (3H, s), 5.01 (2H, s), 6.64 (2H, m), 6.77 (1H, d, J = 8.8
Hz), 6.83 (2H, m), 7.30 (1H, d, J = 8 Hz), 7.34 (1H, m), 7.42 (1H,
dd, J = 8 and 8 Hz), 7.48 (1H, m), 7.56 (1H, m). P-200 1H NMR
(CDCl3, 400 MHz): d = 7.52-7.56 (m, 2 H), 7.48 (dt, J = 7.6, 1.7
Hz, 2 H), 7.25-7.34 (m, 7 H), 7.19-7.24 (m, 5 H), 7.07-7.17 (m, 7
H), 6.69-6.73 (m, 3 H), 6.31 (s, 2 H), 3.94 (s, 5 H), 3.76 (s, 7
H), 2.99 (s, 7 H), 1.55 ppm (s, 4 H) P-202 1H NMR (CDCl3, 400 MHz):
d = 2.96 (3H, s), 3.79 (3H, s), 5.07 (2H, s), 6.38 (1H, s), 6.79
(1H, J = 8.8 Hz), 6.98 (2H, m), 7.20 (2H, m), 7.30 (1H, d, J = 8
Hz), 7.34 (1H, m), 7.42 (1H, dd, J = 8 and 8 Hz), 7.50 (1H, m),
7.56 (1H, m). P-204 1H NMR (CDCl3, 400 MHz): d = 3.83 (overlap, 6),
5.17 (s, 2H), 6.88 (s, 2H), 6.96 (d, J = 8.4 MS(APCI+): Hz, 1H),
7.46 (d, J = 2.4 Hz, 1H), 7.5 (dd, J = 8.4, 2.4 Hz, 1H), 7.51-7.57
(t, 1H), 7.82-7.85 (m, 368 (M + 1), 1H), 8.15-8.18 (m, 1H), 8.39
(dd, J = 2 Hz, 1H) LCMS: 100% P-205 1H NMR (CDCl3, 400 MHz): d =
3.81 (s, 3H), 5.31 (s, 2H), 6.92 (dd, J = 9.2, 1.6 Hz, 1H), 6.96
MS(APCI+): (d, J = 9.2 Hz, 1H), 7.15 (dd, J = 9.6, 4 Hz, 1H), 7.4
(d, J = 2 Hz, 1H), 7.5 (dd, J = 8.4, 2.4 Hz, 1H), 338 (M + 1),
7.52-7.56 (t, 1H), 7.76 (dd, J = 4, 1.6 Hz, 1H), 7.81-7.84 (m, 1H),
8.15-8.18 (m, 1H), 8.39 (dd, LCMS: 96% 1H) P-206 1H NMR (CDCl3, 400
MHz): d = 3.81 (overlap, 6), 5.17 (s, 2H), 6.1 (t, 1H), 6.57 (dd, J
= 7.6, MS(APCI+): 1.6 Hz, 1H), 6.94 (dd, J = 7.6, 1.6 Hz, 1H)),
6.96 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.39 367 (M +
1), (dd, J = 8.4, 2.4 Hz, 1H), 7.51-7.57 (t, 1H), 7.79-7.81(m, 1H),
8.15-8.18 (m, 1H), 8.37 (dd, J = LCMS: 100% 2 Hz, 1H) P-216 1H NMR
(CDCl3, 400 MHz): d = 3.74 (3H, s), 3.89 (2H, s), 4.61 (1H, s),
6.68 (1H, dd, J = 8.4 and 1 Hz), 6.75 (2H, m), 7.07 (1H, dd, J = 8
and 8 Hz), 7.09 (2H, m), 7.26-7.36 (3H, m), 7.39 (1H, m). P-217 1H
NMR (CDCl3, 400 MHz): d = 3.74 (3H, s), 3.91 (2H, s), 4.72 (1H,
br), 6.65-6.71 (3H, m), 6.81 (1H, d, J = 8 Hz), 7.09 (1H, dd, J =
8.4 and 8.4 Hz), 7.15 (1H, dd, J = 7.6 and 7.6 Hz), 7.26- 7.36 (3H,
m), 7.39 (1H, m). P-219 1H NMR (CDCl3, 400 MHz): d = 2.57 (4H, m),
2.78 (2H, t, J = 6 Hz), 3.72 (4H, m), 3.74 (3H, s), 3.90 (2H, s),
4.08 (2H, t, J = 6 Hz), 6.68 (1H, dd, J = 8.4 and 1 Hz), 6.83 (2H,
m), 7.07 (1H, dd, J = 8.4 and 8.4 Hz), 7.13 (2H, m), 7.26-7.36 (3H,
m), 7.39 (1H, m). P-220 1H NMR (CDCl3, 400 MHz): d = 2.56 (4H, m),
2.78 (2H, t, J = 6 Hz), 3.72 (4H, m), 3.75 (3H, s), 3.92 (2H, s),
4.08 (2H, t, J = 6 Hz), 6.69 (1H, d, J = 8 Hz), 6.71-6.78 (2H, m),
6.83 (1H, d, J = 8 Hz), 7.11 (1H, dd, J = 8.4 and 8.4 Hz), 7.19
(1H, dd, J = 8 and 8 Hz), 7.26-7.36 (3H, m), 7.39 (1H, m). P-221 1H
NMR (CDCl3, 400 MHz): d = 3.75 (3H, s), 3.96 (2H, s), 4.96 (2H,
br), 6.69 (1H, dd, J = 8 and 1 Hz), 7.05 (2H, m), 7.09 (1H, dd, J =
8.4 and 8.4 Hz), 7.22 (2H, m), 7.26-7.36 (3H, m), 7.39 (1H, m).
P-222 1H NMR (CDCl3, 400 MHz): d = 3.75 (3H, s), 3.96 (2H, s), 4.98
(2H, br), 6.69 (1H, d, J = 8.8 Hz), 6.99 (2H, m), 7.07-7.12 (2H,
m), 7.26-7.36 (4H, m), 7.39 (1H, m). P-225 1H NMR (400 MHz, CDCl3)
d ppm 8.21 (br. s., 1 H) 7.93 (br. s., 1 H) 7.35 (d, J = 9.7 Hz, 4
H) 7.00 (br. s., 2 H) 6.75 (br. s., 1 H) 4.27 (br. s., 2 H) 3.78
(s, 3 H) P-226 1H NMR (400 MHz, CDCl3) d ppm 8.29 (d, J = 1.9 Hz, 1
H) 7.48 (dd, J = 8.2, 2.3 Hz, 1 H) 7.28- 7.39 (m, 3 H) 7.20-7.29
(m, 2 H) 7.10 (t, J = 8.5 Hz, 1 H) 6.72 (d, J = 8.6 Hz, 1 H) 3.94
(s, 2 H) 3.76 (s, 3 H) P-227 1H NMR (CDCl3, 400 MHz): d = 7.29-7.41
(m, 7 H), 7.26 (s, 8 H), 7.18-7.29 (m, 4 H), 7.07- 7.18 (m, 7 H),
6.72 (s, 2 H), 6.26 (s, 2 H), 3.94 (s, 4 H), 3.76 (s, 7 H), 2.99
(s, 7 H), 1.54 ppm (s, 3 H) P-228 1H NMR (CDCl3, 400 MHz): d =
7.37-7.43 (m, 7 H), 7.33 (d, J = 9.7 Hz, 5 H), 7.26 (s, 9 H), 7.07
(s, 4 H), 6.70 (s, 3 H), 3.92 (s, 5 H), 3.75 (s, 7 H), 2.16 (s, 6
H), 1.54 ppm (s, 5 H) P-231 1H NMR (DMSO-d6, 400 MHz): d = 2.03
(3H, s), 3.77 (3H, s), 5.05 (2H, s), 6.71 (1H, m), 7.01 (1H, d, J =
8 Hz), 7.10 (1H, m), 7.19 (1H, dd, J = 8 and 8 Hz), 7.32 (1H, m),
7.37 (1H, m), 7.42 (1H, m), 7.44-7.49 (2H, m), 7.55 (1H, dd, J =
8.8 and 8.8 Hz).. P-232 1H NMR (CDCl3, 400 MHz): d = 3.65 (2H, s),
3.77 (3H, s), 5.04 (2H, s), 6.29-6.34 (2H, m), 6.41 (1H, m), 6.67
(1H, d, J = 8 Hz), 7.06 (1H, dd, J = 8 and 8 Hz), 7.27-7.37 (3H,
m), 7.40- 7.45 (2H, m). P-233 1H NMR (DMSO-d6, 400 MHz): d = 2.00
(3H, s), 3.73 (3H, s), 3.89 (2H, s), 6.92 (2H, m), 7.19 (1H, dd, J
= 8 and 8 Hz), 7.28 (2H, m), 7.38 (2H, m), 7.44 (3H, m), 9.85 (1H,
s). P-234 1H NMR (DMSO-d6, 400 MHz): d = 3.73 (3H, s), 3.92 (2H,
s), 6.88-7.02 (4H, m), 7.22-7.38 (4H, m), 7.40-7.48 (2H, m). P-235
CDCl3, 3.83 (s, 3H), 5.04 (s, 2H), 6.99 (d, J = 8.4 Hz, 1H), 7.27
(d, J = 2 Hz, 1H), 7.3-7.36 (m, MS(APCI+): 4H), 7.49 (s, 1H), 7.68
(d, J = 3.2 Hz, 1H), 8.54 (d, J = 3.2 Hz, 1H) 406 (M + 1), LCMS:
90% P-237 1H NMR (DMSO-d6, 400 MHz): d = 7.73 (s, 2 H), 7.17 (s, 9
H), 5.47 (s, 4 H), 4.12 (s, 4 H), 3.92 (s, 5 H), 3.74 (s, 7H), 2.09
ppm (s, 8 H) P-242 1H NMR (CDCl3, 400 MHz): d = 3.75 (3H, s), 3.87
(2H, s), 5.91 (2H, s), 6.68-6.74 (4H, m), 7.09 (1H, dd, J = 8 and 8
Hz), 7.26-7.36 (3H, m), 7.39 (1H, br). P-249 1H NMR (CDCl3, 400
MHz): d = 7.52 (s, 2 H), 7.20-7.31 (m, 14 H), 7.09-7.16 (m, 5 H),
3.95 (s, 4 H), 3.76 (s, 5 H), 2.99 (s, 5 H), 2.62 (s, 5 H), 2.05
(s, 2 H), 1.54 (s, 4 H), 1.26 ppm (s, 2 H) P-250 1H NMR (CDCl3, 400
MHz): d = 7.26 (s, 11 H), 7.18 (s, 7 H), 6.71 (s, 2 H), 6.13 (s, 2
H), 3.92 (s, 4 H), 3.75 (s, 6 H), 3.28 (s, 4 H), 1.56 (s, 7 H),
1.14 ppm (t, J = 7.2 Hz, 5 H) P-256 1H NMR (DMSO-d6, 400 MHz): d =
3.73 (3H, s), 3.88 (2H, s), 6.75 (1H, m), 6.85 (1H, br), 6.95 (1H,
d, J = 8 Hz), 7.24 (1H, d, J = 8 Hz), 7.26-7.33 (2H, m), 7.37 (1H,
br), 7.40-7.48 (2H, m). P-257 1H NMR (CDCl3, 400 MHz): d = 3.77
(3H, s), 3.98 (2H, s), 6.74 (1H, d, J = 8 Hz), 6.85 (1H, dd, J =
8.8 and 1.6 Hz), 6.97 (1H, d, J = 1.6 Hz), 7.13 (1H, dd, J = 8 and
8 Hz), 7.27 (1H, m), 7.32- 7.36 (2H, m), 7.38 (1H, m), 8.01 (1H, d,
J = 8.8 Hz), 10.62 (1H, s). P-259 1H NMR (400 MHz, DMSO-d6) d ppm
13.83 (br. s., 1 H) 8.03 (br. s., 2 H) 7.75-7.87 (m, 2 H) 7.40-7.49
(m, 2 H) 7.26-7.40 (m, 3 H) 6.97 (dd, J = 8.7, 5.8 Hz, 2 H) 3.85
(s, 2 H) 3.74 (s, 3 H) P-262 1H NMR (DMSO-d6, 400 MHz): d = 3.72
(3H, s), 3.78 (2H, s), 6.12 (2H, s), 6.58 (1H, d, J = 8.8 Hz), 6.62
(1H, s), 6.92 (1H, d, J = 8.8 Hz), 7.23-7.30 (2H, m), 7.37 (1H, s),
7.40-7.48 (2H, m), 7.68 (1H, d, J = 8 Hz), 7.91 (1H, s), 9.84 (1H,
s). P-263 1H NMR (CDCl3, 400 MHz): d = 3.76 (3H, s), 3.98 (2H, s),
6.71 (1H, d, J = 8 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.04 (1H, d, J =
8 Hz), 7.07 (1H, s), 7.10 (1H, dd, J = 8.4 and 8.4 Hz), 7.28 (1H,
m), 7.31-7.36 (2H, m), 7.38 (1H, m), 8.03 (1H, br). P-264 1H NMR
(CDCl3, 400 MHz): d = 2.98 (3H, s), 3.75 (3H, s), 3.89 (2H, s),
6.23 (2H, br), 6.71 (1H, d, J = 8.4 Hz), 6.80 (1H, m), 6.82 (1H,
s), 7.11 (1H, dd, J = 8.4 and 8.4 Hz), 7.17 (1H, d, J = 8 Hz),
7.26-7.40 (4H, m). P-265 1H NMR (CDCl3, 400 MHz): d = 3.03 (3H, s),
3.28 (3H, s), 3.76 (3H, s), 3.95 (2H, s), 6.72 (1H, d, J = 8 Hz),
6.97 (1H, br), 7.12 (1H, dd, J = 8.4 and 8.4 Hz), 7.18-7.22 (2H,
m), 7.26-7.28 (1H, m), 7.31-7.40 (3H, m), 7.61 (1H, d, J = 8.8 Hz).
P-273 1H NMR (DMSO-d6, 400 MHz): d = 10.49 (s, 3 H), 8.14 (br. s.,
7 H), 7.51 (d, J = 8.5 Hz, 5 H), 7.43 (s, 5 H), 7.21 (s, 6 H), 6.94
(s, 3 H), 3.90 ppm (s, 5 H) P-274 1H NMR (CDCl3, 400 MHz): d = 3.78
(3H, s), 4.01 (2H, s), 6.74 (1H, d, J = 8.8 Hz), 7.05 (1H, d, J =
9.2 Hz), 7.08-7.14 (2H, m), 7.24-7.28 (1H, m), 7.32-7.38 (3H, m),
7.53 (1H, dd, J = 8 and 8 Hz). P-275 1H NMR (DMSO-d6, 400 MHz): d =
3.73 (3H, s), 3.98 (2H, s), 4.01 (2H, br), 6.95 (1H, d, J = 8.8
Hz), 7.10-7.16 (2H, m), 7.25-7.28 (1H, m), 7.37-7.38 (2H, m),
7.42-7.49 (3H, m), 8.25 (3H, br). P-278 1H NMR (400 MHz, DMSO-d6) d
ppm 8.45 (s, 2 H) 7.24-7.50 (m, 6 H) 6.96 (d, J = 8.6 Hz, 1 H) 3.85
(s, 2 H) 3.74 (s, 3 H) P-279 1H NMR (400 MHz, DMSO-d6) d ppm 7.98
(br. s., 1 H) 7.75-7.85 (m, 2 H) 7.37-7.49 (m, 3 H) 7.24-7.36 (m, 2
H) 6.95 (t, J = 8.1 Hz, 2 H) 4.03 (q, J = 6.8 Hz, 2 H) 3.84 (s, 2
H) 1.19 (t, J = 6.9 Hz, 3 H) P-285 1H NMR (DMSO-d6, 400 MHz): d =
3.72 (3H, s), 3.82 (2H, s), 6.93 (1H, d, J = 8.8 Hz), 7.10 (1H, d,
J = 8.4 Hz), 7.21 (1H, d, J = 8 Hz), 7.26-7.37 (4H, m), 7.41-7.46
(2H, m), 8.68 (3H, br). P-286 1H NMR (CDCl3, 400 MHz): d = 2.85
(3H, s), 3.76 (3H, s), 3.95 (2H, s), 4.35 (2H, d, J = 6.4 Hz), 4.61
(1H, br), 6.72 (1H, dd, J = 8.4 and 1.2 Hz), 6.94 (1H, d, J = 11.2
Hz), 7.02 (1H, dd, J = 8 and 1.2 Hz), 7.10 (1H, dd, J = 8.4 and 8.4
Hz), 7.25-7.28 (2H, m), 7.30-7.35 (2H, m), 7.38 (1H, m). P-287 1H
NMR (DMSO-d6, 400 MHz): d = 3.72 (3H, s), 3.92 (2H, s), 4.15 (2H,
d, J = 6 Hz), 5.52 (2H, s), 6.33 (1H, m), 6.93 (1H, d, J = 8.8 Hz),
6.90-7.04 (2H, m), 7.20-7.38 (4H, m), 7.41-7.46 (2H, m). P-289 1H
NMR (DMSO-d6, 400 MHz): d = 10.57 (s, 2 H), 8.90 (br. s., 4 H),
7.51 (d, J = 8.5 Hz, 4 H), 7.41-7.47 (m, 4 H), 7.21 (d, J = 8.5 Hz,
4 H), 6.94 (s, 2 H), 3.90 (s, 8 H), 3.72 (s, 6 H), 2.61 (s, 6 H),
0.00 ppm (s, 6 H) P-290 1H NMR (400 MHz, DMSO-d6) d ppm 13.34-13.96
(m, 1 H) 7.91-8.04 (m, 3 H) 7.74-7.90 (m, 3 H) 7.59 (d, J = 4.7 Hz,
2 H) 7.35 (t, J = 8.7 Hz, 1 H) 6.97 (dd, J = 8.7, 2.5 Hz, 2 H) 3.86
(s, 2 H) 2.60 (s, 3 H) P-291 1H NMR (400 MHz, DMSO-d6) d ppm 8.41
(s, 2 H) 7.24-7.50 (m, 5 H) 6.95 (d, J = 8.6 Hz, 1 H) 3.83 (s, 2 H)
3.74 (s, 3 H)
P-292 1H NMR (400 MHz, CDCl3) d ppm 8.49 (s, 2 H) 7.29-7.42 (m, 3
H) 7.14 (t, J = 8.5 Hz, 1 H) 6.74 (d, J = 8.5 Hz, 1 H) 3.90 (s, 2
H) 3.77 (s, 3 H) 3.44 (s, 3 H) P-295 1H NMR (CDCl3, 400 MHz): d =
3.77 (3H, s), 3.95 (2H, s), 5.50 (1H, s), 6.72 (1H, dd, J = 8.4
Hz), 6.82 (1H, m), 6.88 (1H, d, J = 8 Hz), 7.10 (1H, dd, J = 8.4
and 8.4 Hz), 7.27 (1H, m), 7.33- 7.39 (3H, m), 7.42 (1H, d, J = 8
Hz). P-296 1H NMR (DMSO-d6, 400 MHz): d = 3.73 (3H, s), 3.87 (2H,
s), 3.88 (2H, m), 6.74 (2H, m), 6.94 (2H, m), 7.20 (1H, d, J = 8
Hz), 7.27-7.32 (2H, m), &.35 (1H, s), 7.42-7.48 (2H, m), 7.94
(3H, br), 10.01 (1H, s). P-297 1H NMR (400 MHz, CDCl3) d ppm 8.12
(s, 2 H) 7.90-8.00 (m, 2 H) 7.47-7.65 (m, 2H) 7.24 (d, J = 8.9 Hz,
1 H) 7.13 (t, J = 8.6 Hz, 1 H) 6.75 (d, J = 8.6 Hz, 1 H) 3.90 (s, 2
H) 3.76 (s, 3 H) 3.11 (s, 3 H) 2.62 (s, 3 H) P-299 1H NMR (CDCl3,
400 MHz): d = 2.84 (3H, s), 3.75 (3H, s), 3.90 (2H, s), 4.28 (2H,
d, J = 6.4 Hz), 4.82 (1H, br), 5.81 (1H, s), 6.69 (1H, s), 6.71
(1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 8 Hz), 7.08 (1H, d, J = 8.8
Hz), 7.11 (1H, d, J = 8 Hz), 7.27 (1H, m), 7.32-7.35 (2H, m), 7.38
(1H, m). P-300 1H NMR (acetone-d6, 400 MHz): d = 1.90 (3H, s), 3.79
(3H, s), 3.98 (2H, s), 4.35 (2H, d, J = 5.6 Hz), 6.93 (1H, d, J =
8.8 Hz), 6.98 (1H, d, J = 11.2 Hz), 7.05 (1H, d, J = 8 Hz),
7.27-7.34 (3H, m), 7.38-7.46 (3H, m). P-301 1H NMR (CDCl3, 400
MHz): d = 3.72 (3H, s), 3.85 (2H, s), 4.14 (2H, d, J = 5.2 Hz),
4.71 (2H, br), 5.41 (1H, br), 6.64-6.68 (2H, m), 6.76 (1H, s), 6.90
(1H, d, J = 8 Hz), 7.08 (1H, dd, J = 8.4 and 8.4 Hz), 7.24-7.32
(3H, m), 7.37 (1H, s). P-302 1H NMR (CDCl3, 400 MHz): d = 2.00 (3H,
s), 3.74 (3H, s), 3.89 (2H, s), 4.28 (2H, d, J = 6.8 Hz), 6.25 (1H,
br), 6.66-6.71 (2H, m), 6.80 (1H, d, J = 1.6 Hz), 6.97 (1H, d, J =
8 Hz), 7.11 (1H, dd, J = 8.4 and 8.4 Hz), 7.26-7.35 (3H, m), 7.38
(1H, s). P-313 1H NMR (CDCl3, 400 MHz): d = 2.17 (3H, s), 3.96 (2H,
s), 6.31 (1H, t, 73 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.08 (1H, br),
7.12 (1H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.31 (2H, m),
7.42 (2H, d, J = 8 Hz), 7.51-7.54 (2H, m). P-316 1H NMR (DMSO-d6,
400 MHz): d = 3.93 (2H, s), 5.78 (2H, s), 7.17 (1H, t, 73 Hz), 7.10
(2H, d, J = 8.4 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4
Hz), 7.43 (1H, dd, J = 8.4 and 8.4 Hz), 7.78 (1H, d, J = 8.4 Hz),
7.86 (1H, m), 8.23 (1H, s), 8.29 (1H, m), 8.44 (1H, s). P-317 1H
NMR (DMSO-d6, 400 MHz): d = 4.00 (2H, s), 7.14 (1H, t, 73 Hz),
7.12-7.20 (3H, m), 7.29 (2H, d, J = 8.4 Hz), 7.36 (1H, m), 7.40-7.4
(2H, m), 7.55 (1H, m), 7.62 (1H, m), 9.20-9.80 (3H, br). P-318 1H
NMR (400 MHz, DMSO-d6) d ppm 13.27 (br. s., 1 H) 8.58-8.75 (m, 1 H)
7.63-7.87 (m, 3 H) 7.36-7.51 (m, 3 H) 7.20-7.41 (m, 2 H) 6.97 (t, J
= 9.9 Hz, 1 H) 3.87 (s, 2 H) 3.28-3.41 (m, 2 H) 1.20 (t, J = 7.2
Hz, 3 H) P-322 1H NMR (DMSO-d6, 400 MHz): d = 1.18 (3H, t, J = 7
Hz), 2.00 (3H, s), 3.86 (2H, s), 4.01 (2H, q, J = 7 Hz), 6.90 (1H,
d, J = 8 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 8.4 and
8.4 Hz), 7.33- 7.40 (2H, m), 7.47 (2H, d, J = 8.4 Hz), 7.52-7.56
(2H, m), 9.85 (1H, s). P-323 1H NMR (DMSO-d6, 400 MHz): d = 3.90
(2H, s), 5.77 (2H, s), 7.13 (1H, t, 73 Hz), 7.09 (2H, d, J = 8.4
Hz), 7.11 (1H, d, J = 9.2 Hz), 7.31 (2H, d, J = 9.2 Hz), 7.37 (2H,
d, J = 8.4 Hz), 7.43 (2H, dd, J = 8 and 8 Hz), 7.57 (1H, s), 7.63
(1H, m), 8.44 (1H, s). P-329 1H NMR (CDCl3, 400 MHz): d = 1.99 (3H,
s), 2.62 (3H, s), 3.76 (3H, s), 3.94 (2H, s), 4.43 (2H, d, J = 5.6
Hz), 5.73 (1H, br), 6.73 (1H, d, J = 8.4 Hz), 6.91 (1H, d, J = 8
Hz), 6.99 (1H, d, J = 8 Hz), 7.12 (1H, dd, J = 8.4 and 8.4 Hz),
7.26 (1H, m), 7.51 (1H, m), 7.60 (1H, m), 7.94 (1H, m), 7.99 (1H,
m). P-330 1H NMR (DMSO-d6, 400 MHz): d = 2.59 (3H, s), 3.72 (3H,
s), 3.94 (2H, s), 4.15 (2H, d, J = 5.6 Hz), 5.51 (2H, br), 6.35
(1H, t, J = 5.6 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.00-7.04 (2H, m),
7.22 (1H, dd, J = 8 and 8 Hz), 7.32 (1H, dd, J = 8.8 and 8.8 Hz),
7.57 (2H, m), 7.86 (1H, s), 7.95 (1H, m). P-336 1H NMR (CDCl3, 400
MHz): d = 7.99 (s, 2 H), 7.93-7.96 (m, 1 H), 7.58-7.61 (m, 1 H),
7.51 (t, Calc. 364.4; J = 7.6 Hz, 1 H), 7.31 (dd, J = 7.6, 2.4 Hz,
1 H), 7.09 (t, J = 8.4 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H),
APCI.sup.+(M + 1): 6.35 (d, J = 8.8 Hz, 1 H), 4.47 (br, s, 1 H),
3.82 (s, 2 H), 3.74 (s, 3 H), 2.90 (d, J = 4.4 Hz, 3 H), 365, 98%
2.62 (s, 3 H) P-337 1H NMR (DMSO-d6, 400 MHz): d = 9.08 (s, 1 H),
8.06 (br, s, 2 H), 7.93-7.96 (m, 1 H), 7.87 (br, Calc. 364.4; s, 1
H), 7.58 (d, J = 5.2 Hz, 2 H), 7.53 (dd, J = 8.8, 2.4 Hz, 1 H),
7.30 t, J = 9.2 Hz, 1 H), 7.26 (d, APCI.sup.+(M + 1): J = 8.8 Hz, 1
H), 6.95 (d, J = 8.8 Hz, 1 H), 3.87 (s, 2 H), 3.72 (s, 3 H),
3.13-3.20 (m, 2 H), 2.59 (s, 3 365, 98% H), 1.07 (t, J = 7.2 Hz, 3
H) P-339 1H NMR (DMSO-d6, 400 MHz): d = 8.78 ((br, s, 1 H), 7.97
(br, s, 1 H), 7.86 (s, 1 H), 7.73-7.76 Calc. 378.36; (m, 2 H),
7.58-7.59 (m, 2 H), 7.35 (t, J = 8.8 Hz, 1 H), 6.96-7.02 (m, 2 H),
3.88 (s, 2 H), 3.73 (s, 3 APCI.sup.+(M + 1): H), 3.35-3.39 (m, 2H),
2.59 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H) 379.1, 100% P-345 1H NMR
(CDCl3, 400 MHz): d = 8.09-8.15 (m, 2 H), 7.94-7.98 (m, 2 H), 7.86
(br, s, 1 H), 7.50- Calc. 392.43; 7.60 (m, 3 H), 7.10 (t, J = 8.8
Hz, 1 H), 6.73 (d, J = 8.8 Hz, 1 H), 3.93 (s, 2 H), 3.76 (s, 3 H),
2.62 APCI.sup.+(M + 1): (s, 3 H), 2.19 (s, 3 H) 393, >95% P-357
1H NMR (400 MHz, CDCl3) d ppm 1.31 (t, J = 7.11 Hz, 3 H) 3.76 (s, 3
H) 3.90 (s, 2 H) 4.23 (q, J = 7.16 Hz, 2 H) 6.70 (d, J = 8.32 Hz, 1
H) 7.08 (t, J = 8.59 Hz, 1 H) 7.29-7.42 (m, 4 H) 7.48-7.60 (m, 2 H)
7.88 (d, J = 8.45 Hz, 1 H) 8.14 (d, J = 1.48 Hz, 1 H) P-359 1H NMR
(400 MHz, CDCl3) d ppm 1.21 (t, J = 6.98 Hz, 3 H) 1.27-1.33 (m, 3
H) 3.76 (s, 3 H) 3.93 (s, 2 H) 3.99 (q, J = 7.02 Hz, 2 H) 4.23 (q,
J = 7.11 Hz, 2 H) 6.71 (d, J = 8.59 Hz, 1 H) 7.11 (t, J = 8.52 Hz,
1 H) 7.27-7.42 (m, 4 H) 7.45-7.56 (m, 2 H) 8.28 (d, J = 1.21 Hz, 1
H) P-387 1H NMR (CDCl3, 400 MHz): d = 8.09-8.15 (m, 2 H), 7.81 (br,
s, 1 H), 7.55-7.55 (m, 1 H), 7.31- : Calc. 384.84; 7.38 (m, 3 H),
7.24-7.26 (m, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.71 (d, J = 8.4 Hz,
1 H), 3.91 (s, 2 H), APCI.sup.+(M + 1): 3.76 (s, 3 H), 2.19 (s, 3
H) 385, 100% P-392 1H NMR (400 MHz, CDCl3) d ppm 3.78 (s, 3 H) 3.94
(s, 2 H) 6.75 (d, J = 8.45 Hz, 1 H) 7.13 (t, J = 8.52 Hz, 1 H)
7.31-7.40 (m, 3 H) 8.50 (s, 2 H) P-407 1H NMR (DMSO-d6, 400 MHz): d
= 11.85 (s, 1 H), 8.47 (s, 1 H), 8.14 (dd, J = 9.2, 2.0 Hz, 1 H),
Calc. 420.86; 8.07 (br, a, , 1 H), 7.73 (d, J = 8.4 Hz, 1 H),
7.61-7.65 (m, 1 H), 7.26-7.45 (m, 5H), 6.95 (d, J = 8.4
APCI.sup.+(M + 1): Hz, 1 H), 6.42 (d, J = 10.0 Hz, 1 H), 3.96 (s, 2
H), 3.72 (s, 3 H). 421, 94.1% P-410 1H NMR (CDCl3, 400 MHz): d =
8.91 (d, J = 2.4 Hz, 1 H), 8.61 (s, 1 H), 8.17 (dd, J = 8.0, 2.4
Hz, : Calc. 483.77; 1 H), 7.63-7.65 (m, 1 H), 7.57 (d, J = 8.0 Hz,
1 H), 7.24-7.39 (m, 5 H), 7.15 (t, J = 8.4 Hz, 1 H), APCI.sup.+(M +
1): 6.73 (d, J = 8.8 Hz, 1 H), 4.02 (s, 2 H), 3.77 (s, 3 H) 485,
96% P-411 1H NMR (CDCl3, 400 MHz): d = 7.90 (br, s, 1 H), 7.39 (s,
1 H), 7.25-7.35 (m, 4 H), 7.07 (d, Calc. 386.86; J = 8.6 Hz, 1 H),
6.70 (d, J = 8.8 Hz, 1 H), 6.44 (d, J = 8.8 Hz, 1 H), 5.02 (br, s,
1 H), 3.77-3.80 (m, APCI.sup.+(M + 1): 4 H), 3.75 (s, 3 H),
3.48-3.51 (m., 2 H). 387, 100% P-412 1H NMR (CDCl3, 400 MHz): d =
9.13 (s, 1 H), 8.03 (s, 1 H), 8.08 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1
Calc. 394.84; H), 7.72 (dd, J = 8.4, 2.4 Hz, 1 H), 7.38 (s, 1 H),
7.26-7.35 m, 3 H), 7.14 (t, J = 8.4 Hz, 1 H), 6.74 APCI.sup.+(M +
1): (d, J = 8.0 Hz, 1 H), 4.02 (s, 2 H), 3.77 (s, 3 H). 395, 100%
P-416 1H NMR (400 MHz, CDCl3) d ppm 3.70-3.81 (m, 3 H) 4.88 (br.
s., 2 H) 6.72 (d, J = 8.59 Hz, 1 H) 7.27-7.41 (m, 5 H) 7.65 (d, J =
12.08 Hz, 1 H) 9.34 (s, 1 H) P-418 1H NMR (400 MHz, CDCl3) d ppm
3.81 (s, 3 H) 6.80 (d, J = 8.86 Hz, 1 H) 6.99-7.18 (m, 4 H) 7.30
(d, J = 7.25 Hz, 1 H) 7.33-7.39 (m, 2 H) 7.41 (s, 1 H) 7.47 (dd, J
= 8.45, 5.50 Hz, 2 H) 7.55 (t, J = 8.59 Hz, 1 H) P-419 1H NMR (400
MHz, CDCl3) d ppm 3.76 (s, 3 H) 6.50-6.64 (m, 3 H) 6.95 (t, J =
8.65 Hz, 2 H) 7.14 (t, J = 8.59 Hz, 1 H) 7.21-7.30 (m, 3 H)
7.31-7.37 (m, 2 H) 7.37-7.42 (m, 1 H) P-424 1H NMR (CDCl3, 400
MHz): d = 7.71 (s, 1 H), 7.58 (s, 1 H), 7.39 (br, s, 1 H),
7.21-7.435 (m, 6 Calc. 407.88; H), 6.75 (d, J = 6.8 Hz, 1 H), 6.68
(d, J = 6.4 Hz, 2 H), 5.33 (s, 2 H), 3.77 (s, 3 H), APCI.sup.+(M +
1): 408, 98% P-431 1H NMR (CDCl3, 400 MHz): d = 8.09 (s, 1 H),
7.25-7.39 (m, 5 H), 7.08 (t, J = 8.4 Hz, 1 H), 6.68 Calc. 483.97;
(d, J = 8.4 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 4.17 (q, J = 7.1
Hz, 2 H), 3.84 (s, 2 H), 3.74 (s, 3 H), APCI.sup.+(M + 1):
3.48-3.60 (m., 8 H), 1.28 (t, J = 7.2 Hz, 3 H),) 484, 93% P-432 1H
NMR (DMSO-d6, 400 MHz): d = 7.96 (s, 1 H), 7.69 (br, s, 1 H),
7.27-7.48 (m, 5 H), 7.06- Calc. 454; 7.16 (br, s, 1 H), 6.94 (d, J
= 8.8 Hz, 1 H), 6.44-6.64 (m, 2 H), 3.44-4.66 (m, 18 H).
APCI.sup.+(M): 454, 93% P-435 1H NMR (DMSO-d6, 400 MHz): d = 8.49
(s, 1 H), 8.10 (s, 1 H), 7.80 (s, 1 H), 7.24-7.47 (m, 9 Calc.
450.9; H), 7.00 (d, J = 8.8 Hz, 1 H), 5.80 (s, 2 H), 5.33 (s, 2 H),
3.74 (s, 3 H). APCI.sup.+(M + 1): 451, 93.8% P-436 1H NMR (CDCl3,
400 MHz): d = 7.76 (s, 1 H), 7.65 (s, 1 H), 7.23-7.42 (m, 9 H),
6.75 (d, J = 8.4 Calc. 478.96; Hz, 1 H), 6.17 (s, 1 H), 5.34 (s, 2
H), 4.61 (br, s, 1 H), 3.77 (s, 3 H), 3.31 (q, J = 7.2 Hz, 2 H),
1.15 APCI.sup.+(M + 1): (t, J = 7.2 Hz, 3 H) 479, 100% P-451 1H NMR
(CDCl3, 400 MHz): d = 8.35 (s, 1 H), 8.24-8.28 (m, 1 H), 7.78 (d, J
= 7.6 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.16-7.21 (m, 2 H), 7.06
(t, J = 8.4 Hz, 1 H), 6.94 (t, J = 8.8 Hz, 2 H), 4.91 (s, 1 H),
3.94 (s, 2 H) P-453 .sup.1H NMR (400 MHz, CD.sub.3OD): 3.76 (s, 3
H), 4.02 (s, 2 H), 6.87 (d, J = 8.6 Hz, 1 H), 7.17-7.35 (m, 5 H),
7.34-7.45 (m, 3 H), 7.45-7.53 (m, 1 H) ppm. P-471 1H NMR (CDCl3,
400 MHz): d = 7.52 (s, 4 H), 7.30-7.39 (m, 7 H), 7.26 (s, 10 H),
7.14 (s, 4 H), Calc. 399.9; 4.47 (s, 3 H), 3.79 (s, 11 H), 1.25 (s,
7 H), 0.07 ppm (s, 2 H) APCI.sup.+(M - NH2): 383, 100% P-496 1H NMR
(CDCl3, 400 MHz): d = 7.57-7.63 (m, 2 H), 7.34-7.40 (m, 2 H),
7.15-7.19 (m, 2 H), Calc. 375.22; 7.02 (t, J = 8.4 Hz, 1 H),
6.55-7.02 (m, 2 H), 6.72 (dd, J = 8.4, 1.2 Hz, 1 H), 4.97 (br. s.,
1 H), 3.91 APCI-(M): 375 (s, 3 H) 100% P-497 1H NMR (CDCl3, 400
MHz): d = 7.55 (br, s 1 H), 7.46-7.48 (m, 1 H), 7.25-7.33 (m, 2 H),
7.15- 7.19 (m, 2 H), 7.07 (t, J = 6.8 Hz, 1 H), 6.95-6.99 (m, 2 H),
6.69 (dd, J = 6.8, 0.8 Hz, 1 H), 3.92 (s., 2 H), 3.44 (s, 3 H)
P-498 1H NMR (CDCl3, 400 MHz): d = 3.80 (3H, s), 3.90 (2H, s), 4.70
(1H, s), 6.76 (2H, m), 6.93 (1H, d, J = 8 Hz), 7.06 (2H, m),
7.12-7.19 (2H, m), 7.52 (1H, dd, J = 8 and 8 Hz), 7.81 (1H, m),
8.14 (1H, m), 8.38 (1H, m). P-499 1H NMR (400 MHz, CDCl3) d ppm
8.29 (s, 2 H) 8.03 (d, J = 2.0 Hz, 1 H) 7.62-7.79 (m, 2 H) 7.48
(dd, J = 8.5, 2.3 Hz, 1 H) 7.02 (d, J = 8.3 Hz, 1 H) 6.70 (d, J =
8.5 Hz, 1 H) 6.51 (d, J = 8.2 Hz, 1 H) 3.91 (s, 3 H) 3.87 (s, 2 H)
P-500 1H NMR (400 MHz, CDCl3) d ppm 8.21-8.37 (m, 3 H) 7.64-7.80
(m, 2 H) 7.52 (dd, J = 8.2, 2.3 Hz, 1 H) 7.23 (d, J = 8.2 Hz, 1 H)
7.03 (d, J = 8.3 Hz, 1 H) 6.52 (d, J = 8.3 Hz, 1 H) 4.87-4.94 (m, 1
H) 4.83 (s, 1 H) 3.92 (s, 2 H) P-502 1H NMR (DMSO-d6, 400 MHz): d =
8.14 (s, 2 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.36 (s, 2 H), 7.21 (s, 7
H), 6.99 (s, 2 H), 4.31 (d, J = 5.8 Hz, 4 H), 3.94 (s, 7 H), 3.75
(s, 5 H), 3.38 (d, J = 7.0 Hz, 3 H), 2.80 (s, 11 H), 1.09 ppm (t, J
= 7.0 Hz, 2 H) P-505 1H NMR (400 MHz, DMSO-d6) d ppm 10.31 (br. s.,
1 H) 10.12 (br. s., 1 H) 7.63 (br. s., 3 H) 7.39-7.49 (m, 3 H)
7.24-7.35 (m, 4 H) 7.21 (br. s., 2 H) 6.83 (d, J = 8.5 Hz, 1 H)
4.43 (br. s., 2 H) 2.05 (s, 3 H) P-507 1H NMR (400 MHz, DMSO-d6) d
ppm 7.91-8.00 (m, 2 H) 7.87 (s, 1 H) 7.76-7.84 (m, 2 H) 7.59 (d, J
= 4.8 Hz, 2 H) 7.35 (t, J = 8.8 Hz, 1 H) 6.97 (dd, J = 8.7, 5.8 Hz,
2 H) 3.86 (s, 2 H) 3.73 (s, 3 H) 2.60 (s, 3 H) P-517 1H NMR (400
MHz, DMSO-d6) d ppm 3.77 (s, 3 H) 5.39 (s, 2 H) 7.07 (d, J = 8.59
Hz, 1 H) 7.28- 7.64 (m, 5 H) 7.77 (br. s., 1 H) 8.18 (s, 1 H) 8.52
(br. s., 1 H) 8.66 (br. s., 1 H) 9.11 (s, 1 H) P-574 1H NMR (CDCl3,
400 MHz): d = 8.22 (d, J = 2.8 Hz, 1 H), 7.65 (dd, J = 8.8, 2.4 Hz,
1 H), 7.28- 7.45 (m, 5 H), 6.76 (d, J = 6.8 Hz, 1 H), 6.70 (d, J =
7.2 Hz, 1 H), 5.37 (s, 2 H), 3.79 (s, 3 H). P-575 1H NMR (CDCl3,
400 MHz): d = 8.22 (d, J = 9.2 Hz, 2 H), 7.26-7.42 (m, 5 H), 7.05
(d, J = 9.3 Hz, Calc. 387.8; 2 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.18
(s, 2 H), 3.81 (s, 3 H). APCI-(M - 1):
386, 100% P-576 1H NMR (CDCl3, 400 MHz): d = 9.70 (br. S, 2 H),
7.56 (t, J = 8.8 Hz, 1 H), 7.24-7.50 (m, 6 H), Calc. 357.8; 7.12
(d, J = 8.8 Hz, 2 H), 7.01 (d, J = 8.8 Hz, 1 H), 5.10 (s, 2 H),
3.77 (s, 3 H). APCI+(M + 1): 358, 97.4% P-583 1H NMR (DMSO-d6, 400
MHz): d = 8.17 (d, J = 8.4 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H),
7.35-7.48 Calc. 370.8; (m, 6 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.15
(s, 1 H), 3.75 (s, 3 H). APCI.sup.+(M - OH): 353, 97.7% P-584 1H
NMR (DMSO-d6, 400 MHz): d = 8.42 (s, 1 H), 7.26-7.47 (m, 8 H), 7.20
(d, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 1 H), 5.76 (s, 2 H),
5.67 (s, 1 H), 3.74 (s, 3 H). P-585 1H NMR (CDCl3, 400 MHz): d =
8.14 (d, J = 2.8 Hz, 1 H), 7.24-7.41 (m, 7 H), 6.80 (dd, J = 7.2,
Calc. 378.2; 2.4 Hz, 1 H), 5.11 (s, 2 H), 3.80 (s, 3 H)
APCI.sup.+(M): 378, 100% P-586 1H NMR (CDCl3, 400 MHz): d = 7.95
(dd, J = 3.2, 0.8 Hz, 1 H), 7.26-7.43 (m, 5 H), 7.20 (dd, Calc.
398.89; J = 8.9, 3.0 Hz, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 6.26 (dd,
J = 8.9, 0.5 Hz, 1 H), 5.02 (s, 2 H), 3.98 (t, APCI.sup.+(M + 1): J
= 7.3 Hz, 4 H), 3.79 (s, 3 H), 2.36 (quin, J = 7.3 Hz, 2 H). 399,
99% P-589 1H NMR (DMSO-d6, 400 MHz): d = 8.32 (s, 1 H), 7.43-7.55
(m, 3 H), 7.40 (s, 1 H), 7.27-7.33 Calc. 400.8; (s, 3 H), 7.01 (d,
J = 8.4 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 2 H), 5.70 (s, 2 H), 5.02
(s, 2 H), 3.76 (s, 3 APCI.sup.+(M + 1): H) 401, 100% P-594 1H NMR
(CDCl3, 400 MHz): d = 7.27-7.45 (m, 6 H), 7.09 (br. s., 1 H), 6.94
(d, J = 9.2 Hz, 2 H), Calc. 399.85; 6.78 (d, J = 8.8 Hz, 1 H),),
5.06 (s, 2 H), 3.79 (s, 3 H), 2.15 (s, 3 H). APCI.sup.+(M + 1):
400, 95% P-603 1H NMR (CDCl3, 400 MHz): d = 8.20 (d, J = 5.6 Hz, 1
H), 7.52 (br. s., 1 H), 7.32-7.41 (m, 5 H), Calc. 360.24; 7.01 (d,
J = 8.4 Hz, 1 H), 6.92 (d, J = 2.1 Hz, 1 H), 6.82 (dd, J = 5.8, 2.2
Hz, 1 H), 5.06 (s, 2 H), 3.84 APCI.sup.+(M): 360, (s, 3 H). 97%
P-604 1H NMR (CDCl3, 400 MHz): d = 8.21 (d, J = 5.8 Hz, 1 H),
7.26-7.42 (m, 5 H), 6.94 (d, J = 2.1 Calc. 378.23; Hz, 1 H),
6.79-6.87 (m, 2 H), 5.12 (s, 2 H), 3.81 (s, 3 H). APCI.sup.+(M):
378, 99% P-607 1H NMR (CDCl3, 400 MHz): d = 8.01 (d, J = 6.4 Hz, 1
H), 7.52 (br. s., 1 H), 7.29-7.41 (m, 5 H), 7.00 (d, J = 8.4 Hz, 1
H), 6.23 (dd, J = 6.0, 2.0 Hz, 1 H), 5.89 (d, J = 2.0 Hz, 1 H),
5.03 (s, 2 H), 3.83 (s, 3 H), 3.41-3.45 (m, 4 H), 1.97-2.05 (m, 4
H). P-608 1H NMR (CDCl3, 400 MHz): d = 8.01 (d, J = 6.4 Hz, 1 H), .
7.28-7.45 (m, 4 H), 6.79 (d, J = 8.8 Hz, 1 H), 6.23 (dd, J = 6.0,
2.4 Hz, 1 H), 5.90 (d, J = 2.0 Hz, 1 H), 5.10 (s, 2 H), 3.79 (s, 3
H), 3.41- 3.45 (m, 4 H), 1.97-2.05 (m, 4 H). P-620 1H NMR (CDCl3,
400 MHz): d = 2.16 (3H, s), 3.90 (2H, s), 4.95 (1H, s), 6.71 (1H,
d, J = 9.2 Hz), 7.02 (1H, dd, J = 8.4 and 8.4 Hz), 7.07 (1H, br),
7.17 (2H, d, J = 8.4 Hz), 7.34-7.37 (2H, m), 7.41 (1H, d, J = 8.4
Hz), 7.55-7.59 (2H, m).
* * * * *