US2012157403A1PendingUtilityA1
Bicyclic and tricyclic derivatives as thrombin receptor antagonists
Est. expiryOct 4, 2026(~0.2 yrs left)· nominal 20-yr term from priority
A61P 37/06A61P 43/00A61P 7/12A61P 3/10A61P 9/06A61P 9/10A61P 9/12A61P 9/00A61P 9/04A61P 7/02A61P 7/00A61P 25/00A61P 25/06A61P 29/00A61P 27/02A61P 3/14A61P 27/06A61P 35/00A61P 25/28A61P 11/06A61P 11/00A61P 1/16C07D 401/06A61P 15/00A61P 13/10A61P 15/10A61P 11/08A61P 1/00A61P 19/00C07D 417/06A61P 17/00A61P 17/06A61P 13/12A61P 19/10A61P 17/02A61P 1/02A61P 19/02A61K 31/443
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Claims
Abstract
Heterocyclic-substituted tricyclics of the formula or a pharmaceutically acceptable salt or solvate of said compound, isomer or racemic mixture wherein represents an optional double bond, the dotted line is optionally a bond or no bond, resulting in a double bond or a single bond, as permitted by the valency requirement and wherein E, A, G M, Het, B, X, R 3 , R 10 , R 11 , R 32 and R 33 are herein defined and the remaining substituents are as defined in the specification, are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.
Claims
exact text as granted — not AI-modified1 . A compound represented by structural formula I:
or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein
represents a double bond or a single bond, as permitted by the valency requirement; with the proviso that R 3 is absent when the carbon to which R 3 would be attached is part of a double bond;
B is —(CH 2 ) n3 —, —(CH 2 )—O—, —(CH 2 )S—, —(CH 2 )—NR 6 —, —C(O)NR 6 —, —NR 6 C(O)—,
—(CH 2 ) n4 CR 12 ═CR 12a (CH 2 ) n5 — or —(CH 2 ) n4 C≡C(CH 2 ) n5 —, wherein n 3 is 0-5, n 4 and n 5 are independently 0-2, and R 12 and R 12a are independently selected from the group consisting of hydrogen, alkyl and halogen;
A, E, G, M and J are independently selected from the group consisting of —N(R 54 )—, —(CR 1 R 2 )—, —O—,
—S—, —S(O)—, —S(O) 2 — and
X is
—CH— or —N—, with the proviso that selection of A, G, M and X do not result in adjacent oxygen or sulfur atoms;
each n is 0, 1 or 2 with the proviso that all n variables cannot be 0;
Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, with the proviso that there are no adjacent oxygen or sulfur atoms present in the heteroaromatic group, wherein a ring nitrogen can form an N-oxide or a quaternary group with an alkyl group, wherein Het is attached to B by a carbon atom ring member of Het, and wherein the Het group is substituted by 1 to 4 moieties, W, wherein each W is independently selected from the group consisting of hydrogen; alkyl; fluoroalkyl; difluoroalkyl; trifluoroalkyl; cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted by alkyl or alkenyl; alkenyl; R 21 -aryl; R 21 -heteroaryl; R 21 -arylalkyl; R 21 -aryl-alkenyl; heteroaryl; heteroarylalkyl; heteroarylalkenyl; hydroxyalkyl; dihydroxyalkyl; aminoalkyl; alkylaminoalkyl;
di-(alkyl)-aminoalkyl; thioalkyl; alkoxy; alkenyloxy; halogen; —NR 4 R 5 ; —CN; —OH; —C(O)OR 17 ; —COR 16 ; —OS(O 2 )CF 3 ; —CH 2 OCH 2 CF 3 ; alkylthio; —C(O)NR 4 R 5 ; —OCHR 6 -phenyl; phenoxyalkyl; —NHCOR 16 ; —NHSO 2 R 16 ; biphenyl; —OC(R 6 ) 2 COOR 7 ; —OC(R 6 ) 2 C(O)NR 4 R 5 ; alkoxy substituted by alkyl, amino or —NHC(O)OR 17 ; aryl; or alkyl optionally substituted with —NR 1 R 2 , —NR 1 COR 2 , —NR 1 CONR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O) 2 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)OH, —C(O)OR 1 , —CONR 1 R 2 , hydroxyalkyl, alkyl or —S(O) 2 -alkyl; —C(O)NR 4 R 5 and heteroaryl; wherein adjacent carbons on the Het ring can optionally form a ring with a methylenedioxy group;
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; or
R 1 and R 2 when attached to nitrogen, taken together, form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, with 1-3 heteroatoms selected from —O—, —N—, —S—, —S(O)—, —S(O) 2 — and
with the proviso that S and O ring atoms are not adjacent to each other, where said heterocyclic ring is unsubstituted or substituted with one or more groups selected from alkyl, halogen, hydroxy, alkoxy, aryloxy and arylalkoxy;
R 3 is aralkoxy, aryloxy, heteroaryl, heteroaralkoxy, —CN, —NO 2 , —O-aryl, —O-heteroaryl, N 3 , —C(O)NR 18 R 19 , —C(═NR 1 )NR 1 , R 2 , —N(R 1 )C═(NR 1 )NR 1 R 2 ; —N═C(R 1 )NR 1 R 2 , —NR 18 C(O)R 19 , —NR 18 C(O)NR 18 R 19 , —NR 18 C(O)OR 19 , —NR 18 S(O) 2 R 19 , —NR 18 S(O) 2 NR 18 R 19 , —NHNR 18 R 19 , —NR 18 NR 18 R 19 or -alkyl-NR 18 R 19 ;
R 6 is hydrogen, alkyl or phenyl;
R 7 is hydrogen or alkyl;
each R 13 is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, halogen, —(CH 2 ) n6 NHC(O)OR 16b , —(CH 2 ) n6 NHC(O)R 16b , —(CH 2 ) n6 NHC(O)NR 4 R 5 , —(CH 2 ) n6 NHSO 2 R 16 , —(CH 2 ) n6 NHSO 2 NR 4 R 5 , and —(CH 2 ) n6 C(O)NR 28 R 29 , where n 6 is 0-4;
each R 14 is independently selected from the group consisting of hydrogen, alkyl, —OH, alkoxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, —(CH 2 ) n6 NHC(O)OR 16b , —(CH 2 ) n6 NHC(O)R 16b , —(CH 2 ) n6 NHC(O)NR 4 R 5 , —(CH 2 ) n6 NHSO 2 R 16 , —(CH 2 ) n6 NHSO 2 NR 4 R 5 , and —(CH 2 ) n6 C(O)NR 28 R 29 where n 6 is 0-4; where R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, phenyl, benzyl and cycloalkyl, or R 4 and R 5 together can form a ring with the nitrogen to which they are attached, wherein said ring formed by R 4 and R 5 is optionally substituted with ═O, OH, OR 1 or —C(O)OH; or
R 13 and R 14 taken together form a spirocyclic or a heterospirocyclic ring of 3-6 ring atoms, wherein said heterospirocyclic ring contains 2 to 5 carbon ring atoms and 1 or 2 hetero ring atoms selected from the group consisting of O, S and N;
R 16 is independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl;
R 16a is independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl;
R 16b is hydrogen, alkoxy, alkyl, alkoxyalkyl-, R 22 —O—C(O)-alkyl-, cycloalkyl, R 21 -aryl, R 21 -arylalkyl, haloalkyl, alkenyl, halo substituted alkenyl, alkynyl, halo substituted alkynyl, R 21 -heteroaryl, (R 21 -heteroaryl)-alkyl-, (R 21 -heterocycloalkyl)-alkyl-, R 28 R 29 N-alkyl-, R 28 R 29 N—C(O)-alkyl-, R 28 R 29 N—C(O)O-alkyl-, R 28 OC(O)N(R 29 )-alkyl-, R 28 R 29 N-alkyl-, R 28 R 29 N—C(O)—N(R 29 )-alkyl-, R 28 R 29 N—S(O) 2 N(R 29 )-alkyl-, R 28 —C(O)N(R 29 )-alkyl-, R 28 R 29 N—S(O) 2 -alkyl-, HOS(O) 2 -alkyl-, (OH) 2 P(O) 2 -alkyl-, R 28 —S-alkyl-, R 28 —S(O) 2 -alkyl- or hydroxyalkyl;
R 17 is independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl;
R 18 and R 19 are hydrogen, alkyl, aryl, R 21 -aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, cycloalkyloxyalkyl, (heterocyclyl)alkyloxyalkyl, alkoxyalkyloxyalkyl, —S(O) 2 -alkyl, —C(NH)NR 1 R 2 or alkyl substituted with one or two moieties selected from cycloalkyl, halogen, hydroxy, —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O) 2 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)OH, —C(O)OR 1 and —C(O)NR 1 R 2 ; or
R 18 and R 19 together with the nitrogen to which they are attached, form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, having 1-3 hetero ring atoms selected from —O—, —N—, —S—, —S(O)—, —S(O) 2− and
with the proviso that S and O atoms are not adjacent to each other, the ring being unsubstituted or substituted with one or more groups selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —NR 1 R 2 , —NR 1 COR 2 , —NR 1 C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O) 2 R 2 , —NR 1 S(O 2 )NR 1 R 2 , —C(O)OR 1 , —CONR 1 R 2 and alkyl substituted with —NR 1 R 2 , —NR 1 COR 2 , —NR 1 CONR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O) 2 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)OR 1 or —CONR 1 R 2 ;
R 21 is 1 to 3 moieties and each R 21 is independently selected from the group consisting of hydrogen, —CN, —CF 3 , —OCF 3 , halogen, —NO 2 , alkyl, —OH, alkoxy, alkylamino-, di-(alkyl)amino-, —NR 25 R 26 alkyl-, hydroxyalkyl-, —C(O)OR 17 , —COR 17 , —NHCOR 16 , —NHS(O) 2 R 16 , —C(NH)—NH 2 , —NHS(O) 2 CH 2 CF 3 , —C(O)NR 25 R 26 , —NR 25 —C(O)—NR 25 R 26 , —S(O)R 13 , —S(O) 2 R 13 , —SR 13 ; —SO 2 NR 4 R 5 and —CONR 4 R 5 ; or two adjacent R 21 moieties can form a methylenedioxy group;
R 22 is hydrogen, alkyl, phenyl, benzyl, —COR 16 , —CONR 18 R 19 , —COR 23 , —S(O)R 31 , —S(O) 2 R 31 , —S(O 2 )NR 24 R 25 or —C(O)OR 27 ;
R 23 is
wherein R 35 and R 36 are independently selected from the group consisting of hydrogen, alkyl, and R 37 -substituted alkyl, wherein R 37 is selected from the group consisting of HO—, HS—, CH 2 S—, —NH 2 , phenyl, p-hydroxyphenyl and indolyl; or R 23 is alkyl; haloalkyl; alkenyl; haloalkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of alkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O) 2 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)OH, —C(O)OR 1 and —CONR 1 R 2 ; aryl; aralkyl; heteroaryl; heterocycloalkyl; alkyl substituted with —NR 1 R 2 , —NR 1 COR 2 , —NR 1 CONR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O 2 )R 2 , —NR 1 S(O 2 )NR 1 R 2 , —C(O)OH, —C(O)OR 1 , —CONR 1 R 2 and —SO 3 H;
R 24 , R 25 and R 26 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, hydroxy and alkoxy;
R 27 is 1 to 3 moieties and each R 27 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein R 27 is optionally substituted with —OH, —C(O)OH, halogen and alkoxy;
R 28 and R 29 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, and haloalkyl; or
R 28 and R 29 taken together form a spirocyclic or a heterospirocyclic ring having 3-6 ring atoms;
R 32 and R 33 are independently selected from the group consisting of hydrogen, R 34 -alkyl, R 34− alkenyl, R 34 -alkynyl, R 40 -heterocycloalkyl, R 38 -aryl, R 38 -aralkyl, R 42 -cycloalkyl, R 42 -cycloalkenyl, —OH, —OC(O)R 43 , —C(O)OR 43 , —C(O)R 43 , —C(O)NR 43 R 44 , —NR 43 R 44 , —NR 43 C(O)R 44 , —NR 43 C(O)NR 44 R 45 , —NHS(O) 2 R 43 , —OC(O)NR 43 R 44 , R 37 -alkoxy, R 37 -alkenyloxy, R 37 -alkynyloxy, R 40 -heterocycloalkyloxy, R 42 -cycloalkyloxy, R 42 -cyclo-alkenyloxy, R 42 -cycloalkyl-NH—, —NHSO 2 NHR 16 and —CH(═NOR 17 );
or R 32 and R 33 can be combined to form a ring structure Q, below
where
R 9 is hydrogen, OH, alkoxy, halogen or haloalkyl;
Q is fused R-substituted aryl, R-substituted heteroaryl, R-substituted heterocyclic ring of 4-8 atoms containing 1-3 heteroatoms selected from O, S, S(O), S(O) 2 and NR 22 with the proviso that S and O cannot be adjacent to one another; or
Q is
wherein R 10 and R 11 are independently selected from the group consisting of R 1 and —OR 1 , provided that when ring Q is aromatic and the carbon atoms bearing R 10 and R 11 are connected by a double bond, R 10 and R 11 are absent;
R is 1 to 5 moieties and each R is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy, —COR 16 , —C(O)OR 17 , —C(O)NR 4 R 5 , —SOR 16 , —S(O 2 )R 16 , —NR 16 COR 16a , —NR 16 C(O)OR 16a , —NR 16 CONR 4 R 5 , —NR 16 S(O 2 )NR 4 R 5 , fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl and thioalkyl;
R 34 is 1 to 3 moieties and each R 34 is independently selected from the group consisting of hydrogen, halogen, —OH, alkoxy, R 47 -aryl, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)—, heterocycloalkyl, R 39 -cycloalkyl, R 39 -cycloalkenyl, —OC(O)R 43 , —C(O)OR 43 , —C(O)R 43 , —C(O)NR 43 R 44 , —NR 43 R 44 , —NR 43 C(O)R 44 , —NR 43 C(O)NR 44 R 45 , —NHSO 2 R 43 , —OC(O)NR 43 R 44 , R 34 -alkenyloxy, R 34 -alkynyloxy, R 40 -heterocycloalkyloxy, R 42 — cycloalkyloxy, R 42 -cycloalkenyloxy, R 42 -cycloalkyl-NH—, —NHSO 2 NHR 16 and —CH(═NOR 17 );
R 38 is 1 to 3 moieties and each R 38 is independently selected from the group consisting of hydrogen, heterocycloalkyl, halogen, —C(O)OR 48 , —CN, —C(O)NR 49 R 50 , —NR 51 C(O)R 52 , —OR 48 , cycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, haloalkylcycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, and R 52 -heteroaryl; or two R 38 groups on adjacent ring carbons form a fused methylenedioxy group;
R 39 is 1 to 3 moieties and each R 39 is independently selected from the group consisting of hydrogen, halogen and alkoxy;
R 40 is 1 to 3 moieties and each R 40 is independently selected from the group consisting of hydrogen, R 41 -alkyl, R 41 -alkenyl and R 41 -alkynyl;
R 41 is hydrogen, —OH or alkoxy;
R 42 is 1 to 3 moieties and each R 42 is independently selected from the group consisting of hydrogen, alkyl, —OH, alkoxy and halogen;
R 43 , R 44 and R 45 are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, R 38 -arylalkyl, R 46 -cycloalkyl, R 53− cycloalkylalkyl, R 38 -aryl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl and heteroarylalkyl;
R 46 is hydrogen, alkyl, hydroxyalkyl or alkoxy;
R 47 is 1 to 3 moieties and each R 47 is independently selected from the group consisting of hydrogen, alkyl, —OH, halogen, —CN, alkoxy, trihaloalkoxy, alkylamino, di(alkyl)amino, —OCF 3 , hydroxyalkyl, —CHO, —C(O)alkylamino, —C(O)di(alkyl)amino, —NH 2 , —NHC(O)alkyl and —N(alkyl)C(O)alkyl;
R 48 is hydrogen, alkyl, haloalkyl, dihaloalkyl or trifluoroalkyl;
R 49 and R 50 are independently selected from the group consisting of hydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R 49 and R 50 together are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —NR 39 —(CH 2 ) 2 — and form a ring with the nitrogen to which they are attached;
R 51 and R 52 are independently selected from the group consisting of hydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R 51 and R 52 in the group —NR 39 C(O)R 40 , together with the nitrogen atoms to which they are attached, form a cyclic lactam having 5-8 ring members;
R 53 is hydrogen, alkoxy, —SOR 16 , —SO 2 R 17 , —C(O)OR 17 , —C(O)NR 18 R 19 , alkyl, halogen, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, aralkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl, thioalkyl, alkoxyalkyl or alkylaminoalkyl; and
R 54 is selected from the group consisting of hydrogen; alkyl; fluoroalkyl; difluoroalkyl; trifluoroalkyl; cycloalkyl; cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of alkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O)NR 1 R 2 , —NR 1 C(O)OR 2 , —NR 1 S(O) 2 R 2 , —NR 1 S(O) 2 NR 1 R 2 , —C(O)OH, —C(O)OR 1 and —CONR 1 R 2 ; alkenyl; alkoxy; arylalkyl; arylalkenyl; heteroarylalkyl; heteroarylalkenyl; hydroxy; alkoxy; hydroxyalkyl; alkoxyalkyl; aminoalkyl; aryl; heteroaryl; thioalkyl and alkyl substituted by 1 to 3 substituents selected from the group consisting of urea, sulfonamide, carboxamide, carboxylic acid, carboxylic ester and sulfonyl urea.
2 . A compound of claim 1 wherein
3 . A compound of claim 2 wherein
4 . A compound of claim 1 wherein
E is —O—;
A is —O—,
or —(CR 1 R 2 )—;
G is
or —(CR 1 R 2 )—;
M is —(CR 1 R 2 )—;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or alkyl;
R 11 is H or alkyl;
R 32 is H or alkyl;
R 33 is H or alkyl;
B is CR 12 ═cR 12a —
R 12 and R 12a are H;
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
5 . A compound of claim 1 wherein
E is —O—;
A is
G is —CH 2 —;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or —CH 3 ;
R 11 is H or —CH 3 ;
R 32 is H or —CH 3 ;
R 33 is H or —CH 3 ;
B is —CH═CH—;
Het is
and
W is
6 . A compound of claim 1 wherein
E is —O—;
A is —O—,
or —(CR 1 R 2 )—;
G is
or —(CR 1 R 2 )—;
M is —(CR 1 R 2 )—;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or alkyl;
R 11 is H or alkyl;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
7 . A compound of claim 1 wherein
E is —O—;
A is
G is —CH 2 —;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or —CH 3 ;
R 11 is H or —CH 3 ;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
B is —CH═CH—;
Het is
and
W is
8 . A compound of claim 1 wherein
E is —N(H)— or —N(alkyl)-;
A is —N(H)—, —N(alkyl)-,
or —(CR 1 R 2 )—;
G is
or —(CR 1 R 2 )—;
M is —(CR 1 R 2 )—;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or alkyl;
R 11 is H or alkyl;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
9 . A compound of claim 1 wherein
E is —N(H)— or —N(alkyl)-;
A is
G is —CH 2 —;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or —CH 3 ;
R 11 is H or —CH 3 ;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
B is —CH═CH—;
Het is
and
W is
10 . A compound of claim 1 wherein
E is
A is —N(H)— or —N(alkyl)-;
G is —N═;
M is —(CR 1 R 2 )—;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or alkyl;
R 11 is H or alkyl;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
11 . A compound of claim 10 wherein
A is —N(H)— or —N(CH 3 )—;
R 10 is H or —CH 3 ;
R 11 is H or —CH 3 ;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
B is —CH═CH—;
Het is
and
W is
12 . A compound of claim 1 wherein
E is —O—;
A is —O—,
or —(CR 1 R 2 )—;
G is
or —(CR 1 R 2 )—;
M is —(CR 1 R 2 )—;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or alkyl;
R 11 is H or alkyl;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
13 . A compound of claim 1 wherein
E is —O—;
A is
G is —CH(CH 3 )—;
X is —C(H)—;
R 3 is H;
R 9 is H;
R 10 is H or —CH 3 ;
R 11 is H or —CH 3 ;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
B is —CH═CH—;
Het is
and
W is
14 . A compound selected from the group consisting of:
15 . A compound of claim 1 wherein
16 . A compound of claim 15 wherein
17 . A compound of claim 16 wherein
R 3 is absent or R 3 is H;
R 9 is H;
R 10 is H or alkyl;
R 11 is H or alkyl;
R 32 is H or alkyl;
R 33 is H or alkyl; or R 32 and R 33 are combined to form a ring structure Q, below
where Q is
B is —CH═CH—
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
18 . A compound of claim 17 wherein
R 3 is H;
R 9 is H;
R 10 is H or —CH 3 ;
R 11 is H or —CH 3 ;
R 32 is H or —CH 3 ;
R 33 is H or —CH 3 ;
Het is
and
W is
19 . A compound of claim 17 wherein
R 3 is absent or R 3 is H;
R 9 is H;
R 10 is H;
R 11 is H;
R 32 and R 33 are combined to form a ring structure Q, below
where Q is
R 13 is (—CH 2 ) n6 NHC(O)OR 16b ;
R 16b is alkyl;
B is —CH═CH—
Het is aryl, aryl substituted by W, heteroaryl or heteroaryl substituted by W; and
W is aryl or aryl substituted with the 1 to 3 moieties comprising halogen, alkyl, —CF 3 , —CN, —OH or —O-alkyl.
20 . A compound of claim 19 wherein
R 13 is —NHC(O)OCH 2 CH 3 ;
Het is
and
W is
21 . A compound selected from the group consisting of:
22 . A compound selected from the group consisting of:
23 . A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable carrier.
24 . A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1 .
25 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, acute coronary syndrome, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, cerebral infarction, migraine, erectile dysfunction, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, renal disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, bladder inflammation, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, renal cell carcinoma, neuropathy, malignant tumors, neurodegenerative and/or neurotoxic diseases, conditions or injuries, Alzheimer's disease, an inflammatory disease or condition, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction disorders of the liver, kidney or lung, inflammatory disorders of the lungs and gastrointestinal tract, respiratory tract disease or condition, radiation fibrosis, endothelial dysfunction, periodontal diseases or wounds, or a spinal cord injury, or a symptom or result thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1 .
26 - 29 . (canceled)
30 . The method of claim 25 further comprising administering at least two therapeutically effective agents.
31 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, acute coronary syndrome, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, cerebral infarction, migraine, erectile dysfunction, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, renal disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, bladder inflammation, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, renal cell carcinoma, neuropathy, malignant tumors, neurodegenerative and/or neurotoxic diseases, conditions or injuries, Alzheimer's disease, an inflammatory disease or condition, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction disorders of the liver, kidney or lung, inflammatory disorders of the lungs and gastrointestinal tract, respiratory tract disease or condition, radiation fibrosis, endothelial dysfunction, periodontal diseases or wounds, or a spinal cord injury, or a symptom or result, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1 in combination with at least one additional cardiovascular agent.
32 . The method of claim 31 wherein the additional cardiovascular agent or agents is selected from the group consisting of thromboxane A2 biosynthesis inhibitors, GP IIb/IIIa antagonists, thromboxane antagonists, adenosine diphosphate inhibitors, cyclooxygenase inhibitors, angiotensin antagonists, endothelin antagonists, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, anticoagulants, diuretics, and platelet aggregation inhibitors.
33 . The method of claim 32 wherein the additional cardiovascular agent or agents are selected from the group consisting of aspirin, cangrelor, clopidogrel bisulfate, prasugrel and fragmin.
34 - 44 . (canceled)Cited by (0)
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