Claims
- 1. A compound of Formula I:
- 2. The compound of claim 1 wherein X is —N— and X2, X3, and X4 are —CR5— where R5 is hydrogen.
- 3. The compound of claim 1 wherein X1 is —N—; X2 and X4 are —CR5— where R5 is hydrogen and X3 is —CR5— where R5 is halo.
- 4. The compound of claim 1 wherein X1 is —CH— and X2, X3, and X4 are —CR5— where R5 is hydrogen.
- 5. The compound of claim 1 wherein X1 is —CH—; x2 and X4 are —CR5— where R5 is hydrogen and X3 is —CR5— where R5 is halo.
- 7. The compound of claim 2 where R1, R2, and R13 are hydrogen; R3 is a group of formula (a) where n is 0, R8 and R10 are hydrogen and one of R9 and R11 is hydrogen and the other of R9 and R11 is ethyl.
- 8. The compound of claim 2 where R1, R2, and R13 are hydrogen; R3 is a group of formula (a) where n is 0, R8, R9, R10 and R11 are hydrogen.
- 9. The compound of claim 4 where R1, R2, and R13 are hydrogen; R3 is a group of formula (a) where n is 0, R8 and R10 are hydrogen and one of R9 and R11 is hydrogen and the other of R9 and R11 is ethyl.
- 10. The compound of claim 4 where R1, R2, and R3 are hydrogen; R3 is a group of formula (a) where n is 0, R8, R9, R10 and R11 are hydrogen.
- 11. The compound of claim 8 wherein R4 is hydroxy or hydroxymethyl and is located at the 2′-position of the biphenyl ring and R6 and R7 are hydrogen.
- 12. The compound of claim 8 wherein R4 is hydroxy and is located at the 2′-position of the biphenyl ring, R6 is hydrogen, and R7 is located at the 5′-position of the biphenyl ring.
- 13. The compound of claim 12 wherein R7 is alkyl, halo, hydroxy, hydroxyalkyl, carboxy, alkoxy, cyano, nitro, amino, aminocarbonyl, alkylsulfonylamino, aminoalkyl, aminosulfonyl, ureido, ureidoalkyl, alkylureidoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl, heteroaryl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, —NHSO2NR27R28 where R27 and R28 are independently hydrogen or alkyl, or —COR12 where R12 is alkyl.
- 14. The compound of claim 12 wherein R7 is methyl, isopropyl, chloro, fluoro, hydroxy, hydroxymethyl, 2-hydroxyethyl, carboxy, methoxy, cyano, nitro, aminocarbonyl, methylsulfonylamino, aminomethyl, ureidomethyl, —CH2NHCONHCH3, imidazol-2-yl, amino, ureido, cyanomethyl, 2-cyanoethyl, carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl, dimethylaminosulfonylamino, acetyl, or aminosulfonyl.
- 15. The compound of claim 8 wherein R4 is hydroxymethyl and is located at the 2′-position of the biphenyl ring, R6 is hydrogen, and R7 is located at the 5′-position of the biphenyl ring.
- 16. The compound of claim 15 wherein R7 is alkyl, halo, hydroxy, hydroxyalkyl, carboxy, alkoxy, cyano, nitro, amino, aminocarbonyl, alkylsulfonylamino, aminoalkyl, aminosulfonyl, ureido, ureidoalkyl, alkylureidoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl, heteroaryl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, —NHSO2NR27R28 where R27 and R28 are independently hydrogen or alkyl, or —COR12 where R12 is alkyl.
- 17. The compound of claim 15 wherein R7 is methyl, isopropyl, chloro, fluoro, hydroxy, hydroxymethyl, 2-hydroxyethyl, carboxy, methoxy, cyano, nitro, aminocarbonyl, methylsulfonylamino, aminomethyl, ureidomethyl, —CH2NHCONHCH3, imidazol-2-yl, amino, ureido, cyanomethyl, 2-cyanoethyl, carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl, dimethylaminosulfonylamino, acetyl, or aminosulfonyl.
- 18. The compound of claim 8 wherein R4 is aminosulfonyl and is located at the 2′-position of the biphenyl ring, R6 is hydrogen, and R7 is located at the 5′-position of the biphenyl ring.
- 19. The compound of claim 18 wherein R7 is alkyl, halo, hydroxy, hydroxyalkyl, carboxy, alkoxy, cyano, nitro, amino, aminocarbonyl, alkylsulfonylamino, aminoalkyl, aminosulfonyl, ureido, ureidoalkyl, alkylureidoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl, heteroaryl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, —NHSO2NR27R28 where R27 and R28 are independently hydrogen or alkyl, or —COR12 where R12 is alkyl.
- 20. The compound of claim 18 wherein R7 is methyl, isopropyl, chloro, fluoro, hydroxy, hydroxymethyl, 2-hydroxyethyl, carboxy, methoxy, cyano, nitro, aminocarbonyl, methylsulfonylamino, aminomethyl, ureidomethyl, —CH2NHCONHCH3, imidazol-2-yl, amino, ureido, cyanomethyl, 2-cyanoethyl, carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl, dimethylaminosulfonylamino, or acetyl.
- 21. The compound of claim 8 wherein R4 and R5 are hydrogen and R7 is located at the 3′-position of the biphenyl ring.
- 22. The compound of claim 21 wherein R7 is aminosulfonyl, haloalkoxy, hydroxy, hydroxyalkyl, aminocarbonyl, ureidoalkyl, cyanoalkyl, alkoxyalkyl, carboxyalkyl, aminocarbonylalkyl, heterocycloalkylalkyl, —COR12 (where R12 is alkyl) or cyano.
- 23. The compound of claim 1 wherein the moiety:
- 24. The compound of claim 1 wherein the moiety:
- 25. A compound selected from the group consisting of:
2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3′-(1,1-difluoro-methoxy)-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[3′-acetyl-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,3′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3′-aminocarbonyl-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3′-cyano-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-chloro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-2′-hydroxymethyl-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-indol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-carboxy-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′,5′-trihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-cyano-6-hydroxy-2′-methoxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-aminocarbonyl-6-hydroxy-2′-methoxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′,6′-trihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-nitro-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-2′-cyano-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-3′-hydroxymethyl-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-cyano-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-aminocarbonyl-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[3′-bromo-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′,6′-trihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-methylsulfonylamino-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-isopropyl-biphenyl-3-yl]-succinic acid; 2-[5′-aminomethyl-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-imidazol-2-yl-biphenyl-3-yl]-succinic acid; 2-[5′-amino-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureido-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-(2-morpholin-4-ylethylaminocarbonyl-biphenyl-3-yl]-succinic acid; 2-[3′-bromo-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-cyanomethylbiphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-(2-cyanoethyl)-6,2′-dihydroxybiphenyl-3-yl]-succinic acid; 2-[3′bromo-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-carboxymethyl-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-(2-carboxyethyl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[2′-acetyl-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[3′-bromo-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-aminocarbonylmethyl-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-indol-2-yl)-5′-aminocarbonyl-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3′,5′-dichloro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-[2-(2-hydroxyethoxy)ethylaminocarbonyl]-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-4′,6′-dichloro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-dimethylaminosulfonylamino-biphenyl-3-yl]-succinic acid; 2-[3′-bromo-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-chloro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-(4-methyl-piperazin-1-ylcarbonyl)-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-(4-methyl-piperazin-1-ylmethyl)-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-carbamimidoyl-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-(2-dimethylaminoethylaminocarbonyl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-hydroxymethyl-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-methylureidomethylbiphenyl-3-yl]-succinic acid; 2-[3′-aminosulfonyl-5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-dimethylaminosulfonyl-amino-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-6-fluoro-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-6-chloro-1H-indol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; diethyl 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinate; 2-[5-(5-carbamimidoyl-5-fluoro-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-2-methylsuccinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid 1-ethyl ester; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid 4-ethyl ester; (Z)-2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6-hydroxy-2′methoxy-biphenyl-3-yl]-but-2-enedioic acid; (Z)-2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-but-2-enedioic acid; (E)-2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-but-2-enedioic acid; 3-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-propionic acid; methyl 3-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-propionate; methyl 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-acetate; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-biphenyl-3-yl]-acetic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-acetic acid; 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; diethyl 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinate; 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-methylsulfonylaminobiphenyl-3-yl]-succinic acid; diethyl 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethylbiphenyl-3-yl]-succinate; 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-acetic acid; diethyl 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-hydroxymethylbiphenyl-3-yl]-succinate; dimethyl 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-5′-aminocarbonyl-6,2′-dihydroxybiphenyl-3-yl]-succinate; and 2-[5-(5-N-hydroxycarbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethylbiphenyl-3-yl]-succinic acid; or a pharmaceutically acceptable salt thereof.
- 26. A compound selected from the group consisting of:
2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-hydroxymethylbiphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-succinic acid; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-aminocarbonyl-6,2′-dihydroxy-biphenyl-3-yl]-succinic acid; and 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3′-aminosulfonyl-6-hydroxy-biphenyl-3-yl]-succinic acid; or a pharmaceutically acceptable salt thereof.
- 27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.
- 28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 25.
- 29. A method of treating a disease in an animal mediated by Factor VIIa which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
- 30. A method of treating a disease in an animal mediated by Factor VIIa which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 25 and a pharmaceutically acceptable carrier.
- 31. The method of claim 29 wherein the disorder is a thromboembolic disorder.
- 32. The method of claim 30 wherein the disorder is a thromboembolic disorder.
- 33. A method of treating a a thromboembolic disorder, which method comprises administering to said animal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 in combination with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, a factor Xa inhibitor, Aspirin®, and Plavis®.
- 34. A method for inhibiting the coagulation of a biological sample comprising the administration of a compound of claim 1.
- 35. An intermediate of Formula II:
- 36. A process of preparing a compound of claim 1 where X1 is —N— comprising reacting a compound of Formula II:
CROSS REFERENCE
[0001] This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Applications Serial Nos. 60/303953, filed on Jul. 9, 2001 and 60/351054, filed on Jan., 22, 2002, the disclosures of which are incorporated herein by reference in their entirety.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60303953 |
Jul 2001 |
US |
|
60351054 |
Jan 2002 |
US |