Thiophene analogues for the treatment or prevention of flavivirus infections

1. A compound of formula IA:

wherein,

R 1 is C 1-6 alkyl or C 3-6 cycloalkyl;

X is

M is

R 5 is cyclohexyl which is unsubstituted or substituted one or more times by R 13 ;

R 6 is

 or cyclohexyl which is substituted in the 4 position by R 14 ;

Y is COOR 7 , COCOOR 7 , P(O)OR a OR b , S(O)OR 7 , S(O) 2 OR 7 , tetrazole, CON(R 7 )CH(R 7 )COOR 7 , CONR 8 R 9 , CON(R 7 )—SO 2 —R 7 , CONR 7 OH and halogen;

R 7 , R 8 and R 9 are each independently H, C 1-12 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-12 alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-12 alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6-14 aryl which is unsubstituted or substituted one or more times by R 11 , C 7-16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 , or R 8 and R 9 are taken together with the nitrogen atom to form a 3 to 10 member heterocycle which is unsubstituted or substituted one or more times by R 12 or a 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 ; and

R a and R b are each independently chosen from H, C 1-12 alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-12 alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-12 alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6-14 aryl which is unsubstituted or substituted one or more times by R 11 , C 7-16 aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 , or R a and R b are taken together with the oxygen atoms to form a 5 to 10 member heterocycle which is unsubstituted or substituted one or more times by R 10 or a 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 11 ;

R 10 is halogen, oxo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —NHCOH, —N(C 1-4 alkyl)COH, —N(C 1-4 alkyl)COC 1-4 alkyl, —NHCOC 1-4 alkyl, —C(O)H, —C(O)C 1-4 alkyl, carboxy, —C(O)OC 1-4 alkyl, hydroxyl, C 1-4 alkoxy, nitro, nitroso, azido, cyano, —S(O) 0-2 H, —S(O) 0-2 C 1-4 alkyl, —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —NHSO 2 H, —N(C 1-4 alkyl)SO 2 H, —N(C 1-4 alkyl)SO 2 C 1-4 alkyl, or —NHSO 2 C 1-4 alkyl;

R 11 is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —NHCOH, —N(C 1-4 alkyl)COH, —N(C 1-4 alkyl)COC 1-4 alkyl, —NHCOC 1-4 alkyl, —C(O)H, —C(O)C 1-4 alkyl, carboxy, —C(O)OC 1-4 alkyl, hydroxyl, C 1-6 alkoxy, nitro, nitroso, azido, cyano, —S(O) 0-2 H, —S(O) 0-2 C 1-4 alkyl, —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —NHSO 2 H, —N(C 1-4 alkyl)SO 2 H, —N(C 1-4 alkyl)SO 2 C 1-4 alkyl, or —NHSO 2 C 1-4 alkyl;

R 12 is halogen, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —NHCOH, —N(C 1-4 alkyl)COH, —N(C 1-4 alkyl)COC 1-4 alkyl, —NHCOC 1-4 alkyl, —C(O)H, —C(O)C 1-4 alkyl, carboxy, —C(O)OC 1-4 alkyl, hydroxyl, C 1-6 alkoxy, nitro, nitroso, azido, cyano, —S(O) 0-2 H, —S(O) 0-2 C 1-4 alkyl, —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —NHSO 2 H, —N(C 1-4 alkyl)SO 2 H, —N(C 1-4 alkyl)SO 2 C 1-4 alkyl, or —NHSO 2 C 1-4 alkyl;

R 13 is OH, halogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, C 1-6 -alkoxy, halogenated C 1-6 -alkoxy, cyano, nitro, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —NHCOH, —N(C 1-4 alkyl)COH, —N(C 1-4 alkyl)COC 1-4 alkyl, —NHCOC 1-4 alkyl, —C(O)H, —C(O)C 1-4 alkyl, carboxy, —C(O)OC 1-4 alkyl, —S(O) 0-2 C 1-4 alkyl, —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —N(C 1-4 alkyl)SO 2 H, —N(C 1-4 alkyl)SO 2 C 1-4 alkyl, —NHSO 2 C 1-4 alkyl, C 6-14 -aryl, C 6-14 -aryloxy, or C 6-14 -aryloxy-C 1-6 -alkyl,;

R 14 is OH, halogen, C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -alkyl-CO—NH—, C 1-6 -alkyl-CO—N(C 1-6 -alkyl)-, or heteroaryl; and

R 14a is C 1-6 -alkyl, C 3-7 -cycloalkyl, halogenated C 1-6 -alkyl, C 1-6 -alkyl-CO—, —S(O) 0-2 C 1-4 alkyl, heteroaryl or C 6-14 -aryl; or

a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein Y is COOR 7 and R 7 is H, methyl, or ethyl.

3. A compound according to claim 2 , wherein Y is COOR 7 and R 7 is H.

4. A compound according to claim 1 , wherein R 14 is OH, fluoro, C 1-6 -alkoxy, or triazole.

5. A compound according to claim 4 , wherein R 14 is OH, —OCH 3 , 1,2,3 triazole or 1,2,4 triazole.

6. A compound according to claim 1 , wherein R 1 is C 1-6 alkyl or C 3-6 cycloalkyl which are unsubstituted or substituted one or more times by —NH 2 , NHCH 3 , N(CH 3 ) 2 , or hydroxyl.

7. A compound according to claim 6 , wherein R 1 is C 1-6 alkyl or C 3-6 cycloalkyl.

8. A compound according to claim 4 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

9. A compound according to claim 6 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl or tert.-butyl.

10. A compound according to claim 1 , wherein X is —NR 6 —CO—R 5 and R 5 is cyclohexyl which is unsubstituted or substituted in the 4-position by OH, halogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, C 1-6 -alkoxy, halogenated C 1-6 -alkoxy, cyano, nitro, —NH 2 , —NH(C 1-4 alkyl), or —N(C 1-4 alkyl) 2 , wherein the 4-position substituent is in the trans position relative to the carbonyl group.

11. A compound according to claims 10 , wherein R 5 is cyclohexyl which is unsubstituted or substituted one or more times by OH, halogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, C 1-6 -alkoxy, halogenated C 1-6 -alkoxy, cyano, nitro, —NH 2 , —NH(C 1-4 alkyl), or —N(C 1-4 alkyl) 2 .

12. A compound according to claim 10 , wherein R 5 is cyclohexyl which is substituted in the 4-position one or more times by OH, halogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, C 1-6 -alkoxy, halogenated C 1-6 -alkoxy, cyano, nitro, —NH 2 , —NH(C 1-4 alkyl), or —N(C 1-4 alkyl) 2 .

13. A compound according to claim 10 , wherein R 5 is cyclohexyl which is substituted in the 4-position by C 1-6 -alkyl.

14. A compound according to claim 10 , wherein R 5 is cyclohexyl which is substituted in the 4-position by —CH 3 .

15. A compound according to claim 1 , wherein R 6 is cyclohexyl which is substituted one or more times by OH, halogen, C 1-6 -alkyl, or C 1-6 -alkoxy.

16. A compound according to claim 15 , wherein R 6 is cyclohexyl which is substituted in the 4-position one or more times by OH, halogen, C 1-6 -alkyl, or C 1-6 -alkoxy.

17. A compound according to claim 15 , wherein R 6 is cyclohexyl which is substituted in the 4-position and the 4-position substituent is in the trans position relative to the amino group.

18. A compound according to claim 15 , wherein R 6 is cyclohexyl which is substituted in the 4-position by OH or C 1-6 -alkoxy.

19. A compound according to claim 15 , wherein R 6 is cyclohexyl which is substituted in the 4-position by OH or methoxy.

20. A compound according to claim 1 , wherein:

R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R 5 is cyclohexyl which is unsubstituted or substituted one or more times by OH, C 1-4 -alkyl, or C 1-4 -alkoxy;

R 6 is cyclohexyl which is substituted by OH, F, C 1-4 -alkoxy, C 1-4 -alkyl, or halogenated C 1-4 -alkyl;

Y is COOH.

21. A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical combination comprising at least one compound according to claim 1 and at least one additional agent.

23. A pharmaceutical combination according to claim 22 , wherein said at least one additional agent is selected from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).

24. A pharmaceutical combination according to claim 22 , wherein said at least one additional agent is selected from ribavirin and interferon-α.

25. A pharmaceutical combination according to claim 22 , wherein said at least one additional agent is selected from ribavirin and pegylated interferon-α.

26. A method for treating a Hepatitis C viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to claim 1 .

27. A method according to claim 26 , further comprising administering at least one additional agent.

28. A method according to claim 26 , wherein said at least one additional agent is selected from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).

29. The method according to claim 28 , wherein said at least one additional agent is selected from ribavirin and interferon-α.

30. The method according to claim 28 , wherein said at least one additional agent is selected from ribavirin and pegylated interferon-α.