HCV NS3 protease inhibitors

1. A compound of formula (I):

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

p and q are independently 1 or 2;

R 1 is CO 2 R 10 , CONR 10 SO 2 R 6 , CONR 10 SO 2 NR 8 R 9 , or tetrazolyl;

R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 3 -C 8 cycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;

R 3 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl, or Het, wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ;

Het is a 5- or 6-membered saturated cyclic ring having 1 or 2 heteroatoms selected from N, O and S, wherein said ring is optionally substituted with 1 to 3 substituents selected from halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ;

R 4 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, or aryl(C 1 -C 8 )alkyl; wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ;

R 5 is H, halo, OR 10 , C 1 -C 6 alkyl, CN, CF 3 , SR 10 , SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 7 ) 2 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, or alkyl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , S(O)(C 1 -C 6 alkyl), NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ; wherein 2 adjacent substituents of said cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl, if present, are optionally taken together to form a 3- to 6-membered cyclic ring containing 0-3 heteroatoms selected from N, O and S;

R 6 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, or heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents; and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen;

Y is C(═O), SO 2 , or C(═N—CN);

Z is C(R 10 ) 2 , O, or N(R 4 );

M is C 1 -C 12 alkylene or C 2 -C 12 alkenylene, wherein said alkylene or alkenylene is optionally substituted with 1 or 2 substituents selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl); and 2 adjacent substituents of M, if present, are optionally taken together to form a 3- to 6-membered cyclic ring containing 0-3 heteroatoms selected from N, O and S;

each R 7 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, or heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents; and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen;

each W is independently halo, OR 10 , C 1 -C 6 alkyl, CN, CF 3 , NO 2 , SR 10 , CO 2 R 10 , CON(R 10 ) 2 , C(O)R 10 , N(R 10 )C(O)R 10 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), NR 10 SO 2 R 10 , SO 2 N(R 10 ) 2 , NHCOOR 10 , NHCONHR 10 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen;

R 8 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), aryl, aryl(C 1 -C 4 alkyl), heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C(O)R 10 , C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and C(O)N(R 10 ) 2 ; wherein each aryl is independently phenyl or naphthyl; each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein 2 adjacent substituents of said cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl, if present, are optionally taken together to form a 3- to 6-membered cyclic ring containing 0-3 heteroatoms selected from N, O and S;

R 9 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, aryl, aryl(C 1 -C 4 alkyl), heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C(O)R 10 , C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and C(O)N(R 10 ) 2 ; wherein each aryl is independently phenyl or naphthyl; each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein 2 adjacent substituents of said cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl, if present, are optionally taken together to form a 3- to 6-membered cyclic ring containing 0-3 heteroatoms selected from N, O and S;

or R 8 and R 9 are optionally taken together, with the nitrogen atom to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0-2 additional heteroatoms selected from N, O and S; and

each R 10 is independently H or C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt or hydrate thereof, wherein the sum of p and q is ≦3.

3. The compound of claim 2 , wherein R 1 is CO 2 R 10 , CONR 10 SO 2 R 6 or CONHSO 2 NR 8 R 9 .

4. The compound of claim 3 , wherein R 1 is CONHSO 2 R 6 .

5. The compound of claim 4 , wherein R 6 is C 3 -C 8 cycloalkyl.

6. The compound of claim 3 , wherein R 1 is CONHSO 2 NR 8 R 9 wherein R 8 is C 1 -C 3 alkyl and R 9 is C 1 -C 3 alkyl or —(CH 2 ) 1-2 -phenyl.

7. The compound of claim 3 , wherein R 2 is C 2 -C 4 alkenyl.

8. The compound of claim 7 , wherein R 3 is C 5 -C 6 cycloalkyl optionally substituted with C 1 -C 6 alkyl or C 1 -C 8 alkyl optionally substituted with 1 to 3 substituents selected from halo and OR 10 .

9. The compound of claim 8 , wherein R 5 is H, halo or C 1 -C 6 alkoxy.

10. The compound of claim 9 , wherein Y is C═O.

11. The compound of claim 10 , wherein Z is O, C(R 10 ) 2 , NH or N(C 1 -C 8 alkyl).

12. The compound of claim 11 , wherein M is unsubstituted C 4 -C 8 alkylene or unsubstituted C 4 -C 8 alkenylene.

13. The compound of claim 1 , wherein the compound is selected from the group consisting of compounds III-1 to III-240, or a pharmaceutically acceptable salt or hydrate thereof:

14. The compound of claim 1 , wherein:

p and q are both 1;

R 1 is CONR 10 SO 2 R 6 ;

R 2 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl;

R 3 is C 5 -C 6 cycloalkyl or C 1 -C 8 alkyl optionally substituted with 1 to halo substitutents;

R 5 is H, F or Cl;

R 6 is C 3 -C 6 cycloalkyl;

Y is C(═O);

Z is O, CH 2 , NH or N(CH 3 );

M is C 1 -C 8 alkylene or C 2 -C 8 alkenylene, wherein said alkylene or alkenylene is optionally substituted with 1 or 2 substituents selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl) or aryl(C 1 -C 8 alkyl), and 2 adjacent substituents of M, if present, are optionally taken together to form a 3- to 6-membered cyclic ring containing 0-2 heteroatoms selected from N, O, and S; and

R 10 is H or C 1 -C 6 alkyl.

15. The compound of claim 14 , wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt or hydrate thereof.

16. The compound of claim 15 , wherein R 6 is cyclopropyl.

17. The compound of claim 16 , wherein R 2 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl.

18. The compound of claim 17 , wherein R 3 is C 5 -C 6 cycloalkyl or C 1 -C 4 alkyl.

19. The compound of claim 18 , wherein M is either

20. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 , 2 , 13 , 14 , or 15 , and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20 , further comprising a second therapeutic agent selected from the group consisting of a HCV protease inhibitor and HCV NS5B polmerase inhibitor.

22. A method of inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of any one of claims 1 , 2 , 13 , 14 or 15 .

23. A method of preventing or treating infection by HCV in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of any one of claims 1 , 2 , 13 , 14 or 15 .

24. The method of claim 23 , wherein said method further comprises administering at least one second therapeutic agent selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.

25. The method of claim 24 , wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.

26. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or hydrate thereof.

27. A pharmaceutical composition comprising an effective amount of the compound of claim 26 and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27 , further comprising a second therapeutic agent selected from a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.

29. A method of inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of claim 26 .

30. A method of preventing or treating infection by HCV in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of claim 26 .

31. The method of claim 30 , wherein said method further comprises administering at least one second therapeutic agent selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.

32. The method of claim 31 , wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.

33. The compound of claim 26 , wherein said compound is

or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising an effective amount of the compound of claim 33 and a pharmaceutically acceptable carrier.

35. A method of inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of claim 33 .

36. A method of preventing or treating infection by HCV in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of claim 33 .

37. The compound of claim 26 , wherein said compound is

or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising an effective amount of the compound of claim 37 and a pharmaceutically acceptable carrier.

39. A method of inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of claim 37 .

40. A method of preventing or treating infection by HCV in a subject in need thereof, said method comprising administering to said subject an effective amount of the compound of claim 37 .