Acylsulfonamide compounds as inhibitors of hepatitis C virus NS3 serine protease

1. A compound, or enantiomers, stereoisomers, rotamers, tautomers, and racemates of said compound, said compound having the general structure shown in Formula I:

or a pharmaceutically acceptable salt, solvate or ester thereof,

wherein:

R 8 is selected from the group consisting of alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, heteroarylalkyl-, and heterocyclylalkyl-;

R 9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and cycloalkyl;

A and M can be the same or different, each being independently selected from R, OR, N(H)R, N(RR′), SR, S(O 2 )R, and halo; or A and M are connected to each other (in other words, A-E-L-M taken together) such that the moiety:

shown above in Formula I forms either a three, four, five, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH 2 C(R), or C(R)CH 2 ;

R and R′ can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in N(RR′) are connected to each other such that N(RR′) forms a four to eight-membered heterocyclyl;

R 2 and R 3 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

Y is selected from the following moieties:

wherein G is NH; and R 15 , R 16 , R 17 , R 18 , R 19 and R 20 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R 17 and R 18 are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R 15 and R 19 are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R 15 and R 16 are connected to each other to form a four to eight-membered heterocyclyl; and (iv) likewise independently R 15 and R 20 are connected to each other to form a four to eight-membered heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, spiro-linked cycloalkyl, and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties independently selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

2. The compound of claim 1 , wherein R 8 is selected from the group consisting of alkyl-, aryl-, heteroaryl-, cycloalkyl-, arylalkyl- and heteroarylalkyl-.

3. The compound of claim 2 , wherein R 8 is an aryl or cycloalkyl.

4. The compound of claim 3 , wherein R 8 is phenyl or cyclopropyl.

5. The compound of claim 1 , wherein R 9 is H, alkyl, alkenyl or cycloalkyl.

6. The compound of claim 1 , wherein R 9 is H, methyl, allyl or cyclopropyl.

7. The compound of claim 1 , wherein R 2 is selected from the group consisting of the following moieties:

8. The compound of claim 7 , wherein R 2 is selected from the group consisting of:

9. The compound of claim 1 , wherein R 3 is selected from the group consisting of:

wherein R 31 is OH or O-alkyl; and

R 32 is H, C(O)CH 3 , C(O)OtBu or C(O)N(H)tBu.

10. The compound of claim 9 , wherein R 3 is selected from the group consisting of the following moieties:

11. The compound of claim 1 , wherein G is NH.

12. The compound of claim 1 , wherein Y is selected from the following moieties:

wherein R 15 , R 16 , R 17 , R 18 , R 19 and R 20 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R 17 and R 18 are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R 15 and R 19 are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R 15 and R 16 are connected to each other to form a four to eight-membered heterocyclyl; and (iv) likewise independently R 15 and R 20 are connected to each other to form a four to eight-membered heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

13. The compound of claim 12 , wherein the moiety:

is selected from the following:

wherein Y 32 is selected from the group consisting of:

14. The compound of claim 12 , wherein Y is selected from:

15. The compound of claim 1 , wherein the moiety:

is selected from the following structures:

16. The compound of claim 15 , wherein the moiety:

is selected from the following structures:

17. The compound of claim 16 , wherein the moiety:

is selected from the following structures:

18. The compound of claim 1 , wherein R 8 is phenyl or cyclopropyl;

R 9 is H, methyl, allyl or cyclopropyl;

R 2 is selected from the group consisting of the following moieties:

R 3 is selected from the group consisting of the following moieties:

the moiety:

and Y is selected from:

19. A pharmaceutical composition comprising as an active ingredient at least one compound of claim 1 additionally comprising at least one pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 , additionally containing at least one antiviral agent.

21. The pharmaceutical composition of claim 20 , additionally containing at least one interferon.

22. The pharmaceutical composition of claim 21 , wherein said at least one antiviral agent is ribavirin and said at least one interferon is α-interferon or pegylated interferon.

23. A method of treating HCV infection, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of at least one compound of claim 1 and a pharmaceutically acceptable carrier thereof.

24. The method of claim 23 , wherein said administration is oral or subcutaneous.

25. A method of treating HCV infection, said method comprising administering to a patient in need of such treatment therapeutically effective amounts of at least one compound of claim 1 and therapeutically effective amounts of at least one antiviral agent.

26. The method of claim 25 , wherein said at least one compound and said at least one antiviral agent are administered simultaneously, concurrently or sequentially.

27. The method of claim 25 , wherein said at least one compound and said at least one antiviral agent are administered in different amounts or in a fixed dose said fixed dose containing fixed amount of said at least one compound and fixed amount of said at least one antiviral agent.

28. The method of claim 25 , wherein said administration is oral or subcutaneous.

29. A compound exhibiting HCV protease inhibitory activity, or enantiomers, stereoisomers, rotamers, tautomers, and racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, said compound being selected from the compounds of structures listed below:

30. A pharmaceutical composition for treating a HCV infection, said composition comprising therapeutically effective amount of one or more compounds in claim 29 and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition of claim 30 , additionally containing at least one antiviral agent.

32. The pharmaceutical composition of claim 31 , additionally containing at least one interferon or PEG-interferon alpha conjugate.

33. The pharmaceutical composition of claim 32 , wherein said at least one antiviral agent is ribavirin and said at least one interferon is α-interferon.

34. A method of treatment of a hepatitis C virus infection, comprising administering an effective amount of one or more compounds of claim 29 to a person in need thereof.

35. A method of treating, or ameliorating one or more symptoms of hepatitis C, comprising administering a therapeutically effective amount of one or more compounds of claim 29 to a mammal in need thereof.

36. A compound of claim 1 in isolated and purified form.

37. A compound, or enantiomers, stereoisomers, rotamers, tautomers, and racemates of said compound, said compound having the general structure shown in Formula II:

or a pharmaceutically acceptable salt, solvate or ester thereof,

wherein:

R 8 is selected from the group consisting of alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, heteroarylalkyl-, spiro-linked cycloalkyl, and heterocyclylalkyl;

R 9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and cycloalkyl;

X is S(O) or S(O 2 );

R 2 is selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, non-spiro-linked cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

R 3 is selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

Y is selected from the following moieties:

wherein G is NH; and R 15 , R 16 , R 17 , R 18 , R 19 and R 20 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R 17 and R 18 are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R 15 and R 19 are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R 15 and R 16 are connected to each other to form a four to eight-membered heterocyclyl; and (iv) likewise independently R 15 and R 20 are connected to each other to form a four to eight-membered heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

38. The compound of claim 37 , wherein R 8 is selected from the group consisting of alkyl-, aryl-, heteroaryl-, cycloalkyl-, arylalkyl- and heteroarylalkyl-.

39. The compound of claim 38 , wherein R 8 is aryl or cycloalkyl.

40. The compound of claim 39 , wherein R 8 is phenyl or cyclopropyl.

41. The compound of claim 37 , wherein R 9 is H, methyl, allyl or cyclopropyl.

42. The compound of claim 37 , wherein R 2 is selected from the group consisting of:

43. The compound of claim 37 , wherein R 3 is selected from the group consisting of:

wherein R 31 is OH or O-alkyl; and

R 32 is H, C(O)CH 3 , C(O)OtBu or C(O)N(H)tBu.

44. The compound of claim 43 , wherein R 3 is selected from the group consisting of the following moieties:

45. The compound of claim 37 , wherein G is NH.

46. The compound of claim 37 , wherein Y is selected from the following moieties:

wherein R 15 , R 16 , R 17 , R 18 , R 19 and R 20 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R 17 and R 18 are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R 15 and R 19 are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R 15 and R 16 are connected to each other to form a four to eight-membered heterocyclyl; and (iv) likewise independently R 15 and R 20 are connected to each other to form a four to eight-membered heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

47. The compound of claim 46 , wherein the moiety:

is selected from the following:

wherein Y 32 is selected from the group consisting of:

48. The compound of claim 37 , wherein Y is selected from:

49. The compound of claim 37 , wherein X is S(O 2 ).

50. The compound of claim 37 , wherein R 8 is phenyl or cyclopropyl;

R 9 is H or methyl;

X is S(O 2 );

R 2 is selected from the group consisting of the following moieties:

R 3 is selected from the group consisting of the following moieties:

and Y is selected from:

51. A pharmaceutical composition for treating a HCV infection, said composition comprising therapeutically effective amount of one or more compounds in claim 37 and a pharmaceutically acceptable carrier.

52. The pharmaceutical composition of claim 51 , additionally containing at least one antiviral agent.

53. The pharmaceutical composition of claim 51 , additionally containing at least one interferon or PEG-interferon alpha conjugate.

54. The pharmaceutical composition of claim 53 , wherein said at least one antiviral agent is ribavirin and said at least one interferon is α-interferon or pegylated interferon.

55. A method of treatment of an infection of hepatitis C virus, comprising administering an effective amount of one or more compounds of claim 37 to a mammal in need thereof.

56. A method of treating or ameliorating one or more symptoms of hepatitis C, comprising administering a therapeutically effective amount of one or more compounds of claim 37 to a mammal in need thereof.

57. A compound of claim 37 in isolated and purified form.