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Claims for Patent: 8,642,025

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Claims for Patent: 8,642,025

Title:Hepatitis C virus inhibitors
Abstract: The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
Inventor(s): Bachand; Carol (Candiac, CA), Belema; Makonen (North Haven, CT), Deon; Daniel H. (Montreal, CA), Good; Andrew C. (Wallingford, CT), Goodrich; Jason (Wallingford, CT), James; Clint A. (Candiac, CA), Lavoie; Rico (Candiac, CA), Lopez; Omar D. (Wallingford, CT), Martel; Alain (Delson, CA), Meanwell; Nicholas A. (East Hampton, CT), Nguyen; Van N. (Middletown, CT), Romine; Jeffrey Lee (Meriden, CT), Ruediger; Edward H. (Greenfield Park, CA), Snyder; Lawrence B. (Killingworth, CT), St. Laurent; Denis R. (Newington, CT), Yang; Fukang (Madison, CT), Langley; David R. (Meriden, CT), Hamann; Lawrence G. (North Grafton, MA)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:13/650,374
Patent Claims: 1. A compound of Formula (I) ##STR01403## or a pharmaceutically acceptable salt thereof, wherein m and n are independently 0, 1, or 2; q and s are independently 0, 1, 2, 3, or 4; u and v are independently 0, 1, 2, or 3; X is selected from O, S, S(O), SO.sub.2, CH.sub.2, CHR.sup.5, and C(R.sup.5).sub.2; provided that when m is 0, X is selected from CH.sub.2, CHR.sup.5, and C(R.sup.5).sub.2; Y is selected from O, S, S(O), SO.sub.2, CH.sub.2, CHR.sup.6, and C(R.sup.6).sub.2; provided that when n is 0, Y is selected from CH.sub.2, CHR.sup.6, and C(R.sup.6).sub.2; each R.sup.1 and R.sup.2 are each independently selected from alkoxy, alkoxycarbonyl, alkyl, carboxy, halo, haloalkyl, hydroxy, --NR.sup.aR.sup.b, (NR.sup.aR.sup.b)alkyl, and (NR.sup.aR.sup.b)carbonyl; R.sup.3 and R.sup.4 are each independently selected from hydrogen and R.sup.9--C(O)--; each R.sup.5 and R.sup.6 is independently selected from alkoxy, alkyl, halo, haloalkyl, hydroxy, and --NR.sup.aR.sup.b, wherein the alkyl can optionally form an unsubstituted fused cyclopropyl ring with an adjacent carbon atom; R.sup.7 and R.sup.8 are each independently selected from hydrogen, alkoxycarbonyl, alkyl, carboxy, haloalkyl, (NR.sup.aR.sup.b)carbonyl, and trialkylsilylalkoxyalkyl; and each R.sup.9 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, and (NR.sup.cR.sup.d)carbonyl; wherein the alkyl part of the arylalkyl is optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and --NR.sup.cR.sup.d, wherein the heterocyclyl is further optionally substitued with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstitued arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and --NR.sup.xR.sup.y; wherein the alkyl part of the heterocyclylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, hydroxy, and --NR.sup.cR.sup.d, wherein the aryl is further optionally substituted with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and --NR.sup.xR.sup.y; wherein the alkyl part of the (cycloalkyl)alkyl and the (NR.sup.cR.sup.d)alkyl is unsubstituted; wherein the aryl, the aryl part of the arylalkenyl, the arylalkoxy, the arylalkyl, and the aryloxyalkyl are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, NR.sup.xR.sup.y, (NR.sup.xR.sup.y)alkyl, and oxo; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted, and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; wherein the cycloalkyl and the cycloalkyl part of the (cycloalkyl)alkenyl, (cycloalkyl)alkyl, and cycloalkyloxyalkyl are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and --NR.sup.xR.sup.y, wherein the aryl and the heterocyclyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro; and wherein the heterocyclyl and the heterocyclyl part of the heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, and the heterocyclyloxyalkyl are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.xR.sup.y, (NR.sup.xR.sup.y)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R.sup.a and R.sup.b are independently selected from hydrogen, alkenyl, and alkyl; R.sup.c and R.sup.d are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, arylsulfonyl, formyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, (NR.sup.eR.sup.f)alkyl, (NR.sup.eR.sup.f)alkylcarbonyl, and (NR.sup.eR.sup.f)carbonyl; wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one --NR.sup.eR.sup.f group; and wherein the aryl part of the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, and the arylsulfonyl, and the heterocyclyl part of the heterocyclylalkyl, the heterocyclylalkylcarbonyl, and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkxoy, haloalkyl, and nitro; R.sup.e and R.sup.f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, (NR.sup.xR.sup.y)alkyl, and (NR.sup.xR.sup.y)carbonyl; and R.sup.x and R.sup.y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, and unsubstituted heterocyclyl; wherein each heterocycle is monocyclic or fused bicyclic.

2. A compound of claim 1 wherein m and n are each 1.

3. A compound of claim 2 wherein at least one of X and Y is S.

4. A compound of claim 2 wherein X and Y are each S.

5. A compound of claim 4 wherein q and s are each 0; and u and v are each 0.

6. A compound of claim 5 wherein at least one of R.sup.3 and R.sup.4 is hydrogen.

7. A compound of claim 5 wherein R.sup.3 and R.sup.4 are --C(O)--R.sup.9.

8. A compound of claim 7 wherein each R.sup.9 is independently selected from arylalkyl and heterocyclyl.

9. A compound of claim 2 wherein X is selected from CHR.sup.5, and C(R.sup.5).sub.2; and Y is selected from CH.sub.2, CHR.sup.6, and C(R.sup.6).sub.2.

10. A compound of claim 9 wherein each R.sup.5 and R.sup.6 is independently selected from halo and hydroxy.

11. A compound of claim 10 wherein each R.sup.1 and R.sup.2 is independently selected from C.sub.1 alkyl, and halo or u and v are 0.

12. A compound of claim 11 wherein u and v are 0.

13. A compound of claim 12 wherein at least one of R.sup.3 and R.sup.4 is hydrogen.

14. A compound of claim 12 wherein R.sup.3 and R.sup.4--C(O)--R.sup.9.

15. A compound of claim 14 wherein each R.sup.9 is independently selected from alkoxy and arylalkyl.

16. A compound of claim 2 wherein X and Y are each CH.sub.2.

17. A compound of claim 16 wherein at least one of q and s is 0.

18. A compound of claim 17 wherein q and s are each 0.

19. A compound of claim 18 wherein R.sup.1 and R.sup.2 are independently selected from alkyl, halo, and haloalkyl or u and v are 0.

20. A compound of claim 19 wherein at least one of R.sup.3 and R.sup.4 is hydrogen.

21. A compound of claim 19 wherein R.sup.3 and R.sup.4 are --C(O)--R.sup.9.

22. A compound of claim 21 wherein each R.sup.9 is independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, (NR.sup.cR.sup.d)alkyl, and (NR.sup.cR.sup.d)carbonyl.

23. A compound of claim 21 wherein each R.sup.9 is arylalkyl.

24. A compound of claim 21 wherein one R.sup.9 is heterocyclyl and the other is arylalkyl.

25. A compound of claim 21 wherein one R.sup.9 is heterocyclylalkyl and the other is arylalkyl.

26. A compound of claim 21 wherein each R.sup.9 is (NR.sup.cR.sup.d)alkyl.

27. A compound of claim 21 wherein one R.sup.9 is (NR.sup.cR.sup.d)alkyl and the other is arylalkyl.

28. A compound of claim 21 wherein one R.sup.9 is selected from alkoxy, alkyl, aryl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, and hydroxyalkyl; and the other is selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl, arylalkenyl, aryl, arylalkoxy, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, heterocyclyl, hydroxyalkyl, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)carbonyl.

29. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

30. The composition of claim 29 further comprising an interferon and ribavirin.

31. The composition of claim 30 further comprising a second compound having anti-HCV activity.

32. The composition of claim 31 wherein the second compound having anti-HCV activity is an interferon.

33. The composition of claim 32 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.

34. The composition of claim 31 wherein the second compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

35. A method of inhibiting the function of HCV NS5A protein comprising contacting the HCV NS5A protein with a compound of claim 1.

36. A method of relieving or causing regression of an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.

37. The method of claim 36 further comprising administering a second compound having anti-HCV activity prior to, after or simultaneously with the compound of claim 1.

38. The method of claim 37 wherein the second compound having anti-HCV activity is an interferon.

39. The method of claim 38 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.

40. The method of claim 37 wherein the second compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
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