Claims for Patent: 8,642,025

Summary 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):	Carol Bachand, Makonen Belema, Daniel H. Deon, Andrew C. Good, Jason Goodrich, Clint A. James, Rico Lavoie, Omar D. Lopez, Alain Martel, Nicholas A. Meanwell, Van N. Nguyen, Jeffrey Lee Romine, Edward H. Ruediger, Lawrence B. Snyder, Denis R. St. Laurent, Fukang Yang, David R. Langley, Lawrence G. Hamann
Assignee:	Bristol Myers Squibb Co
Application Number:	US13/650,374
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,642,025
Patent Claims:	1. A compound of Formula (I) 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), SO2, CH2, CHR5, and C(R5)2; provided that when m is 0, X is selected from CH2, CHR5, and C(R5)2; Y is selected from O, S, S(O), SO2, CH2, CHR6, and C(R6)2; provided that when n is 0, Y is selected from CH2, CHR6, and C(R6)2; each R1 and R2 are each independently selected from alkoxy, alkoxycarbonyl, alkyl, carboxy, halo, haloalkyl, hydroxy, —NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; R3 and R4 are each independently selected from hydrogen and R9—C(O)—; each R5 and R6 is independently selected from alkoxy, alkyl, halo, haloalkyl, hydroxy, and —NRaRb, wherein the alkyl can optionally form an unsubstituted fused cyclopropyl ring with an adjacent carbon atom; R7 and R8 are each independently selected from hydrogen, alkoxycarbonyl, alkyl, carboxy, haloalkyl, (NRaRb)carbonyl, and trialkylsilylalkoxyalkyl; and each R9 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, —NRcRd, (NRcRd)alkyl, and (NRcRd)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 —NRcRd, 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 —NRxRy; 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 —NRcRd, 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 —NRxRy; wherein the alkyl part of the (cycloalkyl)alkyl and the (NRcRd)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, NRxRy, (NRxRy)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 —NRxRy, 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, —NRxRy, (NRxRy)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; Ra and Rb are independently selected from hydrogen, alkenyl, and alkyl; Rc and Rd are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, arylsulfonyl, formyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, (NReRf)alkyl, (NReRf)alkylcarbonyl, and (NReRf)carbonyl; wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NReRf 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; Re and Rf are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, (NRxRy)alkyl, and (NRxRy)carbonyl; and Rx and Ry 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 R3 and R4 is hydrogen. 7. A compound of claim 5 wherein R3 and R4 are —C(O)—R9. 8. A compound of claim 7 wherein each R9 is independently selected from arylalkyl and heterocyclyl. 9. A compound of claim 2 wherein X is selected from CHR5, and C(R5)2; and Y is selected from CH2, CHR6, and C(R6)2. 10. A compound of claim 9 wherein each R5 and R6 is independently selected from halo and hydroxy. 11. A compound of claim 10 wherein each R1 and R2 is independently selected from C1 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 R3 and R4 is hydrogen. 14. A compound of claim 12 wherein R3 and R4—C(O)—R9. 15. A compound of claim 14 wherein each R9 is independently selected from alkoxy and arylalkyl. 16. A compound of claim 2 wherein X and Y are each CH2. 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 R1 and R2 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 R3 and R4 is hydrogen. 21. A compound of claim 19 wherein R3 and R4 are —C(O)—R9. 22. A compound of claim 21 wherein each R9 is independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, (NRcRd)alkyl, and (NRcRd)carbonyl. 23. A compound of claim 21 wherein each R9 is arylalkyl. 24. A compound of claim 21 wherein one R9 is heterocyclyl and the other is arylalkyl. 25. A compound of claim 21 wherein one R9 is heterocyclylalkyl and the other is arylalkyl. 26. A compound of claim 21 wherein each R9 is (NRcRd)alkyl. 27. A compound of claim 21 wherein one R9 is (NRcRd)alkyl and the other is arylalkyl. 28. A compound of claim 21 wherein one R9 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, —NRcRd, and (NRcRd)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.