Macrocyclic inhibitors of hepatitis C virus replication
The embodiments provide compounds of the general Formulae I through general Formula VIII, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
1. A compound having the Formula V:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
R 1 is H, C 1-7 alkyl, C 3-7 cycloalkyl, pyridyl, thioazolo, naphthyl, fused heterocycle, phenyl, substituted phenyl, benzyloxy, or substituted benzyloxy;
R 2 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, substituted phenyl, C 1-6 alkoxy, or substituted C 1-6 alkoxy;
R 3 is H, C 1-6 alkyl, C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6 , C(S)NR 5 R 6 , or S(O) 2 R 5 ;
R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 3-7 cycloalkyl fused to C 6 aryl or C 6 aryl heterocyclyl, benzyl, phenyl, or substituted phenyl;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 4 or a carboxylic acid of the formula —C(O)OH,
wherein R 4 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 6 aryl, or substituted C 6 aryl;
Z is a bond, O, or S; and
the dashed line represents an optional double bond.
2. The compound of claim 1 , wherein R 1 is phenyl substituted with halo, C 1-3 alkyl, substituted C 1-3 alkyl substituted with up to 3 fluoro, C 1-3 alkoxy, substituted C 1-3 alkoxy substituted with up to 3 fluoro, cyano, hydroxy, nitro, NH 2 , NHR 2 , or NR 2 R 3 .
3. The compound of claim 1 , wherein R 1 is benzyloxy substituted with halo, C 1-3 alkyl, substituted C 1-3 alkyl with up to 3 fluoro, C 1-3 alkoxy, substituted C 1-3 alkoxy substituted with up to 3 fluoro, cyano, hydroxy, nitro, NH 2 , NHR 2 , or NR 2 R 3 .
4. The compound of claim 1 , wherein R 2 is phenyl substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, substituted C 1-6 alkyl substituted with up to 5 fluoro, C 1-6 alkoxy, or substituted C 1-6 alkoxy substituted with up to 5 fluoro.
5. The compound of claim 1 , wherein R 5 and R 6 are each individually phenyl substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, substituted C 1-6 alkyl substituted with up to 5 fluoro, C 1-6 alkoxy, or substituted C 1-6 alkoxy substituted with up to 5 fluoro.
6. The compound of claim 1 , wherein R 4 is C 6 aryl substituted with up to three halo.
7. A compound having a formula selected from the group consisting of the compounds in Tables 1 through 7 as described in the specification and compounds numbered 100, 701-706, 801, 922, 927, 1001-1018, 2001-2011, 2101-2154, 2201-2252, 2301-2322, 2401-2404, 2501-2502, and 2601-2604.
8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 or 7 .
9. A method of inhibiting NS3/NS4 protease activity, comprising contacting a NS3/NS4 protease with a compound of claim 1 or 7 .
10. The method of claim 9 in which the contacting is conducted in vivo.
11. The method of claim 9 , further comprising identifying a subject suffering from a hepatitis C infection and administering the compound or composition to the subject in an amount effective to treat the infection.
12. The method of claim 9 in which the contacting is conducted ex vivo.
13. A method of treating a hepatitis C virus infection, liver fibrosis resulting from or associated with a hepatitis C virus infection, or impaired liver function resulting from or associated with a hepatitis C virus infection, the method comprising administering to an individual in need thereof an amount of a compound of claim 1 or 7 that is effective to treat a least one condition selected from the group consisting of a hepatitis C virus infection, liver fibrosis resulting from or associated with a hepatitis C virus infection, and impaired liver function resulting from or associated with a hepatitis C virus infection.
14. The method of claim 13 , wherein a sustained viral response is achieved.
15. The method of claim 13 , wherein the method further comprises administering to the individual a nucleoside analog.
16. The method of claim 15 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
17. The method of claim 13 , wherein the method further comprises administering to the individual pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg.
18. The method of claim 13 , wherein the method further comprises administering to the individual an NS5B RNA-dependent RNA polymerase inhibitor.
19. The method of claim 13 , wherein the method further comprises administering to the individual a tumor necrosis factor antagonist selected from the group consisting of etanercept, infliximab, and adalimumab.
20. The method of claim 13 , wherein the method further comprises administering to the individual interferon-gamma (IFN-γ).
21. The method of claim 20 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
22. The method of claim 13 , wherein the method further comprises administering to the individual interferon-alpha (IFN-α).
23. The method of claim 22 , wherein the IFN-α is monoPEG (30 kD, linear)-ylate consensus IFN-α administered at a dosing interval of every 8 days to every 14 days.
24. The method of claim 22 , wherein the IFN-α is monoPEG (30 kD, linear)-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
25. The method of claim 22 , wherein the IFN-α is INFERGEN consensus IFN-α.
26. The method of claim 22 , wherein the IFN-α is PEGASYS® PEGylated IFN-α2a or PEG-INTRON® PEGylated IFN-α2b.
27. The method of claim 13 , further comprising administering an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2-,3-didehydro-2′,3′-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, ritonavir, and an inosine monophosphate dehydrogenase inhibitor.
28. The method of claim 13 , further comprising administering interferon, another NS3 protease inhibitor, a NS5b polymerase inhibitor, or a NS3 helicase inhibitor.
29. The method of claim 28 , wherein the another NS3 protease inhibitor is selected from