NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
The embodiments provide compounds of the general Formula I, 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 structure of Formula (I):
or a pharmaceutically acceptable salt or prodrug thereof,
wherein W 1 , W 2 , W 2 and W 4 are independently -D or —H, provided that at least one of W 1 , W 2 , W 2 and W 4 is -D;
R 1 is selected from the group consisting of —C(O)OR 1e , optionally substituted heteroaryl, and aryl optionally substituted with one or more substituents each independently selected from the group consisting of halo, amino, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro, C 2-6 alkenyl, C 2-6 alkynyl, —C(O)NR 1a R 1b , —NHC(O)NR 1a R 1b , —C(O)OR 1c , and heteroaryl;
R 1e is selected from the group consisting of t-butyl, cycloalkyl, and heterocyclyl;
R 1a and R 1b are taken together with the nitrogen to which they are attached to form piperazinyl or morpholinyl, each optionally substituted with one or more substituents independently selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(O)OR 1c , —C(O)R 1d , optionally substituted aryl, and optionally substituted heteroaryl;
R 1c and R 1d are each separately selected from the group consisting of —H, C 1-4 alkoxy, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylalkyl and heteroaryl;
R 3 is —OH, —NHS(O) 2 R 3a , —NHS(O) 2 OR 3a or —NHS(O) 2 NR 3b R 3c ; where R 3a is selected from the group consisting of C 1-6 alkyl, —(CH 2 ) q C 3-7 cycloalkyl, —(CH 2 ) q C 6 or 10 aryl, and a heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, —COOH, —(CH 2 ) t C 3-7 cycloalkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, and C 1-6 alkoxy optionally substituted with up to 5 fluoro;
wherein R 3b and R 3c are each separately a hydrogen atom, or separately selected from the group consisting of C 1-6 alkyl, —(CH 2 ) q C 3-7 cycloalkyl, and C 6 or 10 aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, —(CH 2 ) t C 3-7 cycloalkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, phenyl, C 1-6 alkyl substituted with up to 5 fluoro, and C 1-6 alkoxy substituted with up to 5 fluoro; or R 3b and R 3c are taken together with the nitrogen to which they are attached to form a three- to six-membered heterocyclic ring, bonded to the parent structure through a nitrogen, and the heterocylic ring is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, and phenyl;
each t is independently 0, 1 or 2;
each q is independently 0, 1 or 2; and
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond.
2 . The compound of claim 1 selected from the group consisting of:
3 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
4 . A method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound of claim 1 .
5 . The method of claim 4 in which the contacting is conducted in vivo.
6 . The method of claim 5 , further comprising identifying a subject suffering from a hepatitis C infection and administering the compound to the subject in an amount effective to treat the infection.
7 . The method of claim 6 , wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
8 . The method of claim 7 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
9 . The method of claim 6 , wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.
10 . The method of claim 9 , wherein the protease inhibitor is ritonavir.
11 . The method of claim 6 , wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
12 . The method of claim 6 , wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
13 . The method of claim 12 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
14 . The method of claim 6 , wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α).
15 . The method of claim 14 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days.
16 . The method of claim 14 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
17 . The method of claim 14 , wherein the IFN-α is INFERGEN consensus IFN-α.
18 . The method of claim 6 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine), combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
19 . The method of claim 6 , wherein a sustained viral response is achieved.
20 . The method of claim 4 , in which the contacting is conducted ex vivo.
21 . A method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a compound of claim 1 .
22 . The method of claim 21 , wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
23 . The method of claim 22 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
24 . The method of claim 21 , wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.
25 . The method of claim 24 , wherein the protease inhibitor is ritonavir.
26 . The method of claim 21 , wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
27 . The method of claim 21 , wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
28 . The method of claim 27 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
29 . The method of claim 21 , wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α).
30 . The method of claim 29 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days.
31 . The method of claim 29 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
32 . The method of claim 29 , wherein the IFN-α is INFERGEN consensus IFN-α.
33 . The method of claim 21 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine), combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
34 . A method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a compound of any one of claim 1 .
35 . The method of claim 34 , wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
36 . The method of claim 35 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
37 . The method of claim 34 , wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.
38 . The method of claim 37 , wherein the protease inhibitor is ritonavir.
39 . The method of claim 34 , wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
40 . The method of claim 39 , wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
41 . The method of claim 40 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
42 . The method of claim 34 , wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α).
43 . The method of claim 42 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days.
44 . The method of claim 42 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
45 . The method of claim 42 , wherein the IFN-α is INFERGEN consensus IFN-α.
46 . The method of claim 34 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine), combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.