Methods of Treating Hepatitis C Virus with Oxoacetamide Compounds
Provided herein are hepatitis C virus entry inhibitor oxoacetamide compounds, pharmaceutical compositions thereof, and methods for their use in treatment or prevention of hepatitis C virus infection in a subject in need thereof.
1 . A method for the treatment of a hepatitis C virus infection in a host, comprising administering to a host infected with a hepatitis C virus an effective amount of a compound of formula I or II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein
X is
R 1 is methyl, ethyl, isopropyl,
R 2 is C 1 -C 8 alkyl; C 5 -C 8 cycloalkyl, or C 7 -C 10 arylalkyl;
R 3 is hydrogen, cyano, —CONHR 6 , —NHSO 2 R 7 or —SO 2 N(R 8 ) 2 ;
R 4 is C 1 -C 4 alkyl;
R 5 is C 1 -C 4 alkoxy or —N(R 8 ) 2 ;
R 6 is 2-pyridyl or C 1 -C 6 alkyl, wherein one or more carbon atoms is optionally replaced by an oxygen atom;
R 7 is C 1 -C 4 alkyl, CH 2 CF 3 , benzyl or phenyl;
R 8 is C 1 -C 4 alkyl;
R 9 is bromo or 6-(methylamino)pyridin-3-yl;
R 10 is hydrogen or —CONHR 11 ; and
R 11 is hydrogen or C 1 -C 4 alkyl;
provided that if R 3 is —NHSO 2 R 7 and R 7 is methyl, then R 1 is not methyl;
provided that if R 10 is hydrogen, R 9 is 6-(methylamino)pyridin-3-yl; and
provided that if R 11 is cyclopropyl, R 9 is bromo.
2 . The method of claim 1 , further provided that if R 2 is methyl, then R 3 is not —NHSO 2 R 9 .
3 . The method of claim 1 , further provided that if R 2 is methyl and R 3 is —NHSO 2 R 9 , then R 9 is not methyl.
4 . The method of claim 1 , further provided that if R 3 is —NHSO 2 R 9 , then R 2 is not methyl.
5 . The method of claim 1 , further provided that if R 3 is —NHSO 2 R 9 and R 9 is methyl, R 2 is not methyl.
6 . The method of claim 1 , wherein R 1 is methyl, ethyl, isopropyl or
7 . The method of claim 1 , wherein R 1 is isopropyl or
8 . The method of claim 1 , wherein R 2 is methyl, tert-butyl, cyclohexyl or 1-methyl-1-phenylethyl.
9 . The method of claim 1 , wherein R 2 is tert-butyl, cyclohexyl or 1-methyl-1-phenylethyl.
10 . The method of claim 1 , wherein R 2 is tert-butyl.
11 . The method of claim 1 , wherein R 3 is hydrogen.
12 . The method of claim 1 , wherein R 3 is —NHSO 2 R 9 and R 9 is methyl.
13 . The method of claim 1 , wherein R 4 is t-butyl.
14 . The method of claim 1 , wherein R 5 is methoxy or dimethylamino;
15 . The method of claim 1 , wherein R 6 is methyl, ethyl, propyl, methoxyethyl, methylenecyclopropyl or 2-pyridyl.
16 . The method of claim 1 , wherein R 7 is methyl or ethyl.
17 . The method of claim 1 , wherein each R 8 is methyl.
18 . The method of claim 1 , wherein R 11 is methyl or ethyl.
19 . The method of claim 18 , wherein R 9 is 6-(methylamino)pyridin-3-yl.
20 . The method of claim 1 , wherein
R 9 is bromo;
R 10 is —CONHR 11 ; and
R 11 is C 1 -C 4 alkyl.
21 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
22 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
23 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
24 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
25 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
26 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
27 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
28 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
29 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
30 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
31 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
32 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
33 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
34 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
35 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
36 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
37 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
38 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
39 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
40 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
41 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
42 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
43 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
44 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the formula:
45 . A method for the treatment of a hepatitis C virus infection in a host, comprising administering to a host infected with a hepatitis C virus an effective amount of a compound of formula I or II of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination or alternation with one or more antiviral agents selected from the group consisting of a nucleoside polymerase inhibitor, a non-nucleoside polymerase inhibitor, a protease inhibitor, a cyclophilin modulator, an interferon and ribavirin.
46 . The method of claim 45 , wherein the compound of formula I or II, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered in combination or alternation with an interferon.
47 . The method of claim 45 , wherein the compound of formula I or II, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered in combination or alternation with an interferon and ribavirin.
48 . A compound of formula I or II of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a hepatitis C virus infection.
49 . Use of a of formula I or II of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a hepatitis C virus infection.