Inhibitors of hepatitic C virus
The invention provides compounds of formula (I): wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.
1. A method of treating hepatitis C viral infection in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (III):
wherein
R 1 is selected from C 1-6 alkyl, phenyl, and C 3-6 cycloalkyl, wherein C 1-6 alkyl is optionally substituted with —OR q , wherein R q is hydrogen or C 1-3 alkyl;
R 2 is selected from hydrogen and C 1-6 alkyl;
R 3 is selected from hydrogen, C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)NR a R b , —C(O)C 3-6 cycloalkyl, and —S(O) 2 C 1-3 alkyl;
wherein
R a and R b are independently hydrogen or C 1-6 alkyl;
R 5 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, —C(R k R d )NR e R f , —NR g R h , heteroaryl, heterocycle, and —CH 2 -heteroaryl;
wherein:
any heteroaryl or heterocycle has 5 or 6 ring atoms;
C 1-6 alkyl is optionally substituted with one or two substituents independently selected from —OR c , —NHC(O)C 1-3 alkyl, and —NHC(O)OC 1-3 alkyl;
C 1-6 alkoxy is optionally substituted with —OR d ;
C 3-6 cycloalkyl is optionally substituted with one or two substituents independently selected from C 1-3 alkyl and halo;
any heterocycle is optionally substituted with one, two, or three substituents independently selected from C 1-3 alkyl, halo, 13 C(O)OC 1-3 alkyl, —C(O)C 1-6 alkyl, —C(O)C 3-6 cycloalkyl, —C(O)NHC 1-6 alkyl, and —C(O)NHC 3-6 cycloalkyl;
wherein any —C(O)C 1-6 alkyl is optionally substituted with 13 NHC(O)OC 1-3 alkyl, —OR n , —NR d R e , or heterocycle,
any —C(O)C 3-6 cycloalkyl is optionally substituted with one or two C 1-3 alkyl, and
any —C(O)NHC 1-6 alkyl is optionally substituted with —OR n or C 3-6 cycloalkyl;
any heteroaryl is optionally substituted with C 1-3 alkyl;
R c is independently selected from hydrogen, C 1-6 alkyl, and phenyl;
R k , R d , R e , R g , and R h are each independently hydrogen or C 1-3 alkyl;
R f is selected from hydrogen and —C(O)C 1-3 alkyl;
R n is independently hydrogen or C 1-3 alkyl;
R 7 is selected from halo, C 1-3 alkyl, and C 1-3 alkoxy wherein C 1-3 alkyl, and C 1-3 alkoxy are optionally substituted with one, two, or three halo; and
R 9 is C 1-3 alkyl;
a is 1 or 2; and
c is 1 or 2.
2. The method of claim 1 wherein R 5 is selected from C 3-4 cycloalkyl, —CH 2 NR e R f , —NR g R h , imidazolyl, pyrazolyl, pyrimidinyl, and pyrrolidinyl;
wherein:
C 3-4 cycloalkyl is optionally substituted with one or two C 1-3 alkyl;
pyrrolidinyl is substituted with methyl and a substituent selected from —C(O)OC 1-3 alkyl, —C(O)C 1-6 alkyl, and —C(O)NHC 1-6 alkyl, wherein
—C(O)C 1-6 alkyl is substituted with —NHC(O)OC 1-3 alkyl, —OR n , —NR d R e , or heterocycle.
3. The method of claim 1 wherein:
R 1 is C 1-6 alkyl, R 2 is hydrogen; and R 3 is —C(O)OC 1-6 alkyl; and
R 5 is selected from —NHCH 3 , 2,2-dimethylcyclopropyl,
4. The method of claim 1 wherein:
R l is isopropyl, R 2 is hydrogen; and R 3 is —C(O)OCH 3 ;
R 7 is selected from fluoro, chloro, —CF 3 , and —OCF 3 ; and R 9 is methyl; and
R 5 is selected from —NHCH 3 , 2,2-dimethylcyclopropyl, and
5. The method of claim 1 wherein the compound is selected from:
and pharmaceutically-acceptable salts thereof.
6. The method of claim 1 wherein the method further comprises administering to the mammal one or more other therapeutic agents useful for treating hepatitis C viral infections.
7. The method of claim 6 wherein the one or more other therapeutic agents is selected from HCV NS3 protease inhibitors, HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, interferons and pegylated interferons, and ribavirin.
8. A method of inhibiting replication of the hepatitis C virus in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (III):
wherein
R 1 is selected from C 1-6 alkyl, phenyl, and C 3-6 cycloalkyl, wherein C 1-6 alkyl is optionally substituted with —OR q , wherein R q is hydrogen or C 1-3 alkyl;
R 2 is selected from hydrogen and C 1-6 alkyl;
R 3 is selected from hydrogen, C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)NR a R b , —C(O)C 3-6 cycloalkyl, and —S(O) 2 C 1-3 alkyl;
wherein
R a and R b are independently hydrogen or C 1-6 alkyl;
R 5 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, —C(R k R d )NR e R f , —NR g R h , heteroaryl, heterocycle, and —CH 2 -heteroaryl;
wherein:
any heteroaryl or heterocycle has 5 or 6 ring atoms;
C 1-6 alkyl is optionally substituted with one or two substituents independently selected from —OR c , —NHC(O)C 1-3 alkyl, and —NHC(O)OC 1-3 alkyl;
C 1-6 alkoxy is optionally substituted with —OR d ;
C 3-6 cycloalkyl is optionally substituted with one or two substituents independently selected from C 1-3 alkyl and halo;
any heterocycle is optionally substituted with one, two, or three substituents independently selected from C 1-3 alkyl, halo, —C(O)OC 1-3 alkyl, —C(O)C 1-6 alkyl, —C(O)C 3-6 cycloalkyl, —C(O)NHC 1-6 alkyl, and —C(O)NHC 3-6 cycloalkyl;
wherein any —C(O)C 1-6 alkyl is optionally substituted with —NHC(O)OC 1-3 alkyl, —OR n , —NR d R e , or heterocycle,
any —C(O)C 3-6 cycloalkyl is optionally substituted with one or two C i -3 alkyl, and
any —C(O)NHC 1-6 alkyl is optionally substituted with —OR n or C 3-6 cycloalkyl;
any heteroaryl is optionally substituted with C 1-3 alkyl;
R c is independently selected from hydrogen, C 1-6 alkyl, and phenyl;
R k , R d , R e , R g , and R h are each independently hydrogen or C 1-3 alkyl;
R f is selected from hydrogen and —C(O)C 1-3 alkyl;
R n is independently hydrogen or C 1-3 alkyl;
R 7 is selected from halo, C 1-3 alkyl, and C 1-3 alkoxy wherein C 1-3 alkyl, and C 1-3 alkoxy are optionally substituted with one, two, or three halo; and
R 9 is C 1-3 alkyl;
a is 1 or 2; and
c is 1 or 2.
9. The method of claim 8 wherein R 5 is selected from C 3-4 cycloalkyl, —CH 2 NR e R f , —NR g R h , imidazolyl, pyrazolyl, pyrimidinyl, and pyrrolidinyl;
wherein:
C 3-4 cycloalkyl is optionally substituted with one or two C 1-3 alkyl;
pyrrolidinyl is substituted with methyl and a substituent selected from —C(O)OC 1-3 alkyl, —C(O)C 1-6 alkyl, and —C(O)NHC 1-6 alkyl, wherein
—C(O)C 1-6 alkyl is substituted with —NHC(O)OC 1-3 alkyl, —OR n , —NR d R e , or heterocycle.
10. The method of claim 8 wherein:
R l is C 1-6 alkyl, R 2 is hydrogen; and R 3 is —C(O)OC 1-6 alkyl; and
R 5 is selected from —NHCH 3 , 2,2-dimethylcyclopropyl,
11. The method of claim 8 wherein:
R 1 is isopropyl, R 2 is hydrogen; and R 3 is —C(O)OCH 3 ;
R 7 is selected from fluoro, chloro, —CF 3 , and —OCF 3 ; and R 9 is methyl; and
R 5 is selected from —NHCH 3 , 2,2-dimethylcyclopropyl, and
12. The method of claim 8 wherein the compound is selected from:
and pharmaceutically-acceptable salts thereof.
13. The method of claim 8 wherein the method further comprises administering to the mammal one or more other therapeutic agents useful for inhibiting replication of the hepatitis C virus in a mammal.
14. The method of claim 13 wherein the one or more other therapeutic agents is selected from HCV NS3 protease inhibitors, HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, interferons and pegylated interferons, and ribavirin.