Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis C

1. A compound having structural formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

A is C 3 -C 6 cycloalkyl,

wherein the azetinidyl is substituted with 1 or 2 substituents selected from halo and C 1 -C 6 alkyl;

or a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, oxo, halo, and —O—C 1 -C 6 haloalkyl;

Z 1 , Z 2 , and Z 3 are independently CH or N wherein no more than one of Z 1 , Z 2 , and Z 3 is N;

Z 4 is N, Z 5 is CH, and the attached to Z 5 is a double bond, or

Z 4 is CH, Z 5 is NH, and the attached to Z 5 is a single bond;

R 2 is hydrogen, C 1 -C 6 alkyl or —O—C 1 -C 6 alkyl;

R 3 is hydrogen or C 1 -C 6 alkyl;

R 4 is C 1 -C 6 alkyl or —O—C 1 -C 6 alkyl;

R 5 is hydrogen, C 1 -C 6 alkyl, or —CH 2 COOR a , —SO 2 CH 3 ;

R a is hydrogen or C 1 -C 6 alkyl;

R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, alkyl-COOR a , —CH 2 SO 2 CH 3 , —CH 2 NH 2 , —CH 2 N(CH 3 )CH 2 CON(CH 3 ) 2 , —C 0 -C 6 alkyl-(4- to 7-membered monocyclic heterocycloalkyl), alkyl-(6- to 9-membered bicyclic heterocycloalkyl), —CH 2 -triazole, —CH 7 PO(OCH 2 CH 3 ) 2 , or —NH 2 ;

wherein the 4- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or two substituents independently selected from oxo, F, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, —COCH 3 , —OR a , C 3 -C 6 cycloalkyl, cyano and —SO 2 CH 3 ;

R 7 is hydrogen or C 1 -C 6 alkyl;

or R 6 and R 7 together form oxo or ether with the C to which they are attached form a C 3 -C 4 cycloalkyl; and

R 8 is hydrogen, halo, or cyano;

R 9 and R 10 are independently hydrogen or halo;

wherein when the adjacent to NR 5 is a double bond, R 5 and R 7 are absent.

2. The compound of claim 1 , wherein R 2 and R 4 are independently C 1 -C 6 alkyl.

3. The compound of claim 2 , wherein R 2 , R 3 and R 4 are methyl.

4. The compound of claim 3 , wherein two or three of R 8 , R 9 and R 10 are hydrogen.

5. The compound of claim 4 , wherein each halo is F.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula:

7. The compound of claim 4 , wherein A is C 3 -C 6 cycloalkyl, or a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, oxo, halo, and —O—C 1 -C 6 haloalkyl.

8. The compound of claim 7 , wherein A is cyclopropyl,

wherein each R 1a is independently selected m o hydrogen, F, methyl, ethyl, and —OCHF 2 ; R 1b is independently selected from hydrogen, F, methyl, ethyl, —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , —OCH 2 CF 3 , and —OCHF 2 ; R 1c is independently selected from hydrogen, and methyl; R 1d is independently selected from hydrogen, methyl, and ethyl.

9. The compound of claim 8 , wherein A is cyclopropyl,

10. The compound of claim 4 , wherein R b is hydrogen, —CH 2 SO 2 CH 3 , —CH 2 PO(OCH 2 CH 3 ) 2 ,

11. The compound of claim 4 , wherein R 6 is

wherein R z is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, alkyl-COOH, or —C 0 -C 6 alkyl-(3- to 7-membered monocyclic cycloalkyl).

12. The compound of claim 1 which is any one of

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 which is any one of

pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 1 or a pharmaceutically acceptable salt thereof, in an amount effective to treat HCV.

15. The pharmaceutical composition of claim 14 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

16. The pharmaceutical composition of claim 15 , wherein the second therapeutic agent is selected from the group consisting of HCV NS3 and NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

17. A method of treating a patient infected with HCV, the method comprising administering to the patient the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat infection by HCV in the patient.

18. The method of claim 17 , further comprising administering to said patient an effective amount of at least one second therapeutic agent selected from the group consisting of HCV NS3 and NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.