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 a C 3 -C 6 cycloalkyl or an aromatic ring system selected from:

(i) 5-6 membered monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N, S or O, 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, cyano, oxo, halo, —O—C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, phenyl, pyrrolidinyl, and —O—C 3 -C 6 cycloalkyl; and

(ii) 8-10 membered bicyclic rings with 2 or 3 heteroatom ring atoms selected from N and O;

Z is N or CR a ;

Z 1 , Z 2 and Z 3 are independently selected from CH and N, wherein 1 or 2 of Z 1 , Z 2 and Z 3 are N;

p is 0, 1, or 2;

q is 0 or 1;

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, —OH, halo, or a 4- to 7-membered heterocycloalkyl substituted with halo;

R 9 is hydrogen; or

R 5 and R 9 together with the C to which they are attached form a C 3 -C 6 cycloalkyl,

R 6 is hydrogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —CH 2 SO 2 CH 3 , —C 1 -C 6 -(4- to 6-membered monocyclic heterocycloalkyl);

wherein the 4- to 6-membered monocyclic heterocycloalkyl is optionally substituted with one or two F substituents;

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

or R 6 and R 7 together with the C to which they are attached form an oxo;

R 8 is hydrogen, halo or —OR b ;

R 10 is hydrogen or C 1 -C 6 alkyl;

R a is hydrogen, halo, or cyano;

each R b is independently H or C 1 -C 6 alkyl;

wherein

when q is 0, p is 0 or 1;

when q is 1 and p is 2, is a single bond; and

when is a double bond, R 7 and R 9 are absent.

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

3. The compound of claim 1 or 2 , wherein R 2 , R 3 and R 4 are methyl.

4. The compound of any one of claims 1 to 3 , wherein one of R a and R 8 is hydrogen.

5. The compound of any one of claims 1 to 4 , wherein halo is F.

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

7. The compound of claim 6 wherein

R 5 is hydrogen or methyl;

R 6 is hydrogen, methyl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 ,

R 7 is hydrogen or methyl.

8. The compound of any one of claims 1 to 7 , 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 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.

9. The compound of any one of claims 1 to 7 , wherein A is cyclopropyl,

wherein R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, F, methyl, ethyl, hydroxymethyl, isopropyl, methoxy, ethoxy, —OCHF 2 , —OCH 2 CF 3 , cyclopropyl, phenyl, pyrrolidinyl, —O-cyclopropyl, —CHF 2 , cyano, —CF 3 and —CH 2 CF 3 .

10. The compound of claim 9 , wherein A is

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) an effective amount of the compound of any one of claims 1 - 12 or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 13 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

15. The pharmaceutical composition of claim 14 , 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.

16. A method of treating a patient infected with HCV, the method comprising administering to the patient the compound of any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat infection by HCV in the patient.

17. The method of claim 16 , 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.