Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis C
View Patent ↗The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
Z 1 , Z 2 and Z 3 are independently CH or N;
Z 4 is CH or N;
A is C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkenyl, 4- to 6-membered monocyclic heterocycloalkyl, 4- to 6-membered monocyclic heterocycloalkenyl, —C(═O)NR a R b , —C(═O)— (4- to 6-membered monocyclic heterocycloalkyl), —C(R c )═NOR d , or HetA, wherein cycloalkyl is optionally substituted by 1 or 2 substituents selected from C 1 -C 6 alkyl and halo, wherein HetA is optionally substituted by 1 or 2 ring substituents R′, and wherein the 4- to 6-membered monocyclic heterocycloalkyl is optionally substituted with oxo;
HetA is a 5- or 6-membered aromatic monocyclic ring with 1, 2 or 3 heteroatom ring atoms independently selected from N, O and S;
R a , R b , R c , R d are independently selected from H and C 1 -C 6 alkyl;
each occurrence of R 1 is independently selected from halo, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), oxo, cyano, and —O— phenyl-F;
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 or C 1 -C 6 hydroxyalkyl;
R 6 and R 7 are independently hydrogen, halo, cyano or C 1 -C 4 alkyl.
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 no more than one of R 6 and R 7 are halo.
5. The compound of claim 4 , wherein each halo is F.
6. The compound of claim 5 , wherein R 5 is hydrogen or —CH 2 OH.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula:
8. The compound of claim 3 , wherein A is
C 3 -C 6 cycloalkyl; C 2 -C 4 alkenyl; C 3 -C 6 cycloalkenyl; 4- to 6-membered monocyclic heterocycloalkyl; 4- to 6-membered monocyclic heterocycloalkenyl 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; or a 5-6 membered aromatic monocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from N, O, and S wherein the 5-6 membered aromatic monocyclic ring is 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, —O-4-F-phenyl, and —O—C 1 -C 6 haloalkyl.
9. The compound of claim 8 , wherein A is cyclopropyl,
wherein R 1a is F, methyl, ethyl, methoxy, ethoxy, —O-isoproyl, —OCHF 2 , —OCH 2 CF 3 , —CHF 2 , or —CF 3 , R 1b is hydrogen or methyl, R 1c is methyl, ethyl, or isopropyl, and R 1d is methyl or ethyl.
10. The compound of claim 9 , wherein A is cyclopropyl,
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 claim 1 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 claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to prevent and/or 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.