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

Patent metadata

Field	Value
Publication number	US-9493461-B2
Application number	US-201414766487-A
Country	US
Kind code	B2
Filing date	Feb 3, 2014
Priority date	Feb 7, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

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.

First claim

What is claimed is:

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 ther

Assignees

• Merck Sharp & Dohme

Inventors

• Dai Xing
• Liu Hong
• Palani Anandan
• He Shuwen
• Lai Zhong
• Nargund Ravi
• Marcantonio Karen
• Xiao Dong
• Brockunier Linda L
• Zorn Nicolas
• Dang Qun
• Peng Xuanjia
• Li Peng

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D471/14 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title