Heterocyclic compounds and methods of use thereof for the treatment of hepatitis C

Patent metadata

Field	Value
Publication number	US-9549921-B2
Application number	US-201414897966-A
Country	US
Kind code	B2
Filing date	Jun 19, 2014
Priority date	Jun 24, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

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.(I)

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
X is a 5 or 6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O;
A is fluorophenyl;
B is a) hydrogen;
b) —C(O)CH═C(CH 3 ) 2 ;
c) Ar;
d) —C(O)—Ar;
e) —C(O)CHR y —Ar;
f) —C(O)CH(NHR x )—Ar;
g) —SO 2 (CH 2 ) 0-2 —Ar;
h) —SO 2 —CH═CH—Ar;
i) —CO-Cyc;
j) —COCH 2 -Cyc;
k) —SO 2 -Cyc;

Ar is an aromatic ring system selected from:
(i) 5-6 membered monocyclic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N or O, optionally substituted with 1 or 2 substituents independently selected from fluorophenyl, C 1 -C 6 alkyl, and halo; and
(ii) 8-10 membered bicyclic rings with 1, 2 or 3 heteroatom ring atoms selected from N, O and S, optionally substituted with 1, 2 or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , cyano, oxo, —NH 2 , and cyclopropylmethyl;

Cyc is C 3 -C 6 cycloalkyl optionally substituted with fluorophenyl or pyridine; or 3-oxabicyclo[3.1.0]hexane;
D is H or NR 3 SO 2 R 4 ;
R 2 , R 3 , and R 4 are independently C 1 -C 6 alkyl;
R a is hydrogen or C 1 -C 6 alkyl;
R x is hydrogen or C(O)OC(CH 3 ) 3 ; and
R y is hydrogen, morpholinyl or Ar.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4 are methyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein D is N(CH 3 )SO 2 CH 3 .

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, 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 6 , or a pharmaceutically acceptable salt thereof, wherein X is

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein B is Ar, —C(O)—Ar, or —SO 2 —Ar; wherein Ar is a 9-membered bicyclic ring with 1, 2, or 3 heteroatom ring atoms selected from N, O and S, optionally substituted with 1, 2 or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, F, CF 3 , and cyano.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein Ar is

wherein each R p is independently selected from hydrogen, methyl, methoxy, F, CF 3 , or cyano, and R q is hydrogen, methyl or ethyl.

10. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein B is —SO 2 —Ar, —SO 2 CH 2 —Ar, —SO 2 CH 2 CH 2 —Ar, —C(O)—Ar; or —C(O)CH 2 —Ar; wherein Ar is phenyl, methylphenyl, fluorophenyl, difluorophenyl, pyridine, or fluoropyridine.

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 amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof effective to treat hepatitis C virus (HCV) infection.

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 hepatitis C (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.

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.

Assignees

• He Shuwen
• Lai Zhong
• Dai Xing
• Xiao Dong
• London Clare
• Zorn Nicolas
• Nargund Ravi
• Palani Anandan
• Mccomas Casey C
• Li Peng
• Peng Xuanjia
• Soll Richard
• Merck Sharp & Dohme

Inventors

• He Shuwen
• Lai Zhong
• Dai Xing
• Xiao Dong
• London Clare
• Zorn Nicolas
• Nargund Ravi
• Palani Anandan
• Mccomas Casey C
• Li Peng
• Peng Xuanjia
• Soll Richard

Classifications

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title