Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-2016136172-A1
Application number	US-201414898768-A
Country	US
Kind code	A1
Filing date	Jun 19, 2014
Priority date	Jun 24, 2013
Publication date	May 19, 2016
Grant date	—

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

1 . A compound having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
X is

A is fluorophenyl;
B is a) hydrogen;
b) Ar;
c) C 1 -C 6 alkyl-Ar;
d) —CHR a —Ar; or
e) cyclopropyl;

Ar is a 5-6 membered monocyclic aromatic ring with 0 or 1 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkoxy, halo, and cyano;
D is H or NR 3 SO 2 R 4 ;
R 2 is C 1 -C 6 alkyl;
R 3 is C 1 -C 6 alkyl;
R 4 is C 1 -C 6 alkyl;
R a is C 1 -C 6 hydroxyalkyl, or alkylalkoxy;
R c is hydrogen, C 1 -C 6 alkyl, alkylalkoxy, or —CH 2 NHC(O)CH 3 ;
R d is hydrogen, F, Cl or C 1 -C 6 alkyl;
R e and R f are independently hydrogen or C 1 -C 6 alkyl; and
R g is hydrogen or C 1 -C 6 alkoxy.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4 are methyl.

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

4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, 3 , wherein each halo is F.

5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein B is —CH 2 —Ar, —CH 2 CH 2 —Ar, —CH(CH 3 )—Ar, or —C(CH 3 ) 2 —Ar.

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

or a pharmaceutically acceptable salt thereof.

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 R c is hydrogen or methyl and R g is hydrogen.

9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein B is
hydrogen; phenyl; fluorophenyl; —(CH 2 ) 1-2 -phenyl; —CH 2 -fluorophenyl; —CH(CH 3 )-fluorophenyl; —C(CH 3 ) 2 -fluorophenyl; —CH 2 -chlorophenyl; —CH 2 -phenyl-OCH 3 ; —CH 2 -phenyl-cyano; —CH 2 -fluoropyridine; thiophene; cyclopropyl; —CH(CH 2 OCH 3 )-fluorophenyl; —CH(CH 2 OH)-phenyl; —CH(CH 2 OH)-fluorophenyl; —CH(CH 2 CH 2 OH)-fluorophenyl; —CH 2 -4-fluoro-2-methoxyphenyl; or —CH 2 -difluorophenyl.

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

or a pharmaceutically acceptable salt thereof.

11 . 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.

12 . The pharmaceutical composition of claim 11 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

13 . The pharmaceutical composition of claim 12 , 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.

14 - 15 . (canceled)

16 . A method of treating a patient infected with HCV, the method comprising administering to the patient the compound of claim 1 0 , 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

• Dai Xing
• Liu Hong
• Palani Anandan
• He Shuwin
• Nargund Ravi
• Xiao Dong
• Zorn Nicolas
• Dang Qun
• Mccomas Casey C
• Peng Xuanjia
• Li Peng
• Soll Richard
• Merck Sharp & Dohme

Inventors

• Dai Xing
• Liu Hong
• Palani Anandan
• He Shuwen
• Nargund Ravi
• Xiao Dong
• Zorn Nicolas
• Dang Qun
• Mccomas Casey C
• Peng Xuanjia
• Li Peng
• Soll Richard

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/5365 Primary

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title