Hepatitis C virus inhibitors

Patent metadata

Field	Value
Publication number	US-9770439-B2
Application number	US-201514753564-A
Country	US
Kind code	B2
Filing date	Jun 29, 2015
Priority date	Jul 2, 2013
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.

First claim

What is claimed is:

1. A combination comprising an NS5A-targeting compound and an NS5A synergist, which, when administered, provides synergistic anti-HCV activity against variants that contain mutation(s) conferring resistance to the NS5A-targeting compound alone, wherein the NS5A-targeting compound is a compound of formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:
L is absent;
A is selected from aryl, wherein the aryl is phenyl;
B is selected from aryl, wherein the aryl is phenyl;
each R 1 is independently selected from

each m is independently 0, 1, or 2;
each X is independently selected from CH 2 , NH, and NR a ; wherein R a is alkyl;
each R 2 is independently selected from alkyl, halo, and hydroxy; wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon, a bridged four- or five-membered ring with another carbon atom on the ring, or a spirocyclic three- to six-membered ring with the carbon atom to which it is attached; wherein each ring is optionally substituted with one or two groups independently selected from alkyl, halo, and haloalkyl; or
R 2 , together with the carbon atom to which it is attached, forms a C 2 olefin;
each R 3 is independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, (NR c R d )alkenyl, and (NR c R d )alkyl;
R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkynyloxycarbonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cyanoalkyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, haloalkyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR x R y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each R p is independently selected from hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; and
each R q is independently selected from hydrogen, alkyl, halo, and —P(O)—(OR) 2 , wherein each R is the same or a different alkyl group; and
wherein the NS5A synergist is selected from:

R

Assignees

• Bristol Myers Squibb Co

Inventors

• Hewawasam Piyasena
• Lopez Omar D
• Tu Yong
• Wang Alan Xiangdong
• Xu Ningning
• Kadow John F
• Meanwell Nicholas A
• Gupta Samayamunthula Venkata Satya Arun Kumar
• Kumar Indasi J Gopi
• Ponugupati Suresh Kumar
• Belema Makonen

Classifications

• A61K31/695

  Silicon compounds · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61K31/4178 Primary

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/4245

  Oxadiazoles · CPC title