Hepatitis C virus inhibitors

Patent metadata

Field	Value
Publication number	US-9546160-B2
Application number	US-201213465298-A
Country	US
Kind code	B2
Filing date	May 7, 2012
Priority date	May 12, 2011
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

First claim

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
L is a bond;
A and A′ are

wherein “ ” represents the point of attachment to X and X′ and “ ” represents the point of attachment to L; and wherein:
R 2 is selected from hydrogen, alkyl, and halo; and
R 3 is selected from hydrogen, alkoxy, alkyl, cyano, halo, and haloalkoxy;
X and X′ are

wherein each group is drawn with the carbon atom being attached to A or A′ and with the nitrogen atom attached to the carbonyl group and wherein:
n is 1;
s is 0, 1, 2, 3, or 4;
Y is selected from CH 2 ,CHR 4 , and C(R 4 ) 2 ; and
each R 4 is independently selected from alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, —NR a R b , and thioalkyl, wherein the alkyl can optionally form a fused three- to six-membered ring or a bridged four-or five-membered ring with another carbon atom on the ring; or can optionally form a spirocyclic three- to six-membered ring with the carbon to which it is attached, wherein each formed ring system optionally contains one or two oxygen atoms, and wherein each formed ring system is optionally substituted with one or two groups independently selected from alkyl and halo;
R is (NR c R d )alkyl, which is attached to the parent molecular moiety through the alkyl part of the (NR c R d )alkyl, wherein the alkyl part of the (NR c R d )alkyl is a C 1 -C 3 branched or straight chain group and wherein the alkyl part of the (NR c R d )alkyl is substituted with bicycloalkyl, fused bicycloheterocyclyl, cycloalkyl-substituted-heterocyclyl, ethenylcycloalkyl, heterocyclylethenyl, oxocycloalkyl, or spirocycloheterocyclyl, wherein the bicycloalkyl, bicycloheterocyclyl, oxocycloalkyl, and spirocycloheterocyclyl are optionally substituted with one or two groups independently selected from alkyl, halo, and haloalkyl;
R′ is (NR c R d )alkyl, which is attached to the parent molecular moiety through the alkyl part of the (NR c R d )alkyl, wherein the alkyl part of the (NR c R d )alkyl is a C 1 -C 3 branched or straight chain group and wherein the alkyl part of the (NR c R d )alkyl is optionally substituted with bicycloalkyl, fused bicycloheterocyclyl, cycloalkyl-substituted-heterocyclyl, ethenylcycloalkyl, heterocyclylethenyl, oxocycloalkyl, or spirocycloheterocyclyl, wherein the bicycloalkyl, bicycloheterocyclyl, oxocycloalkyl, and spirocycloheterocyclyl are optionally substituted with one or two groups independently selected from alkyl, halo, and haloalkyl;
R a and R b are independently selected from hydrogen and alkyl;
R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, cycloalkyl, cycloalkyloxycarbonyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, (NR e R f )carbonyl,
R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, (NR x R y )alkyl, and (NR x R y )carbonyl; and
R x and R y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR x′ R y′ )carbonyl, wherein R x′ and R y′ are independently selected from hydrogen and alkyl.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R and R′ are each (NR c R d )alkyl, which is attached to the parent molecular moiety through the alkyl part of the (NR c R d )alkyl, wherein the alkyl part of the (NR c R d )alkyl is a C 1 -C 3 branched or straight chain group and wherein the wherein the alkyl part of each (NR c R d )alkyl is substituted with bicycloalkyl, fused bicycloheterocyclyl, cycloalkyl-substituted-heterocyclyl, or spirocycloheterocyclyl, wherein the bicycloalkyl and the bicycloheterocyclyl are optionally substituted with one or two halo groups.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the alkyl part of each (NR c R d )alkyl is substituted with spirocycloheterocyclyl, wherein spirocycloheterocyclyl is a six-membered saturated ring containing one oxygen atom adjoined to a three-membered saturated carbocyclic ring via one single carbon atom.

4. A compound selected from
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 1);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)-2oxo-2,1-ethanediyl)))biscarbamate (diastereomer 2);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 3);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 1);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 2);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 3);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3r,5S)-bicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 1);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3r,5S)-bicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 2);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3r,5S)-bicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 3);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,5S,6s)-3-oxabicyclo[3.1.0]hex-6-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 1);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,5S,6s)-3-oxabicyclo[3.1.0]hex-6-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 2);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,5S,6s)-3-oxabicyclo[3.1.0]hex-6-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 3);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3s,5S)-bicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 1);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1-((1R,3s,5S)-bicyclo[3.1.0]hex-3-yl)-2-oxo-2,1-ethanediyl)))biscarbamate (diastereomer 2);
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1

Assignees

• Chen Qi
• Lopez Omar D
• Bender John A
• Wang Gan
• Nguyen Van N
• Kadow John F
• Meanwell Nicholas A
• Belema Makonen
• Bristol Myers Squibb Co

Inventors

• Chen Qi
• Lopez Omar D
• Bender John A
• Wang Gan
• Nguyen Van N
• Kadow John F
• Meanwell Nicholas A
• Belema Makonen

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title