Hepatitis C virus inhibitors

Patent metadata

Field	Value
Publication number	US-10787441-B2
Application number	US-201716094621-A
Country	US
Kind code	B2
Filing date	Apr 17, 2017
Priority date	Apr 21, 2016
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

Abstract

A compound of Formula (I) or (II), for treating or preventing an HCV infection in a subject.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X is —O—, —C(O)—, —C(R A R B )—, NR A , or SO 2 ;
Y is —O—, —C(O)—, —C(R A R B )—, NR A , or SO 2 , such that one of X and Y is —O—, and the other of X and Y is other than —O—;
V is CH;
W is N;
V 1 is CH;
W 1 is N;
R A is H, halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, 4 to 6-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl, 6 to 10-membered bicyclic heterocycloalkyl, C 6 -C 10 aryl, or —O—(C 1 -C 6 alkyl), wherein said C 3 -C 7 cycloalkyl group, said 4 to 6-membered monocyclic heterocycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group, said 6 to 10-membered bicyclic heterocycloalkyl, or said C 6 -C 10 aryl group, can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O—C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-O—C 1 -C 6 alkyl and —O—(C 1 -C 6 haloalkyl);
R B is H, halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, 4 to 6-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl, 6 to 10-membered bicyclic heterocycloalkyl, C 6 -C 10 aryl, or —O—(C 1 -C 6 alkyl), wherein said C 3 -C 7 cycloalkyl group, said 4 to 6-membered monocyclic heterocycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group, said 6 to 10-membered bicyclic heterocycloalkyl, or said C 6 -C 10 aryl group, can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O—C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-O—C 1 -C 6 alkyl and —O—(C 1 -C 6 haloalkyl);
A is:

A′ is:

each occurrence of R 1 is H;
each occurrence of R 1A fis independently selected from H, and halo;
each occurrence of R 1B is H;
each occurrence of R 3 is independently H, —C(O)—C(R 4 ) 2 NHC(O)O—R 5 , —C(O)O—R 5 , C(O)NHR 5 or —C(O)—C(R 4 ) 2 NR′R 8 ;
each occurrence of R 4 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, 4 to 8-membered monocyclic heterocycloalkyl, 6 to 10-membered bicyclic heterocycloalkyl and C 3 -C 7 cycloalkyl, wherein said 4 to 8-membered monocyclic heterocycloalkyl group, said 6 to 10-membered bicyclic heterocycloalkyl group, said C 6 -C 10 aryl group and said C 3 -C 7 cycloalkyl group can be optionally substituted with up to 5 groups, each independently selected from halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, —O—C 1 -C 6 alkyl, —N(R 6 ) 2 and —O—(C 1 -C 6 haloalkyl), and wherein said C 3 -C 7 cycloalkyl group can be optionally fused to a 4 to 6-membered monocyclic heterocycloalkyl group, and wherein said 4 to 8-membered monocyclic heterocycloalkyl group and said C 3 -C 7 cycloalkyl group can be substituted on a ring carbon atom with a spirocyclic C 3 -C 6 cycloalkyl group; and wherein said C 3 -C 7 cycloalkyl group can be substituted on a ring carbon atom with a spirocyclic 3 to 6-membered monocyclic heterocycloalkyl group, and wherein two R 4 groups, that are attached to a common carbon atom, together with the common carbon atom to which they are attached, can join to form a C 3 -C 7 cycloalkyl group;
each occurrence of R 5 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl;
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl;
each occurrence of R 7 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or phenyl, or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 3 to 6-membered monocyclic heterocycloalkyl group; and
each occurrence of R 8 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or phenyl, or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 3 to 6-membered monocyclic heterocycloalkyl group.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A and A′ are each independently

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently H, —C(O)CH(CH(CH 3 ) 2 )(NHC(O)OCH 3 ), —C(O)OC(CH 3 ) 3 , C(O)NHC(CH 3 ) 3 ,

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1A is independently H or fluoro.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A and R B are independently H, halo, or —C 1 -C 6 alkyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R A and R B are independently H, fluoro, —CH 3 or —CH 2 CH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently H, —CH(CH 3 ) 3 ,

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently CH 3 or —C(CH 3 ) 3 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are independently H or —C 1 -C 6 alkyl.

10. The compound of claim 1 which is
methyl [(1R)-1-({(2R)-2-[5-(9-{2-[(2R)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-7-oxo-7H-benzo[c]xanthen-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1S)-1-({(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-12-methyl-12H-benzo[a]xanthen-9-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1S)-1-({(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-12-methyl-12H-benzo[a]xanthen-9-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1S)-1-({(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-7-methyl-7H-benzo[c]xanthen-9-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1 S)-1-({(2S)-2-[5-(12-ethyl-3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-12H-benzo[a]xanthen-9-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1 S)-1-({(2S)-2-[5-(12-ethyl-3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-12H-benzo[a]xanthen-9-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1S)-1-({(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-12,12-dimethyl-12H-benzo[a]xanthen-9-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate,
methyl [(1R)-1-({(2S)-2-[5-(12,12-diethyl-3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidaz

Assignees

• Merck Sharp & Dohme

Inventors

• Kozlowski Joseph A
• Yu Wensheng
• Hu Bin
• Zhong Bin
• Hao Jinglai
• Wang Dahai
• Lei Zhixin

Classifications

• A61K38/19

  Cytokines; Lymphokines; Interferons · CPC title

• A61K38/21

  Interferons {[IFN]} · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title