Thiophene-substituted tetracyclic compounds and methods ofuse thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-2016257697-A1
Application number	US-201314761259-A
Country	US
Kind code	A1
Filing date	Dec 31, 2013
Priority date	Jan 16, 2013
Publication date	Sep 8, 2016
Grant date	—

Abstract

Thiophene-substituted tetracyclic compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A, A′, R 2 , R 3 , R 4 and R 5 are as defined herein. The compositions comprising at least one thiophene-substituted tetracyclic compound, and methods of using the thiophene-substituted tetracyclic compounds for treating or preventing HCV infection in a patient are also provided.

First claim

1 . A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
A is:

A′ is:

each occurrence of R 1 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl and halo, or two R 1 groups that are attached to the same carbon atom, and the common carbon atom to which they are attached, can combine to form a spirocyclic C 3 -C 7 cycloalkyl group;
each occurrence of R 1A is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl and halo, or one R 1A group and an R 1 group that are attached to same ring, together with the ring carbon atoms to which they are attached, can combine to form a fused C 3 -C 7 cycloalkyl group, or two R 1A groups that are attached to the same carbon atom, and the common carbon atom to which they are attached, can combine to form a spirocyclic C 3 -C 7 cycloalkyl group;
each occurrence of R 1B is independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl or halo, or an R 1B group and an R 1A group that are attached to the same ring, together with the carbon atoms to which they are attached, can combine to form a fused C 3 -C 7 cycloalkyl group, or an R 1B group and an R 1 group that are attached to the same ring, can combine to form a bridging group having the formula —CH 2 — or —CH 2 CH 2 —, or or two R 1B groups that are attached to the same carbon atom, and the common carbon atom to which they are attached, can combine to form a spirocyclic C 3 -C 7 cycloalkyl group
R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or halo;
R 3 is thiophenyl, wherein said thiophenyl group can be optionally substituted on one or more ring carbon atoms with R 6 ;
each occurrence of R 4 is independently selected from —C(O)O—(C 1 -C 6 alkyl), —C(O)—C(R 7 ) 2 NHC(O)O—R 8 , —C(O)—CH(R 7 )(R 8 ) and —C(O)—CH(R 7 )N(R 9 ) 2 ;
R 5 represents up to 2 substituents, each independently selected from H, halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylene) m -C 3 -C 7 cycloalkyl, 4 to 6-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl, C 6 -C 10 aryl, benzyl and —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 C 6 -C 10 aryl group, or the phenyl moiety of said benzyl 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 6 represents up to 2 substituents, each independently selected from halo, —CN, C 1 -C 6 alkyl, —C(O)OH, C 1 -C 6 haloalkyl, —O—(C 1 -C 6 haloalkyl), C 2 -C 6 alkynyl, C 1 -C 6 hydroxyalkyl, —O—C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —N(R 6 ) 2 , —C(O)N(R 6 ) 2 , optionally substituted C 6 -C 10 aryl, —(C 1 -C 6 alkylene), —(C 3 -C 7 cycloalkyl), —O—(C 6 -C 10 aryl), —(C 2 -C 6 alkynyl)-(C 3 -C 7 cycloalkyl), 4 to 7-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl, —O-(5 or 6-membered monocyclic heteroaryl), 8 to 10-membered bicyclic heteroaryl and —O-(8 to 10-membered bicyclic heteroaryl), wherein said C 6 -C 10 aryl group, said C 3 -C 7 cycloalkyl group, said 4 to 7-membered monocyclic heterocycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group and said 8 to 10-membered bicyclic heteroaryl group, can be optionally substituted with up to 3 groups, each independently selected from halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and —O—C 1 -C 6 alkyl, and wherein said C 6 -C 10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group, can be optionally fused with a 3 to 6 membered cycloalkyl group; and wherein said thiophenyl group can be optionally fused to a benzene ring, a 5 or 6-membered monocyclic heterocycloalkyl group, a 5 or 6-membered monocyclic heteroaryl group or a C 5 -C 6 cycloalkyl group, wherein said 5 or 6-membered monocyclic heterocycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group and said C 5 -C 6 cycloalkyl group can form a spirocycle with a C 3 -C 7 cycloalkyl group or a 4 to 7-membered monocyclic heterocycloalkyl group each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylene)-O—C 1 -C 6 alkyl, phenyl, 4 to 8-membered monocyclic heterocycloalkyl, 6 to 10-membered bicyclic heterocycloalkyl and —(C 1 -C 6 alkylene) m -C 3 -C 7 cycloalkyl, wherein said 4 to 8-membered monocyclic heterocycloalkyl group, said 6 to 10-membered bicyclic heterocycloalkyl 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 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, —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 7 groups, that are attached to a common carbon atom, together with the common carbon atom to which they are attached, join to form a C 3 -C 7 cycloalkyl group;
each occurrence of R 8 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl;
each occurrence of R 9 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl; and
each occurrence of m is independently 0 or 1.

2 . The compound of claim 1 , wherein R 3 is:

which can be optionally substituted as described in claim 1 .

3 . The compound of claim 1 , wherein each occurrence of R 4 is independently —C(O)—C(R 7 ) 2 NHC(O)O—R 8 .

4 . The compound of claim 1 , wherein A and A′ are each independently selected from:

5 . The compound of claim 4 , wherein each occurrence of R 4 is independently —C(O)CH(R 7 )—NHC(O)O—(C 1 -C 6 alkyl) and R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or 4 to 6-membered monocyclic heterocycloalkyl, wherein said 4 to 6-membered monocyclic heterocycloalkyl group can be optionally substituted with up to five C 1 -C 6 alkyl groups or said 4 to 6-membered monocyclic heterocycloalkyl group can be optionally substituted on a ring carbon atom with a spirocyclic C 3 -C 6 cycloalkyl group.

6 . The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 is H;
each R 1A is H, or an R 1A groups and an R 1 group that are attached to same ring, together with the ring carbon atoms to which they are attached, can combine to form a fused cyclopropyl group;
R

Assignees

• Merck Sharp & Dohme

Inventors

• Tong Ling
• Yu Wensheng
• Kozlowski Joseph A
• Chen Lei
• Selyutin Oleg
• Kim Seong Heon
• Dwyer Michael
• Hu Bin
• Zhong Bin
• Wang Dahai
• Hao Jinglai
• Shen Changmao
• Lei Zhixin
• Wang Weijun

Classifications

• A61K38/212

  IFN-alpha · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• A61K38/005

  Enzyme inhibitors (protease inhibitors A61K38/55) · CPC title

• A61K45/06

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

• A61K31/5365

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