Chromane-substituted tetracyclic compounds and uses thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-10738062-B2
Application number	US-201716326043-A
Country	US
Kind code	B2
Filing date	Aug 14, 2017
Priority date	Aug 18, 2016
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

The present invention relates to novel Chromane-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 present invention also relates to compositions comprising a Chromane-Substituted Tetracyclic Compound, and methods of using the Chromane-Substituted Tetracyclic Compounds for treating or preventing HCV infection in a patient.

First claim

What is claimed is:

1. A compound having the formula (I):

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

A′ is:

each occurrence of R 1 is H;
each occurrence of R 1A is independently selected from H 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;
each occurrence of R 1B is independently selected from H—;
R 2 is selected from H and halo;
R 3 is selected from:

each occurrence of R 4 is independently selected from —C(O)—C(R 7 ) 2 NHC(O)O—R 8 ;
R 5 represents up to 3 optional substituents, each independently selected from halo;
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and 4 to 8-membered monocyclic heterocycloalkyl, wherein said 4 to 8-membered monocyclic heterocycloalkyl group, can be optionally substituted with up to 5 groups, each independently selected from C 1 -C 6 alkyl;
each occurrence of R 8 is independently selected from C 1 -C 6 alkyl;
R 10 is H;
R 11 is H;
R 12 is H;
each occurrence of R 13 is independently selected from H, and C 1 -C 6 alkyl, or both R 13 groups and the common carbon atom to which they are each attached, can combine to form a spirocyclic C 3 -C 7 cycloalkyl group;
each occurrence of R 14 is independently selected from H, C 1 -C 6 alkyl, and halo; or both R 14 groups and the common carbon atom to which they are each attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group; or an R 14 group and R 13 group, together with the carbon atoms to which they are each attached, join to form a fused C 3 -C 7 cycloalkyl group; or an R 14 group and R 15 group, together with the carbon atoms to which they are each attached, can combine to form a fused C 3 -C 7 cycloalkyl group; and
each occurrence of R 15 is independently selected from H, C 1 -C 6 alkyl, and halo, or both R 15 groups and the common carbon atom to which they are each attached, can combine to form a spirocyclic C 3 -C 7 cycloalkyl group.

2. The compound of claim 1 , wherein each occurrence of R 4 is independently —C(O)CH(R 7 )NHC(O)OCH 3 , or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 is H;
each R 1A is independently H or F, or an 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 cyclopropyl group;
R 3 is selected from:

R 5 is H, F or methyl;
each occurrence of R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl and 4 to 6-membered monocyclic heterocycloalkyl, wherein said 4 to 6-membered monocyclic heterocycloalkyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl;
each occurrence of R 13 is independently selected from H and C 1 -C 6 alkyl, or both R 13 groups and the common carbon atom to which they are each attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group;
each occurrence of R 14 is independently selected from H, halo and C 1 -C 6 alkyl; or both R 14 groups and the common carbon atom to which they are each attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group; or an R 14 group and R 13 group, together with the carbon atoms to which they are each attached, join to form a fused C 3 -C 7 cycloalkyl group; or an R 14 group and R 15 group, together with the carbon atoms to which they are each attached, join to form a fused C 3 -C 7 cycloalkyl group; and
each occurrence of R 15 is independently selected from H, C 1 -C 6 alkyl and halo, or both R 15 groups and the common carbon atom to which they are each attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group.

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

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 3 is selected from:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein each occurrence of R 7 is independently selected from isopropyl, —CF(CH 3 ) 2 ,

or a pharmaceutically acceptable salt thereof.

7. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8 further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

10. The pharmaceutical composition according to claim 9 , further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

11. A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, effective to treat infection by HCV in said patient.

12. The method according to claim 11 , further comprising administering a second additional therapeutic agent to said patient, wherein said second additional therapeutic agent is independently selected from HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

13. The method according to claim 12 , further comprising administering a third additional therapeutic agent to said patient, wherein said third additional therapeutic agent is independently selected from HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

14. The method according to claim 12 , wherein said second additional therapeutic agent is grazoprevir.

Assignees

• Merck Sharp & Dohme

Inventors

• Yu Wensheng
• Kozlowski Joseph A
• Tong Ling
• Coburn Craig A
• Hu Bin
• Zhong Bin
• Hao Jinglai
• Wang Dahai

Classifications

• A61K45/06

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

• A61P31/14

  for RNA viruses · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5365

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