Fused tetracyclic heterocyclic compounds and methods of use thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-9828365-B2
Application number	US-201415104584-A
Country	US
Kind code	B2
Filing date	Dec 15, 2014
Priority date	Dec 20, 2013
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

The present invention relates to novel Fused Tetracyclic Heterocyclic Compounds of Formula I: (I), wherein A, A′, R 2A , R 2B , R 7 , R 8 , R 9 , and R 10 are defined herein. The compounds and their pharmaceutically acceptable salts are useful for the prophylaxis or treatment of infection by HCV and the prophylaxis, treatment, or delay in the onset of disease caused by HCV. The present invention also relates to pharmaceutical compositions comprising at least one Fused Tetracyclic Heterocyclic Compound, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines, and methods of using the Fused Tetracyclic Heterocyclic Compounds for treating or preventing HCV infection in a patient.

First claim

What is claimed is:

1. A compound of 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 1 -C 6 haloalkyl and halo;
each occurrence of R 1A is independently selected from H, C 1 -C 6 alkyl, 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 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 of the formula —CH 2 — or —CH 2 CH 2 —;
R 2A 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 2B is H; or alternatively, R 2A and R 2B , together with the common carbon atom to which they are attached, form a carbonyl group;

each occurrence of R 3 is independently —C(O)—C(R 4 ) 2 NHC(O)O—R 5 , —C(O)O—R 5 ; or —C(O)—C(R 4 ) 2 NR 11 R 12 ;
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;
R 7 and R 8 each represent up to 2 substituents, each independently selected from 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, C 6 -C 10 aryl, phenyl 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 said phenyl 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 9 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or halo;
each occurrence of R 10 is independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or halo;
each occurrence of R 11 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or phenyl; and
each occurrence of R 12 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or phenyl.

2. The compound according to claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2A and R 2B , together with the common carbon atom to which they are attached, form a carbonyl group.

3. The compound according to claim 1 , or pharmaceutically acceptable salt thereof, wherein, R 2A is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, thiazole, thiophene, or phenyl, wherein said C 3 -C 7 cycloalkyl group, said thiophene group or said phenyl group can be optionally substituted with up to 3 groups, and said thiazole group can be optionally substituted with up to 2 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); and R 2B is H.

4. The compound according to claim 1 , or pharmaceutically acceptable salt thereof, wherein A and A′ are each independently selected from:

5. The compound according to claim 4 , or pharmaceutically acceptable salt thereof, wherein each occurrence of R 3 is independently —C(O)—C(R 4 ) 2 NHC(O)O—R 5 .

6. The compound according to claim 4 , or pharmaceutically acceptable salt thereof, wherein each occurrence of R 3 is independently —C(O)O—R 5 .

7. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
R 2A is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, thiophene, or thiazole, wherein said C 3 -C 7 cycloalkyl group, said thiophene group, or said phenyl group can be optionally substituted with up to 3 groups, and said thiazole group can be optionally substituted with up to 2 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); and
R 2B is H;
or alternatively, R 2A and R 2B , together with the common carbon atom to which they are attached, form a carbonyl group;
R 7 and R 8 are as defined in claim 1 ,
each occurrence of R 9 and R 10 are independently H, F, Cl, CH 3 , or isopropyl;
each occurrence of R 4 is independently C 1 -C 6 alkyl;
each occurrence of R 5 is independently C 1 -C 6 alkyl;
R 1 is H, and
each occurrence of R 1A is independently selected from H or F.

8. The compound of claim 7 , or pharmaceutically acceptable salt thereof, wherein at least one occurren

Assignees

• Merck Sharp & Dohme
• Kozlowski Joseph
• Coburn Craig
• Yu Wensheng
• Tong Ling
• Hu Bin
• Zhong Bin
• Hao Jinglai
• Wang Dahai
• Ji Tao

Inventors

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

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/4985

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

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/4178

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