Amides as modulators of sodium channels

Patent metadata

Field	Value
Publication number	US-9421196-B2
Application number	US-201514809841-A
Country	US
Kind code	B2
Filing date	Jul 27, 2015
Priority date	Jan 31, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The invention relates to amide compounds of formula I and I′ or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels:

The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain.

First claim

We claim:

1. A compound of formula I′

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
Y is N
R 1 is H, halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 2 is H, halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 3 is H, halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 4 is H, halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 5 is H, halogen, CN, or —X—R X ;
R 5′ is H, halogen, CN, or —X—R X ;
R 6 is H, halogen, CN, or —X—R X ;
R 6′ is H, halogen, CN, or —X—R X ;
R 7 is H, halogen, CN, or —X—R X ;
X is a bond or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C 1 -C 4 alkyl;
R 8 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
p is an integer from 0 to 4 inclusive.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is H or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen; R 2 is H halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—; R 3 is halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen; and R 5 and R 7 are each independently halogen, or —X—R X and R 5′ , R 6 , and R 6′ are each hydrogen.

3. The compound according to claim 2 , wherein R 1 is CF 3 ; R 2 is F, Cl, CF 3 or OCF 3 ; R 3 is t-butyl Cl, CF 3 or CF 2 CF 3 ; and R 5 and R 7 are each independently F, Cl, CH 3 or OCH 3 .

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from:

5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein p is 0.

6. The compound of claim 1 , wherein the compound has formula I′-B:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
Y is N;
R 3 is halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 5 is H, halogen, CN, or —X—R X ;
R 5′ is H, halogen, CN, or —X—R X ;
R 6 is H, halogen, CN, or —X—R X ;
R 6′ is H, halogen, CN, or —X—R X ;
R 7 is H, halogen, CN, or —X—R X ;
X is a bond or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C 1 -C 4 alkyl;
R 8 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
p is an integer from 0 to 4 inclusive.

7. The compound or pharmaceutically acceptable salt according to claim 6 , wherein R 3 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen.

8. The compound or pharmaceutically acceptable salt according to claim 6 , wherein R 3 is t-butyl, Cl, CF 3 or CF 2 CF 3 ; and R 5 and R 7 are each independently F, Cl, CH 3 or OCH 3 .

9. The compound or pharmaceutically acceptable salt according to claim 6 , wherein ring A is selected from:

10. The compound or pharmaceutically acceptable salt according to claim 6 , wherein p is 0.

11. The compound according to claim 1 , wherein the compound has formula I′-C:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
Y is N;
R 2 is halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 3 is halogen, CN, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 5 is H, halogen, CN, or —X—R X ;
R 5′ is H, halogen, CN, or —X—R X ;
R 6 is H, halogen, CN, or —X—R X ;
R 6′ is H, halogen, CN, or —X—R X ;
R 7 is H, halogen, CN, or —X—R X ;
X is a bond or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C 1 -C 4 alkyl;
R 8 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
p is an integer from 0 to 4 inclusive.

12. The compound or pharmaceutically acceptable salt according to claim 11 , wherein R 2 is H, halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—; and R 3 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen.

13. The compound or pharmaceutically acceptable salt according to claim 11 , wherein R 2 is F, Cl, CF 3 or OCF 3 ; R 3 is t-butyl Cl, CF 3 or CF 2 CF 3 ; and R 5 and R 7 are each independently F, Cl, CH 3 or OCH 3 .

14. The compound or pharmaceutically acceptable salt according to claim 11 , wherein ring A is selected from:

Assignees

• Vertex Pharma

Inventors

• Hadida-Ruah Sara Sabina
• Anderson Corey
• Arumugam Vijayalaksmi
• Asgian Iuliana Luci
• Bear Brian Richard
• Termin Andreas P
• Johnson James Philip

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title