Amides as modulators of sodium channels
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.
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:
15. The compound or pharmaceutically acceptable salt according to claim 11 , wherein p is 0.
16. A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 1 and one or more pharmaceutically acceptable carriers or vehicles.
17. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound or pharmaceutically acceptable salt of claim 1 .
18. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of the compound or pharmaceutically acceptable salt.