Pyridone amides as modulators of sodium channels

1. A compound of formula I or I′

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

G is

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 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 ;

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 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

2. The compound according to claim 1 , wherein R 3 is C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen; and G is

wherein:

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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and

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.

3. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R 3 is t-butyl, CF 3 or CF 2 CF 3 ; and G is:

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein G is:

and G is

5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein G is —X—R X and —X—R X is:

6. The compound or pharmaceutically acceptable salt according to claim 1 , wherein p is 0; and R 9 is H.

7. The compound of claim 1 , wherein the compound has formula I-F or I′-F:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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 halogen, CN, or —X—R X ;

R 7 is 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 and 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 and 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 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

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

9. The compound or pharmaceutically acceptable salt according to claim 8 , wherein R 3 is t-butyl, CF 3 or CF 2 CF 3 .

10. The compound according to claim 7 , wherein p is 0; and R 9 is H.

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

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

R 2 is 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 3 is 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 5 is halogen, CN, or —X—R X ;

R 7 is 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 and 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 and 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 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

12. The compound or pharmaceutically acceptable salt according to claim 11 , wherein R 2 is F, Cl, CN, CF 3 or OCF 3 ; 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 12 , wherein R 3 is t-butyl, CF 3 or CF 2 CF 3 .

14. The compound or pharmaceutically acceptable salt according to claim 12 , wherein ring A is:

15. The compound or pharmaceutically acceptable salt according to claim 14 , wherein p is 0.

16. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 9 is H.

17. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or a pharmaceutically acceptable salt is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of claim 1 and one or more pharmaceutically acceptable carriers or vehicles.

19. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof of claim 1 .

20. 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, or idiopathic pain comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 1 .

21. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is

2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;

or a pharmaceutically acceptable salt thereof.

22. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is

2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;

or a pharmaceutically acceptable salt thereof.

23. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is

4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

24. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is

2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide;

or a pharmaceutically acceptable salt thereof.

25. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is

4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

26. The method of claim 20 , wherein the method comprises treating or lessening the severity in a subject of neuropathic pain.

27. The method of claim 20 , wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain.

28. The method of claim 27 , wherein the musculoskeletal pain comprises osteoarthritis pain.

29. The method of claim 20 , wherein the method comprises treating or lessening the severity in a subject of inflammatory pain.