Substituted quinolines as modulators of sodium channels

1. A compound of formula I

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

Y is CH;

Ar 1 is a 5-6 membered momocyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-membered monocyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar 1 has m substituents, each independently selected from —WR W ;

m is 0, 1, 2, 3, 4, or 5;

W 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—, —CO—, —S—, —SO—, or —SO 2 —;

R W is absent, H, halogen, OH, NH 2 , NHR′, NO 2 , CN, CF 3 , OCF 3 , or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R′ is C 1 -C 6 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 ;

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—; 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.

2. The compound according to claim 1 , wherein the compound has formula I-A:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

Y is CH;

A 1 is a 5-6 membered monocyclic aromatic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3, 4, or 5;

W 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—, —CO—, —S—, —SO—, or —SO 2 —;

R W is absent, H, halogen, OH, NH 2 , NHR′, NO 2 , CN, CF 3 , OCF 3 , or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R′ is C 1 -C 6 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 ;

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—; 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 1 , R 2 , R 3 and R 4 are each H.

4. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R 5 and R 7 are each independently halogen, or —X—R X ; and R 5′ , R 6 , and R 6′ are each H; and ring A 1 is:

5. The compound or pharmaceutically acceptable salt according to claim 4 , wherein R 5 and R 7 are each independently F, Cl, CH 3 , OCF 3 , or OCH 3 ; and ring A 1 is:

6. The compound or pharmaceutically acceptable salt according to claim 5 , wherein ring A is:

7. The compound according to claim 1 , wherein the compound has formula I-E:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

Y is CH;

A 1 and A 2 , together, form an 8-9 membered bicyclic aromatic ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3, 4, or 5;

W 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—, —CO—, —S—, —SO—, or —SO 2 —;

R W is absent, H, halogen, OH, NH 2 , NHR′, NO 2 , CN, CF 3 , OCF 3 , or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R′ is C 1 -C 6 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 ;

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—; 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.

8. The compound or pharmaceutically acceptable salt according to claim 7 , wherein R 5 and R 7 are each independently halogen, or —X—R X ; and R 5′ , R 6 , and R 6′ are each H; and A 1 and A 2 , together, are:

9. The compound or pharmaceutically acceptable salt according to claim 8 , wherein R 5 and R 7 are each independently F, Cl, CH 3 , OCF 3 , or OCH 3 ; and A 1 and A 2 , together with WR W , are:

10. The compound according to claim 8 , wherein ring A is:

11. 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; and 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 unit of said C 1 -C 6 alkyl is replaced with —O—.

12. The compound or pharmaceutically acceptable salt according to claim 11 , wherein R 1 is CF 3 ; and R 2 is F, Cl, CF 3 or OCF 3 .

13. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is H, halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen; and R 4 is H, halogen or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen.

14. The compound or pharmaceutically acceptable salt according to claim 13 , wherein R 3 is t-butyl, Cl, CF 3 or CF 2 CF 3 ; and R 4 is CF 3 .

15. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 and R 7 are each independently halogen, or —X—R X ; and R 5′ , R 6 , and R 6′ are each H.

16. The compound or pharmaceutically acceptable salt according to claim 15 , wherein R 5 and R 7 are each independently F, Cl, CH 3 , OCF 3 , or OCH 3 .

17. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each H.

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

19. The compound according to claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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

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

22. The method according to claim 21 , wherein the voltage-gated sodium channel is Nav1.8.

23. The method of claim 22 , wherein the subject is suffering from chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain.