Substituted quinoxalines as sodium channel modulators
The invention relates to compounds of formula 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;
Ar 1 is a 5-6 membered aromatic monocyclic 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 N;
A 1 is a 5-6 membered 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 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-B:
or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
Y is N;
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 according to claim 7 , wherein the compound has formula I-B-2:
or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
Y is N;
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 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, 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.
9. The compound according to claim 7 , wherein the compound has formula I-B-4:
or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
Y is N;
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 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, 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.
10. 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 N;
A 1 and A 2 , together, form an 8-9 membered aromatic, bicyclic 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.
11. The compound or pharmaceutically acceptable salt according to claim 10 , 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:
12. The compound or pharmaceutically acceptable salt according to claim 11 , 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:
13. The compound or pharmaceutically acceptable salt according to claim 11 , wherein ring A is:
14. 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.
15. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 3 is t-butyl, Cl, CF 3 or CF 2 CF 3 ; and R 4 is CF 3 .
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 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 2 unit of said C 6 alkyl is replaced with —O—.
18. The compound or pharmaceutically acceptable salt according to claim 17 , wherein R 1 is CF 3 and R 2 is F, Cl, CF 3 or OCF 3 .
19. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 are H.
20. 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.
21. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is:
22. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 22 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of claim 23 and one or more pharmaceutically acceptable carriers or vehicles.
25. 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.
26. 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 .
27. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the pharmaceutical composition of claim 24 .
28. A method of inhibiting voltage-gated sodium channel Na V 1.8 in a subject comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
29. The method of claim 28 , wherein the subject is suffering from chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain.
30. The method of claim 29 , wherein the subject is suffering from inflammatory pain.
31. The method of claim 29 , wherein the subject is suffering from neuropathic pain.
32. The method of claim 29 , wherein the subject is suffering from musculoskeletal pain.
33. The method of claim 32 , wherein the musculoskeletal pain comprises osteoarthritis pain.
34. A method of inhibiting voltage-gated sodium channel Na V 1.8 in a subject comprising administering to the subject the compound of claim 23 , or a pharmaceutically acceptable salt thereof.
35. The method of claim 34 , wherein the subject is suffering from chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain.