Pyridone amides as modulators of sodium channels
The invention relates to pyridone 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 process for preparing a compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
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;
comprising:
treating a compound of formula A
with a compound of formula B
in the presence of a first base to afford the compound of formula I; and
optionally, treating the compound of formula I with an acid or a second base to afford the pharmaceutically acceptable salt.
2. The process of claim 1 , wherein the first base is Cs 2 CO 3 or K 2 CO 3 .
3. The process of claim 1 , wherein the compound of formula A is obtained by transforming a compound of formula C
to the compound of formula A.
4. The process of claim 3 , wherein transforming the compound of formula C to the compound of formula A comprises treating the compound of formula C with HBr.
5. The process of claim 3 , wherein the compound of formula C is obtained by treating a compound of formula D
with 2-methoxypyridin-4-amine in the presence of a third base to afford the compound of formula C.
6. The process of claim 5 , wherein the third base is pyridine.
7. The process of claim 3 , wherein the compound of formula C is obtained by treating a compound of formula E
with 2-methoxypyridin-4-amine in the presence of a coupling agent and a fourth base to afford the compound of formula C.
8. The process of claim 1 , wherein:
R 1 is H;
R 2 is H;
R 3 is CF 3 ;
R 4 is H;
R 5 is CH 3 ;
R 5′ is H;
R 6 is H;
R 6′ is H; and
R 7 is F.
9. The process of claim 1 , wherein:
R 1 is H;
R 2 is CF 3 ;
R 3 is H;
R 4 is H;
R 5 is H;
R 5′ is H;
R 6 is H;
R 6′ is H; and
R 7 is F.
10. A compound of formula A
wherein:
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—; and
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—.
11. The compound of claim 10 , wherein:
R 1 is H;
R 2 is H;
R 3 is CF 3 ; and
R 4 is H.
12. The compound of claim 10 , wherein:
R 1 is H;
R 2 is CF 3 ;
R 3 is H; and
R 4 is H.
13. A compound of formula C
wherein:
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—; and
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—.
14. The compound of claim 13 , wherein:
R 1 is H;
R 2 is H;
R 3 is CF 3 ; and
R 4 is H.
15. The compound of claim 13 , wherein:
R 1 is H;
R 2 is CF 3 ;
R 3 is H; and
R 4 is H.