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:
transforming a compound of formula F
to the compound of formula I; and
optionally, treating the compound of formula I with an acid or a first base to afford the pharmaceutically acceptable salt.
2. The process of claim 1 , wherein transforming the compound of formula F to the compound of formula I comprises treating the compound of formula F with TMSI or HBr.
3. The process of claim 1 , wherein the compound of formula F is obtained by treating a compound of formula G
with 2-methoxypyridin-4-amine in the presence of a coupling agent and a second base to afford the compound of formula F.
4. The process of claim 2 , wherein the compound of formula F is obtained by treating a compound of formula G
with 2-methoxypyridin-4-amine in the presence of a coupling agent and a second base to afford the compound of formula F.
5. 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.
6. 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.
7. The process of claim 2 , 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.
8. The process of claim 2 , 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.
9. The process of claim 3 , 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.
10. The process of claim 3 , 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.
11. The process of claim 4 , 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.
12. The process of claim 4 , 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.
13. A compound of formula F
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.
14. The compound of claim 13 , 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.
15. The compound of claim 13 , 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.
16. A compound of formula G
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 Cl, CF 3 , or CF 2 CF 3 ;
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 I 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 F, Br, or I;
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 or C 3 -C 5 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 5 cycloaliphatic may be replaced with —O— and said C 3 -C 5 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C 1 -C 4 alkyl.
17. The compound of claim 16 , 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.