Benzenesulfonamide compounds and their use as therapeutic agents
This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.
1. A compound of the following formula:
wherein:
R 1 is an optionally substituted phenyl or optionally substituted pyridyl;
R 2 is an optionally substituted thiazolyl, an optionally substituted thiadiazolyl, an optionally substituted isothiazolyl, or an optionally substituted pyridinyl;
R 3 is —O— or —N(R 13 )—;
R 4 , R 5 , and R 13 are each independently selected from hydrogen, alkyl, and haloalkyl;
each R 6 is independently selected from hydrogen, halo, alkyl, and haloalkyl;
R 7 is halo;
each R 8 is independently selected from hydrogen, alkyl, and haloalkyl;
m is 1 or 2; and
n is 1 or 2;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 , wherein:
R 1 is phenyl or pyridyl, each optionally substituted with halo or alkyl;
R 2 is thiazolyl, thiadiazolyl, isothiazolyl, or pyridinyl, each optionally substituted with halo or alkyl;
R 3 is —O— or —N(R 13 )—;
R 4 and R 5 are each hydrogen;
R 13 is hydrogen, alkyl, or haloalkyl;
each R 6 is independently selected from hydrogen, halo, alkyl, and haloalkyl;
R 7 is halo;
R 8 is hydrogen;
m is 1; and
n is 1 or 2;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
3. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
4. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
6. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
7. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
9. The compound of claim 1 , which is (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
10. The compound of claim 1 , which is (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , which is (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
12. The compound of claim 1 , which is (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
13. The compound of claim 1 , which is (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , which is (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
15. The compound of claim 1 , which is (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
16. The compound of claim 1 , which is (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , which is (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
18. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide, represented by the formula:
.
19. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
21. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide, represented by the formula:
22. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.
24. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide, represented by the formula:
25. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.
27. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
28. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 , which is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.