Benzenesulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-11325902-B2
Application number	US-202016927178-A
Country	US
Kind code	B2
Filing date	Jul 13, 2020
Priority date	Jun 13, 2018
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

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 and/or epileptic seizure disorders.

First claim

What is claimed is:

1. A method of treating a disease or a condition associated with aberrant Nav1.6 activity in a patient, wherein the disease or condition is epilepsy or epileptic seizure disorder, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)

as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof, wherein:
q is 1 or 2;
r is 1 or 2;
R 1 is hydrogen or alkyl;
R 2 is thiazolyl, isothiazolyl or isoxazolyl;
R 3a and R 3b are each independently hydrogen or alkyl;
each R 4 is independently halo or alkyl;
R 5 is halo;
each R 6 is independently halo or alkoxy; and
R 7 is azabicyclo[2.2.1]heptanylalkyl or R 7 is ((methyl)(prop-2-yl)amino)alkyl when r is 2 and at least one R 6 is alkoxy.

2. The method of claim 1 , wherein the disease or condition is epilepsy.

3. The method of claim 1 , wherein the disease or condition is epileptic seizure disorder.

4. The method of claim 1 , wherein the disease or condition is SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).

5. The method of claim 1 , wherein the patient has a SCN8A mutation.

6. The method of claim 1 , wherein R 7 is azabicyclo[2.2.1]heptanylalkyl.

7. The method of claim 6 , wherein R 2 is thiazolyl.

8. The method of claim 7 , wherein r is 1.

9. The method of claim 8 , wherein the compound is selected from:
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; and
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide,
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.

10. The method of claim 7 , wherein r is 2.

11. The method of claim 10 , wherein the compound is selected from:
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
54-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
(S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; and
(R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide,
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.

12. The method of claim 6 , wherein R 2 is isoxazolyl.

13. The method of claim 12 , wherein the compound is selected from:
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide; and
4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide,
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof or a pharmaceutically acceptable salt or solvate thereof.

14. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide.

15. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

16. The method of claim 1 , wherein the compound is 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

17. The method of claim 1 , wherein the compound is 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

18. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide.

19. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

20. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide.

21. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

22. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(i soxazol-3-yl)-3-methylbenzenesulfonamide.

23. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

24. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide.

25. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

26. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide.

27. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

28. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide.

29. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof.

30. The method of claim 1 , wherein the compound is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide.

31. The method of claim 1 , wherein the compound is 4-((2

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Burford Kristen Nicole
• Focken Thilo
• Lofstrand Verner Alexander
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D487/08 Primary

  Bridged systems · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D277/52

  to sulfur atoms, e.g. sulfonamides · CPC title