Benzenesulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-10745392-B2
Application number	US-201916440459-A
Country	US
Kind code	B2
Filing date	Jun 13, 2019
Priority date	Jun 13, 2018
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

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 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 compound of claim 1 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is azabicyclo[2.2.1]heptanylalkyl.

3. The compound of claim 2 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is isothiazolyl.

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

5. The compound of claim 2 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is thiazolyl.

6. The compound of claim 5 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein r is 1.

7. The compound of claim 6 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.

8. The compound of claim 5 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, where r is 2.

9. The compound of claim 8 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.

10. The compound of claim 2 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is isoxazolyl.

11. The compound of claim 10 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.

12. The compound of claim 1 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, where R 7 is ((methyl)(prop-2-yl)amino)alkyl, provided that r is 2 and at least one R 6 is alkoxy.

13. The compound of claim 12 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is isothiazolyl.

14. The compound of claim 12 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is thiazolyl.

15. The compound of claim 14 selected from:
2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;
2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;
2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; and
2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-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.

16. The compound of claim 12 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is isoxazolyl.

17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , as a 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 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide, as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 1 , which is 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-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.

20. The compound of claim 1 , which is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-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.

21. The compound of claim 1 , which is 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide, as an individual stereoisomer, enanti

Assignees

• Xenon Pharmaceuticals Inc

Inventors

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

Classifications

• C07D487/08 Primary

  Bridged systems · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · 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

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title