Benzenesulfonamide compouds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-11174268-B2
Application number	US-202016805895-A
Country	US
Kind code	B2
Filing date	Mar 2, 2020
Priority date	Dec 9, 2016
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

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 (Ib2):

as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof, wherein:
m and n are each 0;
q is 1, 2 or 3;
R 1 is an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic heteroaryl;
R 2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;
R 4 and R 5 are each hydrogen;
each R 6 is independently alkyl, halo, haloalkyl, cyano, or —OR 12 ;
R 7 is alkyl, alkenyl, halo, haloalkyl, cyano, or —OR 12 ; and
each R 8 and R 12 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

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 2 is an optionally substituted 5-membered N-heteroaryl.

3. 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 2 is selected from optionally substituted thiazolyl, optionally substituted thiadiazolyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl or optionally substituted oxazolyl.

4. 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 1 is aryl optionally substituted with optionally substituted heterocyclylalkyl and optionally substituted with one or more substituents selected from halo, alkyl, haloalkyl, optionally substituted cycloalkyl, cyano, —R 9 —OR 12 , —R 9 —N(R 10 )R 11 , —R 9 —N(R 10 )—R 13 —OR 12 , optionally substituted heterocyclyl, and optionally substituted heteroaryl;
wherein:
each R 9 is independently a direct bond or an optionally substituted straight or branched alkylene chain; and
each R 10 , R 11 and R 12 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

R 2 is optionally substituted thiazolyl; and
R 13 is a branched or straight alkylene chain.

5. 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 1 is aryl optionally substituted by one or more substituents selected from halo, alkyl, haloalkyl, optionally substituted cycloalkyl, cyano, —R 9 OR 12 , —R 9 —N(R 10 )R 11 , —R 9 —N(R 10 )—R 13 —OR 12 , optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, and optionally substituted heteroaryl;
wherein:
each R 9 is independently a direct bond or an optionally substituted straight or branched alkylene chain; and
each R 10 , R 11 and R 12 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

R 2 is optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl; and
R 13 is a branched or straight alkylene chain.

6. 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 1 is an optionally aryl; and
R 2 is an optionally substituted 6-membered N-heteroaryl.

7. The compound of claim 6 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from optionally substituted pyridinyl, optionally substituted pyrimidinyl optionally substituted pyridazinyl and optionally substituted pyrazinyl.

8. 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 1 is an optionally substituted monocyclic heteroaryl or an optionally substituted bicyclic heteroaryl.

9. 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.

10. A method of treating a disease or a condition associated with Na V 1.6 activity in a mammal wherein the disease or condition is epilepsy and/or epileptic seizure disorder and wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 , as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

11. A method of decreasing ion flux through Na V 1.6 in a mammalian cell, wherein the method comprises contacting the cell with a compound of claim 1 , as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

12. A method of selectively inhibiting a first voltage-gated sodium channel over a second voltage-gated sodium channel in a mammal, wherein the method comprises administering to the mammal a modulating amount of a compound of claim 1 , as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 12 wherein the first voltage-gated sodium channel is Na V 1.6.

14. The method of claim 13 wherein the second voltage-gated sodium channel is Na V 1.5.

15. The method of claim 13 wherein the second voltage-gated sodium channel is Na V 1.1.

16. The compound of claim 1 , which is 4-((2-(azetidin-1-ylmethyl)benzyl)amino)-5-chloro-2-fluoro-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.

17. The compound of claim 1 , which is 4-((2-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-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 4-((2-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-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.

19. The compound of claim 1 , which is 4-(

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Andrez Jean-Christophe
• Bogucki David Earl
• Burford Kristen Nicole
• Chowdhury Sultan
• Cohen Charles Jay
• Decker Shannon Marie
• Dehnhardt Christoph Martin
• Devita Robert Joseph
• Empfield James Roy
• Focken Thilo
• Grimwood Michael Edward
• Hasan Syed Abid
• Jia Qi
• Johnson Jr James Philip
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• C07D417/12

  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

• C07D403/12

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

• C07D401/12

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

• C07D285/08

  1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles · CPC title