Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-10981905-B2
Application number	US-201916556055-A
Country	US
Kind code	B2
Filing date	Aug 29, 2019
Priority date	Aug 31, 2018
Publication date	Apr 20, 2021
Grant date	Apr 20, 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 (I):

as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein:

each n is 1 or 2;
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 3 and R 4 are each independently hydrogen or alkyl;
each R 5 is independently alkyl, halo, haloalkyl, optionally substituted cycloalkyl, cyano or —OR 7 ;
each R 6 is independently hydrogen, alkyl, halo, haloalkyl, optionally substituted cycloalkyl, cyano or —OR 7 ; and
R 7 is hydrogen, alkyl or haloalkyl.

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 1 is aryl optionally substituted by one or more substituents selected from alkyl, halo, haloalkyl, —R 8 —N(R 9 )R 10 and optionally substituted N-heterocyclylalkyl;
R 3 and R 4 are each hydrogen or alkyl;
R 8 is a direct bond or an optionally substituted straight or branched alkylene chain; and
R 9 and R 10 are each independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

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 1 is phenyl optionally substituted by one or more substituents selected from halo, —R 8 —N(R 9 )R 10 and optionally substituted N-heterocyclylalkyl;
R 3 and R 4 are each hydrogen or alkyl;
R 8 is an optionally substituted straight or branched alkylene chain;
R 9 is hydrogen or alkyl; and
R 10 is hydrogen or alkyl.

4. The compound of claim 3 , as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof: or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following formula (Ia):

5. A compound, which is 5-((3,6-difluoro-2-(pyrrolidin-1-ylmethyl)benzyl)amino)-N-(thiazol-4-yl)imidazo[1,2-α]pyridine-8-sulfonamide; 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 3 , as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following formula (Ib):

7. The compound of claim 6 , which is 4-((2-bromo-6-fluorobenzyl)amino)-N-(6-fluoropyridin-2-yl)-5-methylthiophene-2-sulfonamide; 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 3 , as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following formula (Ic):

9. The compound of claim 8 , which is 5-((2-fluoro-6-(pyrrolidin-1-ylmethyl)benzyl)amino)-N-(6-fluoropyridin-2-yl)-4-methylthiophene-2-sulfonamide; 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 3 , as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following formula (Id):

11. The compound of claim 10 , 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.

12. The compound of claim 11 , as an individual stereoisomer, enantiomer, or tautomer thereof; or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure (Id1):

13. The compound of claim 12 , selected from:
(S)-5-chloro-((1-(5-chloro-2-fluorophenyl)ethyl)amino)-N-(thiazol-4-yl)pyridine-3-sulfonamide;
(S)-5-chloro-6-((1-(2-fluorophenyl)ethyl)amino)-N-(thiazol-4yl)pyridine-3-sulfonamide;
6((2-((tert-(butyl(methyl)amino)methyl)-6-fluorobenzyl)amino)-2-methyl-N-(thiazol-4-yl)pyridine-3-sulfonamide;
6-((2-((tert-butyl(methyl)amino)methyl)-6-fluorobenzyl)amino)-5-methyl-N-(thiazol-4-yl)pyridine-3-sulfonamide;
6((2-((tert-butyl(methyl)amino)methyl)-6-fluorobenzyl(amino)-5-chloro-N-(thiazol-4-yl)pyridine-3-sulfonamide; and
6((2-fluoro-6-(pyrrolidin-1-ylmethyl)benzyl)amino)-2-methyl-N(thiazol-4-yl)pyridine-3-sulfonamide;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 10 , 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 6-membered N-heteroaryl.

15. The compound of claim 14 , as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure (Id2):

16. The compound of claim 15 , selected from:
6((2-fluoro-6-(pyrrolidin-1-ylmethyl)benzyl)amino)-N-(6-fluoropyridin-2-yl)-2-methylpyridine-3-sulfonamide; and
5-chloro-6-((2-fluoro-6-(pyrrolidin-1-ylmethyl)benzyl)amino)-N-(6-fluoropyridin-2-yl)pyridine-3-sulfonamide;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically a acceptable salt or solvate thereof.

17. The compound of claim 3 , as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following formula (Ie):

18. The compound of claim 17 , 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.

19. The compound of claim 18 , as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof,

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Andrez Jean-Christophe
• Burford Kristen Nicole
• Dehnhardt Christoph Martin
• Focken Thilo
• Grimwood Michael Edward
• Jia Qi
• Lofstrand Verner Alexander
• Sun Shaoyi
• Wesolowski Steven Sigmund
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• A61K31/4427

  containing further heterocyclic ring systems · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title