Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-11639351-B2
Application number	US-202117183401-A
Country	US
Kind code	B2
Filing date	Feb 24, 2021
Priority date	Aug 31, 2018
Publication date	May 2, 2023
Grant date	May 2, 2023

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, epileptic seizure disorder, or SCN8A developmental and epileptic encephalopathy (SCN8A-DEE), comprising administering to the patient a therapeutically effective amount of a compound of formula (Ie):

wherein:
each n is 1 or 2;
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 2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;
R 3 and R 4 are each hydrogen or alkyl;
each R 5 is independently alkyl, halo, haloalkyl, optionally substituted cycloalkyl, cyano or —OR 7 ;
R 7 is hydrogen, alkyl, or haloalkyl;
R 8 is an optionally substituted straight or branched alkylene chain; and
R 9 and R 10 are each alkyl; or R 9 , R 10 , and the N they are attached to form a 4- to 6-membered ring;

as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

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

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

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

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

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

7. The method of claim 1 , wherein the compound is 5-((2-((tert-butyl(methyl)amino)methyl)-6-fluorobenzyl)amino)-N-(6-fluoropyridin-2-yl)-6-methylpyridine-2-sulfonamide, represented by the formula:

8. The method of claim 1 , wherein the compound is 5-((2-((tert-butyl(methyl)amino)methyl)-6-fluorobenzyl)amino)-N-(6-fluoropyridin-2-yl)-6-methylpyridine-2-sulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

9. The method of claim 1 , wherein the compound is 5-((2-fluoro-6-((isopropyl(methyl)-amino)methyl)benzyl)amino)-6-methyl-N-(thiazol-4-yl)pyridine-2-sulfonamide, represented by the formula:

10. The method of claim 1 , wherein the compound is 5-((2-fluoro-6-((isopropyl(methyl)-amino)methyl)benzyl)amino)-6-methyl-N-(thiazol-4-yl)pyridine-2-sulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

11. The method of claim 1 , wherein the compound is 5-((2-((azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-fluoro-6-methyl-N-(thiazol-4-y1)pyridine-2-sulfonamide, represented by the formula:

12. The method of claim 1 , wherein the compound is 5-((2-((azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-fluoro-6-methyl-N-(thiazol-4-y1)pyridine-2-sulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 1 , wherein the compound is 3-fluoro-5-((2-fluoro-6-((isopropyl(methyl)-amino)methyl)benzyl)amino)-6-methyl-N-(thiazol-4-yl)pyridine-2-sulfonamide, represented by the formula:

14. The method of claim 1 , wherein the compound is 3-fluoro-5-((2-fluoro-6-((isopropyl(methyl)-amino)methyl)benzyl)amino)-6-methyl-N-(thiazol-4-yl)pyridine-2-sulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

15. The method of claim 1 , wherein the compound is 5-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-N-(thiazol-4-yl)-6-(trifluoromethyl)pyridine-2-sulfonamide, represented by the formula:

16. The method of claim 1 , wherein the compound is 5-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-N-(thiazol-4-yl)-6-(trifluoromethyl)pyridine-2-sulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

17. The method of claim 1 , wherein the compound is 5-((2-((tert-butyl(methyl)amino)-methyl)-6-fluorobenzyl)amino)-3-fluoro-6-methyl-N-(thiazol-4-yl)pyridine-2-sulfonamide, represented by the formula:

18. The method of claim 1 , wherein the compound is 5-((2-((tert-butyl(methyl)amino)-methyl)-6-fluorobenzyl)amino)-3-fluoro-6-methyl-N-(thiazol-4-yl)pyridine-2-sulfonamide, represented by the formula:

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

• C07D417/12 Primary

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

• C07D401/14

  containing three or more hetero rings · CPC title