Benzenesulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-10246453-B2
Application number	US-201715600490-A
Country	US
Kind code	B2
Filing date	May 19, 2017
Priority date	May 20, 2016
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

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.

First claim

What is claimed is:

1. A compound of formula (I):

wherein:
n is 1, 2, or 3;
m is 1, 2, 3 or 4;
X is a direct bond or —C(R 9 )R 10 —;
Y is a direct bond or —C(R 11 )R 12 —;
R 1 is hydrogen, alkyl, —R 17 —OR 14 , an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;
R 2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;
R 3 is —O — or —N(R 13 )—;
R 4 and R 5 are each independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
or R 4 and R 1 , together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted heterocyclyl or an optionally substituted aryl, and R 5 , if present, is hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
each R 6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, —OR 14 or optionally substituted cycloalkyl;
R 7 is halo, haloalkyl, cyano or —OR 14 ;
each R 8 is independently hydrogen, alkyl, halo, haloalkyl or —OR 14 ;
or two R 8 's, together with the carbon to which they are both attached, may form an optionally substituted cycloalkyl;
R 9 ,R 10 , and R 12 are each independently hydrogen, alkyl, haloalkyl or —OR 14 ;
or R 9 and R 11 form an optionally substituted alkylene chain and R 10 and R 12 are as defined above; and
R 13 is hydrogen, alkyl or haloalkyl;
each R 14 are each independently hydrogen, alky, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R 17 is a direct bond or an optionally substituted alkylene chain;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
provided that when R 3 is —O—, R 2 is not optionally substituted thiadiazolyl.

2. The compound of claim 1 , wherein R 3 is —O—, wherein the compound has the following formula (Ia):

wherein m, n, X, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are each as defined above in claim 1 ;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

3. The compound of claim 2 , wherein:
n is 1 or 2;
m is 1 or 2;
X is a direct bond or —C(R 9 )R 10 —;
Y is a direct bond or —C(R 11 )R 12 —;
R 1 is hydrogen, alkyl, —R 17 —OR 14 , an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-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 independently hydrogen, alkyl or haloalkyl;
or R 4 and R 1 , together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R 5 , if present, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;
each R 6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, —OR 14 or optionally substituted cycloalkyl;
R 7 is halo, haloalkyl, cyano or —OR 14 ;
each R 8 is independently hydrogen, alkyl, halo, haloalkyl or —OR 14 ;
or two R 8 's, together with the carbon to which they are both attached, may form an optionally substituted cycloalkyl;
R 9 , R 10 , R 11 and R 12 are each independently hydrogen, alkyl, haloalkyl, alkyl or —OR 14 ;
or R 9 and R 11 form an optionally substituted alkylene chain and R 10 and R 12 are as defined above; and
each R 14 are each independently hydrogen, alky, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R 17 is a direct bond or an optionally substituted alkylene chain.

4. The compound of claim 3 , wherein X and Y are both a direct bond,
wherein the compound has the following formula (Ia1):

wherein m, n, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are each as defined above in claim 3 ;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

5. The compound of claim 4 , wherein R 2 is an optionally substituted 5-membered N-heteroaryl.

6. The compound of claim 5 , wherein R 2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

7. The compound of claim 6 , which is 4((1-benzylazetidin-3-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzene-sulfonamide.

8. The compound of claim 4 , wherein R 2 is an optionally substituted 6-membered N-heteroaryl.

9. The compound of claim 8 , wherein R 2 is optionally substituted pyridinyl.

10. The compound of claim 3 , wherein X is —C(R 9 )R 10 —and Y is a direct bond, wherein the compound has the following formula (Ia 2):

wherein m, n, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each as defined above in claim 3 ;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

11. The compound of claim 10 , wherein R 2 is an optionally substituted 5-membered N-heteroaryl.

12. The compound of claim 11 , wherein R 2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

13. The compound of claim 12 , selected from:
(S)-4((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;
(S)-4((1-benzylpyrrolidin-3-yl)oxy)-3-ethyl-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
(S)-4((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;
(S)-4((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl)benzenesulfonamide;
(S)-4((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)-3-vinylbenzenesulfonamide;
rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;
(S)-4((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;
(R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;
(S)-4((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benze

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Andrez Jean-Christophe
• Burford Kristen Nicole
• Chowdhury Sultan
• Cohen Charles Jay
• Dehnhardt Christoph Martin
• Devita Robert Joseph
• Empfield James Roy
• Focken Thilo
• Grimwood Michael Edward
• Hasan Syed Abid
• Johnson Jr James Philip
• Zenova Alla Yurevna

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• C07D277/52

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

• C07D413/12

  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