Sulfonamide compounds and their use in the modulation retinoid-related orphan receptor

Patent metadata

Field	Value
Publication number	US-9540318-B2
Application number	US-201514819836-A
Country	US
Kind code	B2
Filing date	Aug 6, 2015
Priority date	Sep 27, 2011
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

The present invention is directed to novel retinoid-related orphan receptor gamma (RORγ) modulators, processes for their preparation, pharmaceutical compositions containing these modulators, and their use in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORγ.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein

R 1 is CH 3 or halo;
R 2 ,R 3 and R 4 are H;
R 5 is CH 3 or halo;
R 6 is selected from the group consisting of C 3-5 alkyl and —CH 2 —C 3-4 cycloalkyl;
R 7 is selected front the group consisting of

R 8 is selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, CH 2 CN, CH 2 OH, OH, CN and halo;
R 9 is the group —(CHR 10 ) s —(X) t —(CHR 10 ) u —R 11 ;
each R 10 is independently selected from the group consisting of H, OH or CH 2 OH;
R 11 is selected from the group consisting of

optionally substituted with one or two substituents selected from halo, NH 2 or CH 3 ;
X is CH 2 , NH, O;
r is 0, 1 or 2;
s is 0, 1 or 2;
t is 0 or 1;
u is 0, 1 or 2;
with the proviso that no more than two R 10 groups represent OH or CH 2 OH.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 5 are C 3 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is isobutyl.

4. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 is isobutyl.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is;

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein r is 1 and R 8 is CH 2 OH.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 5 are CH 3 , R 6 is isobutyl, r is 1 and R 8 is CH 2 OH.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein s is 0.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein t is 1 and X is O.

10. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is H.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 5 are CH 3 , R 6 is isobutyl, r is 1, R 8 is CH 2 OH, wherein t is 1, and X is O.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 5 are CH 3 , R 6 is isobutyl, r is 1, R 8 is CH 2 OH, wherein t is 1, and X is O, each R 10 is H, and R 11 is selected from the group consisting of:

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof selected from the group consisting of:
N-(4-butyl-2-methylphenyl)-N-isobutyl-4-(pyridin-4-yloxy)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(4-pyridinylmethyl)oxy]benzenesulfonamide;
N-(5-chloro-2-fluorophenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(3-fluoro-5-methylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(3,5-dimethylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-isobutyl-N-(5-methoxy-2-methylphenyl)-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(2,5-difluorophenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(5-fluoro-2-methylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(2,5-dimethylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(3-ethylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-isobutyl-N-(3-methoxyphenyl)-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-isobutyl-4-(pyridin-4-ylmethoxy)-N-(m-tolyl)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-4-((pyridin-4-yloxy)methyl)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-4-((pyridin-4-ylmethoxy)methyl)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-3-((pyridin-4-ylmethoxy)methyl)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-3-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-4-(2-(pyridin-4-yl)ethoxy)benzenesulfonamide;
N-(2,4-dimethylphenyl)-4-((2-fluoropyridin-4-yl)methoxy)-N-isobutylbenzenesulfonamide;
N-(2,4-dimethylphenyl)-4-(2-hydroxy-2-(pyridin-4-yl)ethoxy)-N-isobutylbenzenesulfonamide;
4-((2-aminopyridin-4-yl)methoxy)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide;
N-(2,4-dimethylphenyl)-4-(1-hydroxy-2-((pyridin-3-ylmethyl)amino)ethyl)-N-isobutylbenzenesulfonamide;
N-(2,4-dimethylphenyl)-4-(1-hydroxy-2-((pyridin-4-ylmethyl)amino)ethyl)-N-isobutylbenzenesulfonamide.

14. A pharmaceutical composition comprising a) a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition comprising a) a compound according to claim 13 , or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients.

Assignees

• Glaxo Group Ltd

Inventors

• Birault Véronique
• Campbell Amanda Jennifer
• Harrison Stephen
• Le Joelle

Classifications

• C07C311/21

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D213/68

  attached in position 4 · CPC title

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• C07D239/34

  One oxygen atom · CPC title

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title