Compounds

Patent metadata

Field	Value
Publication number	US-9428452-B2
Application number	US-201314394105-A
Country	US
Kind code	B2
Filing date	Apr 25, 2013
Priority date	Apr 27, 2012
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

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 (Ia), or a pharmaceutically acceptable salt thereof:

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

each R 8 is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, CN, OH, C(O)OH, C(O)OC 1-3 alkyl and CH 2 OH;
R 9 is the group —(CHR 10 ) s —(X) t —(CHR 10 ) u —R 11 ;
each R 10 is independently selected from H, CH 3 , OH and CH 2 OH;
X is CH 2 , NH or O;
R 11 is a heterocycloalkyl or C 3-6 cycloalkyl group which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of CH 3 , OCH 3 , OH, CH 2 OH and halo;
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 CH 3 , OH or CH 2 OH.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

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

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is:

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein r is 1.

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

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

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein u is 1.

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

10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is H.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is unsubstituted.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-3-[(oxan-4-ylmethoxy)methyl]benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[2-(morpholin-4-yl)ethoxy]benzene-1-sulfonamide;
2-[(2,4-dimethylphenyl)(2-methylpropyl)sulfamoyl]-5-(oxan-4-ylmethoxy)benzoic acid;
N-(2,4-dimethylphenyl)-2-methoxy-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-2-(hydroxymethyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-{[(oxan-4-ylmethyl)amino]methyl}benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-[(cis-3-fluoropiperidin-4-yl)methoxy]-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(piperidin-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(1-methylpyrrolidin-3-yl)methoxy]benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(5-oxomorpholin-2-yl)methoxy]benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-[(3-methyl-5-oxomorpholin-3-yl)methoxy]-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-((cis-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)-N-isobutylbenzenesulfonamide;
4-[(3,5-dihydroxycyclohexyl)oxy]-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)benzene-1-sulfonamide;
4-(((1S,3R,5S)-3,5-dihydroxycyclohexyl)oxy)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide;
4-[2-(3,5-dimethylmorpholin-4-yl)ethoxy]-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(oxan-4-ylmethoxy)methyl]benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(oxetan-3-ylmethoxy)methyl]benzene-1-sulfonamide;
3-chloro-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
3-cyclopropyl-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-[1-hydroxy-2-(morpholin-4-yl)ethyl]-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-3,5-difluoro-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-3-methyl-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-2-methyl-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-2-hydroxy-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
2-chloro-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-2-fluoro-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-3-fluoro-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-3-methoxy-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxolan-3-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-3-hydroxy-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(morpholin-4-yl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-yloxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-2-ethoxy-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-isobutyl-4-(((2R,3R)-2-methylmorpholin-3-yl)methoxy)benzenesulfonamide;
3-cyano-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
2-cyano-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzene-1-sulfonamide;
4-(cyclohexylmethoxy)-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)benzene-1-sulfonamide;
4-[(2,6-dimethylcyclohexyl)methoxy]-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-[(3-hydroxycyclohexyl)oxy]-N-(2-methylpropyl)benzene-1-sulfonamide;
4-{[(2S)-4,4-difluoropyrrolidin-2-yl]methoxy}-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-3-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(6-oxopiperidin-3-yl)oxy]benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-(1,4-dioxan-2-ylmethoxy)-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-[(4-methylcyclohexyl)methoxy]-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-{[1-(morpholin-4-yl)propan-2-yl]oxy}benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(morpholin-2-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(morpholin-3-ylmethoxy)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-(oxan-2-ylmethoxy)benzene-1-sulfonamide;
4-[(6,6-dimethylmorpholin-3-yl)methoxy]-N-(2,4-dimethylphenyl)-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-3-[2-(morpholin-4-yl)ethoxy]benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-{[(2R,3S)-3-hydroxyoxan-2-yl]methoxy}-N-(2-methylpropyl)benzene-1-sulfonamide;
N-(2,4-dimethylphenyl)-4-[(4-flu

Assignees

• Glaxo Group Ltd

Inventors

• Birault Veronique
• Campbell Amanda Jennifer
• Harrison Stephen
• Le Joelle
• Shukla Lena

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title