Compounds

Patent metadata

Field	Value
Publication number	US-9242972-B2
Application number	US-201314394113-A
Country	US
Kind code	B2
Filing date	Apr 25, 2013
Priority date	Apr 27, 2012
Publication date	Jan 26, 2016
Grant date	Jan 26, 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 (I), or a pharmaceutically acceptable salt thereof:

wherein:
R 1 is

each X 1 is independently N or CR a ;
each X 2 is independently N or CR b ;
X 3 is N or CR c ;
each R a is independently selected from H, CF 3 , halo, C 1-4 alkyl and C 1-4 alkoxy;
each R b is independently selected from H, CF 3 , halo, CH 3 and OCH 3 ;
each R c is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, CF 3 , halo, CN, C 3-6 cycloalkyl and C 3-6 heterocycloalkyl;
R 2 is selected from the group consisting of C 3-5 alkyl, —CH 2 C 3-4 cycloalkyl, and —CH 2 oxetanyl;
each R 3 is independently selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, halo, OH and CH 2 OH;
R 4 is the group —X(CHR 5 ) b R 6 ;
X is selected from the group consisting of O, CH 2 , CHOH and CHCH 2 OH;
each R 5 is independently selected from the group consisting of H, OH and CH 2 OH;
R 6 is isoxazole, tetrahydro-2H-pyran, tetrahydrofuran, —NHR 7 or is a 5- or 6-membered heteroaryl group, wherein R 6 may be unsubstituted or substituted with one or two substitutents independently selected from halo and CH 3 ;
R 7 is oxetanyl or tetrahydrofuran, wherein R 7 may be unsubstituted or substituted with one or two substitutents independently selected from halo and CH 3 ;
a is 0, 1 or 2;
b is 0, 1 or 2;
with the proviso that R 1 contains one or two nitrogen atoms.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each Ra represents H, or is independently selected from CH 3 , —OCH 3 and halo.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each Rb represents H, or is independently selected from CH 3 , —OCH 3 and halo.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each Rc represents H, or C 1-4 alkyl.

6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein Rc represents isopropyl.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of isopropyl, isobutyl, isopentyl and 3-methylbutan-2-yl.

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

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein b is 1 or 2.

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

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is isoxazole, tetrahydro-2H-pyran, or tetrahydrofuran, and further wherein R 6 may be unsubstituted or substituted with one or two substituents independently selected from halo and CH 3 .

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is —NHR 7 .

13. The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 7 is unsubstituted oxetanyl.

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

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of CH 3 , —OCH 3 , halo, OH and CH 2 OH.

16. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4,6-dimethylpyrimidin-2-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(5-isopropylpyridin-2-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(5-methylpyridin-2-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(4-methylpyridin-2-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(6-methylpyridin-2-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(3-methylpyridin-2-yl)benzenesulfonamide;
N-(5-chloropyridin-2-yl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-fluoropyridin-2-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(2,6-dimethylpyridin-3-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(6-methylpyridin-3-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(4-methylpyridin-3-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3,5-dimethylpyrazin-2-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(2-methylpyridin-4-yl)benzenesulfonamide;
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(2-methylpropyl)-N-[4-(trifluoromethyl)-2-pyrimidinyl]benzenesulfonamide;
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(3,5-dimethyl-2-pyridinyl)-N-(2-methylpropyl)benzenesulfonamide;
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[2-methyl-6-(2-oxo-1,3-oxazolidin-3-yl)-3-pyridinyl]-N-(2-methylpropyl)benzenesulfonamide;
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[2-methyl-6-(4-morpholinyl)-3-pyridinyl]-N-(2-methylpropyl)benzenesulfonamide;
2-chloro-N-(3,5-dimethylpyridin-2-yl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(6-methoxypyridazin-3-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-ethoxypyridazin-3-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-ethylpyrimidin-2-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(5-methylpyridin-2-yl)benzenesulfonamide;
N-(3,5-dimethylpyridin-2-yl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-ethyl-6-methylpyridin-2-yl)-N-isobutylbenzenesulfonamide;
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[6-(methyloxy)-2-pyridinyl]-N-(2-methylpropyl)benzenesulfonamide;
N-isobutyl-N-(6-methoxypyridin-2-yl)-4-(pyridin-4-ylmethoxy)benzenesulfonamide;
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(4,6-dimethyl-3-pyridinyl)-N-(2-methylpropyl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3,6-dimethylpyrazin-2-yl)-N-isobutylbenzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(4-methylpyrimidin-5-yl)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(2-methyl-6-(pyrrolidin-3-yl)pyridin-3-yl)benzenesulfonamide;
N-isobutyl-N-(5-isopropyl-3-methylpyridin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide;
N-isobutyl-N-(3-methyl-5-(prop-1-en-2-yl)pyridin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide;
N-isobutyl-N-(5-isopropylpyridin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide;
N-(5-chloro-3-methylpyridin-2-yl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide;
4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isopen

Assignees

• Glaxo Group Ltd

Inventors

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

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title