ROR gamma (RORy) modulators

Patent metadata

Field	Value
Publication number	US-10428018-B2
Application number	US-201615579075-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Jun 5, 2015
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

The present invention relates to compounds according to Formula I: or a pharmaceutically acceptable salt thereof. The compounds can be used as inhibitors of RORy and are useful for the treatment of RORy mediated diseases such as autoimmune and inflammatory diseases.

First claim

The invention claimed is:

1. A compound according to Formula I

or a pharmaceutically acceptable salt thereof wherein:
A 1 -A 8 are CR 1 -CR 8 ;
R 1 -R 8 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
R 9 is C(1-6)alkyl;
R 10 and R 11 are independently H, F, methyl, ethyl, hydroxy or methoxy or R 10 and R 11 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
R 12 is H or C(1-6)alkyl;
R 13 is C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6- 10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)hetero-aryl or C(1-9)heteroarylC(1-3)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;
R 14 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-3)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;
or R 13 and R 14 are fused and form a ring having 5 to 7 atoms by joining R 13 being C(1-6)alkyl or C(2-6)alkenyl with an independent substituent within the definition of R 14 , all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;
the term C(1-9)heteroaryl denotes an aromatic group having 1-9 carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms of the aromatic group may optionally be substituted with one or more halogen or methyl;
the term C(2-5)heterocycloalkyl denotes a saturated cyclic hydrocarbon group having 2-5 carbon atoms and 1-3 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms of the saturated cyclic hydrocarbon group may optionally be substituted with one or more halogen or methyl; and
the term heteroatom denotes a nitrogen, sulfur or oxygen atom.

2. The compound according to claim 1 , wherein R 1 -R 8 are independently H, halogen or methyl.

3. The compound according to claim 1 , wherein R 9 is C(1-3)alkyl.

4. The compound according to claim 1 , wherein R 10 and R 11 are both H.

5. The compound according to claim 1 , wherein R 12 is H.

6. The compound according to claim 1 , wherein R 13 is C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(4)heterocycloalkyl-C(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl.

7. The compound according to claim 1 , wherein R 14 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(4)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroarylC(1-3)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl; and
the term C(1-5)heteroaryl denotes an aromatic group having 1-5 carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms in the aromatic group may optionally be substituted with one or more halogen or methyl.

8. The compound according to claim 1 , wherein R 13 and R 14 are fused and form a ring having 5 to 7 atoms by joining R 13 being C(1-6)alkyl or C(2-6)alkenyl with an independent R 14 substituent selected from C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl; and
the term C(1-5)heteroaryl denotes an aromatic group having 1-5 carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom, and all carbon atoms of the aromatic group may optionally be substituted with one or more halogen or methyl.

9. The compound selected from claim 1 , which is selected from the group of:
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide;
N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide;
N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-fluoro-N-phenylbenzamide;
2 chloro-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(1,2-oxazol-3-yl)benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide;
N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide;
N-(dimethyl-1,2-oxazol-4-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-methyl-N-phenylbenzamide;
N-tert-butyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide;
N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;
N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;
N-(3,3-difluorocyclobutyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide 4-{2[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(pyridin-2-yl)benzamide;
6-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide;
N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide;
N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methylbenzamide;
N-(cyclopropylmethyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide;
2-[4-(ethanesulfonyl)phenyl]-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide;
2-[4 (ethanesulfonyl)phenyl]-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide;
2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide;
N,N-dicyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide;
4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(furan-2-ylmethyl)-N-methylbenzamide;
N,N-dibenzyl-4-{2-[4-(ethanesulfo

Assignees

• Lead Pharma Holding Bv
• Sanofi Sa

Inventors

• Cals Joseph Maria Gerardus Barbara
• De Kimpe Vera
• Nabuurs Sander Bernardus

Classifications

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title