ROR gamma (RORγ) modulators

Patent metadata

Field	Value
Publication number	US-10556866-B2
Application number	US-201615579164-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Jun 5, 2015
Publication date	Feb 11, 2020
Grant date	Feb 11, 2020

Abstract

Novel compounds according to Formula I

or a pharmaceutically acceptable salt thereof wherein: A 11 -A 14 are N or CR 11 , CR 12 , CR 13 , CR 14 , respectively, with the proviso that no more than two of the four positions A can be simultaneously N; R 1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino; R 5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, (3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl; the sulfonyl group with R 1 is represented by one of R 7 , R 8 or R 9 ; R 15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl; and R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl. The compounds can be used as inhibitors of RORγ and are useful for the treatment of RORγ mediated diseases.

First claim

The invention claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
A 11 is N or CR 11 ;
A 12 is N or CR 12 ;
A 13 is N or CR 13 ;
A 14 is N or CR 14 ;
with the proviso that no more than two of the four positions A 11 , A 12 , A 13 , and A 14 are simultaneously N;
R 1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino, wherein each carbon atom of said alkyl groups is optionally substituted with one or more F, and each carbon atom of said cycloalkyl groups is optionally substituted with one or more F or methyl;
R 2 and R 3 are independently H, F, methyl, ethyl, hydroxy, or methoxy, or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a carbonyl, wherein each alkyl group, if present, is optionally substituted with one or more F;
R 4 is H or C(1-6)alkyl;
R 5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, each of which is optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano;
the sulfonyl group containing R 1 is in the meta or para position and is represented by one of R 7 , R 8 or R 9 ;
the remaining R 6 -R 14 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl, wherein each alkyl group is optionally substituted with one or more F;
R 15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, each of which is optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano; and
R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, each of which is optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano, and

wherein:
(i) “C(1-9)heteroaryl” is a mono- or bicyclic aromatic group having 1-9 carbon atoms and 1-4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, and which can be attached via a nitrogen atom if feasible, or a carbon atom, and wherein each carbon atom is optionally substituted with one or more halogen or methyl; and
(ii) “C(2-5)heterocycloalkyl” is a saturated cyclic hydrocarbon group having 2-5 carbon atoms and 1-3 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, and which can be attached via a nitrogen atom if feasible, or a carbon atom, and wherein each carbon atom is optionally substituted with one or more halogen or methyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein:
A 11 is N or CR 11 ;
A 12 is N or CR 12 ;
A 13 is N or CR 13 ;
A 14 is N or CR 14 ;
with the proviso that no more than two of the four positions A 11 , A 12 , A 13 , and A 14 are simultaneously N;
R 1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino, wherein each carbon atom of said alkyl groups is optionally substituted with one or more F, and each carbon atom of said cycloalkyl groups is optionally substituted with one or more F or methyl;
R 2 and R 3 are independently H or methyl, or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a carbonyl, wherein the methyl group, if present, is optionally substituted with one or more F;
R 4 is H;
R 5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, each of which is optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano;
the sulfonyl group containing R 1 is represented by R 8 ;
the remaining R 6 -R 14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, wherein each alkyl group is optionally being substituted with one or more F;
R 15 is C(1-6)alkyl optionally substituted with one or more F, or C(1-9)heteroaryl substituted with one C(1-2)alkyl; and
R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, each of which is optionally substituted with one or more F.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A 11 -A 14 are CR 11 , CR 12 , CR 13 , and CR 14 , respectively;
R 1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl, or (di)C(3-6)cycloalkylamino;
R 2 and R 3 are independently H or methyl;
R 4 is H;
R 5 is H, C(1-6)alkyl or C(6-10)arylC(1-3)alkyl;
the sulfonyl group containing R 1 is represented by R 8 ;
the remaining R 6 -R 14 are independently H or C(1-6)alkyl;
R 15 is C(1)alkyl optionally substituted with one or more F, or C(3)heteroaryl substituted with one methyl; and
R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, each of which is optionally substituted with one or more F, and
wherein “C(3)heteroaryl” is a monocyclic aromatic group having 3 carbon atoms and 2 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, and which can be attached via a nitrogen atom if feasible, or a carbon atom.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein:
one of A 11 and A 14 is N, and the other of A 11 and A 14 is CR 11 or CR 14 ;
A 12 and A 13 are CR 12 and CR 13 , respectively;
R 1 is C(3-6)cycloalkylC(1-3)alkyl;
R 2 and R 3 are independently H;
R 4 is H;
R 5 is H;
the sulfonyl group containing R 1 is represented by R 8 ;
the remaining R 6 -R 14 are independently H or methyl; and
R 15 and R 16 are independently C(1)alkyl, the carbon atom of which is optionally substituted with one or more F.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide;
(−)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide;
(+)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-hydroxy-1-methyl-ethyl)benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)butyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-2-methyl-1-(trifluoromethyl)propyl]benzamide;
N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxy-ethyl)benzamide;
4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethy

Assignees

• Lead Pharma Holding Bv
• Sanofi Sa

Inventors

• Cals Joseph Maria Gerardus Barbara
• Nabuurs Sander Bernardus

Classifications

• C07C311/46

  Y being a hydrogen or a carbon atom · CPC title

• C07D213/81 Primary

  Amides; Imides · CPC title

• A61K31/10

  Sulfides; Sulfoxides; Sulfones · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title