ROR gamma (RORγ) modulators

Patent metadata

Field	Value
Publication number	US-10118895-B2
Application number	US-201615578997-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Jun 5, 2015
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

Novel compounds according to Formula I

Meta or para 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 in A 11 -A 14 can be simultaneously N; A 6 , A 7 , A 8 , A 9 , A 10 are N or CR 6 , CR 7 , CR 8 , CR 9 , CR 10 , respectively, with the proviso that at least one but no more than two of the five positions A in A 6 , A 7 , A 8 , A 9 , A 10 is 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, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(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)heterocycloalkyl-C(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)heterocycloalkyl-C(1-3)alkyl.

First claim

The invention claimed is:

1. A compound according to Formula I

Meta or para 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 in A 11 -A 14 can be simultaneously N;
A 6 , A 7 , A 8 , A 9 , A 10 are N or CR 6 , CR 7 , CR 8 , CR 9 , CR 10 , respectively, with the proviso that at least one but no more than two of the five positions A in A 6 , A 7 , A 8 , A 9 , A 10 is 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, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
R 2 and R 3 are independently H, F, methyl, ethyl, hydroxy, methoxy or R 2 and R 3 together is carbonyl, all alkyl groups, if present, optionally being 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)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano;
the sulfonyl group with R 1 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, all of the alkyl groups optionally being substituted with one or more F; and
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)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, 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)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano.

2. The compound according to claim 1 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 in A 11 -A 14 can be simultaneously N;
A 6 , A 7 , A 9 , A 10 are N or CR 6 , CR 7 , CR 9 , CR 10 , respectively, with the proviso that at least one but no more than two of the four positions A in A 6 , A 7 , A 9 , A 10 is N;
A 8 is CR 8 ;
R 1 is C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
R 2 and R 3 are independently H;
R 4 is H;
R 5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano;
the sulfonyl group with 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, all of the alkyl groups optionally being substituted with one or more F or hydroxy; and
R 15 is C(1-6)alkyl or C(3-6)cycloalkyl, all groups optionally substituted with one or more F, 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(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano.

3. The compound according to claim 1 wherein:
A 11 -A 14 are respectively CR 11 , CR 12 , CR 13 , CR 14 ;
A 6 , A 7 , A 9 , A 10 are N or CR 6 , CR 7 , CR 9 , CR 10 , respectively, with the proviso that at least one but no more than two of the four positions A in A 6 , A 7 , A 9 , A 10 is N;
A 8 is CR 8 ;
R 1 is C(3-6)cycloalkylC(1-3)alkyl, all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
R 2 and R 3 are independently H;
R 4 is H;
R 5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl or C(2-5)heterocycloalkylC(1-3)alkyl;
the sulfonyl group with 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, all carbon atoms of alkyl groups optionally substituted with one hydroxy;
R 15 is C(1-6)alkyl or C(3-6)cycloalkyl, all carbon atoms of the alkyl groups optionally substituted with one or more F;
and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl or C(6-10)aryl, all carbon atoms of the alkyl groups optionally substituted with one or more F.

4. The compound according to claim 1 wherein:
A 11 or A 14 is N, the remaining position A being CR 11 or CR 14 ;
A 12 and A 13 are respectively CR 12 and CR 13 ;
A 6 , A 7 , A 9 , A 10 are N or CR 6 , CR 7 , CR 9 , CR 10 , respectively, with the proviso that at least one but no more than two of the four positions A in A 6 , A 7 , A 9 , A 10 is N;
A 8 is CR 8 ;
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 with R 1 is represented by R 8 ;
the remaining R 6 -R 14 are independently H;
R 15 is C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one or more F;
and R 16 is C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one or more F.

5. The compound as defined in claim 1 which is selected from the group of:
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
N-[3-chloro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2-pyridyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)butyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-4-methyl-1-(trifluoromethyl)pentyl]phenyl]acetamide;
N-[4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
N-[4-[1-(cyclopentylmethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
N-[4-[1-(cyclohexylmethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
2-[6-(cyclopropylmeth

Assignees

• Lead Pharma Holding Bv
• Sanofi Sa

Inventors

• Cals Joseph Maria Gerardus Barbara
• Machnik David
• Nabuurs Sander Bernardus
• Sabuco Jean-Francois
• Schio Laurent

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P5/14

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

• A61P35/00

  Antineoplastic agents · CPC title