ROR gamma (RORγ) modulators

Patent metadata

Field	Value
Publication number	US-10259782-B2
Application number	US-201615579143-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Jun 5, 2015
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

Abstract

Compounds according to Formula I:

or a pharmaceutically acceptable salt thereof wherein: A 1 is NR 1 or CR 1 , with R 1 being H or methyl, with methyl, if present, optionally being substituted with one or more F; the cyclopropyl moiety can be optionally substituted with one or more methyl and one or more F; A 2 -A 5 are N or CR 2 -CR 5 , respectively, with the proviso that no more than two of the four positions A in A 2 -A 5 can be simultaneously N; R 2 -R 5 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl; R 6 and R 7 are independently H, F, methyl, ethyl, hydroxyl or methoxy or R 2 and R 3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F; R 8 is H or C(1-6)alkyl; R 9 is selected from the group consisting of Formula II, III, IV and V

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 according to Formula I

or a pharmaceutically acceptable salt thereof wherein
A 1 is NR 1 or CR 1 , with R 1 being H or methyl, with methyl, if present, optionally being substituted with one or more F;
the cyclopropyl moiety can be optionally substituted with one or more methyl and one or more F;
A 2 , A 3 , A 4 and A 5 are independently N or CR 2 , CR 3 , CR 4 and CR 5 , respectively, with the proviso that no more than two of the four positions A in A 2 , A 3 , A 4 and A 5 can be simultaneously N;
R 2 , R 3 , R 4 , and R 5 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
R 6 and R 7 are independently H, F, methyl, ethyl, hydroxyl or methoxy or R 6 and R 7 together is carbonyl, wherein methyl or ethyl groups, if present, may be optionally substituted with one or more F;
R 8 is H or C(1-6)alkyl;
R9 is selected from the group consisting of Formula II, III, IV and V

wherein:
A 10 , A 11 , A 12 , and A 13 are independently N or CR 10 , CR 11 , CR 12 , and CR 13 , respectively, with the proviso that no more than two of the four positions A in A 10 , A 11 , A 12 , and A 13 can be simultaneously N;
R 10 , R 11 , R 12 , and R 13 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
X 14 is either C(6-10)aryl or C(1-9)heteroaryl, with all carbon atoms optionally substituted with halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl;

wherein:
A 20 , A 21 , A 22 , A 23 , A 24 , A 25 , A 26 and A 27 are N or CR 20 , CR 21 , CR 22 , CR 23 , CR 24 , CR 25 , CR 26 and CR 27 , respectively, with the proviso that no more than two of the three positions A in A 20 , A 21 and A 22 can be simultaneously N and that no more than three of the five positions A in A 23 , A 24 , A 25 , A 26 and A 27 can be simultaneously N;
R 20 , R 21 and R 22 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
R 23 , R 24 , R 25 , R 26 and R 27 are independently H, halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl;
X 28 is either C(6-10)aryl or C(1-9)heteroaryl, with all carbon atoms optionally substituted with halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl;

wherein:
A 30 is N or C;
A 31 is O, carbonyl, NR 31 or CR 32 ;
R 31 is H or C(1-6)alkyl;
R 32 is H, OH, or C(1-3)alkyl, with all alkyl groups optionally substituted with one or more F or OH;
A 33 , A 34 , A 35 , A 36 , A 37 , A 38 , A 39 , A 40 , A 41 and A 42 are N or CR 33 , CR 34 , CR 35 , CR 36 , CR 37 , CR 38 , CR 39 , CR 40 , CR 41 and CR 42 respectively, with the proviso that no more than three of the five positions A in A 33 , A 34 , A 35 , A 36 and A 37 can be simultaneously N and that no more than three of the five positions A in A 38 , A 39 , A 40 , A 41 and A 42 can be simultaneously N;
R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 and R 42 are independently H, halogen, amino, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

2. The compound according to claim 1 where A 1 is CR 1 .

3. The compound according to claim 1 where A 1 is NR 1 .

4. The compound according to claim 1 where R 1 is hydrogen.

5. The compound according to claim 1 wherein R 6 , and R 7 are both H.

6. The compound according to claim 1 where R 8 is H.

7. The compound according to claim 1 wherein all positions A in A 2 , A 3 , A 4 and A 5 are CR 2 , CR 3 , CR 4 and CR 5 , and all positions R in R 2 , R 3 , R 4 and R 5 are H.

8. The compound according to claim 1 where R9 is according to Formula II wherein:
A 10 , A 11 , A 12 and A 13 are N or CR 10 , CR 11 , CR 12 and CR 13 respectively, with the proviso that no more than two of the four positions A in A 10 , A 11 , A 12 and A 13 can be simultaneously N;
R 10 , R 11 , R 12 and R 13 are independently H, amino, halogen, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
X 14 is either C(6)aryl or C(1-5)heteroaryl, with all carbon atoms optionally substituted with halogen, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

9. The compound according to claim 1 where R9 is according to Formula III wherein:
A 20 , A 21 , A 22 , A 23 , A 24 , A 25 , A 26 and A 27 are N or CR 20 , CR 21 , CR 22 , CR 23 , CR 24 , CR 25 , CR 26 and CR 27 respectively, with the proviso that no more than two of the three positions A in A 20 , A 21 and A 22 can be simultaneously N and that no more than three of the five positions A in A 23 , A 24 , A 25 , A 26 and A 27 can be simultaneously N;
R 20 , R 21 and R 22 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
R 23 , R 24 , R 25 , R 26 and R 27 are independently H, halogen, cyano, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl;
X 28 is either C(6)aryl or C(1-5)heteroaryl, with all carbon atoms optionally substituted with halogen, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

10. The compound according to claim 1 where R9 is according to Formula IV or V wherein:
A 30 is N or C;
A 31 is O, carbonyl, NR 31 or CR 32 ;
R 31 is H or C(1-6)alkyl;
R 32 is H, OH or C(1-6)alkyl, with all alkyl groups optionally substituted with one or more F or OH;
A 33 , A 34 , A 35 , A 36 , A 37 , A 38 , A 39 , A 40 , A 41 and A 42 are N or CR 33 , CR 34 , CR 35 , CR 36 , CR 37 , CR 38 , CR 39 , CR 40 , CR 41 and CR 42 respectively, with the proviso that no more than three of the five positions A 33 , A 34 , A 35 , A 36 and A 37 can be simultaneously N and that no more than three of the five positions A 38 , A 39 , A 40 , A 41 and A 42 can be simultaneously N;
R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 and R 42 are independently H, halogen, cyano, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-3)alkyl.

11. The compound as defined in claim 1 which is selected from the group of:
2-(4-cyclopropylmethanesulfonylphenyl)-N-(3-phenoxy-4-phenylphenyl)acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-fluorophenyl)-3-(3-methoxyphenoxy)phenyl]acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-methoxyphenoxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl]acetamide;
N-[3-(3-chlorophenoxy)-4-(3-fluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide;
N-[3-(3-chlorophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide;
N-[3-(3-cyanophenoxy)-4-(3,4-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[3-(3-methoxyphenoxy)-4-(5-methyl-1H-pyrazol-1-yl)phenyl]acetamide;
N-[3-(3-chlorophenoxy)-4-(3,5-difluorophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide;
N-[4-(4-cyanophenyl)-3-(3-fluorophenoxy)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide;
N-[3-(3-chlorophenoxy)-4-(3-cyanophenyl)phenyl]-2-(4-cyclopropylmethanesulfonylphenyl)acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(3-fluorophenyl)-3]3-(trifluoromethyl)phenoxy]phenyl]acetamide;
2-(4-cyclopropylmethanesulf

Assignees

• Lead Pharma Holding Bv
• Sanofi Sa

Inventors

• Cals Joseph Maria Gerardus Barbara
• De Kimpe Vera
• Nabuurs Sander Bernardus
• Cadicamo Cosimo Damiano
• Lemmers Jaap Gerardus Henricus

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title