ROR gamma (RORγ) modulators

Patent metadata

Field	Value
Publication number	US-10315996-B2
Application number	US-201615579111-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Jun 5, 2015
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

Abstract

Compounds according to Formula I:

or a pharmaceutically acceptable salt wherein: A 1 is NR 1 or CR 1 , with R 1 herein; the cyclopropyl moiety with one or more methyl and one or more F; A 2 -A 5 are N or CR 2 -CR 5 , with no more than two of the four positions A in A 2 -A 5 can be simultaneously N; R 2 -R 5 are described; R 6 and R 7 are independently H, F, methyl, ethyl, hydroxyl or methoxy or R 6 and R 7 together is carbonyl, all alkyl groups, if substituted with one or more F; R 8 is H or C(1-6)alkyl; A 9 -A 12 are N or CR 9 -CR 12 , with no more than two of the four positions A in A 9 -A 12 can be simultaneously N; R 9 -R 12 herein; R 13 and R 14 herein; or R 13 and R 14 fused forming a ring having 5 to 7 atoms by joining R 13 being C(1-6)alkyl or C(2-6)alkenyl. The RORγ compounds can treat 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 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 6 and R 7 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;
A 9 -A 12 are N or CR 9 -CR 12 , respectively, with the proviso that no more than two of the four positions A in A 9 -A 12 can be simultaneously N;
R 9 -R 12 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl;
R 13 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6-10)aryl, C(6-10)arylC(1-4)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-4)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxyl, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl; and
R 14 is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6-10)aryl, C(6-10)arylC(1-4)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-4)alkyl, all groups optionally substituted with one or more halogen, amino, hydroxyl, 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.

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

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

4. The compound according to claim 1 wherein all of the positions A in A 2 -A 5 are carbon and all of the position R in R 2 -R 5 are H.

5. The compound according to claim 1 where R 6 and R 7 are independently H, methyl or hydroxyl.

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

7. The compound according to claim 1 wherein all positions A of A 9 -A 12 are carbon or wherein position A in either A 9 or A 10 is nitrogen and the remaining positions A in A 9 -A 12 are carbon.

8. The compound according to claim 1 wherein R 9 -R 12 are independently H, halogen, methyl or methoxy.

9. The compound according to claim 1 wherein R 13 and R 14 are independently H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6-10)aryl, C(6-10)arylC(1-4)alkyl, C(1-9)heteroaryl or C(1-9)heteroarylC(1-4)alkyl, all groups optionally substituted with one or more halogen, hydroxyl, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl or C(1-3)alkyl.

10. The compound according to claim 1 wherein R 13 and R 14 are fused and form a ring consisting of 5 to 7 atoms by joining C(1-6)alkyl or C(2-6)alkenyl at R 13 with a substituent at R 14 selected from C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-4)alkyl, C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-4)alkyl, C(6)aryl, C(6)arylC(1-4)alkyl, C(1-5)heteroaryl or C(1-5)heteroarylC(1-4)alkyl, with all groups optionally substituted with one or more halogen, hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, or C(1-3)alkyl.

11. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-phenylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-dimethylbenzamide;
N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-phenylpropan-2-yl)benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-propylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-methylpropyl)benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(cyclopropylmethyl)-N-propylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(2-phenylethyl)benzamide;
N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide;
N,N-dibenzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide;
N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(1-phenylethyl)benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N,N-bis(2-methylpropyl)benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-phenylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-(pyridin-2-yl)benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methyl-N-[(1S)-1-phenylethyl]benzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-phenyl-N-propylbenzamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propyl-N-(pyridin-3-yl)benzamide;
N-benzyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-propylbenzamide;
4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-phenyl-N-propylbenzamide;
N-benzyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}-N-propylbenzamide;
N,N-dibenzyl-4-{2-[4-(cyclopropylsulfamoyl)phenyl]acetamido}benzamide;
ethyl 1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}piperidine-3-carboxylate;
N-tert-butyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide;
N,N-dicyclobutyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-methylpiperidine-1-carbonyl)phenyl]acetamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(4-methylphenyl)benzamide;
methyl 3-{N-ethyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzamido}benzoate;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-ethyl-N-(3-methylphenyl)benzamide;
ethyl 2-(N-benzyl-1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]phenyl}formamido)acetate;
ethyl 6-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-2-carboxylate;
N-cyclohexyl-4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-methylbenzamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(piperidine-1-carbonyl)phenyl]acetamide;
4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]-N-(2-methylpropyl)-N-phenylbenzamide;
ethyl 2-(1-{4-[2-(4-cyclopropylmethanesulfonylphenyl)acetamido]benzoyl}pyrrolidin-2-yl)-1,3-thiazole-4-carboxylate;
2-(4-cyclopropylmethanesulfonylphenyl)-N-{4-[2-(morpholin-4-ylmethyl)piperidine-1-carbonyl]phenyl}acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide;
2-(4-cyclopropylmethanesulfonylphenyl)-N-[4-(2,3-dihydro-1H-indole-1-ca

Assignees

• Lead Pharma Holding Bv
• Sanofi Sa

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P43/00

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

• A61P37/06

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

• A61P5/14

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