3-aminocycloalkyl compounds as RORgammaT inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9663522-B2
Application number	US-201314421062-A
Country	US
Kind code	B2
Filing date	Aug 14, 2013
Priority date	Aug 15, 2012
Publication date	May 30, 2017
Grant date	May 30, 2017

Abstract

The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts or solvates thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.

First claim

The invention claimed is:

1. A compound according to Formula I

or a pharmaceutically acceptable salt or solvate thereof, wherein:
a is a bond or no bond;
z is 1, 2 or 3;
X is C(O);
Y is N;
n=0, 1, 2, 3 or 4;
A 4 is CR 4 or N,
A 5 is CR 5 ,
A 6 is CR 6 ,
A 7 is CR 7 ,
R 1 is
(i) (C 3-12 )carbocyclyl; or
(ii) a 4- to 12-membered heterocyclyl,
both (i) and (ii) are substituted with one, two, or three R 8 ;

R 2 is hydroxycarbonyl or hydroxycarbonyl(C 1-10 )alkyl;
R 3 is hydrogen, halogen, cyano, nitro, hydroxy, (C1-3)alkylC(O)O—, phenyl, (C 1-4 )alkyl, oxo, or (C 1-4 )alkoxy, wherein (C 1-4 )alkyl and (C 1-4 )alkoxy are optionally substituted with one or more halogen;
optionally when z is 3, a represents no bond and two R 3 groups are attached to the two carbons flanking the N atom of the piperidinyl ring formed when z is 3, such that the two R 3 groups join to form a 2- or 3-carbon bridge with the piperidinyl ring to form an azabicyclo [3.2.1]octanyl or azabicyclo [3.3.1]nonanyl ring;
R 4 , R 5 , R 6 and R 7 independently are H, halogen, amino, cyano, hydroxy, (C 1-3 )alkoxy, (C 1-4 )alkyl, (C 0-10 )alkyl)aminocarbonyl, (di)(C 1-6 )alkylaminocarbonyl or amino(C 1-4 )alkyl, wherein (C 1-3 )alkoxy, (C 1-4 )alkyl, (C 0 -C 10 )alkyl)aminocarbonyl, (di)(C 1-6 )alkylaminocarbonyl and amino(C 1-4 )alkyl are optionally substituted with one or more halogen, hydroxyl or (C 1-3 )alkoxy; or a group having the formula

 optionally substituted with one or more of the following: (C 1-10 )alkyl, halogen, amino, cyano, hydroxy, (C 1-3 )alkoxy, and wherein m is 1, 2, 3, or 4;
R 8 is halogen, cyano, amino, (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl, (C 3-7 )cycloalkyl, (C 3-5 )heterocycloalkyl, or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one, two or three halogens.

2. The compound of claim 1 having Formula Ia

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 having Formula Ib

or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3 , wherein the compound is a compound of Formula Ib or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3 having Formula Ic

or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 2 having Formula Id

wherein x is 1, 2, 3, 4 or 5,
or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of claim 6 having Formula Ie

or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 7 having Formula If

or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of claim 1 , wherein A 4 is CR 4 .

10. The compound of claim 9 , wherein R 1 is (C 6-14 )aryl, optionally substituted with one, two, or three R 8 .

11. The compound of claim 10 , wherein R 1 is phenyl substituted with one, two or three R 8 .

12. The compound of claim 11 , wherein R 2 is C(O)OH.

13. A compound selected from:
(3R,4R and 3S, 4S)-1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-methylpiperidine-4-carboxylic acid;
8-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)pyrrolidine-3-carboxylic acid;
(3R,4R and 3S,4S)-1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)-3-methylpiperidine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)-4-methylpiperidine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)-4-(trifluoromethyl)piperidin-4-ol;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)-4-phenylpiperidine-4-carboxylic acid;
cis-4-[(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)amino]cyclohexanecarboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)piperidine-4-carboxylic acid;
[1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-4-fluoro-1H-indazol-3-yl)piperidin-4-yl]acetic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-hydroxypiperidine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-4-fluoropiperidine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropiperidine-4-carboxylic acid;
1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)-4-(trifluoromethyl)piperidin-4-ol;
[1-(1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)azetidin-3-yl]acetic acid;
1-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(dimethylcarbamoyl)-1H-indazol-3-yl]piperidine-4-carboxylic acid;
1-[1-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-6-(hydroxymethyl)-1H-indazol-3-yl]piperidine-4-carboxylic acid;
1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)pyrrolidine-3-carboxylic acid;
1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-methyl-1H-indazol-3-yl)piperidine-4-carboxylic acid;
1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)piperidine-4-carboxylic acid;
1-(1-(2-chloro-6-cyclobutylbenzoyl)-4-fluoro-1H-indazol-3-yl)piperidine-4-carboxylic acid;
(3R,4S and 3S,4R)-1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-3-methylpiperidine-4-carboxylic acid;
(3R,4R and 3S,4S)-1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-3-methylpiperidine-4-carboxylic acid;
8-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
1R,5S)-9-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-ethylpiperidine-4-carboxylic acid;
1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-hydroxypiperidine-4-carboxylic acid;
(3S,4R or 3R,4S)-1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3-hydroxypiperidine-4-carboxylic acid;
(3R,4S or 3S,4R)-1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3-hydroxypipe

Assignees

• Merck Sharp & Dohme

Inventors

• Barr Kenneth J
• Maclean John K
• Zhang Hongjun
• Beresis Richard T
• Anthony Neville J
• Daniels Matthew
• Lapointe Blair T
• Sciammetta Nunzio

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title