3-cyclohexenyl and cyclohexyl substituted indole and indazole compounds as RORgammaT inhibitors and uses thereof
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.
1. A compound according to Formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a is a bond or no bond;
X is C(O);
Y is N a ;
n=0, 1, 2, 3 or 4;
A 4 is CR 4 or N,
A 5 is CR 5 or N,
A 6 is CR 6 or N,
A 7 is CR 7 or N,
with the proviso that no more than two of A 4 -A 7 can be N;
R 1 is
(i) (C 3-12 )carbocyclyl; or
(ii) a 4- to 12-membered heterocyclyl,
both (i) and (ii) optionally substituted with one, two, three, four or five R 8 ;
R 2 is hydroxycarbonyl, or carbamoyl;
R 3 is hydrogen, halogen, cyano, nitro, hydroxy, (C 1-3 )alkylC(O)O—, (C 1-4 alkyl, or (C 1-4 )alkoxy, wherein (C 1-4 )alkyl and (C 1-4 )alkoxy are optionally substituted with one or more halogen;
R 4 -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 0-10 )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, nitro, hydroxy, H 2 NC(O)—, (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl, (C 3-7 )cycloalkyl, (C 3-5 )heterocycloalkyl, (C1-3)alkoxyaminocarbonyl, 4- to 8-membered heterocyclylcarbonyl, (C3-6)cycloalkylaminocarbonyl, amino(C1-4)alkyloxycarbonyl or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl, (C1-3)alkoxyaminocarbonyl, 4- to 8-membered heterocyclylcarbonyl, (C3-6)cycloalkylaminocarbonyl, amino(C 1-4 )alkyloxycarbonyl and (C 1-3 )alkoxy are optionally substituted with oxo, (C 1-4 )alkyl, hydroxy(C 1-3 )alkyl, or one, two or three halogens.
2. A compound having Formula Ix
or a pharmaceutically acceptable salt or solvate thereof wherein,
X is CH 2 or C(O);
Y is CH, N, or CR a ;
n=0, 1, 2, 3 or 4;
A 4 is CR 4 or N,
A 5 is CR 5 or N,
A 6 is CR 6 or N,
A 7 is CR 7 or N,
with the proviso that no more than two of A 4 -A 7 can be N;
R a is (C 1-4 )alkyl;
R 1 is
(i) (C 3-12 )carbocyclyl; or
(ii) a 4- to 12-membered heterocyclyl,
both (i) and (ii) optionally substituted with one, two, three, four or five R 8 ;
R 2 is hydroxycarbonyl, hydroxycarbonyl(C 1-10 )alkyl, or carbamoyl;
R 3 is hydrogen, halogen, cyano, nitro, hydroxy, (C 1-3 )alkylC(O)O—, (C 1-4 )alkyl, or (C 1-4 )alkoxy, wherein (C 1-4 )alkyl and (C 1-4 )alkoxy are optionally substituted with one or more halogen;
R 4 -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 0-10 )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, nitro, hydroxy, H 2 NC(O)—, (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl, (C 3-7 )cycloalkyl, (C 3-5 )heterocycloalkyl, (C 1-3 )alkoxyaminocarbonyl, 4- to 8-membered heterocyclylcarbonyl, (C 3-6 )cycloalkylaminocarbonyl, amino(C 1-4 )alkyloxycarbonyl or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl, (C 1-3 )alkoxyaminocarbonyl, 4- to 8-membered heterocyclylcarbonyl, (C 3-6 )cycloalkylaminocarbonyl, amino(C 1-4 )alkyloxycarbonyl and (C 1-3 )alkoxy are optionally substituted with oxo, (C 1-4 )alkyl, hydroxy(C 1-3 )alkyl, or one, two or three halogens.
3. The compound of claim 2 having Formula Ia
or a pharmaceutically acceptable salt or solvate thereof.
4. The compound of claim 2 having Formula Ib
or a pharmaceutically acceptable salt or solvate thereof.
5. The compound of claim 4 , wherein Y is N.
6. The compound of claim 4 having Formula Ic
or a pharmaceutically acceptable salt or solvate thereof.
7. The compound of claim 3 having Formula Id
wherein x is 1, 2, 3, 4 or 5,
or a pharmaceutically acceptable salt or solvate thereof.
8. The compound of claim 7 having Formula Ie
or a pharmaceutically acceptable salt or solvate thereof.
9. The compound of claim 8 having Formula If
or a pharmaceutically acceptable salt or solvate thereof.
10. The compound of claim 2 having Formula Ig
or a pharmaceutically acceptable salt or solvate thereof.
11. The compound of claim 1 , wherein A 4 , A 5 , A 6 , A 7 is (i) CR 4 , CR 5 , CR 6 , CR 7 ; or (ii) N, CR 5 , CR 6 , CR 7 .
12. The compound of claim 11 , wherein R 1 is (C 6-14 )aryl, optionally substituted with one, two, three, four or five R 8 .
13. The compound of claim 12 , wherein R 1 is phenyl, optionally substituted with one, two or three R 8 .
14. The compound of claim 13 , wherein R 2 is C(O)OH.
15. A compound selected from:
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(dimethylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(2-hydroxyethylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1-methylcyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-2-methylcyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(4-chloro-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-1-methylcyclohex -3-enecarboxylic acid;
4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-methylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclo-hex-3-enecarboxylic acid;
4-(1-(2-chloro-6-methylbenzoyl)-1H-pyrazolo[4,3-b]pyridine-3-yl)cyclohex-3-enecarboxylic acid;
(R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
(S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
(R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-1H-indazol-3-yl)-1-methylcyclohex-3-enecarboxylic acid;
(S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-1H-indazol-3-yl)-1-methylcyclohex-3-enecarboxylic acid;
(R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
(S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3,3-difluoroazetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(cyclopropylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(cyclopropyl(methyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(6-(azetidine-1-carbonyl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-methoxyazetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(pyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((S)-2-methylpyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((R)-2-methylpyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-methoxypyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(2-methylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(cyclohexyl(methyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(morpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(4-methyl-3-oxopiperazine-1-carbonyl)-1H -indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((S)-3-methylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(methyl(tetrahydro-2H-pyran-4-yl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((R)-3-methylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((S)-2-methylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((2-hydroxyethyl)(methyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(isopropylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(isopropyl(methyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((2-methoxyethyl)(methyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-hydroxyazetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3-fluoroazetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(piperidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(((1-hydroxy-3-(methylamino)propan-2-yl)oxy)carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((S)-3-methoxypyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-((R)-3-methoxypyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indol-3-yl)cyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxycyclohex -3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6-hydroxycyclohex -3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxy-6-methylcyclohex-3-enecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-methylcyclohexanecarboxylic acid;
(trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-methyl cyclohexanecarboxylic acid;
(cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-methylcyclohexanecarboxylic acid;
(trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohexanecarboxylic acid;
(cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohexanecarboxylic acid;
(trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohexanecarboxylic acid;
(cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohexanecarboxylic acid;
(R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylic acid;
(R and S) 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylic acid;
(trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohexanecarboxylic acid;
(cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohexanecarboxylic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-5-methylcyclohex-3-enecarboxylic acid; and
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-hydroxycyclohexanecarboxylic acid.
16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
17. The pharmaceutical composition of claim 16 , further comprising at least one additional therapeutically active agent.
18. A method for treating a disease or condition mediated by RORgammaT in a subject comprising administering to the subject an amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, that is effective for treating the disease or condition mediated by RORgammaT in the subject, wherein the disease or condition is multiple sclerosis, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis or mucosal leishmaniasis.
19. The method of claim 18 , wherein the disease or condition is multiple sclerosis, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis or psoriasis.
20. The compound of claim 2 , wherein the compound is a compound of Formula Ix or a pharmaceutically acceptable salt thereof; wherein A 5 is CR 5 , A 6 is CR 6 , and A 7 is CR 7 .
21. The compound of claim 7 , wherein the compound is a compound of Formula Id or a pharmaceutically acceptable salt thereof; wherein A 5 is CR 5 , A 6 is CR 6 , and A 7 is CR 7 .
22. The compound of claim 9 , wherein the compound is a compound of Formula If or a pharmaceutically acceptable salt thereof; wherein A 5 is CR 5 , A 6 is CR 6 , and A 7 is CR 7 .
23. A pharmaceutical composition comprising a compound of claim 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
24. A pharmaceutical composition comprising a compound of claim 21 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.