Dihydropyrrolopyridine inhibitors of ROR-gamma
Provided are novel compounds of Formula (I): pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by ROR . Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I) and methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders.
1. A method of treating dry eye comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the Formula (III):
or a pharmaceutically acceptable salt thereof, wherein
R 2 and R 3 are each independently hydrogen, hydroxy, monocyclic cycloalkyl, monocyclic heterocyclyl, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with 1 to 2 groups independently selected from hydroxy, halo, and cyano;
R 4 is hydrogen, (C 1 -C 3 )alkyl, or ═O;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
Cy 1 is absent or is selected from (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl are each optionally substituted with 1 to 3 groups independently selected from R 5 ;
Cy 2 is absent or is selected from (C 1 -C 6 )alkoxycarbonyl, phenyl(C 1 -C 3 )alkoxycarbonyl, halophenyl(C 1 -C 3 )alkoxycarbonyl, aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, wherein the aryl, heteroaryl, monocyclic cycloalkyl, and moncyclic heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from R 6 ; and
R 5 and R 6 are each independently selected from halo, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, heterocyclyl, hydroxy(C 1 -C 6 )alkyl, CO 2 H, (CH 2 ) 1-3 COOH, (C 1 -C 3 )alkylcarbonyloxy, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkylsulfinyl, (C 3 -C 6 )cycloalkylsulfinyl, (C 4 -C 7 )cycloalkylalkylsulfinyl, halo(C 1 -C 6 )alkylsulfonyl, halo(C 3 -C 6 )cycloalkylsulfinyl, halo(C 4 -C 7 )cycloalkylalkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl, (C 4 -C 7 )cycloalkylalkylsulfonyl, halo(C 1 -C 6 )alkylsulfonyl, halo(C 3 -C 6 )cycloalkylsulfonyl, halo(C 4 -C 7 )cycloalkylalkylsulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclylsulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkyl-carbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, aryl, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, hydroxy(C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylhydroxycarbonyl, (C 1 -C 6 )alkylhydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl(C 4 -C 6 )heterocyclyl](C 1 -C 6 )alkyl, and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl.
2. The method of claim 1 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein the compound is of Formula (V) or (VI):
or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 , wherein the compound is of Formula (VII):
or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 , wherein R 2 and R 3 are each independently hydrogen, hydroxy, or (C 1 -C 3 )alkyl.
6. The method of claim 5 , wherein Cy 2 is present and is selected from aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, each of which is optionally substituted with 1 to 2 groups independently selected from R 6 .
7. The method of claim 6 , wherein Cy 2 is phenyl, pyrimidinyl, cyclohexyl, or pyridinyl, each of which are optionally substituted with 1 to 2 groups independently selected from R 6 .
8. The method of claim 7 , wherein Cy 1 is phenyl, piperidinyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, pyridinyl, piperazinyl, azetidinyl, imidazolyl, tetrahydropyranyl, 1,4-dioxanyl, pyridazinyl, pyrazolyl, pyrrolidinyl, cyclohexyl, morpholinyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 2,3-dihydro-1H-indenyl, or imidazo[1,2-a]pyrimidinyl, each of which is optionally substituted with 1 to 2 groups independently selected from R 5 .
9. The method of claim 8 , wherein Cy 1 is phenyl, piperidinyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, pyridinyl, piperazinyl, azetidinyl, imidazolyl, tetrahydropyranyl, 1,4-dioxanyl, pyridazinyl, pyrazolyl, pyrrolidinyl, cyclohexyl, morpholinyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 2,3-dihydro-1H-indenyl, or imidazo[1,2-a]pyrimidinyl, each of which is optionally substituted with 1 to 2 groups independently selected from R 5 , wherein at least one R 5 is (C 1 -C 3 )alkylsulfonyl or (C 1 -C 3 )alkylaminosulfonyl.
10. The method of claim 9 , wherein
R 2 is (C 1 -C 3 )alkyl;
n is 1 or 2; and
Cy 1 is phenyl, pyridinyl, or piperidinyl, each of which is optionally substituted with 1 to 2 groups independently selected from R 5 , wherein at least one R 5 is (C 1 -C 3 )alkylsulfonyl or (C 1 -C 3 )alkylaminosulfonyl.
11. The method of claim 10 , wherein Cy 2 is cyclohexyl optionally substituted with 1 to 2 groups independently selected from R 6 .
12. The method of claim 11 , wherein
R 5 is selected from halo, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, cyano, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, oxo, hydroxy, (C 1 -C 3 )alkylcarbonyl, hydroxy(C 1 -C 3 )alkylcarbonyl, (C 1 -C 3 )alkylhydroxycarbonyl, (C 1 -C 3 )alkylaminosulfonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, [(C 1 -C 3 )alkyl(C 4 -C 6 )heterocyclyl](C 1 -C 3 )alkyl, and (C 1 -C 3 )alkylhydroxy(C 1 -C 3 )alkyl; and
R 6 is selected from halo, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, cyano, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, oxo, hydroxy, aryl(C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylhydroxy(C 1 -C 3 )alkyl, heteroaryl, and (C 1 -C 3 )alkoxycarbonyl.
13. The method of claim 12 , wherein
R 5 is selected from halo, (C 1 -C 3 )alkoxy, hydroxy, (C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 6 )alkoxycarbonyl, di(C 1 -C 3 )alkylamino(C 2 -C 6 )alkoxy, [(C 1 -C 3 )alkyl(C 4 -C 6 )heterocyclyl](C 1 -C 3 )alkyl, oxo, (C 1 -C 3 )alkylcarbonyl, (C 1 -C 3 )alkylaminosulfonyl, (C 1 -C 3 )alkylsulfonyl, and cyano; and
R 6 is selected from halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, cyano, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylhydroxy(C 1 -C 3 )alkyl, 2-methyl-2H-tetrazolyl, hydroxy(C 1 -C 3 )alkyl, and halo(C 1 -C 3 )alkoxy.
14. The method of claim 13 , wherein R 5 is selected from halo, cyano, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkylaminosulfonyl, and (C 1 -C 3 )alkylsulfonyl; and R 6 is selected from halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, cyano, (C 1 -C 3 )alkoxycarbonyl, 2-methyl-2H-tetrazolyl, and halo(C 1 -C 3 )alkoxy.
15. The method of claim 14 , wherein
Cy 1 is
R 10 is (C 1 -C 3 )alkyl or (C 1 -C 3 )alkylamino; and
Z is CH or N.
16. The method of claim 15 , wherein
R 12 is (C 1 -C 3 )alkoxycarbonyl, halo, dihalo, (C 1 -C 3 )alkoxy, or halo(C 1 -C 3 )alkyl;
R 13 is halo or halo(C 1 -C 3 )alkyl; and
R 14 is halo, cyano, halo(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkoxy, or 2-methyl-2H-tetrazolyl.
17. The method of claim 16 , wherein R 12 to R 14 are each CF 3 .
18. The method of claim 17 , wherein R 2 is isopropyl.
19. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
20. A method of treating dry eye comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:
or a pharmaceutically acceptable salt thereof.