Substituted indoles as modulators 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 RORy. 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 compound having the Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
A is CH;
Y is CR 10 ;
n is 0, 1, 2, or 3;
p is 0, 1, or 2;
L 2 is CH 2 , CH 2 CH 2 , CH(CH 3 ), O, C(═O), CH(OH), or CH 2 O, where the oxygen atom in CH 2 O can either be attached to Cy 2 or to the carbon atom on the center ring bridging NR 2 and A;
L 1 is absent or is CR 7 R 8 ;
Cy 1 is selected from aryl, heteroaryl, heterocyclyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl are each substituted with 1 to 3 groups independently selected from R 5 ;
Cy 2 is selected from aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, wherein the aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from R 6 ;
R 2 is (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 1 -C 4 )haloalkyl, or monocyclic cycloalkyl;
R 5 and R 6 are each independently selected from halogen, —CN, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —OC(═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c C(═O)OR c , —OC(═O)NR d R e , —NR c (C═S)OR c , —OC(═S)NR d R e , —NR c C(═O)NR d R e , —NR c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , (C 1 -C 6 )alkyl, cycloalkyl, —(CH 2 ) 1-4 -cycloalkyl, heterocyclyl, —(CH 2 ) 1-4 -heterocyclyl, aryl, —NHC(═O)-heterocyclyl, —NHC(═O)-cycloalkyl, —(CH 2 ) 1-4 -aryl, heteroaryl and —(CH 2 ) 1-4 -heteroaryl,
wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl portion present in each of said (C 1 -C 6 )alkyl, cycloalkyl, —(CH 2 ) 1-4 -cycloalkyl, heterocyclyl, —(CH 2 ) 1-4 -heterocyclyl, aryl, —(CH 2 ) 1-4 -aryl, heteroaryl and —(CH 2 ) 14 -heteroaryl substituent for R 6 are further optionally substituted with halogen, OR c , —NO 2 , —CN, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, or halo(C 1 -C 3 )alkoxy;
each R c is independently selected from hydrogen and (C 1 -C 6 )alkyl optionally substituted with 1 to 3 halogen;
each R d and R e is independently selected from hydrogen and (C 1 -C 6 )alkyl;
k is 0, 1 or 2;
any heterocyclyl or heteroaryl portion of Cy 1 or Cy 2 is further optionally substituted with ═O;
R 7 and R 8 are each independently hydrogen, OH, (C 1 -C 2 )alkyl, hydroxy(C 1 -C 3 )alkyl, —O(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkyl-O—(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkyl-NH 2 , —(C 1 -C 3 )alkyl-N-di(C 1 -C 3 )alkyl, (CH 2 ) 1-3 COOH, monocyclic heterocyclyl, —CO—(C 1 -C 3 )alkoxy, —(C 1 -C 3 )alkoxy-C(O)—NH 2 , —(C 1 -C 3 )alkoxy-O—(C 1 -C 3 )alkyl-C(O)—NH 2 , —(C 1 -C 3 )alkyl-C(O)—(C 1 -C 3 )alkoxy, —(C 1 -C 3 )alkyl-C(O)—NH 2 , halophenyl, —(C 1 -C 3 )alkyl-halophenyl, or quinolin-2(1H)-on-4-ylmethyl;
R 9 is independently (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, or halogen; and
R 10 is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, or halogen.
2. The compound of claim 1 , wherein the compound is of the Formula (III):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein L 2 is CH 2 , CH(CH 3 ), O, or C(═O).
4. The compound of claim 3 , wherein the compound is of the Formula (IV) or Formula (V):
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , wherein R 7 is hydrogen, (C 1 -C 2 )alkyl, hydroxy(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkylNH 2 , —(C 1 -C 3 )alkyl-N-di(C 1 -C 3 )alkyl, or —(C 1 -C 3 )alkoxy-C(O)—NH 2 ; and R 8 is hydrogen.
6. The compound of claim 5 , wherein R 7 is hydroxy(C 1 -C 3 )alkyl.
7. The compound of claim 5 , wherein R 2 is (C 1 -C 4 )alkyl or cyclopropyl.
8. The compound of claim 7 , wherein Cy 1 is aryl or heteroaryl, each substituted with 1 to 3 groups independently selected from R 5 .
9. The compound of claim 8 , wherein Cy 1 is phenyl or pyridyl, each substituted with 1 to 3 groups independently selected from R 5 .
10. The compound claim 9 , wherein at least 1 R 5 is S(O) 2 (C 1 -C 3 )alkyl.
11. The compound of claim 10 , wherein Cy 1 is pyridyl substituted with 1 to 3 groups independently selected from R 5 , wherein at least 1 R 5 is S(O) 2 (C 1 -C 3 )alkyl.
12. The compound of claim 10 , wherein Cy 2 is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl, cyclopropyl, or cyclobutyl, each optionally substituted with 1 to 3 groups independently selected from R 6 .
13. The compound of claim 12 , wherein Cy 2 is phenyl, pyridyl, cyclohexyl, or tetrahydropyranyl, each optionally substituted with 1 to 3 groups independently selected from R 6 .
14. The compound of claim 13 , wherein Cy 2 is phenyl or cyclohexyl, each optionally substituted with 1 to 3 groups independently selected from R 6 .
15. The compound of claim 14 , wherein Cy 1 is phenyl substituted with 1 to 3 groups independently selected from R 5 , wherein at least 1 R 5 is S(O) 2 (C 1 -C 3 )alkyl; and Cy 2 is cyclohexyl substituted with 1 to 3 groups independently selected from R 6 .
16. The compound of claim 14 , wherein:
R 5 is selected from halogen, —CN, —OR c , —NR d R e , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —C(═O)NR d R e , —NR c C(═O)R c , —NR c C(═O)OR c , —OC(═S)NR d R e , —C(═O)R c , —S(O) 2 (C 1 -C 3 )alkyl, and (C 1 -C 4 )alkyl optionally substituted with halogen; and
R 6 is selected from halogen, —CN, —OR c , —NR d R e , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c C(═O)OR c , —OC(═O)NR d R e , —NR c (C═S)OR c , —OC(═S)NR d R e , —NR c C(═O)NR d R e , —NR c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , S(O) 2 (C 1 -C 3 )alkyl, and (C 1 -C 4 )alkyl optionally substituted with halogen.
17. The compound of claim 16 , wherein:
R 5 is S(O) 2 (C 1 -C 3 )alkyl;
R 6 is halogen, —OR′, or (C 1 -C 4 )alkyl optionally substituted with halogen; and R c is (C 1 -C 4 )alkyl optionally substituted with halogen.
18. The compound of claim 17 , wherein R 6 is CF 3 .
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method for modulating retinoic acid receptor-related orphan receptor gamma activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein the subject has a disease or disorder selected from the group consisting of asthma, chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease, inflammatory bowel syndrome, Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis, adipose tissue-associated inflammation, insulin resistance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related macular degeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis, psoriatic arthritis, steroid resistant asthma, Graves' disease, scleritis, major depression, seasonal affective disorder, post-traumatic stress disorder, bipolar disorder, autism, epilepsy, Alzheimer's, central nervous system disorders associated with altered sleep and/or circadian rhythms, endometriosis, obstructive sleep apnea syndrome, Behçet's disease, dermatomyositis, polymyocitis, graft versus host disease, primary biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease, sarcoidosis, primary sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, celiac disease, neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis, myocardial infarction, pulmonary hypertension, osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, and cancer.
22. The method of claim 21 , wherein the subject has a disease or disorder selected from the group consisting of asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, psoriasis, psoriatic arthritis, steroid resistant asthma, and rheumatoid arthritis.