Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof

1. A compound according to Formula I:

wherein:

Ring A is selected from:

each optionally substituted with one or two substituents independently selected from OH, halogen, (C 1-4 )alkyl and (C═O)O(C 1-4 )alkyl, wherein a carbon in the (C 1-4 )alkyl chain may bond to a carbon on Ring A and form a spirocyclic moiety, wherein (C 1-4 )alkyl is optionally substituted with OH, methylpyrrolidinyl, NH 2 or oxo;

X is N or C, wherein when X is N then the dashed line is absent and when X is C the dashed line represents a double bond;

Y is N or CH;

R 1a is H or (C 1-4 )alkyl;

R 1b is H, OH or (C 1-4 )alkyl;

R 2a is Cl or (C 1-4 )alkyl;

R 2b is cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, each optionally substituted with (C 1-4 )alkyl, F, CF 3 , CHF 2 or CN;

R 2c , is H or F; and

R 2d is H or (C 1-4 )alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein X is C.

3. A compound according to claim 2 , wherein Y is CH.

4. A compound according to claim 3 , wherein R 1a is H.

5. A compound according to claim 4 , wherein R 1b is H or OH.

6. A compound according to claim 3 , wherein R 2a is Cl.

7. A compound according to claim 6 , wherein R 2b is cyclopropyl optionally substituted with CF 3 .

8. A compound according to claim 7 , wherein R 2c is H.

9. A compound according to Claim 1 , wherein R 2d is H.

10. A compound according to claim 1 , wherein Ring A is

optionally substituted with one or two substituents independently selected from halogen and (C 1-4 )alkyl, wherein the (C 1-4 )alkyl is optionally substituted with OH or NH 2 .

11. A compound according to claim 1 , wherein:

Ring A is selected from:

each optionally substituted with one or two substituents independently selected from OH, F, (C 1-4 )alkyl and (C═O)O(C 1-4 )alkyl, wherein a carbon in the (C 1-4 )alkyl chain may bond to a carbon on Ring A and form a spirocyclic moiety, wherein (C 1-4 )alkyl is optionally substituted with OH, methylpyrrolidinyl, NH 2 or oxo;

X is N or C, wherein when X is N then the dashed line is absent and when X is C the dashed line represents a double bond;

Y is N or CH;

R 1a is H or methyl;

R 1b is H, OH or methyl;

R 2a is Cl or methyl;

R 2b is cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, each optionally substituted with methyl, F,

CF 3 , CHF 2 and CN;

R 2c , is H or F; and

R 2d is H or (C 1-4 )alkyl;

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 , wherein the compound is represented by Formula II:

wherein:

Ring A is selected from:

each optionally substituted with one or two substituents independently selected from OH, F, (C 1-4 )alkyl and (C═O)O(C 1-4 )alkyl, wherein a carbon in the (C 1-4 )alkyl chain may bond to a carbon on Ring A and form a spirocyclic moiety, wherein (C 1-4 )alkyl is optionally substituted with OH, methylpyrrolidinyl, NH 2 or oxo;

n is 0 or 1;

R 2d is H or (C 1-4 )alkyl; and

R 3 is methyl, F, CF 3, CHF 2 or CN;

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 , wherein the compound is represented by Formula III:

wherein:

R 1 is independently selected from OH, F, (C 1-4 )alkyl and (C═O)O(C 1-4 )alkyl, wherein a carbon in the (C 1-4 )alkyl chain may bond to a carbon on the cyclohexyl ring and form a spirocyclic moiety, wherein (C 1-4 )alkyl is optionally substituted with OH, methylpyrrolidinyl, NH 2 or oxo;

n is 0 or 1; and

R 3 is methyl, F, CF 3, CHF 2 or CN;

or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 13 ,

wherein the compound is in the form of a free acid.

15. A compound selected from:

4-(1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-{1-[(2-chloro-6-cyclopropylphenyl)carbonyl]-1,4,5 ,7-tetrahydropyrano[3,4-c]pyrazol-3-yl}cyclohex-3-ene-1-carboxylic acid;

4-{1-[(2-chloro-6-cyclopropylphenyl)carbonyl]-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl}cyclohex-3-ene-1-carboxylic acid;

4- (1-{[(2-chloro-6-methylcyclopropyl)phenyl)]carbonyl}-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-(1-{[2-chloro-6-(1-methylcyclopropyl)phenyl]carbonyl}1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-(1 -{[2-chloro-6-(1 -cyanocyclobutyl)phenyl]carbonyl}-1,4,5 ,6-tetrahydrocyclopenta[c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

(S)-4-(1-(2-Chloro-6-cyclobutylbenzoyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

(R)-4-(1-(2-Chloro-6-cyclobutylbenzoyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

(1R or S)-4-(1-{[2-chloro-6-(1-cyanocyclopropyl)phenyl]carbonyl}-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

(1R or S)-4-(1{[2-chloro-6-(1-cyanocyclobutyl)phenyl]carbonyl}-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-4-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-(methoxycarbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-(1′-(2-chloro-6-cyclopropylbenzoyl)-2-oxo-1′,4,4′,5,5′,7′-hexahydro-2H-spiro[furan-3,6′-indazol]-3′-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropyl-3-fluorobenzoyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-(oxetan-3-yObenzoyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-((R or S)-1-hydroxyethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-(hydroxymethyl)-6-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-hydroxy-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-fluoro-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-(1-(2-chloro-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohex-3-ene-1-carboxylic acid;

(R or S)-4-((R or S)-1-(2-chloro-6-cyclopropylbenzoyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1-methylcyclohex-3-ene-1-carboxylic acid;

4-((R or S)-6-(aminomethyl)-1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

4-(1-(2-chloro-6-cyclopropylbenzoyl)-1,5,6,7-tetrahydropyrano[3,2-c]pyrazol-3-yl)cyclohex-3-ene-1-carboxylic acid;

1-(1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)piperidine-4-carboxylic acid;

Trans-(3R or S,4R or S)-1-(1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-hydroxypiperidine-4-carboxylic acid;

Trans-(3R or S,4R or S)-1-(1-(2-chloro-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-4,5,6,7-tetrahydro-1H-indazol-3 -yl)-3 -hydroxypiperidine-4 -carboxylic acid; and

cis 1-(1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-hydroxypiperidine-4-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

17. A pharmaceutical composition comprising a compound of claim 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

18. A method of treating a disorder selected from the group consisting of an autoimmune disorder and an inflammatory disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 to treat the disorder.

19. The method of claim 18 , wherein the disorder is an autoimmune disorder.

20. The method of claim 19 , wherein the autoimmune disorder is rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, or epidermal hyperplasia.

21. The method of claim 18 , wherein the disorder is an inflammatory disorder.

22. A method of inhibiting the activity of a RORγ, comprising exposing a RORγto an effective amount of a compound of claim 1 to inhibit the activity of said RORγ.

23. The method of claim 20 , wherein the compound is a compound of claim 13 .