Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof

1. A compound according to Formula I-1:

wherein:

Ring A is a monocyclic ring formed by an alkylene group taken together with the C═C of the pyrazolyl to which Ring A is fused, wherein 1, 2, or 3 carbon atoms of the alkylene group are optionally replaced with a heteroatom selected from O, N or S, and Ring A is optionally substituted with one to three substituents independently selected from R 3 , wherein R 3 is selected from the group consisting of OH, oxo, (C 1-4 )alkyl, —(C 1-4 )alkylene-N(R a ) 2 , —(C 1-4 )alkylene-(C 3-6 cycloalkyl), (C 1-4 )alkoxy, N(R a ) 2 , N(R 6 )CO 2 R 7 , N(R 6 )C(O)R 8 , C(O)R 8 , C(O)N(R) 2 ,

wherein said alkyl is optionally substituted with one or more halogen or hydroxyl;

Z is C(O) or CH 2 ;

m is 0, 1, or 2;

n is 1, 2 or 3;

R 1 is independently OH, halogen, (C 1-4 )alkyl, CN, CF 3 , or CHF 2 , wherein said alkyl is optionally substituted with one or more halogen;

R 2 is independently halogen, (C 1-4 )alkyl, CF 3 , CHF 2 , or (C 3-4 )cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of CN, (C 1-4 )haloalkyl, and halogen;

R 5 is independently OH, (C 0-4 )alkyl, or S(O) 2 R b ;

R 6 is independently (C 0-4 )alkyl;

R 7 is independently (C 1-6 )alkyl;

R 8 is independently OH, (C 0-4 )alkyl, 2-8 membered heteroalkyl, or one of the following:

a heterocyclyl-containing group selected from 3-10 membered heterocyclyl, —C 1-6 alkylene-(5-6 membered heteroaryl), —O—(C 1-6 alkylene)-(5-6 membered heteroaryl), or -(3-10 membered heterocycloalkylene)-(3-10 membered heterocycloalkyl), each optionally substituted by one or more R 9 ;

a carbocyclyl-containing group selected from C 3-7 carbocyclyl, —C 1-6 alkylene-(C 3-7 carbocyclyl), —O—C 3-7 carbocyclyl, or —O—(C 1-6 alkylene)-C 3-7 carbocyclyl, each optionally substituted by one or more R 9 ;

R 9 is independently halogen, hydroxyl, (C 1-4 )alkyl, (C 1-4 )haloalkyl, (C 1-6 )alkoxyl, N(R a ) 2 , (C 3-4 )cycloalkyl, or cyano, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of CN, (C 1-4 )haloalkyl, and halogen;

R a is independently (C 0-4 )alkyl, (C 1-4 ) haloalkyl, or 3-7 membered heterocycloalkyl; and

R b is (C 1 -4)alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein Z is C(O).

3. A compound of claim 2 , wherein R 1 is independently OH or halogen.

4. A compound of claim 2 , wherein R 1 is independently OH, chloro, or fluoro.

5. A compound of claim 2 , wherein R 1 is OH.

6. A compound of claim 2 , wherein R 1 is fluoro.

7. A compound of claim 3 , wherein m is 1.

8. A compound of claim 6 , wherein R 1 is located meta to the —CO 2 H group.

9. A compound of claim 2 , wherein R 2 is independently halogen, (C 3-4 )cycloalkyl, or (C 3-4 )cycloalkyl substituted by (C 1-4 )haloalkyl.

10. A compound of claim 7 , wherein R 2 is independently chloro, cyclopropyl, or cyclopropyl substituted by trifluoromethyl.

11. A compound of claim 7 , wherein a first occurrence of R 2 is chloro, and a second occurrence of R 2 is cyclopropyl.

12. A compound of claim 7 , wherein a first occurrence of R 2 is chloro, and a second occurrence of R 2 is cyclopropyl substituted by trifluoromethyl.

13. A compound of claim 7 , wherein a first occurrence of R 2 is chloro, and a second occurrence of R 2 is

14. A compound of claim 12 , wherein any R 2 is located at an ortho-position on the phenyl group to which R 2 is attached.

15. A compound of claim 12 , wherein n is 2.

16. A compound of claim 2 , wherein Ring A is a 6-membered monocyclic ring formed by an alkylene group taken together with the C═C of the pyrazolyl to which Ring A is fused, and Ring A is substituted with one R 3 group selected from C(O)R 8 , C(O)N(R 8 ) 2 , and

17. A compound of claim 12 , wherein Ring A is

and R 3 is C(O)R 8 , C(O)N(R 8 ) 2 , or

18. A compound of claim 17 , wherein R 8 is independently (C 0-4 )alkyl, 2-8 membered heteroalkyl, or -(3-10 membered heterocyclyl optionally substituted by one or more R 9 ).

19. A compound of claim 1 , wherein the compound is represented by Formula I-1A:

wherein:

R 1 is halogen;

R 2A is halogen;

R 2B is independently halogen, (C 1-4 )alkyl, CF 3 , CHF 2 , or (C 3-4 )cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of CN, (C 1-4 )haloalkyl, and halogen;

R 3 is N(R a ) 2 , N(R 6 )CO 2 R 7 , N(R 6 )C(O)R, C(O)R 8 , C(O)N(R 8 ) 2 , or

R 6 is independently (C 0-4 )alkyl;

R 7 is independently (C 1-6 )alkyl;

R 8 is independently (C 0-4 )alkyl, 2-8 membered heteroalkyl, or -(3-10 membered heterocyclyl optionally substituted by one or more R 9 );

R 9 is independently halogen, hydroxyl, (C 1-4 )alkyl, or (C 1-4 )haloalkyl; and

R a is independently (C 0-4 )alkyl;

or a pharmaceutically acceptable salt thereof.

20. A compound according to Formula I-2, II, or III, wherein Formula I-2 is represented by:

wherein:

Ring A is a saturated monocyclic ring optionally containing 1, 2, or 3 heteroatoms selected from O, N or S and optionally substituted with one to three substituents independently selected from R 3 , wherein R 3 is selected from the group consisting of OH, oxo, (C 1-4 )alkyl, (C 1-4 )alkyl-N(R a ) 2 , (C 1-4 )alkoxy, N(R a ) 2 , C(O)R 5 , C(O)N(R 5 ) 2 ,

wherein said alkyl is optionally substituted with one or more halogen;

Z is C(O) or CH 2 ;

m is 0, 1, or 2;

n is 1, 2 or 3;

R 1 is independently OH, (C 1-4 )alkyl, CN, CF 3 , CHF 2 or halogen, wherein said alkyl is optionally substituted with one or more halogen;

R 2 is independently selected from halogen, (C 1-4 )alkyl, CF 3 , CHF 2 and (C 3-4 )cycloalkyl, wherein said alkyl may optionally be substituted with CN and one to three halogen;

R 5 is independently selected from OH, (C 0-4 )alkyl, (C 1-4 )alkoxy and S(O) 2 R b ;

R a is independently selected from (C 0-4 )alkyl; and

R b is (C 0-4 )alkyl;

or a pharmaceutically acceptable salt thereof;

Formula II is represented by:

wherein:

Ring A is a saturated monocyclic ring optionally containing 1, 2, or 3 heteroatoms selected from O, N or S and optionally substituted with one to three substituents independently selected from R 3 , wherein R 3 is selected from the group consisting of OH, oxo, (C 1-4 )alkyl, (C 1-4 )alkyl-N(R a ) 2 , (C 1-4 )alkoxy, N(R a ) 2 , C(O)R 5 , C(O)N(R 5 ) 2 ,

wherein said alkyl is optionally substituted with one or more halogen;

m is 0, 1, or 2;

R 1 is independently OH, (C 1-4 )alkyl, CN, CF 3 , CHF 2 or halogen, wherein said alkyl is optionally substituted with one or more halogen;

R 2 is independently selected from halogen, (C 1-4 )alkyl, CF 3 , CHF 2 and (C 3-4 )cycloalkyl, wherein said alkyl may optionally be substituted with CN and one to three halogen;

R 5 is independently selected from OH, (C 0-4 )alkyl, (C 1-4 )alkoxy and S(O) 2 R b ;

R a is independently selected from (C 0-4 )alkyl; and

R b is (C 0-4 )alkyl;

or a pharmaceutically acceptable salt thereof; and

Formula III is represented by:

wherein:

m is 0, 1, or 2;

R 1 is independently OH, methyl or F;

R 2 is independently selected from Cl, CF 3 and (C 3-4 )cycloalkyl, wherein the cycloalkyl may optionally be substituted with CN; and

R 3 is selected from the group consisting of OH, oxo, (C 1-4 )alkoxy, C(O)R 5 , C(O)N(R 5 ) 2 ,

R 5 is independently selected from OH, (C 0-4 )alkyl, (C 1-4 )alkoxy and S(O) 2 R b ; and

R b is methyl;

or a pharmaceutically acceptable salt thereof.

21. A compound of claim 20 , wherein the compound is according to Formula III:

wherein:

m is 0, 1, or 2;

R 1 is independently OH, methyl or F;

R 2 is independently selected from Cl, CF 3 and (C 3-4 )cycloalkyl, wherein the cycloalkyl may optionally be substituted with CN; and

R 3 is selected from the group consisting of OH, oxo, (C 1-4 )alkoxy, C(O)R 5 , C(O)N(R 5 ) 2 ,

R 5 is independently selected from OH, (C 0-4 )alkyl, (C 1-4 )alkoxy and S(O) 2 R b ; and

R b is methyl;

or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1 selected from:

4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-fluorobenzoic acid;

4-(6-(tert-butoxycarbonyl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepin-3-yl)-3-fluorobenzoic acid;

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

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

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

4-(6-(tert-butoxycarbonyl)-1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-fluorobenzoic acid;

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

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

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

4-(1-(2-chloro-6-cyclopropylbenzoyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-cyclobutylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2,6-dichlorobenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)benzoic acid;

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

4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepin-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

3-(4-carboxy-2-fluorophenyl)-1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid;

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

4-(6-(azetidine-1-carbonyl)-1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

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

4-(4-(tert-butoxycarbonyl)-1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluorobenzoic acid;

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

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

4-(6-acetyl-1-(2-chloro-6-cyclopropylbenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(methoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(1-cyanocyclopropyl)benzoyl)-6-(3-methoxyazetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(1-cyanocyclopropyl)benzoyl)-6-(3-methoxyazetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(1-cyanocyclobutyl)benzoyl)-6-(3-(methylsulfonyl)azetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(1-cyanocyclobutyl)benzoyl)-6-(3-(methylsulfonyl)azetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(1-cyanocyclobutyl)benzoyl)-6-(4-methyl-3-oxopiperazine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid;

4-(1-(2-chloro-6-(1-cyanocyclobutyl)benzoyl)-6-(4-methyl-3-oxopiperazine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-fluorobenzoic acid; and

4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-2-methylbenzoic acid;

or a pharmaceutically acceptable salt thereof.

23. A compound in Table 17 or a pharmaceutically acceptable salt thereof:

TABLE 17

Example

No.

Chemical Structure

1A

1B

1C

1D

1E

1F

1G

1H

1I

1J

1K

1L

1M

2A

3A

4A

5A

6A

6B

6C

7A

8A

9A

9B

10A

11A

12A-A

12A-B

13A-A

13A-B

14A-A

14A-B

15A-A

15A-B

16A-B

17A

17B

17C

17D

18A

18B

18C

18D

18E

18F

18G

19A

19B

19C

20A

20B

21A

21B

21C

21D

21E

21F

21G

21H

21I

21J

21K

21L

21M

21N

21O

21P

21Q

21R

21S

21T

21U

21V

21W

21X

21Y

21Z

21AA

21BB

21CC

21DD

21EE

21FF

21GG

21HH

21II

21JJ

21KK

21LL

21MM

21NN

21PP

21QQ

21RR

21SS

21TT

21UU

21VV

21WW

21XX

21YY

21ZZ

21AAA

21BBB

21CCC

22A

23A

24A

25A

25B

26A

27A

27B

28A

29A

30A

31A

32A

33A

34A

35A

36A

37A

37B

24. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers.

25. A method for treating a disease or condition mediated by Retinoic acid receptor-related Orphan Receptor gamma T (RORgammaT) in a subject, comprising administering to the subject an amount of a compound of claim 1 that is effective for treating the disease or condition mediated by RORgammaT in the subject.

26. The method of claim 25 , 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.

27. The method of claim 25 , wherein the disease or condition is a cancer selected from the group consisting of breast cancer, colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, and cancer of the central nervous system tissue.

28. A pharmaceutical composition comprising a compound of claim 19 and one or more pharmaceutically acceptable carriers.

29. A pharmaceutical composition comprising a compound of claim 20 and one or more pharmaceutically acceptable carriers.