Heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators

Patent metadata

Field	Value
Publication number	US-9273047-B2
Application number	US-201414487347-A
Country	US
Kind code	B2
Filing date	Sep 16, 2014
Priority date	May 25, 2012
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The present invention provides heteroaryl ketone fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

First claim

What is claimed is:

1. A method of modulating a glucocorticoid receptor, comprising contacting a glucocorticoid receptor with a compound of Formula I, thereby modulating the glucocorticoid receptor,
wherein the compound of Formula I has the formula:

wherein
R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;
each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —CN, N-oxide, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;
ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, —CN, —OH, —NR 2a R 2b , —C(O)R 2a , —C(O)OR 2a , —C(O)NR 2a R 2b , —SR 2a , —S(O) R 2a , —S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R 2c groups;
alternatively, two R 2 groups linked to the same carbon are combined to form an oxo group (═O);
alternatively, two R 2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2d groups;
R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each R 2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, —CN, and —NR 2a R 2b ;
each R 2d is independently selected from the group consisting of hydrogen and C 1-6 alkyl, or two R 2d groups attached to the same ring atom are combined to form (═O);
R 3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R 3a groups;
each R 3a is independently selected from the group consisting of hydrogen, halogen, and C 1 haloalkyl;
subscript n is an integer from 0 to 3;
or salts thereof.

2. The method of claim 1 , wherein R 1 is selected from the group consisting of pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine, pyrazine, pyrimidine, and pyridazine.

3. The method of claim 1 , wherein R 1 is selected from the group consisting of 2-pyrrole, 3-pyrrole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 3-isoxazole, 4-isooxazole, 5-isooxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol -5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 3-isothiazole, 4-isothiazole, 5-isothiazole, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 3-pyridazine, 4-pyridazine, 5-pyridazine, and 6-pyrdazine.

4. The method of claim 1 , wherein R 1 is selected from the group consisting of pyrazole, imidazole, triazole, furan, oxazole, oxadiazole, thiophene, thiazole, pyridine, pyrazine and pyrimidine.

5. The method of claim 1 , wherein R 1 is selected from the group consisting of 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, and 6-pyrimidine.

6. The method of claim 1 , wherein each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-8 heterocycloalkyl.

7. The method of claim 1 , wherein each R 1a is independently selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, and methoxy.

8. The method of claim 1 , wherein ring J is selected from the group consisting of heterocycloalkyl, aryl and heteroaryl.

9. The method of claim 1 , wherein ring J is selected from the group consisting of aryl and heteroaryl.

10. The method of claim 1 , wherein ring J is selected from the group consisting of phenyl, pyridine, imidazole, pyrazole, triazole, tetrazole, thiadiazole, isothiazole, cyclohexyl, tetrahydrofuran and tetrahydro-2H-pyran.

11. The method of claim 1 , wherein ring J is phenyl.

12. The method of claim 1 , wherein ring J is pyridyl.

13. The method of claim 1 , wherein each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, —CN, —NR 2a R 2b , —C(O)OR 2a , —S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group has 5-6 ring members and 1 to 2 heteroatoms.

14. The method of claim 1 , wherein each R 2 is independently selected from the group consisting of hydrogen, methyl, ethyl, F, Cl, —CF 3 , OMe, OCHF 2 , —CN, —NMe 2 , —S (O) 2 Me, pyrrolidine, piperidine and morpholine.

15. The method of claim 1 , wherein R 3 is 4-F-phenyl.

16. The method of claim 1 , wherein the compound is selected from the group consisting of:
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,
(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl) -4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-3-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-4-yl)methanone,
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6

Assignees

• Corcept Therapeutics Inc

Inventors

• Hunt Hazel
• Johnson Tony
• Ray Nicholas
• Walters Iain

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/56

  Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title