Phenyl linked quinolinyl modulators of RORγt

Patent metadata

Field	Value
Publication number	US-10369146-B2
Application number	US-201615182231-A
Country	US
Kind code	B2
Filing date	Jun 14, 2016
Priority date	Oct 15, 2013
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.

First claim

What is claimed is:

1. A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, and systemic lupus erythematosus, comprising administering to a subject in need thereof an effective amount of a compound of Formula I:

wherein:
R 1 is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolol, and pyrazolol are optionally substituted with SO 2 CH 3 , C(O)CH 3 , C(O)NH 2 , CH 3 , CH 2 CH 3 , CF 3 , Cl, F, —CN, OCH 3 , N(CH 3 ) 2 , —(CH 2 ) 3 OCH 3 , SCH 3 , OH, CO 2 H, CO 2 C(CH 3 ) 3 , or OCH 2 OCH 3 ; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH 3 , and CH 3 ; and wherein said triazolyl, oxazolyl, isoxazol and thiazolyl are optionally substituted with one or two CH 3 groups; and wherein said azetidinyl is optionally substituted with CO 2 C(CH 3 ) 3 , C(O)NH 2 , CH 3 , SO 2 CH 3 , or C(O)CH 3 ;
R 2 is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C (1-2) alkyl-piperidinyl, thiazol-5-yl, 1-methyl imidazol-2-yl, 1-(3-methoxypropyl)-imidazol-5-yl, or 1-C (1-2) alkyl imidazol-5-yl; wherein said 1-C (1-2) alkyl imidazol-5-yl is optionally substituted with up to two additional CH 3 groups, or one substituent selected from the group consisting of SCH 3 , and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two substituents independently selected from the group consisting of C(O)NH 2 , —CN, OCH 3 , CF 3 , Cl, and CH 3 ; and said thiazol-5-yl, oxazolyl, and isoxazolyl are optionally substituted with up to two CH 3 groups; and said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH 3 groups;
R 3 is H, OH, OCH 3 , NHCH 3 , N(CH 3 ) 2 or NH 2 ;
R 4 is H, or F;
R 5 is H, Cl, —CN, CF 3 , SCH 3 , OC (1-3) alkyl, OH, C (1-4) alkyl, N(CH 3 )OCH 3 , NH(C (1-2) alkyl), N(C (1-2) alkyl) 2 , NH-cyclopropyl, OCHF 2 , 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;
R 6 is 2-chloro-thiophen-5-yl, 1-methyl-pyrazol-4-yl, phenyl, pyrimidinyl, or pyridyl, wherein said phenyl, pyrimidinyl, and pyridyl are optionally substituted with SO 2 CH 3 , NHSO 2 CH 3 , CF 3 , F, Cl, —CN, OCH 3 or OCF 3 ;
R 7 is H Cl, —CN, C (1-4) alkyl, OCH 2 CF 3 , OCH 2 CH 2 OCH 3 , CF 3 , SCH 3 , SO 2 CH 3 , OCHF 2 , NA 1 A 2 , C(O)NHCH 3 , N(CH 3 )CH 2 CH 2 NA 1 A 2 , OCH 2 CH 2 NA 1 A 2 , OCH 2 CH 2 NH 2 , OC (1-3) alkyl, OCH 2 -(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted with a CH 3 group;
A 1 is H or C (1-4) alkyl;
A 2 is C (1-4) alkyl, cyclopropyl, C (1-4) alkylOC (1-4) alkyl, C (1-4) alkylOH, C(O)C (1-2) alkyl, or OCH 3 ; or A 1 and A 2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R a is H, F, OCH 3 , or OH;
R b is CH 3 , or phenyl;
R 8 is H, CH 3 , OCH 3 , or F;
R 9 is H, or F;

and pharmaceutically acceptable salts thereof;
provided that (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-3-yl)methanamine, (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol, (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanamine, (4-chlorophenyl)(3-(2,6-dichlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol, (4-chloro-3-phenylquinolin-6-yl)(2-(dimethylamino)pyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol, 4-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(l-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)thiomorpholine 1,1-dioxide, 1-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)pyrrolidin-2-one, (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol, (4-chloro-3-phenylquinolin-6-yl)(2-fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol, (4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol, (2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol, 6-((3-chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile, (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-4-yl)(6-methylpyridin-3-yl)methanol, (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol, (2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol, and (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol are excluded from the claim.

2. The method of claim 1 , wherein the disease is psoriasis.

3. The method of claim 1 , wherein the disease is rheumatoid arthritis.

4. The method of claim 1 , wherein the inflammatory bowel disease is ulcerative colitis.

5. The method of claim 1 , wherein the inflammatory bowel disease is Crohn's disease.

6. The method of claim 1 , wherein the disease is multiple sclerosis.

7. The method of claim 1 , wherein the disease is neutrophilic asthma.

8. The method of claim 1 , wherein the disease is steroid resistant asthma.

9. The method of claim 1 , wherein the disease is psoriatic arthritis.

10. The method of claim 1 , wherein the disease is ankylosing spondylitis.

11. The method of claim 1 , wherein the disease is systemic lupus erythematosus.

12. The method of claim 1 , wherein the disease is chronic obstructive pulmonary disorder.

13. A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 1 or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Leonard Kristi A
• Barbay Kent
• Edwards James P
• Kreutter Kevin D
• Kummer David A
• Maharoof Umar
• Nishimura Rachel
• Urbanski Maud
• Venkatesan Hariharan
• Wang Aihua
• Wolin Ronald L
• Woods Craig R
• Fourie Anne
• Xue Xiaohua
• Cummings Maxwell D

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title