Phenyl linked quinolinyl modulators of RORγt

Patent metadata

Field	Value
Publication number	US-9403816-B2
Application number	US-201314053773-A
Country	US
Kind code	B2
Filing date	Oct 15, 2013
Priority date	Oct 15, 2013
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The present invention comprises compounds of Formula I.

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are defined in the specification.

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. The compounds 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, benzoxazolyl, and pyrazolyl 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, isoxazolyl, 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)(1-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 compounds of claim 1 , wherein:
R 1 is imidazolyl, thiazolyl, pyridyl, pyrimidinyl, or phenyl; wherein said pyridyl, and said phenyl are optionally substituted with —CN, CF 3 , F, or Cl; and wherein said imidazolyl, and thiazolyl are optionally substituted with one or two CH 3 groups;
R 2 is 1-methyl-1,2,3-triazol-5-yl, N-acetyl piperidin-4-yl, N-Boc-piperidin-4-yl, N-methyl piperidin-4-yl, 1-H-piperidin-4-yl, oxazol-2-yl, 2,4-dimethyl thiazol-5-yl, 1-methyl imidazol-2-yl, 1-methyl-imidazol-5-yl, or pyridyl; wherein said pyridyl is optionally substituted with CF 3 ;
R 3 is H or OH;
R 4 is H;
R 5 is H, Cl, —CN, C (1-4) alkyl, OC (1-2) alkyl, SCH 3 , N(CH 3 ) 2 , or N(CH 3 )OCH 3 ;
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 , Cl, —CN, OCH 3 , or OCF 3 ;
R 7 is Cl, —CN, CF 3 , SCH 3 , OCH 2 CF 3 , NA 1 A 2 , N(CH 3 )CH 2 CH 2 NA 1 A 2 , OC (1-3) alkyl, OCH 2 CH 2 OCH 3 , OCH 2 CH 2 NA 1 A 2 , or OCH 2 CH 2 NH 2 ;
A 1 is H, or CH 3 ;
A 2 is OCH 3 , CH 3 , CH 2 CH 2 OH, C(O)C (1-2) alkyl, or CH 2 CH 2 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 8 is H, or CH 3 ;
R 9 is H;

and pharmaceutically acceptable salts thereof;
provided that (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol, 6(( 3 -chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile, (2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol, (2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol, (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol, (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol, and (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol are excluded from the claim.

3. A compound of claim 1 selected from the group consisting of:

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
• Cummings Maxwell D

Classifications

• C07D417/14 Primary

  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

• A61K31/4709 Primary

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title