Phenyl linked quinolinyl modulators of RORγt

Patent metadata

Field	Value
Publication number	US-9309222-B2
Application number	US-201314053707-A
Country	US
Kind code	B2
Filing date	Oct 15, 2013
Priority date	Oct 16, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 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 pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, quinazolinyl, cinnolinyl, benzothiazolyl, indazolyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, benzimidazolyl, indolyl, thiadiazolyl, oxadiazolyl or quinolinyl; wherein said pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, quinazolinyl, cinnolinyl, benzothiazolyl, indazolyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl, benzimidazolyl, indolyl, quinolinyl, and pyrazolyl are optionally substituted with C(O)C (1-4) alkyl, C(O)NH 2 , C(O)NHC (1-2) alkyl, C(O)N(C (1-2) alkyl) 2 , NHC(O)C (1-4) alkyl, NHSO 2 C (1-4) alkyl, C (1-4) alkyl, CF 3 , CH 2 CF 3 , Cl, F, —CN, OC (1-4) alkyl, N(C (1-4) alkyl) 2 , —(CH 2 ) 3 OCH 3 , SC (1-4) alkyl, OH, CO 2 H, CO 2 C (1-4) alkyl, C(O)CF 3 , SO 2 CF 3 , OCF 3 , OCHF 2 , SO 2 CH 3 , SO 2 NH 2 , SO 2 NHC (1-2) alkyl, SO 2 N(C (1-2) alkyl) 2 , C(O)NHSO 2 CH 3 , or OCH 2 OCH 3 ; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, C (1-2) alkyl, SCH 3 , OC (1-2) alkyl, CF 3 , —CN, and F; and wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and thiazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO 2 CH 3 , SO 2 NH 2 , C(O)NH 2 , —CN, OC (1-2) alkyl, (CH 2 ) (2-3) OCH 3 , SCH 3 , CF 3 , F, Cl, and C (1-2) alkyl; and said thiadiazolyl and oxadiazolyl are optionally substituted with C (1-2) alkyl; and said pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl are optionally substituted with up to three additional substituents independently selected from the group consisting of C(O)NHC (1-2) alkyl, C(O)N(C (1-2) alkyl) 2 , NHC(O)C (1-4) alkyl, NHSO 2 C (1-4) alkyl, C(O)CF 3 , SO 2 CF 3 , SO 2 NHC (1-2) alkyl, SO 2 N(C (1-2) alkyl) 2 , C(O)NHSO 2 CH 3 , SO 2 CH 3 , SO 2 NH 2 , C(O)NH 2 , —CN, OC (1-4) alkyl, (CH 2 ) (2-3) OCH 3 , SC (1-4) alkyl, CF 3 , F, Cl, and C (1-4) alkyl;
R 2 is triazolyl, pyridyl, pyridyl-N-oxide, pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C (1-3) alkyl-piperidinyl, thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl, thiadiazolyl, oxadiazolyl, or imidazolyl; wherein said imidazolyl is optionally substituted with up to three additional substituents independently selected from the group consisting of C (1-2) alkyl, SCH 3 , OC (1-2) alkyl, CF 3 , —CN, F, and Cl; and said pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl, are optionally substituted with up to three additional substituents independently selected from the group consisting of SO 2 CH 3 , SO 2 NH 2 , C(O)NH 2 , —CN, OC (1-2) alkyl, (CH 2 ) (2-3) OCH 3 , SCH 3 , CF 3 , F, Cl, or C (1-2) alkyl; and said triazolyl, thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO 2 CH 3 , SO 2 NH 2 , C(O)NH 2 , —CN, OC (1-2) alkyl, (CH 2 ) (2-3) OCH 3 , SCH 3 , CF 3 , F, Cl, and C (1-2) alkyl; and said thiadiazolyl and oxadiazolyl are optionally substituted with C (1-2) alkyl; and said pyrazolyl is optionally substituted with up to three CH 3 groups;
R 3 is H, OH, OCH 3 , or NH 2 ;
R 4 is H, or F;
R 5 is H, Cl, —CN, CF 3 , SC (1-4) alkyl, OC (1-4) alkyl, OH, C (1-4) alkyl, N(CH 3 )OCH 3 , NH(C (1-4) alkyl), N(C (1-4) alkyl) 2 , or 4-hydroxy-piperidinyl;
R 6 is pyridyl, pyrimidinyl, pyridazyl, pyrazinyl, thiazolyl, isothiazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, oxadiazolyl, thiadiazolyl, or phenyl, any of which is optionally substituted with up to two substituents independently selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, pyrazolyl, triazolyl, imidazolyl, —CN, C (1-4) alkyl, OC (1-4) alkyl, C(O)C (1-4) alkyl, CO 2 H, CO 2 C (1-4) alkyl, NH 2 , NHC (1-2) alkyl, N(C (1-2) alkyl) 2 , SONH 2 , SON(CH 3 )2, SO 2 NH 2 , SO 2 NHC (1-2) alkyl, SO 2 N(C (1-2) alkyl) 2 , SCH 3 , OCH 2 CF 3 , SO 2 CH 3 , CF 3 , Cl, F, OH, and OCF 3 ;
R 7 is H, Cl, —CN, C (1-4) alkyl, OC (1-4) alkylCF 3 , OCF 3 , OCHF 2 , OCH 2 CH 2 OC (1-4) alkyl, CF 3 , SCH 3 , C (1-4) alkylNA 1 A 2 , CH 2 OC (2-3) alkylNA 1 A 2 , NA 1 A 2 , C(O)NA 1 A 2 , CH 2 NHC (2-3) alkylNA 1 A 2 , CH 2 N(CH 3 )C (2-3) alkylNA 1 A 2 , NHC (2-3) alkylNA 1 A 2 , N(CH 3 )C (2-4) alkylNA 1 A 2 , OC (2-4) alkylNA 1 A 2 , OC (1-4) alkyl, OCH 2 -(1-methyl)-imidazol-2-yl, phenyl, thiophenyl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl; wherein said phenyl, thiophenyl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, and pyrimidinyl are optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, CH 3 , CF 3 , and OCH 3 ;
A 1 is H, or C (1-4) alkyl;
A 2 is H, C (1-4) alkyl, C (1-4) alkylOC (1-4) alkyl, C (1-4) alkylOH, C(O)C (1-4) alkyl, or OC (1-4) alkyl; 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, OC (1-4) alkyl, CH 2 OH, NH(CH 3 ), N(CH 3 ) 2 , NH 2 , CH 3 , F, CF 3 , SO 2 CH 3 , or OH;
R b is H, CO 2 C(CH 3 ) 3 , C (1-4) alkyl, C(O)C (1-4) alkyl, SO 2 C (1-4) alkyl, CH 2 CH 2 CF 3 , CH 2 CF 3 , CH 2 -cyclopropyl, phenyl, CH 2 -phenyl, or C (3-6) cycloalkyl;
R 8 is H, C (1-3) alkyl, OC (1-3) alkyl, CF 3 , NH 2 , NHCH 3 , —CN, 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, (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol, (4-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(2-methyl-4-(trifluoromethyl)thiazol-5-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-methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-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)(phenyl)(pyridin-2-yl)methanol are excluded from the claim.

2. The compounds of claim 1 , wherein:
R 1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridy

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
• Mirzadegan Taraneh
• Ganamet Kelly

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title