Quinolinyl modulators of RORγt

Patent metadata

Field	Value
Publication number	US-9624225-B2
Application number	US-201414513426-A
Country	US
Kind code	B2
Filing date	Oct 14, 2014
Priority date	Oct 15, 2013
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

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. A compound of Formula I, wherein:

R 1 is imidazolyl, pyrimidinyl, triazolyl, tetrahydropyranyl, thiazolyl, pyridyl, piperidinyl, phenyl, or oxazolyl; wherein said piperidinyl, pyridyl, imidazolyl, and phenyl are optionally substituted with SO 2 CH 3 , C(O)CH 3 , CH 3 , CF 3 , Cl, F, —CN, OCH 3 , or N(CH 3 ) 2 ; and optionally substituted with up to one additional group independently selected from the group consisting of Cl, OCH 3 , and CH 3 ; and wherein said triazolyl, oxazolyl, and thiazolyl are optionally substituted with one or two CH 3 groups;
R 2 is H, CH 3 , —C≡CH, 1-methyl-1,2,3-triazol-5-yl, pyrid-3-yl, 2-trifluoromethyl-pyrid-4-yl, 1-methyl-pyrazol-4-yl, 1,3,5-trimethyl-pyrazol-4-yl, thiazol-5-yl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-acetyl-piperidin-4-yl, N-Boc-piperidin-4-yl, 1-H-piperidin-4-yl, N-methylsulfonyl-piperidin-4-yl, 1,2-dimethyl imidazol-5-yl, or 1-methyl imidazol-5-yl, provided that R 2 is not H when R 5 is H;
R 3 is OH;
R 4 is H;
R 5 is H, Cl, —CN, CF 3 , C (1-2) alkyl, OH, N(CH 3 )OCH 3 , OCH 3 , azetidin-1-yl, or fur-2-yl; provided that R 5 is not H if R 7 is OCH 3 ;
R 6 is C (1-4) alkylene-Q, OC (1-4) alkylene-Q, C(O)NA 3 A 4 , C(O)OC (1-4) alkyl, O-tetrahydropyranyl, —O-(N-methyl)piperidinyl, cyclopentyl, cyclohexyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, or tetrahydropyran-4-yl; provided that R 6 is not CH 2 -phenyl, CH 2 -pyridinyl, nor CH 2 -pyrimidinyl;
Q is H, CF 3 , OH, SO 2 CH 3 , NA 3 A 4 , OC (1-4) alkyl, cyclopropyl, 1-methyl-cyclopropyl, oxetanyl, 3-methyl-oxetanyl, tetrahydrofuranyl, 1,3-dimethyl-pyrazol-5-yl, 3,5-dimethyl-isoxazol-4-yl, thiazol-2-yl, N-methyl-pyrrolidin-2-yl, cyclohexyl, N-acetyl-piperidin-4-yl, N-Boc-piperidin-4-yl, 1-H-piperidin-4-yl, tetrahydropyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl, phenyl, pyridin-3-yl, or pyrimidin-2-yl; wherein said cyclopropyl, and said cyclohexyl are optionally substituted with up to two fluorine atoms;

wherein
A 3 is H, or CH 3 ;
A 4 is CH 3 , CH 2 -cyclopropyl, cyclopropyl, C (1-3) alkylCF 3 , CH 2 CH 2 OCH 2 CF 3 , C(O)C (1-2) alkylCF 3 ,

 or C (0-1) alkyl-trifluoromethyl-cyclohexyl, or A 3 and A 4 may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

wherein
q b is H, F, CF 3 , SO 2 CH 3 , pyrazol-1-yl, or 3-trifluoromethyl-pyrazol-1-yl;
q c is H, F, or CF 3 ,
q d is CH 2 CF 3 ;
provided that if R 6 is OCH 2 -Q, then Q may not be OH, nor NA 3 A 4 ;
R 7 is Cl, —CN, CF 3 , C (1-4) alkyl, cyclopropyl, NA 1 A 2 , C(O)NHCH 3 , OCH 2 CH 2 OCH 3 , 1-methyl imidazol-2-yl, 1-methyl pyrazol-4-yl, OC (1-2) alkyl, pyrimidin-5-yl, thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, fur-2-yl, phenyl, or

A 1 is C (1-2) alkyl;
A 2 is C (1-2) alkyl, CH 2 CH 2 OCH 3 , or OCH 3 ; or A 1 and A 2 may be taken together with their attached nitrogen to form a ring which is:

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

and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , wherein
R 1 is imidazolyl, triazolyl, tetrahydropyranyl, thiazolyl, pyridyl, or phenyl; wherein said pyridyl, imidazolyl, and phenyl are optionally substituted with one substituent selected from the group consisting of CH 3 , CF 3 , Cl, and —CN; and optionally substituted with up to one additional CH 3 ; and wherein said triazolyl, and thiazolyl are optionally substituted with one or two CH 3 groups;
R 2 is H, CH 3 , 1-methyl-1,2,3-triazol-5-yl, pyrid-3-yl, 2-trifluoromethyl-pyrid-4-yl, 1,3,5-trimethyl-pyrazol-4-yl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-acetyl-piperidin-4-yl, N-methylsulfonyl-piperidin-4-yl, N-Boc-piperidin-4-yl, 1-H-piperidin-4-yl, 1,2-dimethyl-imidazol-5-yl, or 1-methyl-imidazol-5-yl, provided that R 2 is not H when R 5 is H;
R 5 is H, Cl, —CN, CF 3 , C (1-2) alkyl, OCH 3 , azetidin-1-yl, or fur-2-yl; provided that R 5 is not H if R 7 is OCH 3 ;
R 7 is Cl, CF 3 , CH 2 CH 3 , cyclopropyl, OCH 3 , pyrimidin-5-yl, thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, fur-2-yl, azetidin-1-yl, phenyl, or

R 8 is H or CH 3 ;

and pharmaceutically acceptable salts thereof.

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
• Xue Xiaohua
• Cummings Maxwell D
• Mcclure Kelly
• Tanis Virginia

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

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

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title