Thiazoles as modulators of RORγt

Patent metadata

Field	Value
Publication number	US-9861618-B2
Application number	US-201514927501-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Oct 30, 2014
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

The present invention comprises compounds of Formula I

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and

are defined in the specification.

The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein the 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 Formula I.

First claim

We claim:

1. A compound of Formula I:

wherein:

Z is N, or CH;

R 1 is H, Cl, OCF 3 , C (1-3) alkyl, —CN, F, OC (1-3) alkyl, OCHF 2 , Br, I, or cyclopropyl; wherein said C (1-3) alkyl is optionally substituted with up to five fluorine atoms;
R 2 is H, F, Cl, —CN, OCH 3 , OCHF 2 , OCF 3 , cyclopropyl, or C (1-4) alkyl; wherein said C (1-4) alkyl is optionally substituted with up to five fluorine atoms, and said cyclopropyl is optionally substituted with OH, CH 3 , CF 3 , —CN, and up to five fluorine atoms; or R 1 and R 2 may be taken together with their attached ring A to form a fused ring system selected from the group consisting of naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl, wherein said naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl are optionally substituted with F, CHF 2 , CH 2 F, CF 3 , or CH 3 ; provided that R 2 may not be H if R 1 is H;
R 3 is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, or pyrrolyl; wherein said oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, or pyrrolyl is optionally substituted with R 6 ;
R 6 is

 C (1-4) alkyl, C(O)NH 2 , or —CN; wherein said C (1-4) alkyl is optionally substituted with up to six fluorine atoms, CO 2 H, OH, or CN;

R 4 is C (3-6) cycloalkyl, isopropyl, C(CH 3 ) 2 OCH 3 , OC (1-4) alkyl, fluorophenyl, difluorophenyl, pyridyl, CH 2 SO 2 CH 3 , or NA 1 A 2 , wherein said C (3-6) cycloalkyl is optionally substituted with OCH 3 , two fluoro groups or two methyl groups;
A 1 is H, or C (1-3) alkyl; wherein said C (1-3) alkyl is optionally substituted with up to five fluorine atoms, Cl, —CN, OCH 3 , OCHF 2 , or OCF 3 ;
A 2 is C (1-4) alkyl, C (0-2) alkyl-C (3-6) cycloalkyl, CH 2 —C 6 H 4 —C(O)NH 2 , —C 6 H 4 —F, or CH 2 —CCH; wherein said C (1-4) alkyl, and said C (0-2) alkyl-C (3-6) cycloalkyl are optionally substituted with up to three fluorine atoms, Cl, —CN, OCH 3 , OCHF 2 , or OCF 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:

thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and morpholinyl; wherein said piperidinyl, pyrrolidinyl, piperazinyl, and morpholinyl are optionally substituted with CF 3 , CH 2 F, CH 2 CH 2 F, C (1-2) alkyl, —CN, OH, CH 2 OH, F, Cl, OCH 3 , OCHF 2 , or OCF 3 , and up to three additional substituents selected from the group consisting of CH 3 , and F;

R 5 is SO 2 NA 3 A 4 , C (1-6) alkyl,

 wherein said C (1-6) alkyl is optionally substituted with OH, Cl, —CN, OCH 3 , OCHF 2 , OCF 3 , or NA 3 A 4 ; and up to six fluorine atoms;
A 3 is H, or C (1-4) alkyl; wherein said C (1-4) alkyl is optionally substituted with OH, Cl, —CN, OCH 3 , OCHF 2 , or OCF 3 ; and up to six fluorine atoms;
A 4 is C (1-6) alkyl, C (3-6) cycloalkyl, oxetanyl, or tetrahydrofuranyl; wherein said C (1-6) alkyl is optionally substituted with cyclopropyl, morpholinyl, OH, OCH 3 , or C(O)NH 2 , and additionally substituted with up to three fluorine atoms; and wherein said C (3-6) cycloalkyl, oxetanyl, and tetrahydrofuranyl are optionally substituted with CF 3 , CH 3 , —CN, or C(O)NH 2 ;
or A 3 and A 4 can be taken together with their attached nitrogen to form a ring selected from the group consisting of azetidinyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl wherein said azetidinyl, piperidinyl, morpholinyl, and piperazinyl are optionally substituted with up to four groups selected from the group consisting of CF 3 , OH, and CH 3 ; and further optionally substituted with up to six fluorine atoms;

R 7 is H, F, OH, or OCH 3 ;
R 8 is H;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein:

R 1 is H, Cl, OCF 3 , C (1-3) alkyl, —CN, F, OC (1-3) alkyl, OCHF 2 , or cyclopropyl, wherein said C (1-2) alkyl is optionally substituted with up to five fluorine atoms;
R 2 is CHF 2 , CF 3 , H, F, Cl, —CN,

 or R 1 and R 2 may be taken together with their attached ring A to form a fused ring system selected from the group consisting of naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl, wherein said naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl are optionally substituted with F, CHF 2 , CH 2 F, CF 3 , or CH 3 ; provided that R 2 may not be H if R 1 is H;
R 3 is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl, pyridyl, pyrimidyl, pyridazyl, or pyrazyl; wherein said oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, pyridyl, pyrimidyl, pyridazyl, or pyrazyl is optionally substituted with R 6 ;
R 6 is

 C (1-2) alkyl, CH 2 C(CH 3 ) 2 CO 2 H, C (0-1) alkylC(CH 3 ) 2 OH, CH 2 C(CH 3 ) 2 CN, C(O)NH 2 , or —CN; wherein said C (1-2) alkyl is optionally substituted with up to five fluorine atoms;

R 4 is C (3-6) cycloalkyl, isopropyl, C(CH 3 ) 2 OCH 3 , OC (1-4) alkyl, fluorophenyl, difluorophenyl, pyridyl, CH 2 SO 2 CH 3 , or NA 1 A 2 , wherein said C (3-6) cycloalkyl is optionally substituted with OCH 3 , two fluoro groups or two methyl groups;
A 1 is H, or C (1-3) alkyl; wherein said C (1-3) alkyl is optionally substituted with up to five fluorine atoms;
A 2 is C (1-4) alkyl, C (0-2) alkyl-C (3-6) cycloalkyl, CH 2 —C 6 H 4 —C(O)NH 2 , —C 6 H 4 —F, CH 2 —CCH, or CH 2 CH 2 —CN; wherein said C (1-4) alkyl, and said C (0-2) alkyl-C (3-6) cycloalkyl are optionally substituted with up to three fluorine atoms;
or A 1 and A 2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and morpholinyl; wherein said piperidinyl, pyrrolidinyl, piperazinyl, and morpholinyl are optionally substituted with CF 3 , CH 2 F, CH 2 CH 2 F, C (1-2) alkyl, —CN, OH, CH 2 OH, or F, and up to three additional substituents selected from the group consisting of CH 3 , and F;

R 5 is SO 2 NA 3 A 4 , C (1-6) alkyl,

 wherein said C (1-6) alkyl is optionally substituted with OH, OCH 3 , or, NA 3 A 4 , and up to six fluorine atoms;
A 3 is H, or C (1-4) alkyl;
A 4 is C (1-6) alkyl, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl; wherein said C (1-6) alkyl is optionally substituted with cyclopropyl, morpholinyl, OH, OCH 3 , or C(O)NH 2 , and additionally substitu

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Goldberg Steven
• Steeneck Christoph
• Gege Christian
• Kinzel Olaf
• Kleymann Gerald
• Hoffmann Thomas

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · 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