Amide substituted thiazoles as modulators of RORyt

Patent metadata

Field	Value
Publication number	US-9845319-B2
Application number	US-201514927502-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Oct 30, 2014
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

Abstract

The present invention comprises compounds of Formula I.

wherein:

R 1 , R 2 , R 3 , R 5 , A 1 , A 2 , 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:

is phenyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazyl;
R 1 is Cl, —CN, H, F, OC (1-4) alkyl, OCHF 2 ,

OCF 3 , C (1-4) alkyl, Br, I, or cyclopropyl; wherein said C (1-4) alkyl is optionally substituted with up to six fluorine atoms;
R 2 is F, Cl, —CN, H, OC (1-4) alkyl, 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 , 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, tetrahydronaphthalenyl, isoquinolinyl, quinolinyl, 2,3-dihydro-1H-indenyl, chromanyl, isochromanyl, and naphthyridinyl; wherein said naphthalenyl, tetrahydronaphthalenyl, isoquinolinyl, quinolinyl, 2,3-dihydro-1H-indenyl, chromanyl, isochromanyl, and naphthyridinyl may optionally be substituted with up to three substituents independently selected from the group consisting of F, OC (1-3) alkyl or C (1-3) alkyl wherein said OC (1-3) alkyl and C (1-3) alkyl is optionally substituted with up to five fluorine atoms (including CHF 2 , CH 2 F, CF 3 , and CH 3 ; provided that R 2 may not be H if R 1 is H;
R 3 is thiadiazolyl, oxadiazolyl, isoxadiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl, pyridyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, furanyl, or phenyl; wherein said thiadiazolyl, oxadiazolyl, isoxadiazolyl, oxazolyl, isoxazolyl, triazolyl, pyridyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, furanyl, or phenyl is optionally substituted with R 4 , and further optionally substituted with one substituent selected from the group consisting of F, CH 3 , CF 3 , and cyclopropyl;
R 4 is H, C (1-6) alkylSO 2 C (1-6) alkyl, C(O)NH 2 , C (1-6) alkyl, CN, C (3-6) cycloalkyl, NH 2 , NH(C (1-6) alkyl), N(C (1-6) alkyl) 2 , NHCO(C (1-6) alkyl), N(C (1-6) alkyl)CO(C (1-6) alkyl), NHSO 2 (C (1-6) alkyl), N(C (1-6) alkyl)SO 2 (C (1-6) alkyl), O(C (1-6) alkyl), C(O)NH 2 , CONH(C (1-6 )alkyl), CON(C (1-6) alkyl) 2 , SO 2 NH 2 , SO 2 NH(C (1-6) alkyl), SO 2 NH(COC (1-6) alkyl), or SO 2 N(C (1-6) alkyl) 2 ; wherein said C (1-6) alkyl or C (3-6) cycloalkyl is optionally substituted independently with up to six fluorine atoms, CF 3 , CO 2 H, OH, —CN, C(O)NH 2 , NH 2 , OCH 3 , OCHF 2 , OCF 3 , —(CX 2 ) m —, or N(CH 3 ) 2 ;
m is 2, 3, 4, or 5;
X is H, or F; wherein each occurance of X in a single molecule is independently defined;

A 1 is H, or C (1-4) alkyl; wherein said C (1-4) alkyl is optionally substituted with up to six fluorine atoms, Cl, —CN, OCH 3 , OCHF 2 , or OCF 3 ;
A 2 is C (1-6) 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 —CC—CH 3 ; wherein said C (1-6) alkyl, and said C (0-2) alkyl-C (3-6) cycloalkyl are optionally substituted with up to six 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, morpholinyl, azetidinyl, and aziridinyl;
wherein said piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, azetidinyl, and aziridinyl are optionally substituted with CF 3 , CH 2 CH 2 F, C (1-2) cycloalkyl, —CN, OH, CH 2 OH, CH 2 F, F, Cl, OCH 3 , OCHF 2 , OCF 3 , —(CX 2 ) n O(CX 2 ) n —, or —(CX 2 ) n —, and up to three additional substituents selected from the group consisting of CH 3 and F;
n is independently 0, 1, 2, 3, or 4;
X is H, or F; wherein each occurrence of X in a single molecule is independently defined;

R 5 is SO 2 NA 3 A 4 , CONA 3 A 4 , NA 3 A 4 , OCH 2 C(CF 3 ) 2 OH, C (3-6) cycloalkyl, or C (1-6) alkyl; wherein said C (3-6) cycloalkyl and said C (1-6) alkyl are optionally substituted with OH, Cl, —CN, H, OCH 3 , OCHF 2 , OCF 3 , or NA 3 A 4 , further optionally substituted with —CH 2 CH 2 — attached to the same carbon atom, and up to seven 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 H, C (1-6) alkyl, C (3-6) cycloalkyl, or C (3-6) heterocycloalkyl; wherein said C (1-6) alkyl is optionally substituted with cyclopropyl, morpholinyl, OH, OCH 3 , C(O)NH 2 , Cl, —CN, OCHF 2 , OCF 3 and additionally substituted with up to three fluorine atoms; and wherein said C (3-6) cycloalkyl, and C (3-6) heterocycloalkyl are optionally substituted with CF 3 , CH 3 , —CN, C(O)NH 2 , and up to three fluorine atoms;
or A 3 and A 4 can be taken together with their attached nitrogen to form a ring selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, aziridinyl, and azetidinyl wherein said piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, aziridinyl, and azetidinyl are optionally substituted with up to four groups selected from the group consisting of CF 3 , OH, CH 3 , CH 2 F, and CHF 2 ; and further optionally substituted with up to four groups selected from the group consisting of CF 3 , OH, CH 3 , CH 2 F, and CHF 2 ; and further optionally substituted with up to six fluorine atoms;
and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein:

R 1 is Cl, —CN, H, F, OCH 3 ,

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

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

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, CH 2 —CCH, or CH 2 —CC—CH 3 ; wherein said C (1-4) alkyl, and s

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutiuca NV

Inventors

• Goldberg Steven
• Venkatesan Hariharan
• Tanis Virginia
• Urbanski Maud
• Wang Aihua
• Kummer David
• Steeneck Christoph
• Gege Christian
• Kinzel Olaf
• Kleymann Gerald
• Hoffmann Thomas
• Fourie Anne M
• Xue Xiaohua

Classifications

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P29/00

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