Bicyclic heterocycle substituted pyridyl compounds useful as kinase modulators

Patent metadata

Field	Value
Publication number	US-9546153-B2
Application number	US-201314441698-A
Country	US
Kind code	B2
Filing date	Nov 7, 2013
Priority date	Nov 8, 2012
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

Compounds having the following formula (I) or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein R 2 is a bicyclic heterocycle, and R 1 , R 3 , R 4 , R 5 and R 6 are as defined herein, that are useful as kinase modulators, including IRAK-4 modulation.

First claim

What is claimed is:

1. A compound of Formula (II)

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is:
(a) C 2-3 hydroxyalkyl substituted with zero to 4 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CN, —CF 3 , —OCH 3 , and cyclopropyl;
(b) C 4-8 alkyl substituted with zero to 7 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CF 3 , —CN—OCH 3 , and cyclopropyl;
(c) —(CH 2 ) 2-4 NHC(O)(C 1-6 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(C 1-6 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)O(C 1-6 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 NH(C 1-6 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 N(C 1-4 alkyl) 2 , —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 (C 3-6 cycloalkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 (C 3-6 fluorocycloalkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(C 1-6 hydroxyalkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)N(C 1-3 alkyl)(phenyl), or —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 R wherein R is phenyl, morpholinyl, pyrrolidinyl, triazolyl, or tetrahydropyranyl;
(d) cyclohexyl substituted with zero to 2 substituents selected from —OH, —OCH 3 , ═O, —NH 2 , C 1-6 alkyl, C 1-6 hydroxyalkyl, —NHS(O) 2 CH 3 , —NO 2 , —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), —C(O)NH(C 1-6 hydroxyalkyl), —C(O)NH(C 3-6 cycloalkyl), —C(O)NH(C 3-6 cyano cycloalkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)(pyridinyl), —NHC(O)(morpholinyl), —NHC(O)(hydroxy bicyclo[2.2.1]heptanyl), —NHC(O)NH(C 1-4 alkyl), and methyl pyrazolyl; or
(e) —(CH 2 ) 2 (phenyl) wherein said phenyl is substituted with —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), or —S(O) 2 NH 2 ; or
(f)

R 2 is benzooxazolyl, pyrazolopyridinyl, pyrrolopyridinyl, benzothiazolyl, thiazolopyridinyl, pyrazolopyrimidinyl, benzooxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1, 5-naphthyrindinyl, pyridopyrazinyl, or pyridopyrimidinyl, each substituted with zero to 2 substituents independently selected from F, Cl, —CH 3 , —CN, —NH 2 , —OCH 3 , ═O, and —C(O)NH 2 ;
R 3 is:
(a) C 2-6 alkyl or C 2-6 fluoroalkyl;
(b) C 1-3 alkyl substituted with 1 to 2 cyclopropyl;
(c) C 1-3 alkyl substituted with phenyl, tetrahydrofuranyl, or morpholinyl;
(d) C 2-6 hydroxyalkyl substituted with zero to 3 substituents selected from F, phenyl, fluorophenyl, difluorophenyl, and dichlorophenyl;
(e) —(CH 2 ) 0-2 (C 3-7 cycloalkyl) substituted with zero to 2 substituents selected from F, —OH, C 1-3 hydroxyalkyl, —CH 3 , —CF 2 H, —NH 2 , and —C(O)OCH 2 CH 3 ;
(f) tetrahydropyranyl or tetrahydrothiopyranyl substituted with zero to 1 substituent selected from F and —CH 3 ;
(g) —(CH 2 ) 0-2 phenyl wherein said phenyl is substituted with zero to 2 substituents selected from F, Cl, C 1-3 alkyl, C 1-3 hydroxyalkyl, —OH, —O(C 1-3 alkyl), —OCF 3 , —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), —C(O)NH(C 1-3 fluoroalkyl), —C(O)NH(C 1-3 hydroxyalkyl), —C(O)NH(C 3-5 cycloalkyl), —C(O)N(C 1-3 alkyl) 2 , —S(O) 2 CH 3 , and pyrazolyl;
(h) thiazolyl substituted with zero to 2 substituents selected from C 1-3 hydroxyalkyl; or
(i)

2. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is:
(a) hydroxypropyl substituted with zero to 3 R 1a wherein R 1a is independently selected from F, —CF 3 , and cyclopropyl;
(b) C 4-8 alkyl substituted with zero to 5 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CF 3 , —CN—OCH 3 , and cyclopropyl;
(c) —(CH 2 ) 2-4 NHC(O)(C 1-3 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(C 1-3 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)O(C 1-3 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 NH(C 1-3 alkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 N(C 1-3 alkyl) 2 , —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 (C 3-6 cycloalkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 (C 3-6 fluorocycloalkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(C 1-6 hydroxyalkyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)N(CH 3 )(phenyl), or —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 R wherein R is phenyl, morpholinyl, pyrrolidinyl, triazolyl, or tetrahydropyranyl;
(d) cyclohexyl substituted with zero or 2 substituents selected from —OH, —OCH 3 , ═O, —NH 2 , C 1-3 alkyl, C 1-3 hydroxyalkyl, —NHS(O) 2 CH 3 , —NO 2 , —C(O)NH 2 , —C(O)NH(C 1-2 alkyl), —C(O)NH(C 1-4 hydroxyalkyl), —C(O)NH(C 3-6 cycloalkyl), —C(O)NH(C 3-4 cyano cycloalkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)(pyridinyl),—NHC(O)(morpholinyl), —NHC(O)(hydroxy bicyclo[2.2.1]heptanyl), —NHC(O)NH(C 1-4 alkyl), and methyl pyrazolyl;
(e) —(CH 2 ) 2 (phenyl) wherein said phenyl is substituted with —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), or —S(O) 2 NH 2 ; or —CH 2 (phenyl); or
(f)

3. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is: —CH 2 CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 C(CH 3 ) 2 OH, —CH 2 CHFCH 2 OH, —CH 2 CHFCH(CH(CH 3 ) 2 )OH, —CH 2 CHFCH(cyclopropyl)OH, —CH 2 CHFCH(CH 3 )OH, —CH 2 CHFCH(cyclopropyl)(CF 3 )OH, —CH 2 CHFC(CH 3 ) 2 OH, —CH 2 CHFC(CH 3 )(CH 2 CH 3 )OH, —CH 2 CHFC(CH 2 CH 3 ) 2 OH, —CH 2 CHFC(CH 3 )(CF 3 )OH, —CH 2 CF 2 C(CH 3 ) 2 OH, —(CH 2 ) 2 NHC(O)CH 3 , —(CH 2 ) 3 NHC(O)CH 3 , —(CH 2 ) 4 NHC(O)CH 3 , —(CH 2 ) 2 CH(CH 3 )NHC(O)CH 3 , —(CH 2 ) 2 CH(CH 3 )NHC(O)OCH(CH 3 ) 2 , —(CH 2 ) 2 CH(CH 3 )NHC(O)OC(CH 3 ) 3 , —(CH 2 ) 2 CH(CH 3 )NHC(O)CH 2 N(CH 3 ) 2 , —(CH 2 ) 2 CH(CH 3 )NHC(O)NHCH(CH 3 ) 2 , —(CH 2 ) 2 CH(CH 3 )NHC(O)(cyclopropyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(3-fluorocyclopentyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(3,3-difluorocyclopentyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(morpholinyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(phenyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(pyrrolidinyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)CH 2 (tetrahydropyranyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)CH 2 (2,2-difluorocyclohexyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)CH 2 (triazolyl), —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 3 C(CH 3 ) 2 OH, —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 4 C(CH 3 ) 2 OH, —(CH 2 ) 2 CH(CH 3 )NHC(O)N(CH 3 )(phenyl),

R 2 is:

and
R 3 is: C 2-5 alkyl, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHFCH 3 , —CH 2 CF 2 CH 3 , —CH(CH 3 )CF 3 , CH 2 CF(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 2 F, —CH(CH 3 )(cyclopropyl), —CH(cyclopropyl) 2 , —CH 2 (cyclopropyl), —CH 2 (tetrahydrofuranyl), —CH 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —(CH 2 ) 2 (cyclopropyl), C 3-7 cycloalkyl, tetrahydropyranyl, tetrahydrothiopyranyl, —CH(CH 3 )CH 2 OH, —CH(phenyl)CH 2 OH, —CH 2 CF 2 C(CH 3 ) 2 OH, —CH(phenyl)CH(OH)CH 2 OH, —CH(3-fluorophenyl)CH(OH)CH 2 OH, —CH(3,5-difluorophenyl)CH(OH)CH 2 OH, —CH(2,5-difluorophenyl)CH(OH)CH

Assignees

• Bristol Myers Squibb Co

Inventors

• Bhide Rajeev S
• Duncia John V
• Hynes John
• Nair Satheesh K
• Pitts William J
• Kumar Sreekantha R
• Gardner Daniel S
• Murugesan Natesan
• Paidi Venkatram Reddy
• Santella Joseph B
• Sistla Ramesh
• Wu Hong

Classifications

• A61P37/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title