Heteroaryl substituted aminopyridine compounds

Patent metadata

Field	Value
Publication number	US-10294229-B2
Application number	US-201615738362-A
Country	US
Kind code	B2
Filing date	Jun 23, 2016
Priority date	Jun 24, 2015
Publication date	May 21, 2019
Grant date	May 21, 2019

Abstract

Disclosed are compounds of Formula (I) or salts thereof, wherein HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3 d]pyrimidinyl, pyrazolo[3,4 b]pyridinyl, pyrazolo[3,4 d]pyrimidinyl, imidazolo[4,5 b]pyridinyl, and imidazolo[4,5 d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in said heteroaryl and wherein said heteroaryl is substituted with zero to 2 R b ; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each substituted with zero or 1 R a ; and R 3 , R a , and R b are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.

First claim

What is claimed is:

1. A compound of Formula (I)

or a salt thereof, wherein:
HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, imidazolo[4,5-b]pyridinyl, and imidazolo[4,5-d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in said heteroaryl and wherein said heteroaryl is substituted with zero to 2 R b ;
A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each substituted with R a ;
R 3 is C 2-3 alkyl, C 2-3 fluoroalkyl, C 3-4 hydroxyalkyl, or a cyclic group selected from C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, wherein said cyclic group is substituted with zero to 2 substituents independently selected from F, —OH, C 1-2 alkyl, and —CH 2 CHF 2 ;
R a is:
(i) H, F, Cl, —OH, —CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-4 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-5 hydroxy-fluoroalkyl, C 2-4 alkenyl, C 1-6 aminoalkyl, —(CH 2 ) 1-3 NHR y , —(CH 2 ) 1-3 NR y R y , —CH 2 CH(OH)(phenyl), —CH(CH 2 OH)(phenyl), —CH 2 CH(OH)CH 2 (phenyl), —CH 2 CH(OH)CH 2 O(methoxyphenyl), —CH 2 CH(NH 2 )CH 2 (phenyl), —(CH 2 CH 2 O) 4 H, —(CH 2 ) 1-3 O(C 1-3 alkyl), —CH 2 CH(OH)CH 2 O(C 1-3 alkyl), —CH 2 C(O)(C 1-3 alkyl), —CH 2 C(O)NR y R y , —(CH 2 ) 1-3 NR y C(O)(C 1-3 alkyl), —CH 2 C(O)O(C 1-3 alkyl), —C(O)NH 2 , —CH 2 NR y C(O)NH 2 , —(CH 2 ) 1-2 NR y C(O)O(C 1-2 alkyl), —(CR y R y ) 1-5 OC(O)CH 2 NR y R y , —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 S(O) 2 (C 1-3 alkyl), —CH 2 S(O) 2 (phenyl), or —NH(aminocyclohexyl); or
(ii) —(CH 2 ) 0-3 R z or —(CH 2 ) 0-1 C(O)R z , wherein R z is C 3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, dioxopyrimidinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, 1,3-dioxolanyl, or 8-azabicyclo[3.2.1]octanyl, each substituted with zero to 4 substituents independently from F, —CN, —OH, —NR y R y , C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, —CH(phenyl) 2 , —O(C 1-4 alkyl), —C(O)(C 1-4 alkyl), —C(O)(C 1-4 deuteroalkyl), —C(O)(C 1-5 hydroxyalkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)(C 3-6 cycloalkyl), —C(O)O(C 1-3 alkyl), —C(O)NR y R y , —C(O)(phenyl), —C(O)(pyridinyl), —C(O)CH 2 (C 3-6 cycloalkyl), —C(O)O(C 1-4 alkyl), —NH(C 1-4 alkyl), —NH(C 1-3 fluoroalkyl), —NHC(O)CH 3 , —NHC(O)O(C 1-3 alkyl), —NHC(O)OC(CH 3 ) 3 , —S(O) 2 (C 1-3 alkyl), —OS(O) 2 (C 1-3 alkyl), methyl oxadiazolyl, and pyrimidinyl;

each R b is independently selected from H, Cl, —CN, —NH 2 , and —C(O)NH 2 ; and
each R y is independently H or C 1-2 alkyl.

2. The compound according to claim 1 or a salt thereof, wherein:
HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, imidazolo[4,5-b]pyridinyl, and imidazolo[4,5-d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 R b ;
A is pyrazolyl, imidazolyl, or triazolyl, each substituted with R a ;
R 3 is —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CHF 2 , —CH(CH 3 )CH 2 OH, cyclopropyl, oxetanyl, tetrahydropyranyl, ethyl pyrazolyl, or 2,2-difluoroethyl pyrazolyl;
R a is:
(i) H, F, Cl, —OH, —CN, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-4 hydroxy-fluoroalkyl, C 2-4 alkenyl, C 1-6 aminoalkyl, —(CH 2 ) 1-3 NHR y , —(CH 2 ) 1-3 NR y R y , —CH 2 CH(OH)(phenyl), —CH(CH 2 OH)(phenyl), —CH 2 CH(OH)CH 2 (phenyl), —CH 2 CH(OH)CH 2 O(methoxyphenyl), —CH 2 CH(NH 2 )CH 2 (phenyl), —(CH 2 CH 2 O) 4 H, —(CH 2 ) 1-3 O(C 1-3 alkyl), —CH 2 CH(OH)CH 2 O(C 1-3 alkyl), —CH 2 C(O)(C 1-3 alkyl), —CH 2 C(O)NR y R y , —CH 2 C(O)O(C 1-3 alkyl), —C(O)NH 2 , —CH 2 NHC(O)NH 2 , —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 S(O) 2 (C 1-3 alkyl), or —CH 2 S(O) 2 (phenyl); or
(ii) —(CH 2 ) 0-3 R z or —CH 2 C(O)R z , wherein R z is C 3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrimidinonyl, benzo[d]imidazolyl, or benzo[d]thiazolyl, each substituted with zero to 4 substituents independently from F, —CN, —OH, —NR y R y , C 1-3 alkyl, C 1-3 fluoroalkyl, —CH(phenyl) 2 , —O(C 1-4 alkyl), —C(O)(C 1-4 alkyl), —C(O)(C 1-4 deuteroalkyl), —C(O)(C 3-6 cycloalkyl), —C(O)O(C 1-3 alkyl), —C(O)NR y R y , —C(O)(phenyl), —C(O)(pyridinyl), —C(O)CH 2 (C 3-6 cycloalkyl), —C(O)O(C 1-4 alkyl), —NHCH(CH 3 ) 2 , —NHC(O)CH 3 , —NHC(O)OCH 3 , —NHC(O)OC(CH 3 ) 3 , —S(O) 2 (C 1-3 alkyl), —OS(O) 2 (C 1-3 alkyl), methyl oxadiazolyl, and pyrimidinyl;

each R b is independently selected from H, Cl, —CN, —NH 2 , and —C(O)NH 2 ; and
each R y is independently H or C 1-2 alkyl.

3. The compound according to claim 1 or a salt thereof, wherein:
A is

R a is:
(i) H, —CN, C 1-5 alkyl, C 1-5 fluoroalkyl, C 1-3 cyanoalkyl, C 1-5 hydroxyalkyl, —CH 2 CH(OH)CF 3 , —CH 2 CHFC(CH 3 ) 2 OH, —CH 2 CH(OH)(phenyl), —CH(CH 2 OH)(phenyl), —CH 2 CH(OH)CH 2 (phenyl), —CH 2 CH(OH)CH 2 O(methoxyphenyl), —CH═CH 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 NHR y , —C(CH 3 ) 2 NH 2 , —(CH 2 ) 5 NH 2 , —CH 2 CH(NH 2 )CH 2 (phenyl), —CH 2 N(CH 2 CH 3 ) 2 , —(CH 2 CH 2 O) 4 H, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 OCH 2 CH 3 , —CH 2 CH(OH)CH 2 OCH 3 , —CH 2 CH(OH)CH 2 OCH 2 CH 3 , —CH 2 C(O)CH 3 , —CH 2 C(O)NH 2 , —CH 2 C(O)NHCH 3 , —CH 2 C(O)OCH 2 CH 3 , —C(O)NH 2 , —CH 2 NHC(O)NH 2 , —CH 2 NR y C(O)NH 2 , —(CH 2 ) 1-2 NR y C(O)O(C 1-2 alkyl), —CH 2 CH 2 CH 2 N(CH 3 )C(O)CH 3 , —CH 2 CH 2 NHC(O)OCH 3 , —CH 2 CH 2 C(CH 3 ) 2 OC(O)CH 2 NR y R, —(CH 2 ) 1-5 OC(O)CH 2 NR y R y , or —CH 2 CH 2 S(O) 2 CH 3 ;
(ii) cyclopropyl, cyclopentyl, hydroxycyclopentyl, oxetanyl, or cyclohexyl substituted with zero or one substituent selected from —OH, C 1-2 alkyl, —NH 2 , —NHCH(CH 3 ) 2 , —NHC(O)CH 3 , —NHC(O)O(C 1-3 alkyl), and —NHCH 2 CHF 2 ;
(iii) phenyl substituted with zero to 2 substituents independently selected from F, —CN, —OH, —OCH 3 , and —C(O)OCH 3 ;
(iv) —CH 2 (cyclopropyl), —CH 2 (difluorocyclopropyl), —CH 2 (cyclobutyl), —CH 2 (oxetanyl), —CH 2 (hydroxyoxetanyl), —CH 2 (morpholinyl), —CH 2 (phenyl), —CH 2 (fluorophenyl), —CH 2 (methoxyphenyl), —CH 2 (pyridinyl), —CH 2 (butoxycarbonyl, hydroxypiperidinyl), —CH 2 (butoxycarbonyl pyrrolidinyl), —CH 2 (acetylazetidinyl), —CH 2 (benzo[d]imidazolyl), —CH 2 (methyl benzo[d]thiazolyl), —CH 2 CH 2 (morpholinyl), —CH 2 CH 2 (phenyl), —CH 2 CH 2 (pyridinyl), —CH 2 CH 2 (dimethylpyrazolyl), —CH 2 CH 2 CH 2 (phenyl), —CH 2 CH 2 CH 2 (pyrrolidinyl), —CH 2 C(O)(morpholinyl), —CH 2 C(O)(piperazinyl), —CH 2 C(O)(acetylpiperazinyl), —CH 2 C(O)(methylsulfonyl piperazinyl), —CH 2 CH(NH 2 )CH 2 (phenyl), —CH 2 S(O) 2 (phenyl), —C(O)(morpholinyl), or —NH(aminocyclohexyl);
(v) pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, pyrrolidinonyl, dioxopyrimidinyl, imidazolyl, 1,3-dioxolanyl, 8-azabicyclo[3.2.1]octanyl, or azetidinyl substituted with zero to 4 substituents independently selected from —CN, —OH, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 OH, —C(O)cyclopropyl, —C(O)phenyl, —C(O)CH 3 , —C(O)CD 3 , —C(O)CH(CH 3 ) 2 , —C(O)C(CH 3 ) 3 , —C(

Assignees

• Bristol Myers Squibb Co

Inventors

• Gardner Daniel S
• Santella Joseph B
• Paidi Venkatram Reddy
• Wu Hong
• Duncia John V
• Nair Satheesh Kesavan
• Hynes John
• Zhu Xiao

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · 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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title