Heteroaryl substituted aminopyridine compounds

Patent metadata

Field	Value
Publication number	US-10618903-B2
Application number	US-201616314574-A
Country	US
Kind code	B2
Filing date	Jun 23, 2016
Priority date	Jun 24, 2015
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

Disclosed are compounds of Formula (I) Formula (I) or salts thereof, wherein HET is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[1,2-b]pyridazin-3-yl, and pyrazolo[1,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 R b ; and R 1 , R 3 , 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 oxazolyl, pyrazolyl, imidazo[1,2-b]pyridazin-3-yl, and pyrazolo[1,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 R b ;
each R b is independently selected from H, F, Cl, —CN, —NH 2 , C 1-3 alkyl, C 1-2 fluoroalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, —NH(C 1-3 alkyl), —NH(C 1-4 hydroxyalkyl), cyanophenyl, pyridinyl, and hydroxypyrrolidinyl;
R 1 is:
(i) C 3-6 alkyl substituted with 1 to 4 substituents independently selected from F, —CN, —OH, —OCH 3 , —OCD 3 , —NHC(O)(C 1-3 alkyl), —S(O) 2 (C 1-3 alkyl), and C 1-2 fluoroalkoxy;
(ii) —(CR y R y ) 1-3 R x or —(CH 2 ) 1-3 C(O)R x , wherein R x is phenyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophenyl, or C 4-6 cycloalkyl, each substituted with zero to 3 substituents independently selected from F, Cl, —OH, C 1-3 alkyl, C 1-2 alkoxy, and —S(O) 2 NH 2 ;
(iii) C 4-6 cycloalkyl substituted with zero to 2 substituents independently selected from —OH, C 1-4 hydroxyalkyl, C 1-3 alkoxy, —(CH 2 ) 1-3 O(C 1-3 alkyl), —C(O)NH(C 1-4 alkyl), —C(O)NH(C 3-6 cycloalkyl), —N(C 1-3 alkyl) 2 , —NHC(O)(C 1-3 alkyl), —NHC(O)O(C 1-3 alkyl), and —NHC(O)(C 1-4 hydroxyalkyl);
(iv) tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, or triazolyl, each substituted with zero to 2 substituents independently selected from C 1-4 hydroxyalkyl, —S(O) 2 (C 1-3 alkyl), —CH 2 C(O)NH(C 1-3 alkyl), —CH 2 C(O)NH(C 1-6 hydroxyalkyl), —CH 2 C(O)NH(C 1-6 fluoroalkyl), and —CH 2 C(O)NH(C 1-6 hydroxy-fluoroalkyl);
or

(v) 1-oxa-7-azaspiro[3.5]nonanyl;

each R y is independently H, F, or —OH; and
R 3 is:
(i) C 2-5 alkyl, C 2-5 fluoroalkyl, C 2-5 hydroxyalkyl, —(CH 2 ) 1-3 R z , —CH(CH 3 )R z , or —CH(CH 2 OH)CH 2 R z , wherein R z is C 4-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl, each substituted with zero to 1 substituent selected from —OH and —CH 3 ;
(ii) C 3-6 cycloalkyl substituted with zero to 3 substituents independently selected from F, Cl, —CN, —OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), and —C(O)(C 1-3 fluoroalkyl);
(iii) oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, thiazolyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, each substituted with zero to 2 substituents independently selected from F, —OH, C 1-4 alkyl, C 1-3 hydroxyalkyl, C 1-4 fluoroalkyl, —CH 2 (C 3-6 cycloalkyl), —(CH 2 ) 1-3 O(C 1-3 alkyl), —C(O)(C 1-3 fluoroalkyl), —S(O) 2 (C 1-3 alkyl), C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, fluoropyrimidinyl, and methoxypyrimidinyl; or
(iv) phenyl substituted with zero to 3 substituents independently selected from F, Cl, —CN, —OH, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), and —C(O)(C 1-3 fluoroalkyl).

2. The compound according to claim 1 or a salt thereof, wherein:
HET is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[1,2-b]pyridazin-3-yl, and pyrazolo[1,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 R b ;
each R b is independently selected from H, F, Cl, —CN, —NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, —NH(C 1-3 alkyl), —NH(C 1-4 hydroxyalkyl), cyanophenyl, pyridinyl, and hydroxypyrrolidinyl;
R 1 is:
(i) C 3-6 alkyl substituted with 1 to 4 substituents independently selected from F, —OH, —OCH 3 , and —OCD 3 ;
(ii) —(CR y R y ) 1-3 R x or —(CH 2 ) 1-3 C(O)R x , wherein R x is phenyl, tetrahydropyranyl, oxetanyl, morpholinyl, or C 4-6 cycloalkyl, each substituted with zero to 3 substituents independently selected from F, Cl, —OH, C 1-3 alkyl, C 1-2 alkoxy, and —S(O) 2 NH 2 ;
(iii) C 4-6 cycloalkyl substituted with C 1-4 hydroxyalkyl, C 1-3 alkoxy, —C(O)NH(C 1-4 alkyl), —C(O)NH(C 3-6 cycloalkyl), —NHC(O)(C 1-3 alkyl), or —NHC(O)(C 1-4 hydroxyalkyl);
(iv) tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, or triazolyl, each substituted with zero to 2 substituents independently selected from C 1-4 hydroxyalkyl, —S(O) 2 (C 1-3 alkyl), —CH 2 C(O)NH(C 1-3 alkyl), —CH 2 C(O)NH(C 1-6 hydroxyalkyl), —CH 2 C(O)NH(C 1-6 fluoroalkyl), and —CH 2 C(O)NH(C 1-6 hydroxy-fluoroalkyl); or
(v) 1-oxa-7-azaspiro[3.5]nonanyl;

each R y is independently H, F, or —OH; and
R 3 is:
(i) C 2-5 alkyl, C 2-5 fluoroalkyl, C 2-5 hydroxyalkyl, —(CH 2 ) 1-3 R z , —CH(CH 3 )R z , or —CH(CH 2 OH)CH 2 R z , wherein R z is C 4-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl, each substituted with zero to 1 substituent selected from —OH and —CH 3 ;
(ii) C 3-6 cycloalkyl substituted with zero to 3 substituents independently selected from F, Cl, —CN, —OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), and —C(O)(C 1-3 fluoroalkyl);
(iii) oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, thiazolyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.1]heptanyl, each substituted with zero to 2 substituents independently selected from F, —OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, —C(O)(C 1-3 fluoroalkyl), —S(O) 2 (C 1-3 alkyl), oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, fluoropyrimidinyl, and methoxypyrimidinyl; or
(iv) phenyl substituted with zero to 3 substituents independently selected from F, Cl, —CN, —OH, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), and —C(O)(C 1-3 fluoroalkyl).

3. The compound according to claim 1 or a salt thereof, wherein:
each R b is independently selected from H, F, Cl, —CN, —NH 2 , —CH 3 , —CHF 2 , —OCH 3 , cyclopropyl, —NHCH 2 CH 2 OH, —NHCH 2 C(CH 3 ) 2 OH, cyanophenyl, pyridinyl, and hydroxypyrrolidinyl;
R 1 is:
(i) —CH 2 CH 2 C(CH 3 ) 3 , —CH 2 CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 C(CH 3 ) 2 F, —CH 2 CHFC(CH 3 ) 2 F, —CH 2 CH 2 C(CH 3 ) 2 CN, —CH 2 CHFC(CH 3 ) 2 OH, —CH 2 CHFC(CH 2 OH) 2 OH, —CH 2 CF 2 C(CH 3 ) 2 OH, —CH 2 CH 2 CH(CH 3 )NHC(O)CH 3 , —CH 2 CHFC(CH 3 ) 2 OCD 3 , —CH 2 CHFC(CH 3 ) 2 OCHF 2 , or —CH 2 CH 2 CH 2 S(O) 2 CH 3 ;
(ii) —CH 2 CH 2 (sulfamoylphenyl), —CH 2 CH 2 (fluorotetrahydropyranyl), —CH 2 CH 2 (hydrotetrahydropyranyl), —CH 2 CHF(hydroxyoxetanyl), —CH 2 CH 2 C(O)(morpholinyl), —CH 2 CH 2 (pyridinyl), —CH 2 CH 2 (thiophenyl), —CH 2 CH 2 (hydroxycyclopentyl), —CH 2 CH 2 (hydroxy, methoxycyclohexyl), —CH 2 CH 2 (dihydroxy, methylcyclohexyl), —CH 2 CH 2 CH 2 (imidazolyl), —CH 2 CHF(piperidinyl), or —CH 2 CHF(dimethyl tetrahydropyranyl);
(iii) cyclohexyl substituted with —OH, —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —N(CH 3 ) 2 , —C(O)NHCH 3 , —C(O)NHCH(CH 3 ) 2 , —C(O)NH(cyclopropyl), —NHC(O)CH 3 , —NHC(O)OCH 3 , —NHC(O)C(CH 3 ) 2 OH, or —NHC(O)CH(OH)CH 3 ;
(iv) piperidinyl, pyrazolyl, or tetrahydropyranyl, each substituted with —CH 2 OH, —S(O) 2 CH(CH 3 ) 2 , —CH 2 C(O)NHCH 3 , or —CH 2 C(O)NHCH 2 CHFC(CH 3 ) 2 OH; or
(iv) 1-oxa-7-azaspiro[3.5]nonanyl; and

R 3 is:
(i) —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CHF 2 , —CH 2 CH 2 CHF 2 , —CH 2 CH(CH 3 )F, —CH 2 CH 2 CHFCH 3 , —CH 2 C(CH 3 ) 2 F, —CH(CH 3 )CH 2 F, —CH(

Assignees

• Bristol Myers Squibb Co

Inventors

• Duncia John V
• Gardner Daniel S
• Hynes John
• Macor John E
• Murugesan Natesan
• Santella Joseph B
• Wu Hong
• Kantheti Durgarao
• Nair Satheesh Kesavan
• Paidi Venkatram Reddy
• Kumar Sreekantha Ratna
• Sarkunam Kandhasamy
• Sistla Ramesh Kumar
• Polimera Subba Rao

Classifications

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

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

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P37/06

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