Heteroaryl substituted pyridyl compounds useful as kinase modulators

Patent metadata

Field	Value
Publication number	US-9657009-B2
Application number	US-201314441705-A
Country	US
Kind code	B2
Filing date	Nov 7, 2013
Priority date	Nov 8, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

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

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 1-3 alkyl substituted with —O(C 1-3 alkyl) and zero to 4 R 1a wherein R 1a is independently selected from F, Cl, —OH, —CHF 2 , —CN, —CF 3 , and cyclopropyl;
(c) 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 , cyclopropyl, and —OP(O)(OH) 2 ;
(d) —(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)(CH 2 ) 0-1 NH(C 1-6 alkyl), or —(CH 2 ) 2 CH(CH 3 )NHC(O)(CH 2 ) 0-1 N(C 1-4 alkyl) 2 ;
(e) cyclohexyl substituted with zero to 2 substituents independently selected from —OH, —OCH 3 , C 1-6 alkyl, C 1-6 hydroxyalkyl, —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 fluoro cycloalkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)O(C 1-3 alkyl), —NHS(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 (C 1-3 alkyl), —S(C 1-3 alkyl), and C 1-3 alkyl substituted with —OH and cyclopropyl; or
(f) —(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 ;

R 2 is pyridinyl substituted with zero to 2 substituents independently selected from F, Cl, —OH, —CN, C 1-3 alkyl, —CH 2 C(O)OCH 3 , —O(C 1-3 alkyl), —NH 2 , —NH(C 1-3 alkyl), —NH(cyclopropyl), —C(O)NH 2 , —NHC(O)(C 1-3 alkyl), and ═O; and
R 3 is:
(a) C 1-6 alkyl substituted with zero to 4 substituents independently selected from F, —OH, —CH 3 , —CF 3 , and C 3-6 cycloalkyl;
(b) C 3-6 cycloalkyl substituted with zero to 2 substituents independently selected from F, —OH, C 1-3 hydroxyalkyl, —CH 3 , —CF 2 H, —NH 2 , and —C(O)OCH 2 CH 3 ;
(c) phenyl substituted with zero to 2 substituents independently selected from —OH, —CN, —O(C 1-3 alkyl), C 1-3 hydroxyalkyl, —C(O)NH 2 , —S(O) 2 NH 2 , and —NHS(O) 2 (C 1-3 alkyl); or
(d)

2. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is:
(a) C 1-3 alkyl substituted with —O(C 1-3 alkyl) and zero to 4 R 1a wherein R 1a is independently selected from F, —OH, and —CF 3 ;
(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 , cyclopropyl, and —OP(O)(OH) 2 ;
(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)NH(C 1-3 alkyl), or —(CH 2 ) 2 CH(CH 3 )NHC(O)N(C 1-3 alkyl) 2 ;
(d) cyclohexyl substituted with zero to 2 substituents independently selected from —OH, —OCH 3 , C 1-3 alkyl, C 1-3 hydroxyalkyl, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), —C(O)NH(C 3-5 cycloalkyl), —C(O)NH(fluoro cyclopropyl), —NHC(O)(C 1-3 alkyl), —NHC(O)O(C 1-3 alkyl), —S(O) 2 NH 2 , —S(O) 2 (C 1-2 alkyl), —S(C 1-2 alkyl), and C 1-3 alkyl substituted with —OH and cyclopropyl; or
(e) —(CH 2 ) 2 (phenyl) wherein said phenyl is substituted with —C(O)NH 2 , —C(O)NH(CH 3 ), or —S(O) 2 NH 2 ;

and
R 3 is:
(a) C 1-5 alkyl substituted with zero to 3 substituents independently selected from F, —OH, —CH 3 , —CF 3 , and cyclopropyl;
(b) C 3-6 cycloalkyl substituted with zero to 2 substituents independently selected from F, —OH, C 1-3 hydroxyalkyl, —CH 3 , —CF 2 H, —NH 2 , and —C(O)OCH 2 CH 3 ;
(c) phenyl substituted with zero to 2 substituents independently selected from —OH, —CN, —OCH 3 , C 1-2 hydroxyalkyl, —C(O)NH 2 , —S(O) 2 NH 2 , and —NHS(O) 2 CH 3 ; or
(d)

3. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is: —CH 2 CHFC(CH 3 ) 2 OH, —CH 2 CHFC(CH 3 ) 2 OCH 3 , —CH 2 CHFC(CH 2 CH 3 ) 2 OH, —CH 2 CHFCH 2 OCH 3 , —(CH 2 ) 3 OCH 3 , —(CH 2 ) 3 OC(CH 3 ) 3 , —CH 2 CF 2 C(CH 3 ) 2 OH, —(CH 2 ) 2 CH(CH 3 )NHC(O)CH 3 , —(CH 2 ) 2 CH(CH 3 )NHC(O)NHCH(CH 3 ) 2 , —CH 2 CHFC(CH 3 ) 2 OP(O)(OH) 2 ,

R 2 is

and
R 3 is C 2-5 alkyl, —CH 2 CF 3 , —CH 2 C(CH 3 ) 2 F, —CH(CH 3 )CHFCH 3 , —CH(CH 3 )CH 2 F, —CH(CH 3 )CH 2 CH 2 F, —CH(CH 3 )CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CF 2 C(CH 3 ) 2 OH, —CH(CH 3 )(cyclopropyl), C 3-4 cycloalkyl,

4. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 1 is:
(a) C 1-3 alkyl substituted with —O(C 1-3 alkyl) and zero to 4 R 1a wherein R 1a is independently selected from F, —OH, and —CF 3 ;
(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 , cyclopropyl, and —OP(O)(OH) 2 ; or
(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)NH(C 1-3 alkyl), or —(CH 2 ) 2 CH(CH 3 )NHC(O)N(C 1-3 alkyl) 2 .

5. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 1 is cyclohexyl substituted with zero to 2 substituents independently selected from —OH, —OCH 3 , C 1-3 alkyl, —OCH 3 , C 1-3 hydroxyalkyl, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), —C(O)NH(C 3-5 cycloalkyl), —C(O)NH(fluoro cyclopropyl), —NHC(O)(C 1-3 alkyl), —NHC(O)O(C 1-3 alkyl), —S(O) 2 NH 2 , —S(O) 2 (C 1-2 alkyl), —S(C 1-2 alkyl), and C 1-3 alkyl substituted with —OH and cyclopropyl.

6. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 3 is C 2-5 alkyl, —CH 2 CF 3 , —CH 2 C(CH 3 ) 2 F, —CH(CH 3 )CHFCH 3 , —CH(CH 3 )CH 2 F, —CH(CH 3 )CH 2 CH 2 F, —CH(CH 3 )CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CF 2 C(CH 3 ) 2 OH, or —CH(CH 3 )(cyclopropyl).

7. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 3 is C 3-4 cycloalkyl,

8. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 3 is

9. The compound according to claim 1 or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 2 is

10. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

11. A compound according to claim 1 or a pharmaceutically-acceptable salt thereof, selected from:
6-((5-Cyano-2-pyridinyl)amino)-4-(((1S,2S)-2,3-dihydroxy-1-phenylpropyl)amino)-N-methylnicotinamide (1);
6-((5-Cyano-2-pyridinyl)amino)-N-((2R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (2);
(R)-6-((5-cyanopyridin-2-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(2,2,2-trifluoroethyl)amino)nicotinamide (3);
(R)-6-((5-cyanopyridin-2-y

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

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title