Heteroaryl substituted pyridyl compounds useful as kinase modulators

Patent metadata

Field	Value
Publication number	US-10544133-B2
Application number	US-201816009389-A
Country	US
Kind code	B2
Filing date	Jun 15, 2018
Priority date	Nov 8, 2012
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

Compounds having the following formula:

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 , and —NHC(O)(C 1-3 alkyl); and
R 3 is oxetanyl, tetrahydropyranyl, or fluoro tetrahydropyranyl.

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, —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; 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 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), or —C(O)NH 2 .

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 ,

and
R 2 is

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 for 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

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

8. A compound according to claim 1 or a pharmaceutically-acceptable salt thereof, selected from:
(R)-6-((5-cyano-3-fluoropyridin-2-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide (49);
6-((5-cyano-3-fluoropyridin-2-yl)amino)-N-((1r,4r)-4-(methylcarbamoyl) cyclohexyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide (61);
N-((1r,4r)-4-acetamidocyclohexyl)-6-((3-chloro-5-cyanopyridin-2-yl)amino)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide (77);
6-((3-chloro-5-cyanopyridin-2-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorotetrahydro-2H-pyran-4-yl)amino)nicotinamide (79);
6-((5-cyano-3-fluoropyridin-2-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide (97-98);
6-((3,5-difluoropyridin-2-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorotetrahydro-2H-pyran-4-yl)amino)nicotinamide (108);
6-((3,5-difluoropyridin-2-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide (109-110);
6-((3-chloro-5-cyanopyridin-2-yl)amino)-N-((1 r,4r)-4-(methylsulfonyl)cyclohexyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide (149); and
(R)-6-((5-cyano-3-fluoropyridin-2-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide (164).

9. A pharmaceutical composition comprising one or more compounds according to claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• A61P43/00

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

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title