Substituted 2-aminopyridine protein kinase inhibitor

Patent metadata

Field	Value
Publication number	US-9708295-B2
Application number	US-201414765313-A
Country	US
Kind code	B2
Filing date	Jan 27, 2014
Priority date	Feb 2, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention discloses substituted 2-aminopyridine derivatives as protein kinase inhibitors; specifically, the invention relates to 2-aminopyridine derivatives having protein kinase inhibitory properties, their manufacture, pharmaceutical compositions containing them, and use of the compounds and the pharmaceutical compositions thereof for the treatment of diseases associated with protein kinase.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
A 1 is selected from the group consisting of hydrogen, —O—(CHR 1 )-A 4 , —CH 2 OR 2 , and aryl substituted by one or more R 3 (s);
R 1 is selected from the group consisting of methyl and methyl substituted by one to three halogen(s);
A 4 is selected from the group consisting of aryl optionally substituted by one or more R 4 (s);
R 2 is selected from the group consisting of aryl optionally substituted by one or more R 3 (s);
R 3 is selected from the group consisting of halogen, —SO 2 (C 1-6 alkyl), —SO 2 NR 6 R 7 , —NR 6 R 7 , —NHSO 2 (C 1-6 alkyl), and —P(O)R 6 R 7 ;
R 4 is selected from the group consisting of halogen, C 1-6 alkyl, —NR 6 R 7 , and —P(O)R 6 R 7 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, or R 6 and R 7 link to form a 3-12 membered heteroalicyclyl with the atom to which they are attached to;
A 2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, and pyrazolyl, all of which are optionally substituted by one or more substituent(s) selected from the group consisting of halogen and —OC 1-6 alkyl in which each hydrogen of the C 1-6 alkyl moiety is optionally substituted by hydroxy, carboxyl, or 3-12 membered heteroalicyclyl;
A 5 is a 3-12 membered heteroalicyclyl, which is optionally substituted by one or more substituent(s) selected from the group consisting of
═O,
unsubstituted C 1-6 alkyl, and
C 1-6 alkyl substituted by one or more substituent(s) independently selected from the group consisting of hydroxy, carboxyl, and 3-12 membered heteroalicyclyl, and
3-12 membered heteroalicyclyl;

A 3 is selected from the group consisting of hydrogen, —NH-aryl, heteroaryl substituted by aryl, heteroaryl substituted by heteroaryl, heteroaryl substituted by arylalkyl, heteroaryl substituted by heteroarylalkyl, heteroarylethynyl substituted by arylalkyl, and heteroarylethynyl substituted by heteroarylalkyl, wherein each of the aryl and heteroaryl is optionally substituted by one or more substituent(s) selected from the group consisting of
halogen,
C 1-6 alkyl optionally substituted by halogen, hydroxy or 3-12 membered heteroalicyclyl, and
—OH, —OC 1-6 alkyl, —CN, —COOH, —C 1-6 -alkyl-NH 2 , —C 1-6 -alkyl-NH(C 1-6 alkyl), —C 1-6 -alkyl-N(C 1-6 alkyl) 2 , —COO—C 1-6 alkyl, —SO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —NR 6 R 7 , —NHSO 2 (C 1-6 alkyl), and —P(O)R 6 R 7 ;

with the proviso that
A 1 and A 3 are not both hydrogen, and one of A 1 and A 3 must be hydrogen; and
when A 1 is —O—(CHR 1 )-A 4 and R 1 is methyl, A 2 is substituted by at least one —OC 1-6 alkyl; and
when A 1 is aryl substituted by one or more R 3 (s) and R 3 is —NR 6 R 7 , R 6 and R 7 are each independently selected from the group consisting of C 1-6 alkyl, or R 6 and R 7 link to form a 3-12 membered heteroalicyclyl with the atom to which they are attached to;

and
the pharmaceutically acceptable salts, stereoisomers, and enantiomers thereof, and mixtures thereof.

2. The compound of claim 1 , wherein
A 3 is selected from the group consisting of —NH-phenyl, heteroaryl substituted by phenyl, heteroaryl substituted by heteroaryl, heteroaryl substituted by phenylmethyl, heteroaryl substituted by heteroarylmethyl, heteroarylethynyl substituted by phenylmethyl, and heteroarylethynyl substituted by heteroarylmethyl, wherein each of the phenyl and heteroaryl is optionally substituted by one or more substituent(s) selected from the group consisting of
halogen,
C 1-6 alkyl optionally substituted by halogen, hydroxy, or 3-12 membered heteroalicyclyl, and
—OH, —OC 1-6 alkyl, —CN, —COOH, —C 1-6 -alkyl-NH 2 , —C 1-6 -alkyl-NH(C 1-6 alkyl), —C 1-6 -alkyl-N(C 1-6 alkyl) 2 , —COOC 1-6 alkyl, —SO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —NR 6 R 7 , —NHSO 2 (C 1-6 alkyl), and —P(O)R 6 R 7 ; or preferably,

A 3 is selected from the group consisting of —NH-phenyl, heteroaryl substituted by phenyl, heteroaryl substituted by heteroaryl, heteroaryl substituted by phenylmethyl, heteroaryl substituted by heteroarylmethyl, heteroarylethynyl substituted by phenylmethyl, and heteroarylethynyl substituted by heteroarylmethyl, wherein each of the phenyl and heteroaryl is optionally substituted by one or more substituent(s) selected from the group consisting of
halogen,
C 1-4 alkyl optionally substituted by halogen, hydroxy or 5 or 6 membered heteroalicyclyl, and
—OH, —OC 1-4 alkyl, —CN, —COOH, —C 1-4 -alkyl-NH 2 , —C 1-4 -alkyl-NH(C 1-4 alkyl), —C 1-4 -alkyl-N(C 1-4 alkyl) 2 , —COOC 1-4 alkyl, —SO 2 (C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —SO 2 NH(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHSO 2 (C 1-4 alkyl), and —P(O)(C 1-4 alkyl) 2 ; or more preferably,

A 3 is selected from the group consisting of —NH-phenyl, pyrazolyl substituted by phenyl, pyrazolyl substituted by phenylmethyl, and pyrazolylethynyl substituted by phenylmethyl, wherein phenyl is optionally substituted by one or more substituent(s) selected from the group consisting of
halogen,
C 1-4 alkyl substituted by halogen or hydroxy, and
—OH, —OC 1-4 alkyl, —CN, —COOH, —C 1-4 alkyl NH 2 , —C 1-4 alkyl NH(C 1-4 alkyl), —C 1-4 alkyl N(C 1-4 alkyl) 2 , —COOC 1-4 alkyl, —SO 2 (C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHSO 2 (C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —SO 2 NH(C 1-4 alkyl), and —P(O)(C 1-4 alkyl) 2 ; or most preferably,

A 3 is selected from the group consisting of —NH-phenyl, pyrazolyl substituted by phenyl, pyrazolyl substituted by phenylmethyl, and pyrazolylethynyl substituted by phenylmethyl, wherein phenyl is optionally substituted by one or more substituent(s) selected from the group consisting of F, Cl, trifluoromethyl, —COOH, —CH 2 OH, —OCH 3 , —OC 2 H 5 , —CN, —SO 2 NHCH(CH 3 ) 2 , —COOCH 3 , —SO 2 CH 3 , —NH 2 , and —P(O)(CH 3 ) 2 .

3. The compound of claim 1 , wherein A 3 is hydrogen.

4. The compound of claim 3 , wherein
R 2 is selected from the group consisting of phenyl optionally substituted by one or more R 3 (s); or preferably,
R 2 is selected from the group consisting of phenyl optionally substituted by one or more R 3 (s) selected from the group consisting of halogen, —SO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NHSO 2 (C 1-6 alkyl), and —P(O)(C 1-6 alkyl) 2 ; or more preferably,
R 2 is selected from the group consisting of phenyl substituted by one or more R 3 (s) selected from the group consisting of F, Cl, —SO 2 CH 3 , —SO 2 N(CH 3 )C 2 H 5 , —SO 2 NHCH(CH 3 ) 2 , —NHCH 3 , —N(CH 3 )C 2 H 5 , —NHSO 2 CH 3 , and —P(O)(CH 3 ) 2 .

5. The compound of claim 3 , wherein
A 4 is selected from the group consisting of phenyl substituted by one or more R 4 (s); or preferably,
A 4 is selected from the group consisting of phenyl substituted by one or more R 4 (s) selected from the group consisting of halogen, C 1-6 alkyl substituted by halogen, —NR 6 R 7 , and —P(O)R 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of C 1-6 alkyl; or more preferably,
A 4 is selected from the group consisting of phenyl substituted by one or more R 4 (s) selected from the group consisting of F, Cl, methyl substituted by halogen, ethyl substituted by halogen, —N(CH 3 ) 2 , and —P(O)(CH 3 ) 2 ; or more preferably,
A 4 is selected from the group consisting of phenyl substituted by one or more R 4 (s) selected from the group consisting of F, Cl, —CHF 2 , —CF 3 , —CF 2 CH 3 , —N(CH 3 ) 2 , and —P(O)(CH 3 ) 2 , and A 4 is substituted b

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Centaurus Biopharma Co Ltd
• Lianyungang Runzhong Pharmaceutical Co Ltd
• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Xiao Dengming
• Xu Xinhe
• Liu Xijie
• Hu Yuandong
• Yu Honghao
• Liu Zhihua
• Peng Yong
• Sun Yinghui
• Luo Hong
• Kong Fansheng
• Han Yongxin
• Sun Jian

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P11/04

  for throat disorders · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title