Kinase modulating compounds, compositions containing the same and use thereof

Patent metadata

Field	Value
Publication number	US-9550781-B2
Application number	US-201213261878-A
Country	US
Kind code	B2
Filing date	Nov 14, 2012
Priority date	Nov 14, 2011
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The invention provides a compound represented by formula (I) which may modulate a kinase, and a pharmaceutical composition thereof, as well as the method for preventing or treating a protein kinase mediated disease or condition.

First claim

We claim:

1. A compound represented by Formula (I):

wherein:
R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkylthio, or halogen, wherein the said groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, lower mono-alkylamino, lower di-alkylamino, and lower cycloalkylamino;
R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkoxycarbonyl, alkylthio, cyano, —OH, and —NH 2 , wherein the above said groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
R 3 is selected from the group consisting of —S(═O) 2 R a and —S(═O)R a ;
R a is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkoxycarbonyl, alkylthio, cyano, —OH, and —NH 2 , wherein those groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, and aryl optionally substituted with one or more halogen, hydroxyl, amino, lower alkyl, lower alkoxy, and lower alkylthio; or
R a is selected from the group consisting of —(CR c R d ) n R e and —(CR c R d ) n OR e ;
R c and R d are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkoxycarbonyl, alkylthio, cyano, —OH, and —NH 2 , wherein those groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
R c and R d combine to form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, aryl optionally substituted with one or more halogen, hydroxyl, amino, lower alkyl, lower alkoxy, and lower alkylthio;
R e is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkoxycarbonyl, alkylthio, cyano, —OH, and —NH 2 , wherein those groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
n is 0, 1, 2, 3, 4, 5 or 6;
X 1 is CR 4 and X 2 is N to form imidazolyl;
R 4 is selected from the group consisting of hydrogen, halogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkylthio, alkoxycarbonyl, cyano, —OH, —NHC(═O)-alkyl, —S(═O) 2 -alkyl, —S(═O) 2 -cycloalkyl, —S(═O) 2 NH 2 , —S(═O) 2 NH-alkyl, —N(alkyl)-S(═O) 2 -alkyl, —C(═O)-alkyl, —NO 2 , —NHS(═O) 2 -alkyl, —NHS(═O) 2 -cycloalkyl, —NHS(═O) 2 -aryl, —NHS(═O) 2 -heteroaryl, —S(═O) 2 N-(alkyl) 2 , —C(═O)NH-alkyl, —C(═O)N-(alkyl) 2 , —S(═O)-alkyl, —S(═O)-lower cycloalkyl, —S(═O)-heteroalkyl, —C(═O)NH 2 , triazolyl, and tetrazolyl, wherein the said groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
X 3 , X 4 , X 5 and X 6 are independently selected from the group consisting of CR 6 and N to form phenyl or pyridinyl;
each R 6 is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkoxycarbonyl, cyano, —OH, —NHC(═O)-alkyl, —S(═O) 2 -alkyl, —S(═O) 2 -cycloalkyl, —S(═O) 2 NH 2 , —S(═O) 2 NH-alkyl, —N(alkyl)-S(═O) 2 -alkyl, —C(═O)-alkyl, —NO 2 , —NHS(═O) 2 -alkyl, —NHS(═O) 2 -cycloalkyl, —NHS(═O) 2 -aryl, —NHS(═O) 2 -heteroaryl, —S(═O) 2 N-(alkyl) 2 , —C(═O)NH-alkyl, —C(═O)N-(alkyl) 2 , —S(═O)-alkyl, —S(═O)-heteroalkyl, —C(═O)NH 2 , triazolyl, and tetrazolyl, wherein the said groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
X 7 , X 8 and X 9 are independently selected from the group consisting of CR 8 and N to form phenyl or pyridinyl;
each R 8 is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkylthio, alkoxycarbonyl, cyano, —OH, —NHC(═O)-alkyl, —S(═O) 2 -alkyl, —S(═O) 2 -cycloalkyl, —S(═O) 2 NH 2 , —S(═O) 2 NH-alkyl, —N(alkyl)-S(═O) 2 -alkyl, —C(═O)-alkyl, —NO 2 , —NHS(═O) 2 -alkyl, —NHS(═O) 2 -cycloalkyl, —NHS(═O) 2 -aryl, —NHS(═O) 2 -heteroaryl, —S(═O) 2 N-(alkyl) 2 , —C(═O)NH-alkyl, —C(═O)N-(alkyl) 2 , —S(═O)-alkyl, —S(═O)-heteroalkyl, —C(═O)NH 2 , triazolyl, and tetrazolyl, wherein the said groups are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, halogen substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; and
P, Y and Z are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein those groups are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, and cyano;
with a provision that when X 3 , X 4 , X 5 and X 6 are independently selected from the group consisting of CR 6 and N to form pyridinyl, X 7 , X 8 and X 9 are independently CR 8 to form phenyl; and
when X 3 , X 4 , X 5 and X 6 are independently selected from the group consisting of CR 6 to form phenyl, X 7 , X 8 and X 9 are independently CR 8 and N to form phenyl or pyridinyl;
or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

2. A compound according to claim 1 , where

Assignees

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

Inventors

• Xiao Dengming
• Li Jijun
• Zhu Yan
• Hu Yuandong
• Wang Huting
• Wang Zhe
• Wang Zanping
• Wei Yongheng
• Sun Yinghui
• Wu Qiong
• Zhang Hui
• Peng Yong
• Kong Fansheng
• Sun Ying
• Luo Hong
• Han Yongxin

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title