Inhibitor of FLT3 kinase and use thereof

Patent metadata

Field	Value
Publication number	US-10266535-B2
Application number	US-201515544676-A
Country	US
Kind code	B2
Filing date	Aug 7, 2015
Priority date	Jan 21, 2015
Publication date	Apr 23, 2019
Grant date	Apr 23, 2019

Abstract

Provided in the present invention is a novel inhibitor of FLT3 kinase, comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof. Also provided in the present invention are a pharmaceutical composition comprising a compound of formula (I) and a use and method for preventing or treating cell proliferative conditions and/or FLT3-related conditions, in particular for conditions responding to the inhibition of FLT3 kinase (especially FLT3/ITD mutant kinases).

First claim

The invention claimed is:

1. A compound of formula (II), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, having the following structure:

n is 2;
Z is

R is selected from the group consisting of unsubstituted C3-C6 cycloalkyl or C3-C6 cycloalkyl optionally substituted with 1 to 3 independent R1 on carbon atoms; amino; carbamoyl; unsubstituted C1-C6 aminoalkyl or C1-C6 aminoalkyl optionally substituted with 1 to 3 independent R1 on carbon atoms or optionally substituted with R2 on heteroatoms; unsubstituted heteroaryl or heteroaryl optionally substituted with 1 to 3 independent R1 on carbon atoms or optionally substituted with R2 on heteroatoms; unsubstituted C3-C6 heterocycloalkyl or heterocycloalkyl optionally substituted with 1to 3 independent R1 on carbon atoms or optionally substituted with R2 on heteroatoms; unsubstituted aryl or aryl optionally substituted with 1 to 3 independent R1 on carbon atoms; unsubstituted di(C1-C4 alkyl)-N-(C1-C4)alkyl or di(C1-C4 alkyl)-N-(C1-C4)alkyl optionally substituted with 1 to 3 independent R1 on carbon atoms; unsubstituted C1-C4 alkyl(C3-C6 heterocycloalkyl) or C1-C4 alkyl(C3-C6 heterocycloalkyl) optionally substituted with 1 to 3 independent R1 on carbon atoms or optionally substituted with R2 on heteroatoms; unsubstituted C1-C4 alkyl(C3-C6 cycloalkyl) or C1-C4 alkyl(C3-C6 cycloalkyl) optionally substituted with 1 to 3 independent R1 on carbon atoms; unsubstituted C1-C4 aminoalkyl(carbamoyl) or C1-C4 aminoalkyl(carbamoyl) optionally substituted with 1 to 3 independent R1 on carbon atoms; unsubstituted C1-C4 alkyl(heteroaryl) or C1-C4 alkyl(heteroaryl) optionally substituted with 1 to 3 independent R1 on carbon atoms or optionally substituted with R2 on heteroatoms; and unsubstituted C1-C4 alkyl(aryl) or C1-C4 alkyl(aryl) optionally substituted with 1 to 3 independent R1 on carbon atoms;
R1 is independently selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, aryl, heteroaryl optionally substituted with R2 on heteroatoms, C1-C8 alkoxycarbonyl, C1-C8 alkyl(heteroaryl) optionally substituted with R2 on heteroatoms, and C1-C8 alkyl(C3-C6 heterocycloalkyl) optionally substituted with R2 on heteroatoms;
R2 is selected from the group consisting of amino protecting groups, C1-C8 alkyl, and C1-C8 alkoxycarbonyl; the amino protecting group is independently selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl and p-methoxyphenyl.

2. The compound of formula (II), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, according to claim 1 , wherein heteroaryl is independently selected from the group consisting of pyridyl, pyrimidinyl, isoxazolyl, benzodioxolyl, imidazolyl and indolyl.

3. The compound of formula (II), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, according to claim 1 , wherein heterocycloalkyl is independently selected from the group consisting of piperazinyl, piperidyl, and morpholinyl.

4. The compound of formula (II), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, according to claim 1 , which is selected from the group consisting of:

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Assignees

• Hefei Inst Physical Sci Cas
• Hefei Cosource Pharmaceutical Co Ltd

Inventors

• Liu Jing
• Liu Qingsong
• Li Xixiang
• Wang Aoli
• Wu Hong
• Chen Cheng
• Wang Wenchao
• Hu Chen
• Zhao Zheng
• Wu Jiaxin
• Liu Juan
• Yu Kailin
• Wang Wei
• Wang Li
• Wang Beilei

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title