Polycyclic substituted pyrazole kinase activity inhibitors and use thereof

Patent metadata

Field	Value
Publication number	US-9550792-B2
Application number	US-201414759516-A
Country	US
Kind code	B2
Filing date	Jan 7, 2014
Priority date	Jan 8, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention relates to the field of medicinal chemistry, and in particular relates to 4-(five-membered heterocyclic pyrimidine/pyridine substituted) amino-1H-3-pyrazolecarboxamide derivatives, the preparation method thereof, pharmaceutical compositions containing these compounds and the medicinal use thereof, especially as protein kinase inhibitors for anti-tumor use.

First claim

The invention claimed is:

1. A compound defined by formula (I):

or a pharmaceutically acceptable salt or tautomer or solvate thereof or a combination thereof,

wherein:
R 1 , R 2 and R 3 each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het;
X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het;
Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het;
A 1 independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het;
A 2 independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het;
Q 1 is selected from aryl and Het, wherein the aryl or Het can each optionally and independently be substituted by one or more R 8 , and R 8 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het;
Q 2 is selected from aryl or Het, wherein the aryl or Het can each optionally and independently be substituted by one or more R 9 , and R 9 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl and Het; and
wherein:
the alkyl refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms;
the alkylene refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein one hydrogen atom is absent;
the alkoxyl refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen;
the alkylthiol refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein each carbon atom is optionally substituted by sulfur;
the alkoxylalkyl refers to the alkyl group as defined above, which is attached to the alkoxyl group as defined above;
the aryl refers to a carbonic ring selected from phenyl, naphthyl, acenaphthenyl and tetralyl, which may be each optionally substituted by 1, 2 or 3 substituents each independently selected from H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl and Het;
the aralkyl or diarylalkyl refers to the alkyl group as defined above, which is attached to the aryl group as defined above;
the Het refers to a monocyclic heterocycle group selected from piperidyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, or a bicyclic heterocycle group selected from quinolyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuryl, benzothienyl, 2,3-dihydro-1,4-benzodioxinyl and 1,3-benzodioxolyl; wherein the monocyclic or bicyclic heterocycle group is each optionally substituted by 1, 2 or 3 substituents each independently selected from halogen, haloalkyl, hydroxyl, alkyl and alkoxyl;
the halogen refers to a substituent selected from fluoro, chloro, bromo and iodo;
the haloalkyl refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein one or more carbon atoms are substituted by one or more halogens.

2. The compound according to claim 1 , wherein:
R 1 , R 2 and R 3 each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl;
X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4 may be H, alkyl, cyano halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl;
Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl;
A 1 independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl;
A 2 independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl;
Q 1 is selected from aryl and Het, wherein the aryl and Het can each optionally and independently be substituted by one or more R 8 , and R 8 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl;
Q 2 is selected from aryl and Het, wherein the aryl and Het can each optionally and independently be substituted by one or more R 9 , and R 9 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl.

3. The compound according to claim 2 , wherein:
R 1 , R 2 and R 3 each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl;
X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4 may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl;
Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH o

Assignees

• Univ China Pharma
• Shanghai Fosun Pharmaceutical Dev Co Ltd

Inventors

• Lu Tao
• Wang Yue
• Chen Yadong
• Lu Yi
• Wang Zhanwei
• Jin Qiaomei
• Yang Taotao
• Lin Guowu
• Guo Qinglong
• Zhao Li

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title