Pyrazole compounds and application thereof

Abstract

The invention provides pyrazole compounds and application thereof. Based on discovery of compensatory activation of VEGFR-2, EphB4 and TIE-2 and taking biphenyl aryl urea as a novel primer, conservative conformation of active sites of three kinds of receptors is analyzed, and a common structural domain is found; a compound library meeting the requirement of the common structural domain is constructed by adopting a strategy of molecular hybridized drug design, and a multi-target inhibitor which can be antagonistic to three compensatory accesses simultaneously is found through multi-level activity screening. A kinase screening test proves that a large groups of compounds have the good kinase inhibition activity, a cell proliferation test proves that a large groups of compounds have the highcell proliferation inhibition activity, the compound has the effects of inhibiting the activity of VEGFR-2, Tie-2 and EphB4 kinase and resisting the cell proliferation activity, can be applied to preparation of anti-angiogenesis drugs, and can serve as a novel pharmacological function segment of design of the multi-target inhibitor.

Description

technical field [0001] The invention relates to a pyrazole compound and its application. Background technique [0002] Anti-angiogenesis is mainly used in the treatment of various angioproliferative diseases including malignant tumors. Designed to reduce blood vessel density and inhibit angiogenesis. It was initially hypothesized that antiangiogenic inhibitors could circumvent typical drug resistance because their target cells are genetically stable endothelial cells. However, multiple proangiogenic factors induce increased tumor invasiveness and subsequent acquired drug resistance, so not all patients benefit from antiangiogenic therapy. [0003] Further studies were conducted to better define the resistance of cancer cells, which allowed them to overcome anti-angiogenic strategies. Acquired resistance to anti-angiogenic inhibitors is mainly caused by compensatory activation of pro-angiogenic factors. Compensatory activation of pro-angiogenic factors enables tumors to e...

AI Technical Summary

Problems solved by technology

[0005] At present, although some innovative progress has been made in the research of anti-angiogenic drugs, there are still the following problems: ① Regulation of angiogenesis is a network involving multiple signaling pathways. After the action of single-target drugs, angiogenesis often appears compensatory. pathway, leading to the generation of drug resistance; ②The target selectivity of the discovered anti-angiogenic drugs is not high, and there are many adverse reactions; ③Single-target anti-angiogenic drugs can only act on one link of the angiogenesis process, and the Multi-factor regulation and its complexity directly limit the effect of single-target drugs

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