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CDK4-FLT3 inhibitor and application thereof

A solvate and compound technology, applied in the field of CDK4-FLT3 inhibitors, can solve problems such as drug resistance

Inactive Publication Date: 2020-07-07
武汉光谷通用名药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to solve the problem of drug resistance existing in existing CDK kinase inhibitors, and then provide a compound that is a dual inhibitor of CDK4-FLT3

Method used

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  • CDK4-FLT3 inhibitor and application thereof
  • CDK4-FLT3 inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] The preparation of embodiment 1 compound I-1

[0068]

[0069] Compound I-1A (281 mg, 1 mmol), compound I-1B (197 mg, 1 mmol) were dissolved in 1,4-dioxane (60 mL), and tris(dibenzylideneacetone) dipalladium (92 mg, 0.1 mmol), 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (95mg, 0.2mmol) and cesium carbonate (2.09g, 6.4mmol), heated to 95°C~ The reaction was stirred at 100°C for 15 hours. Cool to room temperature, concentrate, add water to quench, separate layers, extract the aqueous phase with ethyl acetate (100mL×2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and the crude product is subjected to silica gel column chromatography Purification (methanol:dichloromethane=1 / 20 (V / V), add appropriate amount of 0.2% triethylamine) to obtain the compound represented by formula I-1 (293mg), yield 66.2%, HPLC purity 98.5%.

[0070] m / z:443(M+H) + .

Embodiment 2

[0071] The preparation of embodiment 2 compound 1-2

[0072]

[0073] The preparation method of compound I-2 was tested in a manner similar to that of Example 1, compound I-2A (281 mg, 1 mmol) and compound I-2B (198 mg, 1 mmol). The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1 / 20 (V / V), plus an appropriate amount of 0.2% triethylamine) to obtain the compound shown in formula I-2 (243mg), yield 54.9%, HPLC 99.2% purity.

[0074] m / z:444(M+H) + .

Embodiment 3

[0075] The preparation of embodiment 3 compound 1-3

[0076]

[0077] The preparation method of compound 1-3 was experimented in a manner similar to that of Example 1. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1 / 20 (V / V), plus an appropriate amount of 0.2% triethylamine) to obtain the compound shown in formula I-3 with a yield of 56.0% and a HPLC purity of 96.8% .

[0078] m / z:457(M+H) + .

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Abstract

The invention discloses a CDK4-FLT3 inhibitor and an application of the CDK4-FLT3 inhibitor. The compound is a compound shown as a formula I, and pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof. The compound can be used for preparing medicines for treating and / or preventing cancers.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to a CDK4-FLT3 inhibitor and its application. Background technique [0002] Tumor occurrence is related to the imbalance of various oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes will eventually converge on the cell cycle. Therefore, it can be said that tumors are a type of cell cycle disease (Cell Cycle Disease, CCD), and regulating or blocking the cell cycle is one of the ways to treat tumors. At present, many molecules related to cell cycle regulation have been discovered, among which cyclin-dependent kinases (Cyclin-Dependent-Kinases, CDKs) are the core molecules of the cell cycle regulation network. CDKs are catalytic subunits, a class of serine (Ser) / threonine (Thr) kinases, as important signaling molecules in cells, involved in different phases of the cell cycle. Studies have shown that in the cell cycle regulatory ne...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/519A61K31/5377A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D471/14
Inventor 许勇于静黄祥泉罗亚琼柳少群顿伟刘松林刘均均余艳平范昭泽
Owner 武汉光谷通用名药物研究院有限公司
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