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Pyrazolo[1,5-a]miazine compound and its preparation method and medical use

A compound, 5-a technology, used in pharmaceutical formulations, drug combinations, organic chemistry, etc.

Active Publication Date: 2014-12-31
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are many selective c-Met inhibitors in different stages of research and development. A series of small molecule compounds developed by Sugen can selectively inhibit c-Met kinase activity at nanomolar levels (WO2005004607, WO2005004808, WO2005005378 and WO2005010005), Amgen The company's compound AMG-208 is in Phase I clinical research (WO2008008539, WO2009091374), SGX's SGX126 has terminated Phase I clinical research due to renal toxicity (WO2008051808), Johnson & Johnson's compound JNJ-38877605 (WO2007075567) and Pfizer's PF -04217903 (US2007265272) has entered the first phase of clinical research; however, there is still no small molecule c-Met protein kinase inhibitor on the market at this stage, and the purpose of the present invention is to provide a novel pyrazolo[1,5-a ] Pyrimidine compounds, the series of compounds have c-Met inhibitory activity and can be used to treat or alleviate cancer or similar diseases

Method used

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  • Pyrazolo[1,5-a]miazine compound and its preparation method and medical use
  • Pyrazolo[1,5-a]miazine compound and its preparation method and medical use
  • Pyrazolo[1,5-a]miazine compound and its preparation method and medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Preparation of 6-({5-phenylpyrazolo[1,5-a]pyrimidin-3-yl}sulfanyl)quinoline

[0097]

[0098] Compound 5-aminopyrazole (5g, 60mmol) and ethyl 3-ethoxyacrylate (13g, 90mmol), cesium carbonate (29g, 90mmol) were mixed in 100 ml of N,N-dimethylformamide, heated The reaction was stirred overnight to 110°C. Cooled to room temperature, diluted with 200ml of water, extracted with ether (40mL x3), the aqueous phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain 4H-pyrazolo[1,5 -a] Pyrimidin-5-one (8 g), 99% yield.

[0099]

[0100] Add POCl to 4H-pyrazolo[1,5-a]pyrimidin-5-one (1.35g, 10mmol) 3 (30mL), heated to reflux, reacted for 4h, cooled to room temperature after the reaction was complete, concentrated, then dissolved in CH 2 Cl 2 , followed by water, saturated NaHCO 3 , washed with saturated brine, anhydrous Na 2 SO 4 dry. Filtration and concentration gave 5-chloropyrazolo...

Embodiment 2

[0110] Preparation of 6-{[5-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]sulfanyl}quinoline prepare

[0111]

[0112] 5-Chloro-pyrazolo[1,5-a]pyrimidine (0.15g, 1mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-oxa Boron-1H-pyrazole (0.25g, 1.2mmol), sodium carbonate (0.32g, 3mmol) and Pd(dppf)Cl 2 (0.04g, 0.05mmol) mixed in DME / H2 O (3mL / 3mL), stirred and heated to reflux under nitrogen atmosphere, and reacted overnight. Cool to room temperature, dilute with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and use the residue directly in the next reaction without further purification.

[0113]

[0114] The crude product obtained in the first step was dissolved in DMF, stirred at room temperature, added iodosuccinimide (0.25 g, 1.1 mmol), the reaction solution was stirred at room temperature for 4 hours, diluted with water, extracted with ether, and the organic phase was washed ...

Embodiment 3

[0119] Preparation of 6-{[5-(cyclopropylmethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]sulfanyl}quinoline

[0120]

[0121] Sodium hydride (60%) was added to a solution of cyclopropylmethanol (0.36g, 5mmol) in dichloromethane at room temperature, and the mixture was stirred at room temperature for 30 minutes, and 5-chloro-pyrazolo[1,5-a]pyrimidine (0.15g, 1mmol) was added to the above mixture, and the reaction system was heated to reflux overnight. Cool to room temperature, quench the reaction with ice water, extract the mixture with ether, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and use the residue directly in the next reaction without further purification.

[0122]

[0123] The crude product obtained in the previous step was dissolved in N,N-dimethylformamide, iodosuccinimide (0.25 g, 1.1 mmol) was added at room temperature, the reaction system was stirred at room temperature for 2 hours, diluted with water, and diethyl ...

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Abstract

The invention relates to a pyrazolo[1,5-a]miazine compound and its preparation method and medical use. The invention relates to the preparation method of the pyrazolo[1,5-a]miazine compound shown in the general formula (I) and its salt, a pharmaceutical composition containing the pyrazolo[1,5-a]miazine compound or its medicinal salt, the use of the pyrazolo[1,5-a]miazine compound or the pharmaceutical composition in the medicine field and especially as a receptor tyrosine kinase inhibitor and a c-Met inhibitor, and the use of the pyrazolo[1,5-a]miazine compound or the pharmaceutical composition in preparation of drugs for preventing and / or treating c-Met abnormality-related diseases.

Description

technical field [0001] The present invention relates to a new pyrazolo[1,5-a]pyrimidine derivative, its preparation method, pharmaceutical composition containing the compound and its use as a therapeutic agent, especially as a c-Met protein kinase inhibitor use. Background technique [0002] As a basic regulatory mechanism of cells, signal transduction transmits various extracellular signals to the inside of cells, so that cells respond and realize processes such as proliferation, differentiation, and apoptosis. Protein kinases (PKs) play an important role in this process. PKs can be divided into tyrosine kinases (PTKs) and serine / threonine kinases (STKs). PTKs can phosphorylate tyrosine residues on proteins, and STKs can phosphorylate serine and threonine residues. Tyrosine kinases can be further divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases. [0003] The RTKs family can be divided into many subfamilies, mainly including (1) ErbB (Her) ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P35/00A61P35/02A61P35/04
CPCC07D487/04
Inventor 仝朝龙吕茂云孙兴义杨飞王春娟
Owner SHANGHAI HANSOH BIOMEDICAL
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