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Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof

A pyrazolo, 3-c technology, applied to pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors and the fields of their preparation and use, can solve the production of EGFR and BRAF kinase inhibitors drug resistance and other issues

Inactive Publication Date: 2015-04-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Relevant studies have shown that overactivation of the HGF / MET signal transduction pathway can make patients resistant to EGFR and BRAF kinase inhibitors

Method used

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  • Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof
  • Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof
  • Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] 1-tert-butoxycarbonyl-4-morpholinyl-1,2,5,6-tetrahydropyridine (Y-1)

[0171] Add 10.0g (50mmol) of N-tert-butoxycarbonyl-4-piperidone, 0.50g (5.7mmol) of morpholine, p-toluenesulfonic acid (catalyst), and 120mL of anhydrous toluene into a 250mL single-necked bottle, and reflux overnight , the reaction solution changed from light yellow to reddish brown, the reaction was stopped, and cooled to room temperature, 15.2 g of the reddish brown oily substance concentrated directly from the reaction solution was directly carried out to the next step without purification.

Embodiment 2

[0173] 1-tert-butoxycarbonyl-3-(4-fluorobenzoyl)-4-piperidone (Y-2)

[0174] Add Y-115.0g (56mmol) to a 250mL single-necked bottle, anhydrous CH 2 Cl 2 80mL, put it under ice bath, add 8.5g (84mmol) of triethylamine, slowly add p-fluorobenzoyl chloride 14.0g (86mmol) in anhydrous CH 2 Cl 2Solution 60mL (the color of the solution deepens with the addition of drops), react at 0°C for 2h, heat up to 25°C for 4h, add 100mL of water to the reaction solution, adjust the pH to 6 with 5% HCl aqueous solution, and react at 25°C for 0.5h , TLC detects that new substances are produced. The reaction solution was allowed to stand for stratification, the organic layer was separated, and the aqueous phase was separated with CH 2 Cl 2 Extracted 3 times (40mL×3), combined the organic phases, dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated and then column chromatographed (PE:EA=5:1) to obtain 7.2g of a dark red oily substance, yield 39 %, MS m / z...

Embodiment 3

[0176] 3-(4-fluorophenyl)-5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Y-3)

[0177] Add 4.0g (60mmol) of hydrazine hydrochloride, 5.0g (60mmol) of sodium acetate, and 120mL of absolute ethanol into a 250mL single-necked bottle, heat up to 70°C for 1 hour, filter while hot, transfer the filtrate to a 250mL single-necked bottle, add Y- 27.0g (20mmol), heated to 70°C for 1h (reaction solution changed from clear to turbid), cooled to room temperature and reacted for 5h (reaction solution precipitated a large number of yellow solids), and TLC detected that the raw material disappeared. Stop the reaction, filter the reaction solution with suction, wash the filter cake with absolute ethanol, and dry to obtain 4.5 g of a light yellow solid with a yield of 62%, MS m / z: 316.1 [M-H] - .

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Abstract

The invention relates to a kind of new compounds taking 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as the parent nucleus as well as a preparation method and medical uses thereof and particularly the use as a c-Met kinase inhibitor. The new compounds can be used independently or combined with at least one other medicine for treating the diseases regulated by protein kinase such as cancer.

Description

field of invention [0001] The present invention relates to a class of novel compounds based on 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, their preparation and their medical use, especially as c-Met kinase Use of Inhibitors. The novel composition of compounds can be used alone or in combination with at least one other drug for the treatment of diseases regulated by protein kinases, such as cancer. Background technique [0002] Malignant tumors are one of the major diseases that seriously threaten human life. Antineoplastic drugs play an important role in the clinical treatment of tumors. In recent years, with the development of molecular biology techniques and further understanding of tumor pathogenesis at the molecular level Recognize that the development of new drugs is developing from traditional cytotoxic drugs to new anti-tumor drugs targeting multiple links in the mechanism of tumorigenesis and development. Among them, the inhibition of tumor-related signal transd...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/444A61K31/4545A61K31/4709A61K31/5377A61P35/00A61P35/02
CPCC07D471/04
Inventor 胡诗合陈亚东陆涛金乔梅袁浩亮庄津胡亚宁张立王冰洋赵爽
Owner CHINA PHARM UNIV
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