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New compound used as rearranged during transfection kinase inhibitor

A technology of compounds and derivatives, applied in the treatment or prevention of related diseases mediated by RET kinase, rearrangement during transfection (RET) kinase inhibitor, in the field of preparing the compounds described below, can solve the problem of poor RET selectivity And other issues

Pending Publication Date: 2020-10-16
NANJING INNOCARE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the previous treatment of RET-positive patients, targeted drugs often choose cabozantinib or vandetanib. These two drugs, as multi-target tyrosine kinase inhibitors, are not very selective for RET

Method used

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  • New compound used as rearranged during transfection kinase inhibitor
  • New compound used as rearranged during transfection kinase inhibitor
  • New compound used as rearranged during transfection kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0511] 4-(5-(7-(1-methyl-1 H -pyrazol-4-yl)quinazolin-5-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0512]

[0513]

[0514] first step

[0515] 4-Bromo-2-chloro-6-fluorobenzene(formaldehyde)

[0516] Add anhydrous tetrahydrofuran (400 mL) into a 500 mL three-necked flask, add lithium diisopropylamide (0.26mol, 130 mL, 2 M in THF) at -78 °C, and slowly add compound 1-bromo-3-chloro - A solution of 5-fluorobenzene 1a (25.00 g, 0.12 mol) in anhydrous THF (100 mL). Stir at -78°C for 1 hour, add dropwise N , N -Dimethylformamide (17.50 g, 0.24 mol), -78°C Stirring was continued for 2 hours. Quenched with saturated ammonium chloride solution at low temperature, desolvated under reduced pressure to remove part of the solvent, extracted with dichloromethane (200 mL × 3), washed the organic phase with saturated brine (500 mL), and washed with water (500 mL). The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and...

Embodiment 2

[0532] 7-(1-Methyl-1 H -Pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)quinazoline

[0533]

[0534]

[0535] Compound 4-(5-(7-(1-methyl-1 H -pyrazol-4-yl)quinazolin-5-yl)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester 1 (0.50 g, 1.06 mmol) was dissolved in methanol (5 mL), and hydrochloric acid was added Methanol (80 mmol, 4 M, 20 mL), stirred at room temperature for 3 hours, desolvated under reduced pressure to obtain the crude product, the residue was dissolved in water (20 mL), added saturated aqueous sodium bicarbonate to pH = 8-9, distilled with di Chloromethane (20 mL × 5) was extracted, the organic phase was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the target compound 7-(1-methyl-1 H -pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)quinazoline 2 (0.37 g, yellow solid), yield: 94%.

[0536] MS m / z(ESI): 372 [M+1];

[0537] 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.06(s, 1H), 7.96...

Embodiment 3

[0539] 5-(6-(4-(3-fluorobenzyl)piperazin-1-yl)pyridin-3-yl)-7-(1-methyl-1 H -pyrazol-4-yl)quinazoline

[0540]

[0541]

[0542] Compound 7-(1-methyl-1 H -pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)quinazoline 2 (10 mg, 0.02 mmol), m-fluorobenzaldehyde (5 mg, 0.04 mmol ) and methanol (1 mL), and stirred at room temperature for 5 minutes. Then sodium triacetoxyborohydride (11 mg, 0.04 mmol) was added and stirred at room temperature for 12 hours. The reaction solution was quenched with saturated ammonium chloride (2 mL), extracted with ethyl acetate (5 mL), the organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the crude product was precipitated under reduced pressure, and the residue was prepared with silica gel Plate purification (dichloromethane: methanol = 12: 1 ) to obtain the target product 5-(6-(4-(3-fluorobenzyl)piperazin-1-yl)pyridin-3-yl)-7-(1 -Methyl-1 H -pyrazol-4-yl)quinazoline 3 (7 mg, yellow solid), ...

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Abstract

The present invention relates to a compound, a pharmaceutical composition containing the compound, a preparation method of the compounds, and application of the same as a rearranged during transfection (RET) kinase inhibitor. The compound is a compound shown as formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvent compound, a polymorph, an isomer and a stable isotope derivativethereof. The present invention also relates to the application of the compounds to treatment or prevention of RET kinase mediated related diseases like tumors and a method of using the compounds for the treatment of the diseases.

Description

technical field [0001] The present invention relates to compounds, pharmaceutical compositions containing them and their use as inhibitors of rearrangement during transfection (RET) kinases. More specifically, the present invention provides novel compounds as RET kinase inhibitors, pharmaceutical compositions containing such compounds and methods of using said compounds for the treatment or prevention of related diseases mediated by RET kinase, such as tumor. The invention also relates to processes for the preparation of the compounds described hereinafter. Background technique [0002] The RET (Rearranged during transfection) gene encodes a membrane receptor tyrosine kinase RET protein, which belongs to the cadherin superfamily, is expressed in cells derived from neural crest and genitourinary system, and plays a vital role in the development of neural crest effect. RET kinase binds to one of the four glial cell-derived neurotrophic factor (GDNF) family receptor alpha (G...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D487/10C07D471/08C07D403/14C07D405/14A61K31/517A61K31/496A61K31/497A61K31/4709A61P35/00A61P35/02
CPCC07D401/14C07D487/10C07D471/08C07D403/14C07D405/14A61P35/00A61P35/02
Inventor 孔祥龙周超郑之祥
Owner NANJING INNOCARE PHARMA TECH CO LTD
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