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Heteroaryl fused ring compound as well as preparation method and application thereof

A technology of heteroaryl and compound, applied in the application field of heteroaryl condensed ring compound and TRK inhibitor, can solve the problem of drug resistance, and achieve the effect of low inhibitory dose, good inhibitory effect and high inhibitory activity

Pending Publication Date: 2021-06-18
SCINNOHUB PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, after receiving TRK inhibitor treatment, cancer patients may have some mutations in the TRK gene (such as NTRK1 G595R, NTRK3 G623R mutations), leading to drug resistance. Patients in this period need new therapeutic drugs

Method used

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  • Heteroaryl fused ring compound as well as preparation method and application thereof
  • Heteroaryl fused ring compound as well as preparation method and application thereof
  • Heteroaryl fused ring compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0137] Preparation Example 1: Preparation of (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine

[0138]

[0139] The intermediate of Preparation Example 1 can be prepared by various preparation methods disclosed in the prior art, for example, by the method described in the PCT patent with the publication number WO2011146336 A1 or the US patent with the publication number US20160168156 A1.

preparation example 2

[0140] Preparation Example 2: Preparation of 5-chloro[1,5-a]pyrimidine-3-carbaldehyde

[0141]

[0142] The intermediate of this preparation example 2 can be prepared by various preparation methods disclosed in the prior art, for example, by the method described in the US patent publication number US20140234254 A1 or the Chinese patent publication number CN103965199A.

preparation example 3

[0143] Preparation Example 3: Preparation of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0144]

[0145] Dissolve imidazole (6.8g) in tetrahydrofuran (100mL), add sodium hydride (36.0g) in batches while maintaining 0°C under nitrogen protection, after the addition is complete, stir the system at room temperature for 1 hour, then add chloromethyltrimethylsilyl ethyl Diethyl ether (20.0 g) was dissolved in tetrahydrofuran and slowly added to the reaction system. The system was kept at room temperature for overnight reaction. TLC and LCMS showed that the raw materials were completely consumed. The reaction system was poured into water, extracted twice with ethyl acetate, and the resulting filtrate was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=50:1 (V:V)) to obtain 7.7 g of the title compound.

[0146] MS(ESI)m / z(M+H) + = 199.1.

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Abstract

The invention provides a novel substituted heteroaryl fused ring compound and a preparation method thereof, and the novel substituted heteroaryl fused ring compound can be used as a TRK inhibitor and has a wide and good application prospect in TRK kinase mediated diseases such as melanoma, lung cancer, head and neck cancer, pancreatic cancer, breast cancer, thyroid cancer and glioma.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, and more specifically relates to a substituted heteroaryl condensed ring compound, its preparation method and its application in TRK inhibitors. Background technique [0002] TRK (Tropomyosin receptor kinase), a neurotrophic factor tyrosine kinase receptor, belongs to the receptor tyrosine kinase family. The tyrosine kinase NTRK gene includes NTRK1, NTRK2 and NTRK3, which are responsible for encoding the synthesis of tropomyosin receptor kinase (TRK) family proteins TRKA, TRKB and TRKC respectively; among them, NGF (nerve growth factor) binds TRKA, BDNF (derived from neurotrophic factor) binds TRKB, and NT3 (neurturin 3) binds TRKC. Binding of neurotrophic factors to TRK protein can induce receptor dimerization, phosphorylation and activate downstream signaling cascade pathways of PI3K, RAS / MAPK / ERK and PLC-γ. TRK kinases play important physiological functions in the development of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00A61K31/519
CPCC07D487/04A61P35/00
Inventor 阳安乐邓金根李红波张德伟梁杰濮俊杰
Owner SCINNOHUB PHARM CO LTD
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