Aminopyrimidine derivative as well as preparation method and application thereof

A technology of aminopyrimidine and derivatives, applied in TRK inhibitors, aminopyrimidine derivatives, preparation of therapeutic agents, and its stereoisomers, can solve the problems of no longer effective, loss of TRK protein ectodomain, etc., and achieve good TRK inhibition active effect

Pending Publication Date: 2022-03-01
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, NTRK gene fusions often result in loss of the ectodomain of the TRK protein, which means that inhibitors that target the protein ectodomain, such as monoclonal antibodies, will no longer be effective against NTRK gene fusion cancers

Method used

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  • Aminopyrimidine derivative as well as preparation method and application thereof
  • Aminopyrimidine derivative as well as preparation method and application thereof
  • Aminopyrimidine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] The preparation route of embodiment 1 is as follows:

[0147]

[0148] Concrete synthetic steps are as follows:

[0149] Synthesis of 2,5-dichloro-N-(3-fluorobenzyl)pyrimidin-4-amine (2)

[0150] Dissolve 2,4,5-trichloropyrimidine (1.00g, 5.50mmol) in 15mL of absolute ethanol, add N,N-diisopropylethylamine (1.00mL, 6.05mmol), stir at room temperature for 10min, and add to the reaction solution Add a solution of 3-fluorobenzylamine (0.69mL, 6.05mmol) in absolute ethanol (15mL) dropwise, and react at room temperature. The completion of the reaction of the raw materials was monitored by TLC, the solvent was removed by spin, and purified by column chromatography to obtain a light yellow solid with a yield of 88%.

[0151] Preparation of 4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide (Example 1)

[0152] Intermediate 2 (0.10 g, 0.37 mmol) was dissolved in 3 mL of isopropanol, 4-aminobenzenesulfonamide (0.070 g, 0.41 mmol) and a catalytic ...

Embodiment 14

[0177] The preparation route of embodiment 14 is as follows:

[0178]

[0179] Preparation of 4-({5-chloro-4-[(3-fluorobenzyl)amino)pyrimidin-2-yl)aminobenzoic acid (4)

[0180] Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with p-aminobenzoic acid in equal proportions to obtain intermediate 4.

[0181] [4-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methyl ketone (Example 14) Preparation

[0182] Intermediate 4 (0.10g, 0.27mmol), N-methylpiperazine (0.032g, 0.32mmol), EDCI (0.061g, 0.32mmol), HOBt (0.043g, 0.32mmol) and DIPEA (0.053mL, 0.32 mmol) was dissolved in 3mL DMF and reacted at room temperature. TLC monitored the complete reaction of the raw materials, and the reaction solution was poured into 30 mL of 10% potassium carbonate solution, and a white solid was precipitated. It was filtered under reduced pressure, and the filter cake was washed with water ...

Embodiment 29

[0210] Embodiment 29 adopts following route to prepare:

[0211]

[0212] Preparation of 3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-4-yl)benzamide (Example 29)

[0213] Referring to the method of Preparation Example 17, the morpholine raw material in step c was replaced by N-Boc-piperidin-4-amine in equal proportions to obtain intermediate 7. Intermediate 7 (0.050 g, 0.090 mmol) was dissolved in saturated ethyl acetate solution of hydrogen chloride and stirred at room temperature (step d). TLC monitored the completion of the reaction, filtered under reduced pressure, washed the filter cake three times with ethyl acetate, dissolved the filter cake in 20 mL of water, extracted with ethyl acetate (10 mL×3), and discarded the organic layer. The aqueous layer was adjusted to pH>10 with 10% sodium hydroxide solution under ice bath conditions, extracted with ethyl acetate (10 mL×3), washed with saturated brine (10 mL×3), and dried over anhydrous sodi...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an aminopyrimidine derivative with a structure as shown in a general formula (I) or a general formula (II), a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug of the aminopyrimidine derivative, a preparation method of the aminopyrimidine derivative, and application of the aminopyrimidine derivative in preparation of a therapeutic agent, especially a tropomyosin receptor kinase (TRK) inhibitor. Preferably, the aminopyrimidine derivative, the stereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof have the activity as a protein kinase inhibitor, especially a TRK inhibitor.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to an aminopyrimidine derivative, its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug, its preparation method and the preparation of a therapeutic agent, especially TRK Use in inhibitors. Background technique [0002] Malignant tumors have become one of the diseases that seriously endanger human health. Human beings have been fighting against cancer for nearly a century. The research and development of anticancer drugs is gradually changing from non-selective chemotherapy drugs to highly selective targeted drugs. Since the launch of imatinib, the development of anti-tumor drugs targeting kinases has entered the fast lane. With the introduction of the concept of precision medicine, it is a general trend to classify tumor types based on specific biomarkers. The therapy targeting specific biomarkers to treat tumors has gained a lot ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D487/04C07D403/04C07D401/12C07D401/14C07D495/04C07D403/12C07D413/12A61K31/506A61K31/519A61K31/551A61K31/5377A61K31/505A61P35/00
CPCC07D239/48C07D487/04C07D403/04C07D401/12C07D401/14C07D495/04C07D403/12C07D413/12A61P35/00
Inventor 赵冬梅吴天啸程卯生秦桥花张储吕瑞成刘念孙逸祥
Owner SHENYANG PHARMA UNIVERSITY
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