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Aminopyrimidine derivative and application as EGFR tyrosine kinase inhibitor

A drug, methyl technology, applied in the field of medicine, can solve problems such as adverse reactions of patients, and achieve the effect of high inhibitory activity, high selectivity, and low inhibitory activity

Active Publication Date: 2021-12-10
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the third-generation EGFR inhibitors Osimertinib and CO-1686 have good therapeutic effects on T790M-resistant patients, they still have an inhibitory effect on wild-type EGFR, which causes skin rashes and gastrointestinal tract symptoms in some patients. Adverse reactions

Method used

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  • Aminopyrimidine derivative and application as EGFR tyrosine kinase inhibitor
  • Aminopyrimidine derivative and application as EGFR tyrosine kinase inhibitor
  • Aminopyrimidine derivative and application as EGFR tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Methyl N- (2 - (2-amino-5-methoxy-4 - (4- (1-methyl-1H-indole-3-yl) pyrimidine-2-yl) amino group ) Synthesis of phenyl) (meth) amino) N-methyl glycine ethyl ester (ZJT-4-M)

[0051] Synthesis of A.3- (2-pooprid-4-yl) -1-methyl-1H-indole (ZJT-1)

[0052]

[0053] 2,4-dichloronil (120.0 g, 0.81 mol) was added to a 2L reaction bottle, 880 ml 1, 4-Dioxane, stirred and dissolved, batching anhydrous Alcl 3 (120.0g, 0.90mol), stir until AlCl 3 It is uniformly dispersed in the emulsion, and then 1-methyl hydrazine (110.0 g, 0.84 mol) into the reaction liquid, warmed to 80 ° C insulation reaction for 3 hours, TLC detection reaction, 1-methylindole disappeared, The agent is petroleum ether: ethyl acetate = 1: 1. The reaction liquid was slowly poured into 2.5 L of purified water, stirred vigorously, precipitated the solid, and stirred after 1 hour, filtrate, purified with 1 l. The solid was dried in vacuo to dry overnight at 50 ° C to give 210.0 g of a crude product. The c...

Embodiment 2

[0066] Example 2 Methyl N- (2 - (2-Acrylamide-5-Methoxy-4 - (4- (1-methyl-1H-indole-3-yl) pyrimidine-2-yl ) Synthesis of amino) phenyl) (meth) amino) -N-methyl glycine ethyl alkine (CSJ-IM)

[0067]

[0068] Place the ZJT-4-M crude product in a 100ml flask, add 20 ml of DCM to solve the product, add K 2 CO 3 (0.45 g, 3.24 mmol), the reaction solution was lowered to 0 ° C for 20 min, and acryloyl chloride (0.20 g, 2.16 mmol) was slowly dripped, and the insulation reaction was carried out under low temperature conditions, and the TLC showed the ZJT-4-M reaction (DCM :: Meoh :nh 3 · H 2 O = 50:5:1). Reaction liquid filtration, remove K 2 CO 3 The solid, the mother liquor was added to 40 mL of methanol in 1 hour, and the solvent was evaporated under reduced pressure. The total yield of the step reaction is 29.91%. 1 H-NMR (400 MHz, Chloroform-D) ΔPPM 9.87 (S, 1H), 9.66 (S, 1H), 9.12 (S, 1H), 8.09-8.04 (M, "8.09-8.04 (M, 1H), 7.77 (S, 1H), 7.42-7.39 (m, 1H), 7.29-7.27 (m, 1H), 7.26 (...

Embodiment 3

[0069] Example 3 N- (2- (2- (benzyl (meth) amino) ethyl) (meth) amino) -4-methoxy-5 - (4- (1-methyl-1h) - Synthesis of hydrazine-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (CSJ-IB)

[0070]

[0071] The synthesis method was used as CSJ-I-M, the final product was 0.11g, the light yellow solid, and the total yield of three-step reaction was 17.74%. 1 H-NMR (400 MHz, ChlorOform-D) ΔPPM 9.89 (S, 1H), 9.84 (S, 1H), 9.11 (S, 1H), 8.39 (D, J = 5.3 Hz, 1H), 8.07 (DD, J = 7.5, 1.8 Hz, 1H), 7.72 (S, 1H), 7.40 (D, J = 2.3 Hz, 1H), 7.38 (D, J = 1.2 Hz, 1H), 7.36 (S, 1H), 7.35 (D, J = 1.0 Hz, 1H), 7.33 (D, J = 0.9 Hz, 1H), 7.32-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26 (S, 1H), 7.21 (D, J = 5.3Hz, 1H), 6.77 (S, 1H), 6.46-6.37 (m, 1H), 6.20 (S, 1H), 5.57 (D, J = 10.2 Hz, 1H), 3.98 (S, 3H), 3.87 (S, 3H), 3.58 (S, 2H), 2.60 (S, 3H), 2.40 (S, 2H), 2.25 (S, 3H). ESI-MS M / Z: 576.31 [M + H] + .

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Abstract

The invention provides an aminopyrimidine derivative as shown in a formula I, and a pharmaceutically acceptable salt, an isomer, a solvate and a pharmaceutical composition thereof. The invention also provides a preparation method of the compound as shown in the formula I. The compound can be used as an EGFR high-selectivity ligand molecule of EGFRT790M / L858R and EGFRDel19 mutation, and is used for treating related cancers mediated by EGFR kinase.

Description

Technical field [0001] The present invention relates to the field of medical technology. It is mainly involved in an aminoprimidine derivative and its hydrolyzatics, isomers, solvates, and pharmaceutical compositions, and the preparation method thereof and the application thereof as a drug. In particular, it is used as an application of anti-cancer drugs mediated by EGFR kinase. Background technique [0002] According to the data released by the World Health Organization, cancer has caused huge disease treatment in a global scale, and my country's cancer new cases and deaths are the first place in the world. Among them, lung cancer as one of the most common malignant tumors has become the first place in the death of malignant tumors in my country. In clinical diagnosis, lung cancer is divided into non-small cell lung cancer (NSCLC) accounted for 80-85% of all lung cancer, and about 75% of patients found in the middle and late stage (III or IV), There is a local advanced or metast...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D403/12A61K31/506A61P35/00
CPCC07D403/04A61P35/00A61K31/506A61P35/02
Inventor 郑志兵李鹏运李松李行舟肖军海周辛波钟武曹圣洁樊士勇肖典
Owner ACADEMY OF MILITARY MEDICAL SCI
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