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Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component

A technology of heteroaryl and compound, applied in the field of heteroaryl derivatives, can solve the problems such as the inability of therapeutic agents to exhibit efficacy and the inability of EGFR inhibitors to exert efficacy

Active Publication Date: 2022-01-28
VORONOI INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When first-generation EGFR inhibitors are used for an average of 10 months, acquired resistance known as the T790M mutation, located at the gatekeeper of the EGFR kinase, occurs, so first-generation EGFR inhibitors are not effective
In other words, EGFR_del19_T790M or EGFR_L858R_T790M double mutation occurs, making existing therapeutic agents unable to show efficacy

Method used

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  • Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component
  • Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component
  • Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0207] Preparation of (S)-3-phenylisoxazolidine

[0208]

[0209] Procedure 1: Preparation of tert-butyl (R)-(3-hydroxy-3-phenylpropoxy)carbamate

[0210] Tert-butyl hydroxycarbamate (7.8 g, 58.6 mmol) was dissolved in dimethylformamide (140 ml), then sodium hydride (2.58 g, 64.5 mmol) was added thereto at 0° C., and the reaction was carried out for 30 minutes . Then, (R)-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in dimethylformamide (10 ml) was slowly added dropwise at 0 °C for 10 minutes, followed by Stir at room temperature for 72 hours. Aqueous ammonium chloride solution was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate and brine, whereby the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (ethyl acetate / n-hexane), thereby obtaining the target compound (R)-(3-hydroxy-3-phenylpropa...

preparation example 2

[0218] Preparation of (R)-3-phenylisoxazolidine

[0219]

[0220] Preparation Example 2 was carried out in the same manner as Preparation Example 1, and the compounds of Examples shown in Table 1 below were used for synthesis.

[0221] MS (m / z): 150.08[M+1]+, UPLC retention time (min): 0.72

preparation example 3

[0222] Preparation of (R)-3-(3-fluorophenyl)isoxazolidine

[0223]

[0224] Procedure 1: Preparation of 3-fluoro-N-methoxy-N-methylbenzamide

[0225] 3-Fluorobenzoic acid (90 g, 642.35 mmol, 1 eq) was dissolved in pyridine (150 mL), and N-methoxymethylamine (75.19 g, 770.81 mmol, 1.2 eq, HCl) was added thereto. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 147.77 g, 770.81 mmol, 1.2 eq) was added at 15°C. The reaction mixture was stirred at 50 °C for 30 minutes. As a result of TLC analysis (PE:EA=3:1 ), all starting material disappeared and new low polar spots were detected. The pyridine solvent was removed by concentration under reduced pressure, and the organic layer was extracted with dichloromethane (DCM; 500 mL), hydrochloric acid (500 mL, 2N), and brine (200 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the target compound 3-fluoro-N-methoxy-N-methylbenzamide (110 g, 600.50 mmol, yield 93.4...

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Abstract

The present invention relates to a 6-(isooxazolidin-2-yl)-N-phenylpyrimidin-4-amine derivative, and a pharmaceutical composition for preventing or treating cancer comprising the compound as an effective component. The compound exhibits high inhibitory activity against an epidermal growth factor receptor (EGFR) variant, or wild-type or variants of one or more of ERBB2 and ERBB4, and thus may be usefully used in the treatment of cancers in which same are expressed. In particular, the compound exhibits excellent inhibitory activity on proliferation of lung cancer cell lines, and thus can be usefully used in the treatment of lung cancer.

Description

technical field [0001] The present disclosure relates to heteroaryl derivatives, specifically 6-(isoxazolidin-2-yl)-N-phenylpyrimidin-4-amine derivatives, and more particularly to stereoisomers, hydrates thereof , or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. Background technique [0002] The development of cancer is associated with various environmental factors, including chemicals, radiation, and viruses, as well as changes in oncogenes, tumor suppressor genes, and genes involved in apoptosis and DNA repair. Recently, knowledge of the molecular mechanisms of cancer has enabled targeted chemotherapy, a new approach to treatment. Targeted therapeutics are often designed to work by targeting molecules that are characteristic of cancer cells. Molecular targets are genes associated with cancer cell signal transduction pathways, angioge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D471/08C07D491/08A61K31/506C07D413/14C07D417/14C07D471/04A61P35/00
CPCC07D413/04C07D413/14C07D498/08C07D487/08C07D487/04A61P35/00A61K31/506C07D417/14C07D471/08C07D491/08C07D491/048C07D491/107A61K31/5386A61K31/5377C07D409/14C07D471/04A61K31/407
Inventor 李尹镐姜朱曦姜世仁金焕金承洙石知润高利炅金多恩A.R.韩柳忞汐黄东根高银和崔焕根李宣和孙正范金南斗
Owner VORONOI INC
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