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2-arylamine-4-amido quinazoline compound as well as preparation method and application thereof

A compound, quinazoline technology, used in the field of medicine for diseases and disorders

Inactive Publication Date: 2021-08-13
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, there are no effective therapeutic strategies to overcome L858R / T790M / C797S-mediated tertiary mutational resistance to EGFR-TKIs

Method used

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  • 2-arylamine-4-amido quinazoline compound as well as preparation method and application thereof
  • 2-arylamine-4-amido quinazoline compound as well as preparation method and application thereof
  • 2-arylamine-4-amido quinazoline compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Embodiment 1: Preparation 3-(4-(ethylamino) quinazoline-2-yl)-4-methoxybenzonitrile (I-1)

[0098] Step A: Preparation of 5-cyano-2-methoxybenzaldehyde

[0099] Add DMF (300mL) to a 500ml reaction flask equipped with a thermometer and a drying tube, turn on mechanical stirring, add 5-bromo-2-methoxybenzaldehyde (20g, 93mmol), stir for 10min to dissolve, and then add cyanide Cuprous copper (16.7g, 186mmol), under the protection of nitrogen, stirred and heated to 145-150°C for micro-reflux reaction, the reaction solution gradually dissolved, and then the reaction solution gradually became dark green viscous, reacted for 14-16h, TLC (petroleum Ether / ethyl acetate=4 / 1) the reaction is completed, the reaction solution is cooled to room temperature, and the copper salt is removed by filtration, and the filtrate is slowly added to (800 mL) cold water under stirring, and a brown-green viscous solid is precipitated, and the solid is respectively washed with ammonia solution ( 2...

Embodiment 2

[0106] Embodiment 2: Preparation of 3-(4-(benzylamino)quinazolin-2-yl)-4-methoxybenzonitrile (I-2)

[0107] The procedure is the same as in Example 1, using benzylamine as the reactant in step D.

[0108] Pale yellow solid, yield 94.5%, m.p.187-190℃; 1 H NMR (400MHz, DMSO-d 6 )δ:3.80(s,3H),4.78(d,J=6.0Hz,2H),7.25-7.58(m,4H),7.40-7.42(m,2H),7.55-7.56(m,1H),7.72 -7.90(m,4H),8.33(d,J=7.6Hz,1H),8.95(s,1H,adding D 2 O disappear); 13 CNMR (100MHz, DMSO-d 6 )δ:44.18,56.54,102.79,113.67,113.90,119.45,123.07,126.36,127.25,127.97,128.19,128.71,131.54,133.26,134.86,134.88,140.12,150.13,159.87,160.11,161.18;HRMS(ESITOF)m / z:Calcd.for C 23 h 18 N 4 O[M+H] + 367.1559,found 367.1555.

Embodiment 3

[0109] Example 3: Preparation of 4-methoxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzonitrile (I-3)

[0110] The operation is the same as in Example 1, using 3-aminomethylpyridine as the reactant in step D.

[0111] Pale yellow solid, yield 80.25%, m.p.189-192℃(dec); 1 H NMR (400MHz, DMSO-d 6 )δ:3.81(s,3H),4.78(d,J=5.6Hz,2H),7.29-7.31(m,1H),7.35-7.38(m,1H),7.55-7.59(m,1H),7.74 -7.91(m,5H),8.30(d,J=8.0Hz,1H),8.47(d,J=0.8Hz,1H),8.64(s,1H).8.98-8.99(m,1H,adding D 2 O disappear); 13 C NMR (100MHz, DMSO-d 6 )δ:41.99,56.58,102.85,113.67,113.87,123.04,123.89,126.45,128.23,133.34,134.78,134.93,135.54,135.84,148.57,149.68,159.80,160.11,161.19;HRMS(ESITOF)m / z:Calcd .forC 22 h 17 N 5 O[M+H] + 368.1511,found 368.1507.

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Abstract

The invention provides a 2-arylamine-4-amido quinazoline compound and a preparation method thereof. The 2-arylamine-4-amido quinazoline compound is shown in a formula I. The compound in the formula I has good inhibitory activity on EGFR L858R / T790M / C797S kinase and can be used for preparing drugs for treating diseases or symptoms related to tumors.

Description

technical field [0001] The present invention relates to a 2-arylamine-4-aminoquinazoline compound, a preparation method thereof, and an application in the preparation of medicines for treating diseases and diseases related to tumors. Background technique [0002] Lung cancer has become the leading cause of death for all cancer patients. It is estimated that 1.6 million people die of lung cancer worldwide every year, and the morbidity and mortality show a trend of rapid growth. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gene mutation and dysregulation have been shown to be closely related to the development of many tumor cells. Therefore, EGFR has become a key target for the development of potential antitumor inhibitors. The 4-anilinoquinazoline EGFR inhibitors already on the market, such as gefitinib and erlotin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94C07D401/12C07D403/12A61K31/517A61K31/5377A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D239/94C07D401/12C07D403/12
Inventor 朱永强张明光王佳陈琪杨杨刘兆刚
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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