Heterocyclic derivate tyrosine kinase inhibitor

A compound and cyclic group technology, applied in the field of heterocyclic derivative tyrosine kinase inhibitors, can solve the problems of incomplete mechanism, change of ATP affinity of EGFR kinase region, loss of tumor cell killing effect, etc.

Active Publication Date: 2016-08-24
吉林升通化工有限公司 +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The T790M mutation is the replacement of threonine at position 790 of EGFR by methionine, and the mechanism of drug resistance is not fully understood
The possible mechanism is that methionine occupies a larger space than threonine, forming steric hindrance, which changes the affinity of ATP in the kinase region of EGFR, resulting in the inability of EGFR-TKI small molecule drugs to effectively block EGFR activation signals. Thus losing the killing effect on tumor cells and producing drug resistance
[0007] So far, there are still no EGFR TKI drugs targeting the T790M mutation on the market

Method used

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  • Heterocyclic derivate tyrosine kinase inhibitor
  • Heterocyclic derivate tyrosine kinase inhibitor
  • Heterocyclic derivate tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0215] Preparation of Example 1 tert-butyl (4-bromo-3-nitrophenyl) carbamate

[0216]

[0217] Dissolve 3-nitro-4-bromoaniline (5.0g, 23mmol), di-tert-butyl dicarbonate (7.6g, 35mmol), triethylamine (2.32g, 23mmol) in tetrahydrofuran (50mL), heat at 60°C React for 2 hours. Spin to dry the solvent, add water (50mL), extract with ethyl acetate, separate layers, dry the organic phase, concentrate, and separate by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the product (5.8g, yield 79% ).

preparation example 2

[0218] Preparation Example 2 Preparation of tert-butyl 4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)carbamate

[0219]

[0220] Tert-butyl (4-bromo-3-nitrophenyl) carbamate (5.8g, 18.3mmol), N 1 ,N 1 ,N 2 - Trimethylethyl-1,2-diamine (3.73g, 36.6mmol), potassium carbonate (5.05g, 36.6mmol) were added to N,N-dimethylacetamide (75mL), 100°C oil bath 8 hours. Ethyl acetate (500 mL) was added, washed with saturated brine (500 mL), separated, the organic phase was dried, concentrated, and column chromatography (dichloromethane:methanol=10:1) gave the product (1.87 g, yield 30%) .

preparation example 3

[0221] Preparation Example 3 Preparation of tert-butyl (3-amino 4-((2-(dimethylamino) ethyl) (methyl) amino)-phenyl) carbamate

[0222]

[0223] Dissolve tert-butyl 4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)carbamate (1.87 g, 5.5 mmol) in methanol (25 mL) , a palladium carbon catalyst (187 mg) was added to replace the hydrogen, and the mixture was stirred at room temperature for 2 hours. Suction filtration, washing with a small amount of methanol, concentration of the organic phase, and column chromatography (dichloromethane:methanol=10:1) gave the product (1.4g, yield 82%).

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Abstract

The invention belongs to the technical field of medicine and particularly relates to a heterocyclic derivate tyrosine kinase inhibitor shown in the formula (I), a pharmaceutically acceptable salt and ester thereof and stereoisomers thereof, wherein Y, W, Q m, L, R1, R2, R3, R4, R5, R6, R7, R7', R8 and R8' are defined in the specification. The invention further relates to a preparation method of the compounds and a pharmaceutical preparation and pharmaceutical compositions containing the compounds, and application of the compounds as the tyrosine kinase inhibitor for preparing medicine for preventing and/or treating cancer diseases caused by EGFR mutation and drug resistance diseases caused by EGFR T790M mutation.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, in particular to pyrimidine heterocyclic derivatives tyrosine kinase inhibitors, their pharmaceutically acceptable salts, their esters and their stereoisomers, their preparation methods, pharmaceutical preparations and medicines Compositions, and the application of these compounds as tyrosine kinase inhibitors in the preparation of drugs for preventing and / or treating cancer diseases caused by EGFR mutations and drug-resistant diseases caused by EGFR T790M mutations. 2. Background technology [0002] Cancer, also known as malignant tumor, has seriously threatened human health and life. In 2004, 7.4 million people died of cancer worldwide. In 2008, China conducted the third national survey on the causes of death, which showed that the cancer mortality rate in China had increased by about 80% in the past 30 years, and nearly 2 million people died of cancer every year. The situation is very gri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D401/12C07D405/12A61K31/505A61K31/5377A61K31/506A61P35/00
CPCC07D239/48C07D401/12C07D405/12
Inventor 吴永谦
Owner 吉林升通化工有限公司
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