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Pyrimidine compound as well as preparation method and medical application of pyrimidine compound

A compound, pyrimidine technology, applied in the field of chemical medicine, can solve the problems of poor selectivity, EGFR wild-type cytotoxicity and other problems

Pending Publication Date: 2017-03-08
INVENTISBIO CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] The current EGFR-TKI still cannot solve the clinical problems caused by drug resistance, and most of the existing drugs are EGFR reversible or irreversible inhibitors based on quinazoline or quinoline amines. Toxic side effects caused by poor selectivity of type cells are still unavoidable
Therefore, new types, especially compounds with novel frameworks, are urgently needed to solve the problems of drug resistance, poor selectivity, etc.

Method used

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  • Pyrimidine compound as well as preparation method and medical application of pyrimidine compound
  • Pyrimidine compound as well as preparation method and medical application of pyrimidine compound
  • Pyrimidine compound as well as preparation method and medical application of pyrimidine compound

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Experimental program
Comparison scheme
Effect test

Embodiment 121

[0077]

[0078] 1. Synthesis of intermediate 121-3

[0079]

[0080] Under nitrogen protection, in a 100 milliliter (mL) three-necked flask at room temperature, the raw material 121-1 (3.0 grams (g), 25.6 mmol (mmol)) was dissolved in 50 mL 1,2-dichloroethane (DCE) , the mixture was lowered to 0°C, and methylmagnesium bromide (8.5mL, 25.6mmol) was added dropwise to the reaction system at 0°C. After the addition, the reaction was continued at constant temperature for 30 minutes (min), and then 121-2 (5.4 g, 36.3 mmol) was added into the reaction system, and the temperature was raised to room temperature to react overnight. After the reaction was complete, 100 ml of ice water was added to the reaction mixture to quench the reaction, the mixture was extracted 3 times with 100 ml of dichloromethane, the combined organic phases were washed 3 times with 100 ml of saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica ge...

Embodiment 122

[0113]

[0114] 1. Synthesis of intermediate 122-1

[0115]

[0116]Under nitrogen protection, add 5-fluoroindole (10g, 74.0mmol) into a 500mL three-necked flask, distill 100mL of anhydrous tetrahydrofuran, lower the temperature to 0°C, and add 37.1mL of methylmagnesium bromide ether solution (3.0M ), after the dropwise addition, keep at 0°C for about 30min, add 2,4-dichloropyrimidine (16.5g, 111mmol) in batches at 0°C, and return the reaction system to room temperature to react overnight. After detecting that the reaction is complete, add 100 mL of ammonium chloride aqueous solution dropwise to the reaction system to quench the reaction, extract the resulting mixture twice with 100 mL of ethyl acetate, combine the organic phases, backwash once with 100 mL of saturated brine, and then wash with anhydrous sulfuric acid. After sodium drying and concentration to dryness, the obtained solid was washed once with 100 mL of acetonitrile, filtered with suction, and the filter ca...

Embodiment 123

[0141]

[0142] 1. Synthesis of intermediate 123-1

[0143]

[0144] Under the protection of nitrogen, the raw material 122-1 (2.5 g, 10.1 mmol) was dissolved in 50 mL of anhydrous DMF in a 100 mL three-necked flask at room temperature, and then the temperature was lowered to 0 °C and NaH (65%, 560 mg, 15.2 mmol) was added in batches, After the addition, the reaction system was kept at 0°C for 30 minutes. Then 1,1-difluoro-2-bromoethane (2.9 g, 20.0 mmol) was added dropwise at 0° C. After the dropwise addition, the system was returned to room temperature to react overnight. After detecting that the reaction was complete, the reaction mixture was poured into 200 mL of ice water to quench the reaction, and a solid was precipitated. The mixture was filtered to collect the filter cake, washed once with 50 mL of acetonitrile, and dried to obtain 1.6 g (51%) of product 123-1. It is a yellow solid. LCMS: 312.0.

[0145] 2. Synthesis of Compound 123

[0146]

[0147] The ...

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PUM

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Abstract

The invention discloses a pyrimidine compound, a pharmaceutically-acceptable salt, a stereoisomer, a prodrug and a solvate thereof, as well as a preparation method, a pharmaceutical composition and medical application of the pyrimidine compound. This type of compound can generate an inhibitory effect on variant forms of EGFR (epidermal growth factor receptor) protease, so that the compound can effectively inhibit the growth of various tumor cells, can be used for preparing antitumor drugs, can be applied to treatment, combined treatment or prevention of many different cancers, and can overcome drug tolerance induced by first-generation EGFR inhibitors including existing drugs of gefitinib, erlotinib and the like. More particularly, this type of compound can be used for preparing medicines for treating or preventing diseases, obstacles, disorders or illness states mediated by certain epidermal growth-factor receptors with variant forms (for example, L858R active mutants, Exon19 deletion active mutants, and T790M resistant mutants).

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a class of pyrimidine compounds and their pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates, their preparation method, pharmaceutical composition and medical application. Specifically, the present invention relates to some pyrimidine compounds and their pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates, and their preparation methods, comprising the compounds, their pharmaceutically acceptable salts, stereoisomers Constructs, prodrugs and / or solvates (especially useful polymorphic forms of these compounds and salts), and said compounds and pharmaceutically acceptable salts, stereoisomers, prodrugs thereof and solvates for the preparation of medicaments for the treatment of diseases mediated by various forms (activating mutant and / or resistant mutant forms) of EGFR. Background technique [0002] Cancer is becoming the de...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00A61P35/02
CPCC07B59/002C07B2200/05C07D403/04
Inventor 王耀林江岳恒陈新海
Owner INVENTISBIO CO LTD
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