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Kinase inhibitor as well as preparation, pharmaceutical composition and application thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve problems such as loss of activity, mutation of target protein, etc.

Inactive Publication Date: 2021-02-26
HUNAN WARRANT PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But new genetic mutations and drug-resistant forms also emerge in clinical practice, necessitating further development of new inhibitors
Large doses of drugs can cause mutations in target proteins, leading to loss of activity

Method used

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  • Kinase inhibitor as well as preparation, pharmaceutical composition and application thereof
  • Kinase inhibitor as well as preparation, pharmaceutical composition and application thereof
  • Kinase inhibitor as well as preparation, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0144] Synthesis of Compound 1:

[0145]

[0146] The synthetic route of compound 1 is as follows:

[0147] Synthesis of [5-(2-chloro-4-fluoro-6-methylphenylcarbamoyl)thiazol-2-yl]-carbamic acid tert-butyl ester

[0148]

[0149] N 2 Under gas protection, add 24.4g (0.1mol) of 2-tert-butoxycarbonylaminothiazole-5-carboxylic acid and 0.5ml of DMF (N,N-dimethylformamide) into 250ml of dichloromethane, and slowly add 13ml of Oxalyl chloride solution (0.15mol), reacted for 2h, and removed the solvent by rotary evaporation to obtain a white solid, which was dissolved in 100ml of anhydrous dichloromethane, and slowly added dropwise to 2-chloro-4-fluoro -6-methylaniline 17.5g (0.11mol) and N,N-diisopropylethylamine 38.8g (0.3mol) in dichloromethane solution, N 2 React at room temperature for 10 h under gas protection, distill off the solvent under reduced pressure, add a mixed solvent of 25 ml of ethyl acetate and 25 ml of n-hexane and stir for 2 hours, filter with suction, ...

preparation example 2

[0163] Synthesis of Compound 2:

[0164]

[0165] The synthetic route of compound 2 is as follows:

[0166]Synthesis of 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol

[0167]

[0168] 2-(piperazin-1-yl)ethanol (13..0g, 100mmol) and triethylamine (30.3g, 300mmol) were added to 4,6-dichloro-2-dimethylpyrimidine (16.3g, 100mmol ) in 400 mL of dichloromethane solution, stirred at room temperature for 2 hours (LCMS monitoring the reaction). After the reaction was complete, the reaction solution was washed with saturated brine (50ml×1) and water (50ml×1) respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain 30.8g of a yellow powdery solid with a yield of 82%. 68% purity. MS-ESI(m / Z): [M+H] + , 257.

[0169] Synthesis of 2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxylic acid methyl ester

[0170]

[0171] Compound 2-(4-(6-chloro-2-methylpyrimidin-4-yl)pi...

preparation example 3

[0184] Synthesis of compound 3:

[0185]

[0186] The synthetic route of compound 3 is as follows:

[0187] Preparation of 2-((6-(4-(2-acetoxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5 according to compound 2 synthesis steps 1-4 -carboxylic acid.

[0188] Synthesis of Compound 4-Fluoro-2-isopropenylaniline

[0189]

[0190] Under argon protection, 2-bromo-4-fluoroaniline (10.0g, 52.6mmol), isopropenylboronic acid pinacol ester (9.7g, 57.8mmol), K 2 CO 3 (21.7g, 157.8mmol) and Pd 2 (dppf) 2 Cl (3.8g, 5.2mmol) was added to 250ml of 1,4-dioxane / water (10:1) solution, heated to 80°C, and reacted for 25 hours (reaction monitored by TCL). After the reaction was complete, water (100ml) was added and extracted with ethyl acetate (100ml×3). The combined organic phases were dried and concentrated to give the crude product. Ethyl acetate / petroleum ether (50:1) was used to pass through the chromatographic column, and finally 4.5 g of a yellow liquid produc...

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Abstract

The present application relates to compounds of formula I useful as kinase inhibitors, such as tyrosine kinase inhibitors, processes for their preparation, and pharmaceutical compositions comprising said compounds of formula I. The invention further relates to a treatment application of the compound shown in the formula I or the pharmaceutical composition thereof in immune diseases, tumors, neurological diseases and other diseases.

Description

technical field [0001] The application belongs to the field of medicinal chemistry, and specifically relates to a compound that can be used as a kinase inhibitor (such as a tyrosine kinase inhibitor), a preparation method thereof, and a pharmaceutical composition containing the compound. The present application also relates to the therapeutic use of the compound or its pharmaceutical composition in diseases such as immune diseases, tumors and neurological diseases. Background technique [0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins, thereby altering their substrate activity or ability to bind to other proteins. Kinase signaling is the most common form of reversible post-translational modification and controls many aspects of cellular function. Aberrant activation of protein kinases is a major hallmark of malignancy, including alterations in cell proliferation, survival, motility, and metabolism, as well as disorders such as ang...

Claims

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Application Information

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IPC IPC(8): C07D417/12A61K31/506A61P35/00A61P35/02A61P19/00A61P19/10A61P19/02A61P29/00A61P9/00A61P25/16A61P37/06A61P17/00A61P17/10
CPCC07D417/12A61P35/00A61P35/02A61P19/00A61P19/10A61P19/02A61P29/00A61P9/00A61P25/16A61P37/06A61P17/00A61P17/10A61K31/506A61K31/427C07D417/14A61K31/495
Inventor 皮士卿徐燕杨代鸿周志刚
Owner HUNAN WARRANT PHARMA
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