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Aryne derivatives as protein kinase inhibitors and their medical use

A drug and compound technology, applied in the field of protein kinase inhibitor aryne derivatives, can solve the problem of imatinib not being able to combine

Inactive Publication Date: 2016-05-18
TIANJIN LONGBOGEN PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, with the promotion of the clinical application of this drug, more and more cases are resistant to imatinib. There are many drug resistance mechanisms of imatinib. In fact, more than 50% of the drug resistance is due to Bcr - One or more amino acid mutations in the Abl fusion protein, resulting in the inability of imatinib to bind to the ATP binding site of the fusion protein

Method used

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  • Aryne derivatives as protein kinase inhibitors and their medical use
  • Aryne derivatives as protein kinase inhibitors and their medical use
  • Aryne derivatives as protein kinase inhibitors and their medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Example 1. (R)-N-(3-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)4-methylphenyl)-1-(4-methylpiperazine -1-yl)-2,3-dihydro-1H-indene-5-carboxamide (Compound 1)

[0129]

[0130] Step 1 Synthesis of (R)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carbonyl chloride hydrochloride

[0131]

[0132] (R)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid hydrochloride (prepared according to the synthesis method disclosed in CN101759683A) 3.0g Dissolve in 30ml of dichloromethane, then add 4.2ml of thionyl chloride and a few drops of DMF dropwise, after heating to reflux for 2 hours, a large amount of solids precipitated, filtered, and the filter cake was washed several times with dichloromethane to obtain 4.5g of white solid .

[0133] Step 2 (R)-N-(3-iodo-4-methylphenyl)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-methanol Amide synthesis

[0134]

[0135] 6.7 g of 3-iodo-4-methylaniline hydrochloride was dissolved in dry dichloromethane, an...

Embodiment 2

[0140] Example 2. (S)-N-(3-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)4-methylphenyl)-1-(4-methylpiperazine -1-yl)-2,3-dihydro-1H-indene-5-carboxamide (Compound 2)

[0141]

[0142] Step 1 Synthesis of (S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carbonyl chloride hydrochloride

[0143]

[0144] (S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid hydrochloride (prepared according to the synthesis method disclosed in CN101759683A) 4.0g Dissolve in 25ml of dichloromethane, then add 4.6ml of thionyl chloride and a few drops of DMF dropwise, after heating to reflux for 2 hours, a large amount of solids precipitated, filtered, and the filter cake was washed several times with dichloromethane to obtain 3.5g of white solid .

[0145] Step 2 (S)-N-(3-iodo-4-methylphenyl)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-methanol Amide synthesis

[0146]

[0147] Dissolve 13.4 g of 3-iodo-4-methylaniline hydrochloride in dry dichloromethane, then a...

Embodiment 3

[0151] Example 3. (R)-N-(3-((1H-pyrazol[3,4-b]pyridin-5-yl)ethynyl)-4-methylphenyl)-1-(4-methyl (Piperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxamide (Compound 3)

[0152]

[0153] Step 1: Synthesis of 5-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridine

[0154]

[0155] Dissolve 3.0g of 5-bromo-1H-pyrazol[3,4-b]pyridine in DMF, then add 2.98g of trimethylsilylacetylene, 0.53g of Pd(dppf) 2 Cl 2 , 0.29g cuprous iodide and 3.86g triethylamine were added to the solution, the air was removed, and N 2 Protection, heated to 70 ° C for about 2h to complete the reaction. Extract, dry over anhydrous sodium sulfate, filter and spin dry to obtain a crude product. Silica gel column chromatography was used for gradient elution with ethyl acetate:petroleum ether=1:20-2:1 to obtain 3.5 g of the title compound.

[0156] Step 2: Synthesis of 5-ethynyl-1H-pyrazol[3,4-b]pyridine

[0157]

[0158] Dissolve 4.5g of 5-((trimethylsilyl)ethynyl)-1H-pyrazol[3,4-b]pyridine in methanol...

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Abstract

The invention discloses a class of protein kinase inhibitor aryne derivatives. The compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, R1, R2, R3, R4, ring A, ring B , L, m, n, p or q are defined in the specification. In addition, the invention also discloses a drug with the compound or its salt as active ingredient, which can be used for treating proliferative diseases such as cancer and inflammatory diseases, especially diseases related to Bcr-Abl tyrosine kinase.

Description

technical field [0001] The present invention relates to a class of protein kinase inhibitor aryne derivatives, salts of the compound and medicines with the compound or its salts as active ingredients, which can be used to treat proliferative diseases such as cancer and inflammatory diseases, etc., especially Diseases associated with Bcr-Abl tyrosine kinase. Background technique [0002] Methionine kinases are generally divided into two categories: tyrosine kinases and serine / threonine protein kinases. [0003] Among protein kinases, it is generally accepted that tyrosine protein kinases play very important roles in many cellular functions, especially involved in the transmission of cell signals. A large number of research results prove that tyrosine protein kinase plays an indispensable role in the process of cell proliferation, canceration and division. [0004] Tyrosine protein kinases are divided into two categories: receptors and non-receptors. Receptor tyrosine kinase...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00C07D403/12A61K31/496A61K31/5025A61K31/506A61P35/00A61P35/02A61P29/00A61P17/06
CPCA61P17/06A61P29/00A61P35/00A61P35/02C07D231/12C07D233/64C07D233/90C07D239/42C07D277/40C07D471/04C07D487/04
Inventor 孙树萍
Owner TIANJIN LONGBOGEN PHARMACEUTICAL CO LTD
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