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Benzene sulfonamide pyrazole kinase inhibitor

A carbamoyl and alkyl technology, applied in the field of benzenesulfonamide pyrazole kinase inhibitors, can solve problems such as poor selectivity and insufficient activity

Inactive Publication Date: 2014-08-06
TONGHUA SIHUAN PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These compounds have problems such as poor selectivity or insufficient activity, so it is necessary to carry out corresponding research work to find small molecule inhibitors targeting b-RAF mutations and having good activity

Method used

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  • Benzene sulfonamide pyrazole kinase inhibitor
  • Benzene sulfonamide pyrazole kinase inhibitor
  • Benzene sulfonamide pyrazole kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0067] Step 1 Preparation of TMa

[0068] To an appropriate amount of 1,4-dioxane, add an appropriate amount of SM1, SM2, potassium acetate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex in sequence, and react Under nitrogen protection, stir at 90°C for 16 hours, cool and concentrate under reduced pressure. The obtained solid is dissolved in ethyl acetate, washed with water, and the organic phase is dried with anhydrous sodium sulfate. After concentrated under reduced pressure, the product is separated and purified by silica gel column chromatography. TMa.

[0069] Step 2 Preparation of TMb

[0070] Dissolve TMa in a mixed solution of tetrahydrofuran and water, and add an appropriate amount of NaIO 4 (sodium periodate), stir at room temperature until the system becomes homogeneous, stir overnight at room temperature, remove the solvent under reduced pressure, dissolve the crude product in ethyl acetate, wash with water and saturated aqu...

experiment example

[0099] Experimental example The in vitro enzymatic activity experiment of the compound of the present invention

[0100] Test product: Compound 1 prepared in Example 1.

[0101] experimental method:

[0102] The meanings of the English and English abbreviations in the following tests are as follows:

[0103] HEPES: Hydroxyethylpiperazineethanesulfonic acid;

[0104] Brij-35: lauryl polyethylene glycol ether;

[0105] EDTA: ethylenediaminetetraacetic acid;

[0106] Fluorescein-MAP2K1: Fluorescein-labeled MAP2K1;

[0107] ATP: adenosine triphosphate;

[0108] DMSO: dimethyl sulfoxide;

[0109] MgCl 2 : Magnesium chloride.

[0110] 1. Preparation of test reagents

[0111] ① 1X kinase buffer (50 mM HEPES, pH 7.5, 10 mM MgCl 2 , 1mM EGTA, 0.01% Brij-35);

[0112] ② 2x kinase solution (add corresponding kinase to 1x kinase buffer to prepare 2x kinase solution, the final concentration is b-RAF 3.5 nM, b-RAF V599E 0.35 nM);

[0113] ③ 4-fold substrate solution (add Fluore...

Embodiment 1

[0129] Example 1 N-(3-(5-(2-aminopyrimidin-4-yl)-3-tert-butyl-1H-pyrazol-1-yl)-2-fluorophenyl)-2,6-di Preparation of fluorobenzenesulfonamide (compound 1)

[0130]

[0131] (1) Preparation of 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0132]

[0133] To 1,4-dioxane (20 mL), add 1-bromo-2-fluoro-3-nitrobenzene (2.2 g, 0.01 mol), bispinacol borate (3.81 g, 0.015 mol ), potassium acetate (2.94 g, 0.03 mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (100 mg), the reaction was carried out under nitrogen protection at Stir at 90°C for 16 hours, cool and concentrate under reduced pressure, dissolve the obtained solid in ethyl acetate, wash with water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column chromatography (petroleum ether: ethyl acetate=2 : 1) Separate and purify the product (1.24 g, yield 46%).

[0134] (2) Preparation of 2-fluoro-3...

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Abstract

The invention belongs to the field of medical technology and specifically relates to a benzene sulfonamide pyrazole kinase inhibitor shown in a general formula (I) as described in the specification and pharmaceutically acceptable salts or stereoisomer thereof. In the general formula (I), R1, R2, R3, m and n are as defined in the specification. The invention also relates to a preparation method for the above-mentioned compound, a medicinal preparation and a pharmaceutical composition containing the compound and application of the compound and the pharmaceutically acceptable salts or stereoisomer thereof in preparation of drugs used for treating and / or preventing diseases correlated or non-correlated to cancers caused by b-RAF mutation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to benzenesulfonamide pyrazole kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations and pharmaceutical compositions containing these compounds, and Application of the compound, its pharmaceutically acceptable salt or its stereoisomer in the preparation of medicines for treating and / or preventing cancer-related diseases or non-cancer-related diseases caused by b-RAF mutation. Background technique [0002] Receptor tyrosine kinases (RTKs) are involved in cell growth, differentiation, development, proliferation, division, and adhesion, and are also related to cell transcription regulation, angiogenesis, and endothelial cell proliferation. has a wide range of effects. The regulation of these kinases can control cell proliferation and differentiation, regulate cell cycle, especiall...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00A61P11/00A61P13/08
CPCC07D403/04
Inventor 吴永谦
Owner TONGHUA SIHUAN PHARM
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