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Benzenesulfonamide thiazole kinases inhibitor

An alkyl, selected technology, applied in the field of benzenesulfonamide thiazole kinase inhibitors, can solve problems such as insufficient activity and poor selectivity

Inactive Publication Date: 2014-07-23
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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  • Benzenesulfonamide thiazole kinases inhibitor
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  • Benzenesulfonamide thiazole kinases inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0088] (1) Preparation of SM 1

[0089] Refer to patent document WO2010 / 104899 A1, (2010).

[0090] (2) Preparation of TM 1

[0091] Dissolve SM 1 in an appropriate amount of dry THF, and replace the system with nitrogen. Place the reaction bottle in a dry ice acetone bath, cool to -78°C, slowly add DIBAL-H (3.5 equivalents) to the system dropwise, keep the system at -78°C for 6 hours, rise to room temperature and react overnight, LC-MS Monitor the progress of the reaction. After the reaction was completed, it was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was separated and purified by silica gel column chromatography to obtain intermediate TM1.

[0092] (3) Preparation of TM2

[0093] The intermediate TM 1 was dissolved in an appropriate amount of dichloromethane, and excess manganese dioxide ...

Embodiment 1

[0120] Example 1 N-(3-(2-tert-butyl-5-(quinolin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (compound 1) Preparation

[0121]

[0122] (1) Preparation of 2,2-dimethylthiopropionamide

[0123]

[0124] To a round bottom flask (25 mL), add 4-bromoquinoline (1 g, 4.8 mmol), double pinacol borate (1.2 g, 4.7 mmol), Pd(dppf)Cl 2 (0.1 g, 0.14 mmol), potassium acetate (0.147 g, 1.5 mmol) and 1,4-dioxane (10 mL), the system was replaced with nitrogen, heated to 90 ° C, stirred overnight, and LC-MS monitored the reaction process. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography to obtain the product (0.72 g, yield 60%).

[0125] (2) Preparation of 2,6-difluoro-N-(2-fluoro-3-(hydroxymethyl)phenyl)benzenesulfonamide

[0126]

[0127] 3-(2,6-Difluorobenzenesulfonamido)-2-fluorobenzoic acid methyl ester (6.9 g, 20 mmol) was dissolved in dry THF ...

Embodiment 2

[0151] Example 2 N-(3-(2-tert-butyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2 , Preparation of 6-difluorobenzenesulfonamide (compound 2)

[0152]

[0153] (1) Preparation of 4-chloro-1-p-methylbenzenesulfonyl-1H-pyrrolo[2,3-b]pyridine

[0154]

[0155] Dissolve 4-chloro-1H-pyrrolo[2,3-b]pyridine (2 g, 13.1 mmol) in dichloromethane (60 mL), add triethylamine (3.97 g, 39.3 mmol), and then add p-toluene Sulfonyl chloride (3.75 g, 19.7 mmol) was finally added with 4-dimethylaminopyridine (220 mg, 1.8 mmol), and reacted at room temperature for 12 hours. Water was added to the system, extracted three times with ethyl acetate, and the solvent was removed by rotary evaporation to obtain a crude product (4 g, yield 99%).

[0156] (2) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-methylbenzenesulfonyl-1H-pyrrole Preparation of [2,3-b]pyridine

[0157]

[0158] Add 4-chloro-1-p-methylbenzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (721 mg, 2.35 mmol)...

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Abstract

The invention belongs to the technical field of medicines, and specifically relates to a benzenesulfonamide thiazole kinases inhibitor shown as a general formula (I), and pharmaceutically acceptable salts or other stereisomers thereof, and R1, R2, R3, R4, m, n and p are defined in the specification. The invention also relates to a preparation method of the compounds, medicine preparations and pharmaceutical compositions both containing the compounds, and application of the compounds, the pharmaceutically acceptable salts or other stereisomers to prepare medicines for treating and / or preventing cancer-correlated or non-cancer-correlated diseases caused by b-RAF mutation.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to benzenesulfonamide thiazole kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations and pharmaceutical compositions containing these compounds, and the 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, espec...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D417/04A61K31/4709A61K31/437A61P35/00
CPCC07D471/04C07D417/04
Inventor 吴永谦
Owner TONGHUA SIHUAN PHARM
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