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Pyrazole derivative as well as preparation method and medical application thereof

A compound, selected technology, applied in the field of medicine

Inactive Publication Date: 2020-09-01
CLUES THERAPEUTICS SHANGHAI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still problems in the effectiveness, safety or selectivity of the compounds and experimental drugs disclosed in these prior art. In addition, the current understanding of the role of RET in tumors is also deepening, and it is still necessary to study And develop new small molecule selective RET kinase inhibitors to fill and meet clinical treatment needs for RET abnormal diseases

Method used

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  • Pyrazole derivative as well as preparation method and medical application thereof
  • Pyrazole derivative as well as preparation method and medical application thereof
  • Pyrazole derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] (S)-1-cyano-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5 -methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide 1

[0122] (S)-1-cyano-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6 -((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide 1

[0123]

[0124] first step

[0125] tert-butyl

[0126] 3-((tert-butoxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)amino)-5-methyl-1H-pyrazole-1-carboxy late 1b

[0127] 3-((tert-butoxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)amino)-5-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester 1b

[0128] Dissolve 2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine 1a (2.7g, 12.0mmol) in 24mL dichloromethane, add di Di-tert-butyl carbonate (5.9g, 27.2mmol), triethylamine (4.2mL, 30mmol), and 4-dimethylaminopyridine (147mg, 1.3mmol) were added at 0°C, and reacted overnight at room temperature. TLC detected that the reaction was complete, ...

Embodiment 2

[0189] N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5-methyl-1H -pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohex-1-ene-1-carboxamide 2

[0190] N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5- Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohex-1-ene-1-carboxamide 2

[0191]

[0192] first step

[0193] tert-butyl

[0194] 3-((tert-butoxycarbonyl)(6-methyl-2-(4-oxocyclohexyl)pyrimidin-4-yl)amino)-5-methyl-1H-pyrazol e-1-carboxylate 2a

[0195] 3-((tert-butoxycarbonyl)(6-methyl-2-(4-oxocyclohexyl)pyrimidin-4-yl)amino)-5-methyl-1H-pyrazole-1-carboxylic acid tert butyl ester 2a

[0196] 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-one 1g (6.0g, 21.0mmol) Dissolve in 42mL of dichloromethane, add di-tert-butyl dicarbonate (10.3g, 47.3mmol), triethylamine (7.3mL, 52.5 mmol), add 4-dimethylaminopyridine (256mg, 2.1mmol) at 0°C , reacted at room temperature for 16 hours. TLC detected that th...

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Abstract

The invention relates to a pyrazole derivative as well as a preparation method and medical application thereof. Specifically, the present invention relates to pyrazole derivative represented by a general formula (I), a preparation method, pharmaceutically acceptable salts of the pyrazole derivative, and application of the pyrazole derivative as a therapeutic agent, especially an RET inhibitor; andthe definitions of substituents in the general formula (I) are the same as those in the descriptions.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a pyrazole derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a RET protein kinase inhibitor. Background technique [0002] RET protein (Rerranged during Transfection, rearranged during transfection) belongs to the receptor tyrosine kinase family, as a receptor for nerve growth factor, its function involves the normal growth and development of the nervous system, cell proliferation and survival. Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL) regulate downstream signaling by binding to RET, and the GFL family also includes neurturin (NTRN), artemin (ARTN) and persephin ( PSPN) (Arighi et al., Cytokine Growth Factor rev., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET activation requires a ligand, and the GDNF family receptor α protein and RET protein form ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/12A61K31/506A61P35/00
CPCA61P35/00C07D401/14C07D403/12Y02P20/55
Inventor 王中利郑苏欣赵雯雯刘俊张建平
Owner CLUES THERAPEUTICS SHANGHAI LTD
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