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Nitrile methyl piperazine derivative serving as KRAS G12C mutant protein inhibitor and application of nitrile methyl piperazine derivative

A solvate and alkyl technology, which is applied in the field of preparation of cancer drugs, can solve the problems of difficulty in further improving activity, no performance activity, poor metabolic stability, etc., and achieve significant anti-tumor activity, high selectivity, Effects of High Exposure

Active Publication Date: 2020-05-29
SUZHOU INST OF MATERIA MEDICA CHINA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The literature (Nature.2013; 503:548-551) reported a class of covalent binding inhibitors targeting the KRAS G12C mutation, but the enzymatic activity of these compounds is not high, and there is no activity at the cellular level
Literature (Science 2016; 351:604-608, Cancer Discov 2016; 6:316-29) reported that a class of compounds exhibited μM level of cell anti-proliferation activity at the cellular level, but their metabolic stability was poor and their activity was difficult. Further improve

Method used

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  • Nitrile methyl piperazine derivative serving as KRAS G12C mutant protein inhibitor and application of nitrile methyl piperazine derivative
  • Nitrile methyl piperazine derivative serving as KRAS G12C mutant protein inhibitor and application of nitrile methyl piperazine derivative
  • Nitrile methyl piperazine derivative serving as KRAS G12C mutant protein inhibitor and application of nitrile methyl piperazine derivative

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Experimental program
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Effect test

Embodiment 1

[0048] The synthesis of embodiment 1KS90100-K1-A

[0049]

[0050] step 1:

[0051] 2,6-Dichloro-5-fluoronicotinic acid (20.0g, 95.2mmol) was dissolved in dichloromethane (200mL), cooled to 0°C, oxalyl chloride (24.20g, 19.6mmol) was added dropwise, and raised to React overnight at room temperature, and take a sample to analyze that the reaction is complete. The reaction was concentrated, dissolved by adding 1,4-dioxane (50mL), cooled to 0°C, added dropwise to ammonia water (50mL), added dropwise, raised to room temperature and stirred for 3 hours, then sampled and analyzed for complete reaction. The reaction liquid was quenched with water, extracted with ethyl acetate, combined organic phases, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain KS90100-K1-A1 (19.8 g, yield 99% %).

[0052] Step 2:

[0053] 2-Bromo-3-amino-4-methylpyridine ...

Embodiment 2

[0062] The synthesis of embodiment 2KS90100-K1-B

[0063]

[0064] Referring to the preparation method of Example 1, KS90100-K1-B (crude product) was obtained, which was directly used in the next step. The synthesis of embodiment 3KS90100-K2

Embodiment 3

[0064] Referring to the preparation method of Example 1, KS90100-K1-B (crude product) was obtained, which was directly used in the next step. The synthesis of embodiment 3KS90100-K2

[0065]

[0066] step 1:

[0067] (R)-Piperazine-2-carboxylate hydrochloride (5.0g, 24.6mmol) was dissolved in water (10mL) and 1,4-dioxane (40mL), cooled to 0°C, and NaOH (2.96 g, 74.0mmol) in water (6mL), stir well; add (Boc) 2 O (11.3g, 51.8mmol), stirred at room temperature for 20 hours, the reaction was complete. The pH of the reaction solution was adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated, and the crude product was beaten with PE to obtain a white solid KS90100-K2-1 (7.5g , yield 92%). LC-MS: m / z=329.2 [M-H] -

[0068] Step 2:

[0069] At 0°C, add thionyl chloride (13.2g, 111mmol) dropwise to DMF (8.47g, 116mmol)...

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Abstract

The invention discloses a nitrile methyl piperazine derivative serving as a KRAS G12C mutant protein inhibitor and an application of the nitrile methyl piperazine derivative. The compound has a structure represented by a general formula (I). Compared with an existing compound, the compound provided by the invention has higher selectivity on malignant tumors caused by KRAS G12C mutation; a longer half-life period is shown, and better metabolic stability is achieved; the exposure amount is higher, the oral bioavailability is better, and the anti-tumor activity is more remarkable.

Description

[0001] field of invention [0002] The present invention relates to novel nitrile methylpiperazine derivatives, their derivatives, pharmaceutically acceptable salts or solvates and hydrates, and the application of synthesizing them in the preparation of medicines for treating cancer. [0003] Background of the invention [0004] RAS protein is the product of RAS gene expression, which consists of 189 amino acids and has a molecular weight of 21KDa. The activated RAS protein continues to give downstream protein growth signals, resulting in continuous growth and differentiation of cells, and eventually tumors. It has been found that about 30% of human tumors carry certain mutated RAS genes, among which KRAS mutations are the most prominent, accounting for 86% of all RAS mutations. For KRAS mutations, the most common mutations occurred on glycine 12 (G12), glycine 13 (G13) and glutamine 61 (Q61) residues, of which G12 mutations accounted for 83%. [0005] G12C mutation is a rela...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00
CPCC07D471/04A61K31/519A61P35/00
Inventor 李丹倪帅健
Owner SUZHOU INST OF MATERIA MEDICA CHINA SCI & TECH
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