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set8 lysine methyltransferase inhibitor and its intermediate, preparation method and use

A lysine methyltransferase technology, applied in the field of SET8 lysine methyltransferase inhibitors and intermediates thereof, in the field of preparation

Active Publication Date: 2022-07-08
HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few reports on the compounds targeting SET8 lysine methyltransferase. Therefore, the research of a new class of compounds targeting SET8 lysine methyltransferase is the difficulty and focus of current research.

Method used

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  • set8 lysine methyltransferase inhibitor and its intermediate, preparation method and use
  • set8 lysine methyltransferase inhibitor and its intermediate, preparation method and use
  • set8 lysine methyltransferase inhibitor and its intermediate, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Preparation of tert-butyl 2-((2-(4-methoxyphenyl)thioacetyl)carbamoyl)morpholine-4-carboxylate (Formula II)

[0046]

[0047] The raw materials 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.0 mmol, 231 mg), 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (HATU, 1.1 mmol, 418 mg) was dissolved in 4 mL of dry dichloromethane, under nitrogen protection, and stirred at room temperature for 20 minutes, then the raw material 2-(4-methoxyphenyl) was added to the above system. ) thioacetamide (1.1 mmol, 199 mg), after continuing to stir for 1 hour, N,N-diisopropylethylamine (DIEA, 1.1 mmol, 142 mg) was added dropwise to the above reaction system, and continued under nitrogen protection at room temperature The reaction was stirred for 2 days. After the reaction solution was diluted with 50 mL of ethyl acetate, washed with 20 mL of water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, the reaction ...

Embodiment 2

[0048] Example 2 Preparation of tert-butyl 2-(1-cyclohexyl-3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine-4-carboxylate ( formula III)

[0049]

[0050] Formula II (0.16 mmol, 63 mg), cyclohexylhydrazine hydrochloride (0.2 mmol, 30 mg), and sodium acetate (0.36 mmol, 30 mg) were sequentially dissolved in a mixed solvent of 1 mL of acetic acid and 1 mL of 1,4-dioxane After that, it was sealed and then heated at 80°C until the II reaction was completed. After the reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated sodium carbonate solution and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, the reaction solution was concentrated, and separated by column chromatography [V (petroleum ether): V ( ethyl acetate) = 3:1-1:1] to obtain 40 mg of pale yellow oil III in a yield of 55%.

Embodiment 3

[0051] Example 3 Preparation of 2-(1-cyclohexyl-3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine (Formula I)

[0052] Formula III (0.09 mmol, 41 mg), anisole (0.1 mmol, 11 mg), and 0.5 mL of hydrogen chloride in 1,4-dioxane solution (4M) were dissolved in 3 mL of dichloromethane in turn, and the reaction was sealed for 3 days. , until the III reaction is complete. The reaction solution was evaporated to dryness to obtain a yellow oil, which was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated sodium carbonate solution, and dried over anhydrous sodium sulfate. Chloromethane solution):V(methanol)=25:1-20:1], 26 mg of yellow oil I was obtained, the yield was 81%.

[0053] 1 H NMR (400MHz, CDCl 3 ):δ7.25-7.23(m,2H),6.82-6.80(m,2H),4.67-4.64(m,2H),4.28-4.21(m,2H),3.98(s,2H),3.85-3.79 (m,1H),3.77(s,3H),3.73-3.67(m,1H),3.31-3.25(m,1H),3.19-3.15(m,1H),3.01-2.87(m,2H),1.98 -2.85(m,6H),1.73-1.70(m,1H),1.40-1.26(m,4H). 13 C NMR (400MHz, CDCl3): δ161.8, 158.1,...

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PUM

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Abstract

The invention provides a SET8 lysine methyltransferase inhibitor and its intermediate, preparation method and use. The general structural formula of the inhibitor is as follows, and the inhibitor has significant effect on SET8 lysine methyltransferase. The inhibitory activity of SET8 also has significant in vitro anti-tumor activity, which can be further developed into targeted anti-tumor drugs targeting SET8.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a SET8 lysine methyltransferase inhibitor and an intermediate thereof, a preparation method and an application thereof. Background technique [0002] Epigenetics are changes in gene expression that do not depend on changes in gene sequence, but on DNA methylation and chemical modifications of histones. Genetic mutations, epigenetic mutations, lifestyle and environmental factors together influence human health and disease. Mutations of genes encoding epigenetic regulation are mainly reflected in four aspects of histone modification changes, DNA promoter hypermethylation, extensive DNA hypomethylation and abnormal chromatin structure in the process of tumorigenesis and development. Aberrant DNA methylation is likely to cause transcriptional repression of tumor suppressor genes, genomic instability, and aberrant activation of oncogenes. Mutations of histone-modifying enzymes in ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04A61P35/00A61K31/5377
CPCC07D413/04A61P35/00Y02P20/55
Inventor 苏学明李玮杨超
Owner HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD
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