2-N-aryl-4-N-aryl-5-fluoropyrimidine compound as well as preparation method and application thereof

A technology of fluoropyrimidines and compounds, applied in the field of 2-N-aryl-4-N-aryl-5-fluoropyrimidines and their preparation, can solve the problem of unseen small molecule inhibitors and limit the survival time of tumor patients Prolongation and other issues, to achieve strong inhibitory activity, the effect of increased inhibitory activity

Active Publication Date: 2020-02-04
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First-generation FGFR4 inhibitors or some multi-target inhibitors (such as sorafenib, etc.), usually have obvious secondary drug resistance (such as V550L residue dislocation mutation) after 9 to 12 months of clinical use ), which greatly limits the prolongation of the survival time of tumor patient

Method used

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  • 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound as well as preparation method and application thereof
  • 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound as well as preparation method and application thereof
  • 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0024] Example 1

[0025] Compound synthesis

[0026] The melting point was measured by X-4 microscopic melting point instrument (the temperature was not corrected); the mass spectrum was measured by Agilent 1100 series single quadrupole LC / MS instrument. 1 H-NMR, 13 C-NMR was measured by BrukerAVANCE III500 nuclear magnetic resonance instrument (DMSO-d 6 As solvent, TMS as internal standard); GF for thin layer chromatography 254 The silica gel plate and silica gel powder (200-300 mesh) for column chromatography were purchased from Aladdin Reagent Company (aladdin, Shanghai Jingchun Biochemical Technology Co., Ltd.) and Sinopharm Chemical Reagent Co., Ltd.; other reagents and solvents used are commercially available Analyze pure commodities and use them after anhydrous drying treatment as needed.

[0027] The synthetic route is as follows:

[0028]

[0029] 1.1 General synthesis method of intermediate 3a~3j (take 3a as an example)

[0030] Dissolve 333.94mg (2.0mmol) 2,4-dichloro-5-flu...

Example Embodiment

[0039] Example 2 vs. FGFR4 V550L Protein kinase inhibitory activity test

[0040] Use Caliper EZ Reader drug screening platform to test target compounds 8a~8j against FGFR4 V550L Inhibitory activity of protein kinases. Experimental steps: configure 1.25x kinase reaction buffer (62.5mmol / L HEPES, pH 7.5; 0.001875% Brij-35; 12.5mmol / LMgCl2; 2.5mM DTT) and kinase reaction termination solution (100mmol / L HEPES, pH 7.5; 0.015 %Brij-35; 0.2% Coating Reagent#3); Add 10μl of 2.5x FGFR4 to 5μl of 5x concentration compound solution (dissolved in DMSO, diluted 10 times with water) V550L Kinase solution (add kinase in 1.25x kinase reaction buffer), incubate at room temperature for 10 minutes, then add 10 μl of 2.5x substrate peptide solution (add FAM-labeled peptide and ATP in 1.25x kinase reaction buffer) at 28°C After the reaction for a specific time, add 25μl of kinase reaction stop solution. Test and collect data on Caliper, the inhibition rate of kinase activity=(max-conversion) / (ma...

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Abstract

The invention discloses a 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound as well as preparation and application thereof. The compound has a structural formula (I) shown in the description, in the formula, Ar is substituted or unsubstituted aryl; and the substituent group on the aryl is alkyl, alkoxy, halogen or 4-methyl piperazine-1-yl. Experiment results show that the 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound is capable of effectively inhibiting FGFR4V550L, and can be used as a potential FGFR4V550 seedling compound with high inhibitory activity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound and a preparation method and application thereof. Background technique [0002] Fibroblast growth factor receptor (FGFR) is a type of receptor tyrosine kinase that penetrates the membrane. Currently known FGFR mainly includes four types, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR family members control cell proliferation and play an important role in differentiating signaling pathways. Among the four members of FGFR, FGFR4 and FGFR1-3 are quite different in structure and function. In terms of structure, FGFR4 has the least homology with the other three, and the protein domains are quite different, and the D3 domain structure of the outer part of FGFR4 is also different from FGFR1-3. In terms of function, the high expression of FGFR1 gene is common in squamous non-small cell lung cancer, breast cancer, ovarian cancer, ...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/04A61P35/00A61K31/506A61K31/496
CPCA61P35/00C07D401/04C07D403/04
Inventor 陈文斌施泓亦毛俊楠杨腾郑小辉刘志国梁广
Owner WENZHOU MEDICAL UNIV
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