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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 patients (GAO L, WANG X, TANG Y, et al.FGF19 / FGFR4 signaling contributes to the resistance of hepatocellular carcinoma tosorafenib[J].J ExpClin Cancer Res,2017,36(1 ):8.)
But as of now, there is still no available for the reversal of FGFR4 V550L Literature Reports of Drug-resistant Small Molecule Inhibitors

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

Embodiment 1

[0025] compound synthesis

[0026] The melting point was determined by X-4 micro melting point apparatus (the temperature was not corrected); the mass spectrum was determined by Agilent 1100 series single quadrupole liquid mass spectrometer. 1 H-NMR, 13 C-NMR was measured by Bruker AVANCE III500 nuclear magnetic resonance instrument (DMSO-d 6 as solvent, TMS as internal standard); TLC with GF 254 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 were commercially available Analytical pure commodity, if necessary, use after anhydrous drying treatment.

[0027] The synthetic route is as follows:

[0028]

[0029] 1.1 Synthesis of intermediates 3a~3j (taking 3a as an example)

[0030] Dissolve 333.94 mg (2.0 mmol) of 2,4-dichloro-5-fluoropyrimidine and 516.96 mg (4...

Embodiment 2

[0039] Example 2 to FGFR4 V550L Protein Kinase Inhibitory Activity Test

[0040] The Caliper EZ Reader drug screening platform was used to test the effect of target compounds 8a-8j on FGFR4 V550L Inhibitory activity of protein kinases. Experimental procedure: 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 10 μl of 2.5x FGFR4 to 5 μl of 5x concentration compound solution (dissolved in DMSO and diluted 10 times with water) V550L Kinase solution (add kinase in 1.25x kinase reaction buffer), incubate at room temperature for 10 min, 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 Add 25 μl kinase reaction stop solution after reacting for a specific time. Test and collect data on Caliper, inhibition rate of kinase activity=(max-...

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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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