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Preparation method and application of alkyne pyrimidine compound as FGFR inhibitor

A compound and solvate technology, applied in the field of tumor medicine, can solve problems such as overactivation of FGFR signaling pathway and canceration of normal cells

Pending Publication Date: 2022-08-05
YA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, when FGFR is mutated or overexpressed, it will cause excessive activation of the FGFR signaling pathway and further induce normal cell canceration

Method used

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  • Preparation method and application of alkyne pyrimidine compound as FGFR inhibitor
  • Preparation method and application of alkyne pyrimidine compound as FGFR inhibitor
  • Preparation method and application of alkyne pyrimidine compound as FGFR inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1: (S) -2- (1-acryl-based pyroglyxane-3-aminel) -4- (3,5-dimethyl oxygenyl benzine)

[0092]

[0093] Step 1: Compound 1B synthesis

[0094] Add compounds 1A (1.49g, 10.0mmol), 3,5-dimethyloxyl benzene (1.70g, 10.5 mmol), double tricezyl phosphorus chloride (702 mg, 1.0mmol), iodine iodine Macral copper (190mg, 1.0 mmol), tripleine (5.06g, 50.0 mmol) and n, n, n-di metamimamamide 50ml. Nitrogen replacement 3 times, stirring 90 ° C to react overnight. Cool to room temperature, diluted with ethyl acetate and water in the reaction liquid, and extract ethyl acetate. Organic phase is washed with water and saturated saline, dry sodium sulfate, and the organic phase decompression and steaming. The residue is purified by the column layer, and the compound 1B (2.14g, the yield of 78 %) is yellow solid. LC / MS (ESI): M / Z = 275.1 [M+H] + Then, then, then

[0095] Step 2: synthesis of compound 1C

[0096] Add compounds 1B (0.82g, 3.0mmol) to the reaction bottle, (s) -1-Unitadu...

Embodiment 2

[0101] Example 2: (S) -2- (1-acryl-based pyroglymirrial-3-aminel) -4- (3,5-di oxygenyl benzenel) -5-bromine (compound 2)

[0102]

[0103] Methods similar to Example 1 (the initial raw material was replaced with 5-bromo-2,4-dichloropyline) to obtain compound 2 (156mg and the yield of 37 %, this is the last step rate, the same below) to yellow solid body Essence 1 H nmr (400MHz, DMSO-D 6 ) Δ: 8.34 (s, 1H), 6.72 (d, 2H), 6.51-6.47 (m, 2H), 6.20 (dd, 1H), 5.78 (s, 1H), 5.59 (dd, 1H), 4.09-3.9666 (M, 1H), 3.81-3.58 (m, 9H), 3.53-3.34 (m, 1H), 2.30-1.87 (m, 2H); LC / ms (ESI): m / z = 457.1 [m+h] + Then, then, then

Embodiment 3

[0104] Example 3: (S) -2- (1-acryl-based pyroglymirrial-3-aminel) -4- (3,5-di oxygenyl benzenel) -5-fluoroprimidine (compound 3)

[0105]

[0106] Methods similar to Example 1 (the initial raw material was replaced with 5-fluorine-2,4-dichloropyamine) to obtain compound 3 (149mg, 41 % yield) to pale yellow solid. 1 H nmr (400MHz, DMSO-D 6 ) Δ: 8.23 ​​(s, 1H), 6.71 (d, 2H), 6.52-6.46 (m, 2H), 6.19 (dd, 1H), 5.81 (s, 1H), 5.60 (dd, 1H), 4.14-4.03 (M, 1H), 3.83-3.62 (m, 9H), 3.55-3.36 (m, 1H), 2.28-1.85 (m, 2H); LC / ms (ESI): m / z = 397.2 [m+h] + Then, then, then

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PUM

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Abstract

The invention provides an alkyne pyrimidine skeleton-containing selective inhibitor of FGFR receptor tyrosine kinase, and a compound as shown in a general formula I or a prodrug, a stable isotope derivative, a medicinal salt, a solvate, a polymorphic substance or an isomer thereof. The compound represented by the formula I has excellent FGFR inhibition activity, and can be used in drugs for preventing or treating FGFR kinase-related diseases, especially tumors.

Description

Technical field: [0001] The invention involves a pyrine miscellaneous compound or its medicinal salt that is used as a FGFR inhibitor; a pharmaceutical composition containing the pyrine miscellaneous compound or its medicinal salt; Or the preparation method of the medicinal salt; the pyrimidine miscellaneous compound or its medicinal salt, or the pharmaceutical composition containing the pyrine miscellaneous compound or its medicinal salt is prepared for Treatment and / or prevention of FGFR -related sexual diseases, especially tumor drugs. Background technique: [0002] Fibroblast Growth Factors (FGFS) combined with its receptor (Fibroblast Growth Factor Receptors, FGFRS) to activate the downstream signal pathway of its regulat Play an important role in biological processes such as adjustment, metabolic regulation, etc.). FGFRS is a typical type of receptor delatease (RTK). Its family includes four sub -types: FGFR1, FGFR2, FGFR3, and FGFR4. They are composed of three parts: extra...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D401/12A61P35/00A61K31/506
CPCC07D403/12C07D401/12A61P35/00
Inventor 梁永宏曾兆森严文广凌苑熊方均宋绍迪朱杨伟
Owner YA THERAPEUTICS INC