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Fibroblast growth factor receptor antagonist compound

A growth factor receptor, fibroblast technology, applied in the field of medicine, can solve the problems of not strong and durable drug effect, easy to induce drug resistance, and not good selectivity.

Inactive Publication Date: 2019-10-29
TRANSTHERA SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These small-molecule tyrosine kinase inhibitors (tyrosine kinase inhibitors, TKIs) mostly function in the form of reversible inhibition, which brings some disadvantages: ①The selectivity is not good enough, ②The drug effect is not strong and durable enough, ③ susceptible to drug resistance
At present, there is no irreversible FGFR inhibitor drug, especially an irreversible inhibitor with high selectivity for FGFR is on the market

Method used

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  • Fibroblast growth factor receptor antagonist compound
  • Fibroblast growth factor receptor antagonist compound
  • Fibroblast growth factor receptor antagonist compound

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0157] The described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.

[0158] The abbreviation "NMP" used herein refers to N-methylpyrrolidone; "DIPEA" refers to N,N-diisopropylethylamine; "TLC" refers to thin layer chromatography; "PE:EA" refers to petroleum ether : Ethyl acetate; "TFA" means trifluoroacetic acid; "THF" means tetrahydrofuran; "EA" means ethyl acetate; "DCM:MeOH" means dichloromethane: methanol; "DCM" means dichloro Methane; "MTBE" refers to methyl tert-butyl ether; "TFAA" refers to trifluoroacetic anhydride.

Embodiment 1

[0159] Example 1: (R)-1-(3-(((6-(2,6-Dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)methyl) Synthesis of pyrrolidin-1-yl)prop-2-en-1-one (compound 5)

[0160]

[0161] step:

[0162]

[0163] Synthesis of Intermediate I-1

[0164] Dissolve SM1 (5.00g, 20.5mmol) and SM2 (3.73g, 20.5mmol) in tetrahydrofuran (30ml), add cesium carbonate (20.00g, 61.5mmol) in water (30ml) solution, add a catalytic amount of Pd(PPh) 3 )Cl 2 , The resulting mixture was heated to reflux for 4 hours under a nitrogen atmosphere.

[0165] The reaction solution was concentrated to dryness and extracted with ethyl acetate. The organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was subjected to column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain Intermediate I- 1 (3.80 g, 62% yield), is a pale yellow solid.

[0166] Synthesis of Intermediate I-2

[0...

experiment example 1

[0178] Experimental example 1: Cell activity test of the compound of the present invention

[0179] DMS114 is a small cell lung cancer FGFR abnormal cell

[0180] Test substance: the compound of the present invention, the structure of which is shown above.

[0181] Test equipment: use Espire multi-function microplate reader.

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Abstract

The invention belongs to the technical field of medicines and in particular relates to a fibroblast growth factor receptor (FGFR) invisible inhibitor of a formula (I) as shown in the specification, ora pharmaceutically acceptable salt, a stereisomer or a tautomer thereof. The invention further relates to a medicine preparation, a medicine composition and application of the compounds. R1, R2, a cycle A, m and warhead are defined as in the specification. The compound provided by the invention has an efficient and high-selectivity inhibition function on a fibroblast growth factor receptor, can be applied to treatment on related diseases mediated by FGFR abnormity, and particularly treatment on cancer diseases.

Description

Technical field [0001] The present invention belongs to the technical field of medicine, and relates to a compound of an irreversible inhibitor of fibroblast growth factor receptor (FGFR), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, and a drug containing them Preparations, pharmaceutical compositions and their applications in the treatment of diseases mediated by abnormal FGFR. Background technique [0002] Tyrosine kinase receptors play an important role in tumor angiogenesis, tumor cell proliferation, migration and infiltration. At present, more than 100 tyrosine kinase inhibitor drugs have been marketed or entered clinical trials. These small-molecule tyrosine kinase inhibitors (TKI) mostly work in a reversible way, which brings some shortcomings: ①the selectivity is not good enough, ②the efficacy is not strong enough and lasting, ③ Easy to cause drug resistance. Therefore, scientists are encouraged to focus their research on the development of irre...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D403/12C07D413/12C07D403/14A61K31/517A61K31/55A61K31/5377A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/12C07D403/12C07D403/14C07D413/12
Inventor 吴永谦强晓妍
Owner TRANSTHERA SCIENCES (NANJING) INC
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