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Fibroblast growth factor receptor inhibitors and application thereof

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.

Active Publication Date: 2019-02-26
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
[0008] Currently, there is no irreversible inhibitor of FGFR, especially an irreversible inhibitor with high selectivity for pan-FGFR (FGFR) pan-FGFR

Method used

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  • Fibroblast growth factor receptor inhibitors and application thereof
  • Fibroblast growth factor receptor inhibitors and application thereof
  • Fibroblast growth factor receptor inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0310] 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" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "EA" refers to ethyl acetate; "DCM:MeOH" refers to dichloromethane:methanol; "DCM" refers to dichloromethane Methane; "MTBE" refers to methyl tert-butyl ether; "TFAA" refers to trifluoroacetic anhydride; "TEA" refers to triethylamine; Butoxycarbonyl; "MsCl" is methanesulfonyl chloride; "DEAD" means diethyl azodicarboxylate; "PPh 3 " refers to triphenylphosphine; "mCPBA" refers to m-chloroperoxybenzoic acid; "LC-MS" refers to liquid chromatography-mass spectrometry.

[0311] The present invention can be better understood from the following examples and experimental examples. However, those skilled in the art can easily understand that the content described in the embodiments is only for illustrating ...

preparation example 1

[0312] Preparation example 1: the synthesis of intermediate 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde

[0313]

[0314] Step 1: Synthesis of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate

[0315]

[0316] The raw material 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (15g, 64.4mmol, 1.0eq) was dissolved in tetrahydrofuran (100mL), and triethylamine (19.6g, 193.4mmol, 3.00eq ), cooled to 0°C, slowly added ammonia water (7.8g, 1288mmol, 20.0eq), raised to room temperature and reacted overnight, LC-MS detected that the reaction was complete, left to separate the liquids, extracted the aqueous phase once with ethyl acetate, combined The organic phase was dried and concentrated, and the crude product was slurry-washed with methyl tert-butyl ether to obtain a white solid product (11.8 g, yield: 87%).

[0317] Step 2: Synthesis of (4-amino-2-(methylthio)pyrimidin-5-yl)methanol

[0318]

[0319] The raw material 4-amino-2-(methylthio)pyrimidin...

preparation example 2

[0323] Preparation Example 2: Synthesis of intermediate 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0324]

[0325] Step 1: Synthesis of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0326]

[0327] The raw material tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.1g, 5mmol, 1.0eq) was dissolved in dichloromethane (15mL), triethylamine (1.5g, 15mmol, 3.0eq) and methanesulfonyl chloride (573mg, 5mmol, 1.0eq), react at room temperature for 2 hours. LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, the organic phases were combined, washed twice with saturated brine, dried, and concentrated to give a white solid product (1.2 g, yield: 82%).

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Abstract

The invention specifically relates to irreversible inhibitors used for the fibroblast growth factor receptor (FGFR) and represented by a formula I which is described in the specification and pharmaceutically acceptable salts and stereoisomers thereof, and pharmaceutical preparations, pharmaceutical compositions and application of the compounds, belonging to the field of medical technology. R1, R2,R3, R4, m, X, warhead1 and warhead2 in the formula I are as defined in the specification. The compounds of the invention have high-efficiency high-selectivity inhibitory effects on the fibroblast growth factor receptor and can be applied to the treatment of related diseases mediated by FGF / FGFR abnormalities, especially to the treatment of cancer diseases.

Description

[0001] This application claims the priority of the Chinese patent application with the application number 201710672089.X submitted to the China Patent Office on August 8, 2017, and the title of the invention is "Fibroblast Growth Factor Receptor Inhibitor and Its Use", the entire content of which is passed References are incorporated in this application. technical field [0002] The invention belongs to the technical field of medicine, and relates to an irreversible inhibitor of fibroblast growth factor receptor (FGFR), or its pharmaceutically acceptable salt, stereoisomer and application thereof. Background technique [0003] Tyrosine kinase receptors play an important role in tumor angiogenesis, tumor cell proliferation, migration, and invasion. At present, more than 100 tyrosine kinase inhibitor drugs have been marketed or entered the clinical trial stage. These small-molecule tyrosine kinase inhibitors (tyrosine kinase inhibitors, TKIs) mostly function in the form of rev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04A61K31/519A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D471/04C07D487/04A61K31/519C07D475/00
Inventor 吴永谦
Owner TRANSTHERA SCIENCES (NANJING) INC
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