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Heterocyclic compound used as FGFR inhibitor

A compound, heterocyclic group technology, applied in the field of fibroblast growth factor-related receptor FGFR inhibitors

Inactive Publication Date: 2018-02-16
GUANGZHOU INNOCARE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, targeting FGFR3 therapy may bring a ray of hope to bladder cancer patients

Method used

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  • Heterocyclic compound used as FGFR inhibitor
  • Heterocyclic compound used as FGFR inhibitor
  • Heterocyclic compound used as FGFR inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] ( S )-1-((3,5-dimethoxyphenyl)ethynyl)-3-(1-acryloylpyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8-amine

[0151]

[0152]

[0153] first step

[0154] ( S )-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester

[0155] Compound (3-chloropyrazin-2-yl)methanamine hydrochloride 1a (3.1 g, 21.7 mmol), O-benzotriazole- N , N , N , N -Tetramethylurea tetrafluoroborate (7.1 g, 22 mmol), diisopropylethylamine (9.3 g, 72 mmol) and dichloromethane (100 mL) were mixed and added in portions at room temperature ( S )-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid (4.5 g, 18 mmol), stirred at room temperature for 16 hours. The mixture was quenched with 30 mL of water, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 mL × 2), the combined organic phases were washed with saturated brine (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desicca...

Embodiment 2

[0183] 1-((3,5-dimethoxyphenyl)ethynyl)-3-(1-acryloylazetidin-3-yl)imidazo[1,5-a]pyrazin-8-amine

[0184]

[0185]

[0186] first step

[0187] Benzyl 3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate

[0188] Compound (3-chloropyrazin-2-yl)methanamine hydrochloride 1a (0.9 g, 5.0 mmol), N , N -Dimethylformamide (0.02 mL) and dichloromethane (20 mL) were mixed, and 3-(chloroformyl)azetidine-1-carboxylic acid benzyl ester (1.3 g, 5.0 mmol) was added dropwise at room temperature Dichloromethane solution (5.0 mL), stirred at room temperature for 10 min. The mixture was quenched with 30 mL saturated aqueous sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the combined organic phases were washed with saturated brine (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pres...

Embodiment 3

[0216] ( R )-1-((3,5-dimethoxyphenyl)ethynyl)-3-(1-acryloylpyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8-amine

[0217]

[0218] Synthetic Example 3 with reference to the operating steps of Example 1, but in the first step with ( R )-1-((Benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid instead of ( S )-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid.

[0219] MS m / z (ESI): 418 [M+1]

[0220] 1 H NMR (400 MHz, CDCl3) δ 7.24-7.11 (m, 2H), 6.71 (s, 2H), 6.50-6.37 (m,3H), 6. 19-5.84 (bs, 2H), 5.78-5.70 (m , 1H), 4.16-4.07 (m, 2H), 3.96-3.93 (m,1H), 3.80 (s, 6H), 3.80-3.61 (m, 2H), 2.46-2.22 (m, 2H).

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Abstract

The invention relates to a heterocyclic compound, a pharmaceutical composition containing the same, a preparation method of the same, and an application of the heterocyclic compound as a fibroblast growth factor receptor (FGFR) inhibitor. The inhibitor is a heterocyclic compound as shown in a formula I which is described in the specification, or pharmaceutically acceptable salts, prodrugs, solventcompounds, polymorphs, isomers, stable isotope derivatives thereof, or pharmaceutical compositions containing the same. The compounds provided by the invention can be used for treatment or preventment of related diseases mediated by FGFR, such as cancers.

Description

technical field [0001] The invention relates to a preparation method of a class of heterocyclic compounds and pharmaceutical compositions containing them, and their use as inhibitors of fibroblast growth factor-associated receptor FGFR. The compounds involved in the present invention can be used to treat or prevent related diseases mediated by FGFR, such as cancer. Background technique [0002] Fibroblast Growth Factor Receptor (FGFR, Fibroblast Growth Factors Receptor) belongs to receptor-type protein tyrosine kinases, and this family mainly includes four members: FGFR1, FGFR2, FGFR3 and FGFR4. FGFR is involved in the regulation of cell proliferation, apoptosis, migration, angiogenesis and many other processes. Because of their broad range of roles, FGFRs and other RTKs are normally tightly regulated. In tumors, such as liver cancer, bladder cancer, lung cancer, breast cancer, prostate cancer, etc., FGFR activating mutations or ligand / receptor overexpression lead to its c...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61P35/00
CPCC07D487/04A61K31/437A61K31/525C07D471/04A61P35/04A61P35/00
Inventor 孔祥龙周超陈向阳
Owner GUANGZHOU INNOCARE PHARMA TECH CO LTD
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