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Fused tricyclic derivative as FGFR4 inhibitor

A technology of derivatives and solvates, applied in the field of fused tricyclic derivatives

Inactive Publication Date: 2021-05-11
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still no FGFR4 inhibitor approved for marketing. Highly selective small molecule inhibitors of FGFR4 have great application prospects and development significance in the field of tumor targeting therapy

Method used

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  • Fused tricyclic derivative as FGFR4 inhibitor
  • Fused tricyclic derivative as FGFR4 inhibitor
  • Fused tricyclic derivative as FGFR4 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Compound 1A:

[0122]

[0123] 5-Amino-2-chloropyridine-4-carboxylic acid (24.5 g, 142 mmol) was dissolved in thionyl chloride (600 mL) at room temperature. The reaction solution was heated to 80° C. and stirred for 4 hours.

[0124] After LCMS monitoring showed that the starting material disappeared, the reaction system was cooled to room temperature. The mixture was concentrated under reduced pressure. A solution of the obtained residue in tetrahydrofuran (100 mL) was added dropwise to aqueous ammonia (600 mL) under an ice-water bath. The reaction system was slowly warmed to room temperature and stirred for 2 hours.

[0125] After LCMS monitoring showed that the starting material disappeared, water (500 mL) was added to the above reaction system to quench it. The mixture was extracted with ethyl acetate (1.0 L x 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (300 ml x 3 times), then dried with anhydrous sodium ...

Embodiment 2

[0174] Compound 2A:

[0175]

[0176] tert-Butyl (4-bromo-2-nitrophenyl)carbamate (500 mg, 1.58 mmol) was dissolved in toluene (15.0 mL) at room temperature under nitrogen. Subsequently, N-ethylpiperazine (270 mg, 2.37 mmol), tris(dibenzylideneacetone) dipalladium (290 mg, 0.32 mmol), 4,5-bis-diphenyl Phosphine-9,9-dimethylxanthene (370 mg, 0.64 mmol) and anhydrous cesium carbonate (1.04 g, 3.20 mmol). The reaction solution was heated to 105°C and stirred for 3 hours.

[0177] After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature. Water (50 mL) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, the organic phase was washed with saturated brine (10 ml x 3 times), then dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was decompressed Concentrate. The resulting residue was purified by sili...

Embodiment 3

[0199] Compound 3A:

[0200]

[0201] tert-Butyl (4-bromo2-nitrophenyl)carbamate (1.00 g, 3.14 mmol) was dissolved in toluene (25.0 mL) at room temperature under nitrogen. Subsequently, morpholine (411 mg, 4.72 mmol), tris(dibenzylideneacetone) dipalladium (576 mg, 0.63 mmol), 4,5-bisdiphenylphosphine-9, 9-Dimethylxanthene (728 mg, 1.26 mmol) and anhydrous cesium carbonate (2.05 g, 6.28 mmol). The reaction system was heated to 105 degrees Celsius and stirred for 3 hours.

[0202] After LCMS monitoring showed that the raw materials disappeared, the reaction system was cooled to room temperature, and water (50 ml) was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally decompressed. concentrate. The resulting residue was purified by silica gel co...

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Abstract

The present invention provides a fused tricyclic derivative that is the selective inhibitor of fibroblast growth factor receptor 4 (FGFR4), a pharmaceutical composition containing the compound, a method of making the compound and a method of treating cell proliferative diseases, such as cancer, using the compounds of the invention.

Description

Technical field: [0001] The present invention relates to fused tricyclic derivatives that are selective inhibitors of FGFR4, pharmaceutical compositions containing said compounds, and methods of treating cell proliferative diseases, such as cancer, using the compounds of the invention. Background technique: [0002] Fibroblast growth factors (FGFs) are a family of 22 structurally related polypeptides with distinct biological activities that regulate cell proliferation, differentiation, migration, and expression in limb development, angiogenesis, tissue repair, and tumorigenesis play a major role in the process. [0003] The corresponding receptor for FGF (FGFR) belongs to a family of receptor tyrosine kinases RPTK. Four receptors, FGFR1, FGFR2, FGFR3 and FGFR4, have been discovered so far. Their interaction with the corresponding ligand FGF will lead to receptor dimerization and autophosphorylation, thereby initiating various downstream signaling cascades including MAPK an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14C07D519/00A61P35/00A61K31/519A61K31/5377A61K31/5386
CPCA61P35/00C07D471/14C07D519/00
Inventor 杨莹莹魏忠勇程涛柳东明卢晓琴赵树雍吴瑶
Owner QILU PHARMA
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