Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Heterocyclic compounds as FGFR4 inhibitors

A kind of technology of compound and solvate, applied in the field of treatment of cell proliferative diseases

Inactive Publication Date: 2021-02-09
QILU PHARMA
View PDF0 Cites 3 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Heterocyclic compounds as FGFR4 inhibitors
  • Heterocyclic compounds as FGFR4 inhibitors
  • Heterocyclic compounds as FGFR4 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Compound 1A:

[0129]

[0130] 2-Nitroaniline (5.0 g, 36.2 mmol) was dissolved in tetrahydrofuran (10.0 mL) at room temperature. Subsequently, sodium hydride (1.8 g, 43.5 mmol, 60% dispersion in mineral oil) was added portionwise to the above solution under an ice-water bath. After the reaction solution was stirred at room temperature for 30 minutes, the above reaction solution was slowly added to a THF solution (100.0 mL) of 4,6-dichloropyrimidine (10.8 g, 73.0 mmol). The reaction was continued to stir overnight at room temperature.

[0131] After LCMS monitoring showed that the starting material disappeared, water was added to the reaction system to quench it. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatogr...

Embodiment 2

[0166] Compound 2A:

[0167]

[0168] Compound 1A (420 mg, 1.68 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (12.0 ml, V / V=5 / 1) at room temperature under nitrogen protection. Subsequently, 2,5-difluoro-3-pyridineboronic acid (400 mg, 2.52 mmol), Pd(PPh 3 ) 4 (485 mg, 0.42 mmol) and anhydrous potassium carbonate (463 mg, 3.35 mmol). The reaction solution was heated to 80°C and stirred.

[0169] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 2A, 6-(2,5-difluoropyridin-3-yl)-N-(2-nitrophenyl)pyrimidine-4amino.

[0170] MS(ESI)M / Z:330.1[M+H + ].

[0171] Compound 2B:

[0172]

[0173] Compound 2A (160 mg, 0.48 mmol) and Compound 1C (215 mg, 0.97 mmol) were dissolved in toluene (10.0 mL) at room temperature under nitrogen protection. Subsequently, lithium bistrimethylsilylamide ...

Embodiment 3

[0188] Compound 3A:

[0189]

[0190] At room temperature under nitrogen protection, 4-chloro-6-methylthiopyrimidine (15.0 g, 93.8 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (360 ml, V / V=5 / 1) in. Subsequently, 2-fluoro-3-pyridineboronic acid (26.4 g, 187 mmol), Pd(PPh 3 ) 4 (5.42 g, 4.69 mmol) and anhydrous potassium carbonate (25.9 g, 187 mmol). The reaction system was heated to 80°C and stirred.

[0191] After LCMS monitoring showed that the starting material disappeared, water was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate, and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 3A, 4-(2-fluoropyridin-3-yl)-6-(methylthio)pyrimidine.

[0192] MS(ESI)M / Z:222.2[M+H + ].

[0193] Compound 3B:

[0194]

[0195] Compound 3A (15...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention provides heterocyclic compounds as selective inhibitors of fibroblast growth factor receptor 4 (FGFR4), pharmaceutical compositions containing the compounds, methods of preparingthe compounds, and methods of treating cell proliferative diseases, such as cancer, using the compounds of the invention.

Description

Technical field: [0001] The present invention relates to heterocyclic compounds that are selective inhibitors of FGFR4, pharmaceutical compositions containing the compounds, and methods of treating cell proliferative diseases, such as cancer, using the compounds of the present 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 ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D405/14C07D403/04C07D239/48C07D213/74C07D401/14A61P35/00A61K31/506A61K31/5377A61K31/444
CPCA61P35/00C07D213/74C07D239/48C07D401/04C07D401/14C07D403/04C07D405/14
Inventor 杨莹莹程涛柳东明吴瑶任亚君林栋卢晓琴魏忠勇郑善松张薛赵树雍
Owner QILU PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com