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FGFR4 inhibitor, composition and use thereof in drug preparation

A technology of FGFR4 and inhibitors, applied in the field of FGFR4 inhibitors, compositions and their use in drug preparation, capable of solving problems such as no discovery

Active Publication Date: 2021-10-22
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the covalent inhibitors with high potency and selectivity for FGFR4 inhibition, BLU9931, BLU-554 and H3B-6527 all covalently bind to the Cys552 sulfhydryl group of the hinge region of FGFR4 protein, while PRN1371, FIIN-2 and TAS- 120 is covalently bound to Cys477 in the p-loop of the FGFR4 protein, and can only be covalently bound to one of the cysteine ​​residues. It has not been found that it can be covalently bound to two cysteine ​​residues in the FGFR4 protein covalently bound inhibitor

Method used

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  • FGFR4 inhibitor, composition and use thereof in drug preparation
  • FGFR4 inhibitor, composition and use thereof in drug preparation
  • FGFR4 inhibitor, composition and use thereof in drug preparation

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Embodiment Construction

[0041] Unless otherwise specified, the term "cycloalkyl" as used herein, or as another group includes a saturated or partially unsaturated (comprising 1 or more double bonds) cyclic hydrocarbon groups including 1 to 2 rings. It is preferred to include 3 to 10 carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cycloyl group. "Substituted cycloalkyl" includes a cycloalkyl group, which is used by one or more substituents such as halogen, alkyl, alkoxy, hydroxyl group, aryl group, aryloxy, aryl alkyl, cycloalkyl, alkyl group Amino group, alkyl amyl amino group, oxo, acyl, arylcarbonyl, amino group, nitro, cyano, thiol, and / or alkyl thio, or include any substituent in "substituted alkyl" definitions Optionally for replacement.

[0042] Unless otherwise stated, the term "aryl" or "AR" as used herein is used herein, refers to a monocyclic and polycyclic aromatic group containing 6 to 10 carbon in the ring portion (such as benzene). The group ...

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Abstract

The invention provides an FGFR4 inhibitor which takes 3,4-dihydropyrimidine[4,5-d]pyrimidine-2(1H)-ketone as a mother nucleus and has a covalent structure. According to the embodiment, nine specific compounds are provided, kinase inhibitory activity tests are carried out on the nine compounds, the semi-inhibitory concentration of LX08 on FGFR4 kinase inhibitory activity is only 7 nM, the semi-inhibitory concentration is lower than that of active control FIN-2, and thus LX08 has potential application prospects. Besides, through MALDI-TOF mass spectrum combination experiments on the synthesized compounds, it is found that compounds such as LX01, LX05, LX06, LX07 and LX08 can only be covalently combined with Cys552 in the FGFR4 and cannot be covalently combined with Cys477 in the FGFR4, and LX09 is an FGFR4 inhibitor which can be covalently combined with two cysteine Cys552 and Cys477 in the FGFR4.

Description

Technical field [0001] The present invention describes a method of preparing the compound, and a method of using the compound and a composition to inhibit the activity of tyranoic acid kinase. Background technique [0002] Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase family comprising FGFR1, FGFR2, FGFR3, FGFR4, and other 18 different FGF ligands of high affinity receptors. These ligand-receptor combinations can regulate a variety of signal conduction and endocrine activities in human tissue development. The genetic changes of FGFR, including mutations, fuse, and gene amplification, which cause an abnormal signal path to activate and drive the growth of cancer cells. Researchers have detected genetic changes in FGFR in a variety of cancer types, including breast cancer, liver cancer, squamous non-small cell lung cancer, squamous cervical cancer and bile duct cancer. The clinical verification of FGFR as a treatment target has been confirmed in bladder can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02
CPCC07D487/04A61P35/00A61P35/02
Inventor 陈永恒陈小娟徐广宇付莹陈主初
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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