1000895-53-3Relevant academic research and scientific papers
Pyrazole derivative for FGFR inhibitor and preparation method of pyrazole derivative
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, (2021/03/06)
The invention provides a pyrazole derivative for an FGFR inhibitor and a preparation method of the pyrazole derivative. The invention specifically relates to an amide pyrazole compound serving as an FGFR irreversible inhibitor, and a preparation method and application thereof. The present invention provides a compound as shown in Formula I, or a pharmaceutically acceptable salt, or solvate, isotope substitute, prodrug, or metabolite thereof. The compound as shown in general formula I have FGFR inhibitory activity, and is capable of preventing or treating disorders associated with FGFR activityor expression, preferably such as cancer.
New and convergent synthesis of AZD 4547
Bu, Lehao,Chen, Wenxin,Gao, Lei,Mao, Yongjun,Sun, Cong,Wang, Han
, p. 276 - 282 (2020/06/10)
A practical and convergent synthetic route of AZD 4547 was developed successfully. The intermediate 5-(3,5-dimethoxyphenylethyl)-1H-pyrazol-3-amine (7) was prepared from 3,5-dimethoxybenzaldehyde through 6 simple steps in 52.3% yield. Another intermediate 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzoic acid (14) was synthesized from ethyl 4-fluorobenzoate and (2R,6S)-2,6-dimethylpiperazine in 62% yield over 2 steps. Finally, AZD 4547 was obtained from 7 and 14 in 73% yield and 99.1% purity. Purification methods of the intermediates and the final product involved in the route were developed.
Method for preparing AZD4547, intermediate and preparation method of intermediate
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, (2020/05/14)
The invention provides a method for preparing AZD-4547. The method comprises the following steps: (1) preparing a first intermediate 2-cyano-5-(3, 5-dimethoxyphenyl)-3-oxoethyl valerate; (2) preparinga second intermediate 5-[2-(3, 5-dimethoxyphenyl) ethyl]-1H-pyrazole-3-amine by taking the first intermediate as a raw material; and (3) in an alkali-containing organic solvent, carrying out a reaction on a third intermediate 4-((3S, 5R)-3, 5-dimethylpiperazinyl-1-yl) benzoyl chloride and the second intermediate to prepare the AZD-4547. The method has the advantages of accessible raw materials, simple technique, mild reaction conditions, convenient operation, high yield and low cost and can easily implement industrial production. The invention also provides an intermediate 2-cyano-5-(3, 5-dimethoxyphenyl)-3-oxoethyl valerate for preparing AZD-4547 and a preparation method thereof.
Vinyl sulfamido substituted pyrazolyl benzamide compound
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, (2020/07/02)
The invention provides a vinyl sulfamide substituted pyrazolyl benzamide compound. Specifically, the present invention provides a compound in formula I shown in the specification or a pharmaceuticallyacceptable salt thereof, and a preparation method and use thereof. The compound shown in the formula I has excellent FGFR inhibitory activity and can be used for preventing or treating diseases related to FGFR kinase activity or expression quantity, such as cancer.
Synthetic process for 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-3-amine
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Paragraph 0037-0040, (2018/10/19)
The invention belongs to the field of medicine chemical industries, and particularly relates to a new synthetic process for 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-3-amine of an AZD4547 key intermediate. The synthetic process comprises the following steps: using 2-(3,5-dimethoxyphenyl) ethylpropionate as a starting raw material, in the presence of a basic catalyst and an organic solvent, reacting with acetonitrile, enabling an obtained product to perform cyclization with hydrazine hydrate in the presence of concentrated sulfuric acid, to obtain a target product of the 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-3-amine. Compared with a current technology, the provided synthetic process for the 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-3-amine is capable of greatly shortening thereaction time, enabling the yield of the product to be higher, wherein a process of purifying the intermediate does not exist between two steps of the reactions, shortening a reaction period, and reducing the wastewater discharge, and suitable for the industrialized mass production.
Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors
Fan, Jun,Dai, Yang,Shao, Jingwei,Peng, Xia,Wang, Chen,Cao, Sufen,Zhao, Bin,Ai, Jing,Geng, Meiyu,Duan, Wenhu
supporting information, p. 2594 - 2599 (2016/05/09)
Fibroblast growth factor receptors (FGFRs) are important oncology targets due to the dysregulation of this signaling pathway in a wide variety of human cancers. We identified a series of pyrazolylaminoquinazoline derivatives as potent FGFR inhibitors with low nanomolar potency. The representative compound 29 strongly inhibited FGFR1-3 kinase activity and suppressed FGFR signaling transduction in FGFR-addicted cancer cells; FGFRs-driven cell proliferation was also strongly inhibited regardless of mechanistic complexity implicated in FGFR activation, which further confirmed that 29 was a potent pan-FGFR inhibitor. The flexibility of our structure offered the potential to preserve good affinity for mutant FGFR, which is important for developing TKIs with long-term efficacy.
Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase
Norman, Richard A.,Schott, Anne-Kathrin,Andrews, David M.,Breed, Jason,Foote, Kevin M.,Garner, Andrew P.,Ogg, Derek,Orme, Jonathon P.,Pink, Jennifer H.,Roberts, Karen,Rudge, David A.,Thomas, Andrew P.,Leach, Andrew G.
experimental part, p. 5003 - 5012 (2012/08/14)
The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.
PYRIMIDINE DERIVATIVES AND THEIR USE AS MODULATORS OF FGFR ACTIVITY
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Page/Page column 41-42, (2009/06/27)
There is provided pyrimidine compounds of formula 1: or pharmaceutical salts thereof. There is al so provided processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy, for exampl e in the treatment of proliferative disease such as cancer and particular ly in disease mediated by a FGFR inhibitory effect.
PYRIMIDINE COMPOUNDS HAVING A FGFR INHIBITORY EFFECT
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Page/Page column 49-50, (2009/04/25)
There is provided pyrimidine compounds of formula (I): or pharmaceutical salts thereof. There is also provided processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by a FGFR inhibitory effect.
PYRAZOLE COMPOUNDS 436
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Page/Page column 9-10, (2009/12/28)
There is provided novel compounds of formula (Ia) or (Ib): or pharmaceutically acceptable salsts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
