761440-65-7Relevant academic research and scientific papers
Compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase and application thereof
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Paragraph 0039; 0111-0115, (2021/09/15)
The invention discloses a compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase, and is characterized in that the structural formula is as follows. Among them: Substituent R1 . One of: Substituent R2 . One of: The substituent X is H or Cl. Substituent R3 To H. One of the following.
Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor
Groendyke, Brian J.,Nabet, Behnam,Mohardt, Mikaela L.,Zhang, Haisheng,Peng, Ke,Koide, Eriko,Coffey, Calvin R.,Che, Jianwei,Scott, David A.,Bass, Adam J.,Gray, Nathanael S.
supporting information, p. 30 - 38 (2021/01/11)
Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure-activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline "tail,"which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC50 = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.
Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance
Finlay, M. Raymond V.,Barton, Peter,Bickerton, Sue,Bista, Michal,Colclough, Nicola,Cross, Darren A. E.,Evans, Laura,Floc’h, Nicolas,Gregson, Clare,Guérot, Carine M.,Hargreaves, David,Kang, Xiaoming,Lenz, Eva M.,Li, Xu,Liu, Yi,Lorthioir, Olivier,Martin, Matthew J.,McKerrecher, Darren,McWhirter, Claire,O’Neill, Daniel,Orme, Jonathan P.,Mosallanejad, Arash,Rahi, Amar,Smith, Paul D.,Talbot, Verity,Ward, Richard A.,Wrigley, Gail,Wylot, Marta,Xue, Lin,Yao, Tieguang,Ye, Yang,Zhao, Xiliang
, p. 13704 - 13718 (2021/09/28)
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, andin vivoactivity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.
Preparation method of ALK inhibitor Brigatinib
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Paragraph 0051-0054, (2020/06/02)
The invention relates to the technical field of medicines, and relates to a preparation method of a medicine ALK inhibitor AP26113. The method comprises the following steps: (1) carrying out substitution reaction of aromatic amine on 2,4,5-trichloropyrimi
Novel(1,2,4)triazolo(1,5-a)pyridylphosphine oxide and use thereof
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Paragraph 0210; 0213-0216, (2020/07/24)
The present invention relates to novel(1,2,4)triazolo(1,5-a)pyridinyl phosphorus oxides and uses thereof. Wherein the compound is a compound represented by a formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof, and R1 to R5 are as defined in the specification. The compound disclosed by the invention can be used for preparing a medicine for treating and/or preventing cancers.
ARYL-PHOSPHORUS-OXYGEN COMPOUND AS EGFR KINASE INHIBITOR
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Paragraph 0230; 0238; 0239; 0250; 0254; 0255, (2020/06/16)
Disclosed is a class of new aryl-phosphorus-oxygen compounds as shown in formula (I) as EGFR kinase inhibitors, and pharmaceutically acceptable salts thereof.
Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026
Takahama, Yuji,Obitsu, Kazuyoshi,Takeguchi, Kazuhiro,Hirasawa, Shun,Kobayashi, Koji,Akiba, Takahiro,Ueda, Norihiro,Orii, Ryoki,Ohigashi, Atsushi,Takahashi, Takumi,Okada, Minoru,Ieda, Shigeru
, p. 512 - 523 (2019/03/07)
Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed.
PYRIMIDINE DERIVATIVE AND USE THEREOF
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Paragraph 0140; 0141, (2018/09/27)
The present invention provides a pyrimidine derivative and a use thereof. The pyrimidine derivative is the compound shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein, R1, R2, R3, R4 and R5 are, for example, as defined in the specification. The compound can act as an ALK inhibitor, and is for preparing an anti-tumor medicament for suppressing an anaplastic lymphoma kinase.
Discovery of N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a potent and selective anaplastic lymphoma kinase (ALK) inhibitor
Iikubo, Kazuhiko,Kondoh, Yutaka,Shimada, Itsuro,Matsuya, Takahiro,Mori, Kenichi,Ueno, Yoko,Okada, Minoru
, p. 251 - 262 (2018/03/13)
Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule- associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.
2,4-dibasic miazines compound
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, (2017/08/29)
The invention belongs to the field of medical chemistry, relates to a 2,4-dibasic miazines compound and specifically relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof, a drug compound thereof and an application thereof in treating EGFR or/and ALK mediated diseases.
