459817-82-4Relevant articles and documents
Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation
Fan, Weizheng,Fan, Yiqing,Jiang, Hongyu,Liu, Yan,Tang, Chunlei,Zhang, Yongjie,Zhou, Ying
, (2022/03/15)
As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5-a]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity.
Method for preparing 2-methoxyethylamine hydrochloride
-
, (2021/02/10)
The invention relates to a method for preparing 2-methoxyethylamine. The method comprises the following steps: carrying out ring closing reaction on N-Boc-ethanolamine serving as an original materialto generate 1, 2, 3-oxathiazolidine tert-butyl-3-carboxylate-2-oxide, oxidizing to obtain 1, 2, 3-oxathiazolidine tert-butyl-3-carboxylate-2, 2-dioxide, and carrying out ring opening reaction with methanol to obtain N-Boc-2-methoxyethylamine, and removing the Boc protecting group to obtain the 2-methoxyethylamine hydrochloride. According to the method, the use of a high-toxicity methylation reagent is avoided, meanwhile, the generation of N-methylation impurities is completely avoided, the quality control of raw material medicines is facilitated, and the method is environmentally friendly, mild in reaction condition, simple and convenient to operate and suitable for industrial production.
Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase
Zhang, Rong,McIntyre, Patrick J.,Collins, Patrick M.,Foley, Daniel J.,Arter, Christopher,von Delft, Frank,Bayliss, Richard,Warriner, Stuart,Nelson, Adam
, p. 6831 - 6839 (2019/05/10)
Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3-rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.