19750-02-8Relevant articles and documents
Discovery and structure ? activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors
Chen, Yun,Bai, Gang,Li, Yan,Ning, Yi,Cao, Sufen,Zhou, Jinpei,Ding, Jian,Zhang, Huibin,Xie, Hua,Duan, Wenhu
, (2021/09/28)
Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance- conferring mutations, FLT3D835Y, both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.
Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma
Chen, Yun,Bai, Gang,Ning, Yi,Cai, Shi,Zhang, Tao,Song, Peiran,Zhou, Jinpei,Duan, Wenhu,Ding, Jian,Xie, Hua,Zhang, Huibin
supporting information, (2020/02/04)
Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure?activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell–like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL.
Synthetic method of pesticide intermediate pyrazole-4-ethyl formate
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, (2017/06/02)
The invention discloses a synthetic method of pesticide intermediate pyrazole-4-ethyl formate. The method comprises the following steps: 1) ethyl cyanoacetate and triethyl orthoformate are placed in a flask, acetic anhydride is added for a reaction, an oil pump is used for performing underpressure distillation to obtain efhylene efhoxymethylene cyanoncetata; 2) efhylene efhoxymethylene cyanoncetata is dissolved in ethanol, hydrazine hydrate is added drop by drop, a solvent is used for underpressure distillation to obtain 3-amino-pyrazoles-4-ethyl formate; and 3) adding pyrazoles-4-ethyl formate and glacial acetic acid are added in a reaction bottle, hydrochloric acid is added drop by drop, a sodium nitrite solution is added drop by drop, after the reaction, ethanol is added for backflow and vacuum concentration, dichloromethane and water are added for stirring and layering, and an organic layer is re-crystallized to obtain the finished product. By employing ester condensation, cyclization and deamination reactions, the preparation technology is simple, and the product is easily purified, production cost is low, and the method is suitable for large-scale industrial production.
