Quality Control of 3-Iodo-1H-indazol-5-amine. The mechanism of aromatic electrophilic substitution of aromatic heterocycles is consistent with that of benzene. Compound: 3-Iodo-1H-indazol-5-amine, is researched, Molecular C7H6IN3, CAS is 599183-36-5, about The discovery of orally bioavailable tyrosine threonine kinase (TTK) inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as anticancer agents. Author is Liu, Yong; Lang, Yunhui; Patel, Narendra Kumar; Ng, Grace; Laufer, Radoslaw; Li, Sze-Wan; Edwards, Louise; Forrest, Bryan; Sampson, Peter B.; Feher, Miklos; Ban, Fuqiang; Awrey, Donald E.; Beletskaya, Irina; Mao, Guodong; Hodgson, Richard; Plotnikova, Olga; Qiu, Wei; Chirgadze, Nickolay Y.; Mason, Jacqueline M.; Wei, Xin; Lin, Dan Chi-Chia; Che, Yi; Kiarash, Reza; Madeira, Brian; Fletcher, Graham C.; Mak, Tak W.; Bray, Mark R.; Pauls, Henry W..
The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochem. properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the Ph ring, potent inhibitors with oral exposure were obtained. An x-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (T1/2 > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound I (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclin. evaluation.
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Piperazines – an overview | ScienceDirect Topics