162286-51-3Relevant articles and documents
Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34
Singleton, Justin D.,Dass, Reuben,Neubert, Nathaniel R.,Smith, Rachel M.,Webber, Zak,Hansen, Marc D.H.,Peterson, Matt A.
supporting information, (2019/12/24)
A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (20–93%, ave. = 59%). The straightforward synthesis involved sequential treatment of commercially-available acetonitrile derivatives with DMF-dimethylacetal (120 °C, 20 min), followed by treatment with NH2NH2·HBr (120 °C, 20 min), and 1,1,3,3-tetramethoxypropane or 2-aryl-substituted malondialdehdyes (120 °C, 20 min). Compounds were screened for antimitotic activities against MCF7 breast cancer and/or A2780 ovarian cancer cell lines in vitro. The most active compounds exhibited EC50 values ranging from 0.5 to 4.3 μM, with the 3-(4-(trifluoromethyl)phenyl)-6-[4-(2-(piperidin-1-yl)ethoxy]phenyl analogue (34e) and the 3-(2-fluorophenyl)-6-[4-(2-(4-methylpiperizin-1-yl)ethoxy]phenyl analogue (35a) being two to three fold more active than Compound C (Dorsomorphin) in A2780 and MCF7 assays, respectively. Importantly, a monosubstituted 3-(benzothiazol-2-yl) derivative (13) was equipotent with the more synthetically challenging 3,6-disubstituted derivatives (34a–e and 35a–e), and exhibited a promising and unique selectivity profile when screened against a panel consisting of 403 protein kinases (Kinomescan selectivity score = 0.005, Kd = 0.55 ± 0.055 μM and 0.410 ± 0.20 μM for JAK1 JH2 pseudokinase and VPS34, respectively).
Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics.
Fraley, Mark E,Rubino, Robert S,Hoffman, William F,Hambaugh, Scott R,Arrington, Kenneth L,Hungate, Randall W,Bilodeau, Mark T,Tebben, Andrew J,Rutledge, Ruth Z,Kendall, Richard L,McFall, Rosemary C,Huckle, William R,Coll, Kathleen E,Thomas, Kenneth A
, p. 3537 - 3541 (2007/10/03)
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Reactivity of 7-(2-Dimethylaminovinyl)pyrazolopyrimidines: Synthesis of Pyrazolopyridopyrimidine Derivatives as Potential Benzodiazepine Receptor Ligands. 2.
Bruni, Fabrizio,Selleri, Silvia,Costanzo, Annarella,Guerrini, Gabriella,Casilli, Maria Lucia,Giusti, Laura
, p. 291 - 298 (2007/10/02)
A series of pyrazolopyridopyrimidin-6-ones was obtained by reaction of ammonium acetate with ethyl 7-dimethylaminovinylpyrazolopyrimidine-6-carboxylates and these had been prepared from ethyl 7-methylpyrazolopyrimidine-6-carboxylates by reaction with dimethylformamide dimethylacetat.Under these conditions the compounds bearing a 2-hydroxy group were also O-alkylated.During the preparation of the ethyl 2-hydroxy-7-methyl-3-phenylpyrazolopyrimidine-6-carboxylate the corresponding 5-methyl isomer was isolated and identified.
