Synthesis and biological evaluation of 3-（piperidin-4-yl）isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

An efficient synthesis of novel 3-（piperidin-4-yl）isoxazolo[4,5-d]pyrimidine scaffold has been designed and deveopled. A series of 5-phenylurea derivatives was synthesized using this method. Their cytotoxic activities against breast cancer cell line BT-474 were evaluated by CCK-8 assay. Most of them showed potent anti-proliferative activities, of which compound 20 and 21 exhibited IC50 s of 1.565 mmol/L and1.311 mmol/L, respectively. Furthermore, compound 20 and 21 also showed potent inhibitory activities against PI3 Kd with IC50 s of 0.286 mmol/L and 0.452 mmol/L, respectively. These results indicate that these 3-（piperidin-4-yl）isoxazolo[4,5-d]pyrimidine derivatives are novel antitumor agents through the inhibition of PI3 Kd.