Design And Synthesis Of Bcr-Abl Tyrosine Kinase Inhibitors

Chronic Myelogenous Leukemia?CML? is one of the types of Leukemia and the pathogenesis of CML is closely related to the existence of the Bcr-Abl tyrosine kinase. So the development of selective Bcr-Abl kinase inhibitors is an attractivestrategy to treat CML.Two series of target compoundshave beendesigned and synthesizedbasing on drug resistance?T315I mutation? of Imatinib which is the first molecular targeted tumor drug. The series of pyridineaminopyrimidine derivatives weredesigned by replacingphenylaminopyrimidine moiety of Imatinib with Pyridine aminopyrimidines. The amide pharmacophore and 4-?3-pyridyl? pyrimidine are retained which can form hydrogen bond with Bcr-Abl kinase.The other series of phenyl pyrazole derivatives by replacing alkynyl of Ponatinib withpyrazole ring couldreduce or eliminate the influence of thesteric clash.A computational docking study suggested thatthe binding mode ofall these designed compounds with Bcr-AblT315 I kinase were similar to that of Ponatinib with Bcr-AblT315 I kinase and binding energy is also relatively close. We predicted that these compounds should have moderate inhibitory activities to Bcr-AblT315 I kinase.According to retrosynthetic analysis, we designed reasonable synthesis routes. Viable synthetic routes were selected after the problems were solved in the experiments. Fourteen target compounds of pyridineaminopyrimidine derivatives were synthesized after night steps reactions, and ten phenyl pyrazole target compounds were synthesized after eleven steps reactions.The gained structures of intermediates were confirmed by ¹H NMR and ESI-MS, and the finally target compounds were characterized by ¹H NMR, 13 C NMR and HRMS. The biological activities of the fourteen target compounds of pyridineaminopyrimidines derivatives were tested and half maximal inhibitory concentration(IC₅₀) of the target compounds to Bcr-Abl tyrosine kinase are more than 10 ?M. However,thephenyl pyrazole derivativesinhibit ABL kinase with nanomole IC₅₀ values ranging from 8.472 to 108.6 nM. In particular, compound 25 b displayed the most potent activity with IC₅₀ value of 8.5 nM which provides valid foundation for further study.