Design,Synthesis And Biological Activity Evaluation Of Three Types Of Kinase Inhibitors With Nitrogen-containing Skeletons

Protein kinase is an important signaling messenger in human life.Small molecule protein kinase inhibitor can be designed on the basis of protein kinase structure.In 2001,Imatinib was the first kinase inhibitor,approved by FDA,serving as a milestone in the field of targeted cancer theraphy.Until now,32 small molecule kinase inhibitors have been approved by FDA and achieved great success in clinic.RET,encodes one of the receptor tyrosine kinases,which are cell-surface molecules that transduce signals for cell growth and differentiation has been reported as a new oncogene in NSCLC.Therefore,RET has emerged as a promising therapeutic target for NSCLC therapy.In this thesis,three nitrogen-containing bicyclic scaffolds were utilized for the optimization of lead compound KQF-04-013-01.Based on co-crystal structure analysis,active fragment assembling and scaffold hooping,71 small molecule kinase inhibitors targeting RET were designed and synthesized for the development of novel RET inhibitors with good selectivities and activities.And their activity against RET has been evaluated by MTS experiment.In the first part of this thesis,we focused on the structure-activity relationship study of imidazo-pyrazine and pyrrolopyrimidine compounds.KQF-04-013-01,an imidazopyrazine compound,was identified as an inhibitor of RET kinase by screening the early small molecule compound library.Using KQF-04-013-01 as a lead compound,a series of imidazopyrazine derivatives and pyrrolopyrimidine derivatives were designed and synthesized.Structure-activity relationship study led to the identification of compounds ?A-3,?A-6 and ?A-12 exhibiting improved activities with IC50 values of 4,22 and 51 nmol/L,respectively.In the second part of this thesis,we studied the structure-activity relationship of thienopyrimidine compounds.Based on the structure-activity relationship analysis in the first part,we retained the substituents of the pyrrolopyrimidine derivatives,replaced the nitrogen atom on the pyrrole ring with sulfur atom,and studied the impact of these variations.In summary,we have identified a series of imidazopyrazine and pyrrolopyrimidine derivatives representing by ?A-3,?A-6 with good potency and selectivity against RET.These results provide a good starting point of further drug development for targeting RET.