Design,Synthesis And Biological Activity Evaluation Of ALK Inhibitors From Pyrrolopyrimidine And Thienopyrimidine Scaffolds

Cancer is an important health problem facing human beings,and targeted therapy for cancer has developed rapidly since the beginning of the 21 st century.Anaplastic lymphoma kinase(ALK)is a key member of the tyrosine kinase family.Tne imbalance of ALK protein activity,especially the formation of oncogenic ALK fusion proteins,is closely linked to a variety of cancers and is a validated target to treat non-small cell lung cancer(NSCLC).Drug-resistance is a serious issue raised by the clinical use of ALK kinase inhibitors,among which point mutation of G1202R in ALK is resistant to all currently available ALK targeted therapeutics.Therefore,the development of novel ALK inhibitors with higher activity and better selectivity,which could effectively overcome the existing resistance,especially the ALK(G1202R)mutation,is urgently needed.In this thesis,we have designed and synthesized a focus library of 143 compounds derived from privileged scaffold pyrimidine using scaffold hopping and bioactive fragment stitching strategies.Through the systematic study of the structure-activity relationships,we have identified the key structure features for having the bioactivity against ALK.The ortho-methoxy substitution of the R~2 group in thieno[3,2-d]pyrimidine scaffold had an important effect on its activity.We have obtained five compounds with better activities,including IA-11,IB-6,IC-6,IC-7 and IC-14.Among the compounds derived from pyrrolo[3,2-d]pyrimidine,the introduction of tert-butyl sulfonyl structure,the retention of ortho-methoxy substitution of R~3 group and the displacement of para-substituent group of R~3 group are favorable for having better activities.We have obtained nine compounds with better activities against EML4-ALK(G1202R)compared with Crizotinib and lead compound,which included as IIA-4,?B-2,?B-33,?B-35,?B-39,?B-43,?C-2,?C-6 and ?C-9.The most active compound,IIB-2 exhibited the activity with IC50 values of 5 nM,18 nM and 37 nM against for EML4-ALK,EML4-ALK(L1196M)and EML4-ALK(G 1202R)respectively.In summary,we have developed a series of small molecule ALK kinase inhibitors with high activities.More importantly,some of compounds could effectively overcome the most notorious drug-resistant mutation,EML4-ALK(G1202R),which would lay the foundation for the development of new ALK-targeted therapeutics.