Synthesis Of2-Aminoxazole-5-Carbamides And2-Aminothiazole-5-Carbamides As Potent Inhibitors Of CML

Chronic myeloid leukemia(CML)is a myeloproliferative disorder that is characterized by the presence of a constitutively active tyrosine kinase,Bcr-Abl,which drives the malignant phenotype of leukemic stem cells.Treatment of CML generally relies on Bcr-Abl tyrosine kinase inhibitors.In the first chapter,we main introduce the tyrosine kinase inhibitor and review the progress in domestic and abroad in small-molecule inhibitors of protein tyrosine kinases.In the chapter 2,the methods about synthesis of dasatinib have been listed and we also explain the reason to choose the method.The chapter 3 is the part of experiment,(E)-3-ethoxy-N-aryl-propenamide(3a-c)served as an advanced intermediate,was synthesized by nucleophilic substitution of appropriate aniline onto(E)-3-ethoxyacryloyl chloride(2),2 was obtained in one pot from ethyl vinyl ether(1)and oxalyl chloride by Effenberger addition followed by thermal decarbonylation.Reaction of the advanced enone 3a-c with N-bromosucc-inimide(NBS)followed by a coupling of urea or thiourea installs the oxazole skeleton in 4a-c or thiazole ring in 5a-c.The final step was a nucleophilic displacement of acetic anhydride or different benzoyl chloride onto 4a-c or 5a-c to yield the corresponding target 6a-d and 7a-e,respectively.In the chapter 4,All newly synthesized compounds were evaluated on K562 cell in vitro for anti-CML activity,in comparison with marketed drug Dasatinib and Imatinib used as references.The results demonstrated that all of the new compounds exhibited antiproliferative potency on human K562 leukemia cells especially the compound(7e)and(7h).