Design, Synthesis And Antitumor Activity Of 2,6-disubstituted Imidazo[1,2-b]pyridazine

Anti tumor drugs generally have problems such as difficulty in distinguishing normal cells from tumor cells,susceptibility to tumor resistance,and significant side effects.Therefore,it is urgent to develop new anti tumor drug molecules with unique targets,high selectivity and low toxicity.As an important gateway for controlling cell growth and division,m TOR is an important target for the development of anticancer drugs.In recent years,imidazolo[1,2-b]pyridazine derivatives have received a lot of attention,especially various molecules containing imidazolo[1,2-b]pyridazine are considered as a potential anticancer drug in the field of anti-tumor.Based on the structure of compound 1a and the basis of functional group transformation and molecular docking,this topic investigated the effect of group transformation on activity.A series of target compounds with imidazolo[1,2-b]pyridazine as the mother nucleus were designed.The synthesis route of the target compound was analyzed by reverse synthesis,and a synthesis route was designed using3-amino-6-chloropyridazine as the starting material,through cyclization,hydrolysis,acid amine condensation,substitution,and other reactions to obtain the target compound,The synthesis route was optimized and 32 target compounds were obtained.Their structures were confirmed by ¹H NMR,¹³C NMR,and HRMS.The in vitro anti-tumor activity of the obtained target compounds was evaluated in order to obtain compounds with high anti-tumor activity.The in vitro anti proliferative activity of 32 target compounds against human lung cancer cells（A549）,human colon cancer cells（HCT-116）and human breast cancer cells（MCF-7）was tested by MTT method with 5-fluorouracil and paclitaxel as positive control drugs,The experimental results show that most compounds represented by C6 and B6 have excellent tumor cell inhibitory activity.The preliminary structure-activity relationship indicates that the 2,5 disubstituted amide segment at the C-2 position has better anti proliferative activity compared to the 2-position monosubstituted amide segment,and the aromatic substitution activity of the sulfonamide segment is better than that of the smaller volume fat substitution.In addition,the different types and positions of substituents on the C-6 sulfonamide benzene ring have a significant impact on the activity of the compound.When the 4 position is substituted with fluorine or chlorine,the activity of the compound will be reduced,while the 3 position has better fluorine substitution activity.Introducing 2,4,6-trimethyl on the C-6 sulfonamide benzene ring is also beneficial for improving the activity of the compound.This article further enriched the structure of 2,6-disubstituted imidazolo[1,2-b]pyridazines,laying a foundation for the further research of these anti-tumor drugs.