Design,Syntheses And Biological Evaluations Of Pyridazine-3-carboxamide CB2R Agonists,and Cu(Ⅱ)-catalyzed Direct C3-arylation Of Indoles

The endocannabinoid system is one of the important biological systems that regulate various physiological functions and pathological states in the human body.Its function mainly acts through the cannabinoid CB1 and CB2 receptors and endocannabinoids.In the brain,the CB1 receptor is one of the most ample G protein-coupled receptors（GPCR）.In contrast,the CB2 receptor primarily exists in the immune system but is merely distributed in several neurons.The application of selective ligands developed based on CB1 receptors is largely limited due to mental side effects,while CB2 receptors,due to their peripheral distribution characteristics,can be expected to produce anti-inflammatory,immune regulation,and immune response through the application of exogenous active ligands.Numerous pharmacological effects such as neuroprotection and will not cause central mental side effects,is an ideal medicinal target.At present,a large number of CB2 selective agonists of different chemical junction types have been reported.In extensive in vitro and in vivo model studies,many CB2 selective agonists have been found to be effective in treating inflammation,pain,autoimmune diseases,and other diseases.However,the development of CB2 agonists for clinical treatment is extremely challenging,and there are currently no corresponding drugs on the market.The design and synthesis of CB2 agonists with good selection,high biological activity,and excellent physicochemical and pharmacokinetic properties is of great significance for promoting the development of CB2 receptor-based drugs.In this thesis,based on the CB2 agonists developed in the early stage of the laboratory,25 novel pyridazine-3-carboxamide compounds with novel structures were designed and synthesized through the use of group addition and substitution strategies on the basis of summing up the rules of past experience.The chemical structure was confirmed by ¹H NMR,¹³ C NMR and HRMS spectroscopy.All target compounds were tested for in vitro activity using a calcium flux screening model.Among them,compound 1-37 has the strongest CB2 agonistic activity（CB2 EC50=22.48 n M）,and compound 1-38 is the best compound in the series and has a good CB2 agonistic activity and selectivity.Subsequent testing of the pharmacokinetic properties of the compound and further structural optimization work is underway.In addition,this paper developed an efficient N,N-bidentate guide group（PIP-amide group）assisted copper-catalyzed selective arylation of indole at the C3 position.This method uses aryl boronic acid pinacol ester as the arylation reagent,does not require the participation of ligands,is easy to operate,and has mild conditions,and has good functional group tolerance to various aryl boronic acid esters and indole substrates.The highest yield is 97%.In synthetic applications,the PIP-amide group can be removed under mild conditions reported in the literature to obtain the corresponding carboxylic acid,which facilitates various derivatization reactions.