Design,Synthesis And Structure Activity Relationships Of RIPK3 Inhibitors And Rhodium(Ⅲ)-catalyzed C-H Functionalization For The Construction Of Chiral Dihydrobenzofuran Derivatives

Part Ⅰ: Design,Synthesis and Structure Activity Relationships of RIPK3InhibitorsNecroptosis can be induced by death receptors,and is a Caspase-independent cell death pathway,mainly regulated by receptor-interacting protein kinase 1(RIPK1),receptor-interacting protein kinase 3(RIPK3)and the MLKL protein(mixed lineage kinase domain like protein).It has been shown that necroptosis can trigger a pericellular inflammatory response and leads to many related diseases such as neurodegenerative diseases,cerebral ischemic diseases,viral infectious diseases,malignancies and immune diseases.Systematic and in-depth biological studies have indicated that the development of inhibitors targeting RIPK3,a key protein in the necroptosis signal pathway,will provide a novel and effective way to investigate the pathology of necroptosis and to treat related diseases.Several RIPK3 inhibitors of the necroptosis process have been reported successively.Although these compounds have shown good inhibitory effects on TNFα-induced cell necroptosis models,they all suffer from plenty of drawbacks,such as obvious off-target effects,poor metabolic properties and undruggability.To date,no inhibitors targeting the pathological process of necroptosis have successfully entered the clinical phase.Owing to the shortcomings of the developed inhibitors,the investment of RIPK3 inhibitors with strong activity,high selectivity,good metabolic properties and low toxicity will be a focus of future research.In the second chapter of this paper,we adopted a "fast follow" strategy to design and synthesise a series of small molecules based on a pyrrole ring fused a pyridinone ring structure(Bristol-Myers Squibb,WO2016100166).We used classical medicinal chemistry strategies such as scaffold hopping,ring opening,ring reduction and ring expansion.A series of small molecule inhibitors with independent intellectual property rights was designed and synthesized,and in vitro evaluation based on Fluorescence Polarization(FP)and Cell Titer-Glo showed that the series of compounds exhibited significant anti-necroptosis activity both at molecular and cellular levels.In particular,several molecules showed significantly better activity at the cellular level than the representative compound BMS926430 in the original patent and are close to or better than GSK840,the RIPK3 inhibitor with the most potent necrosis inhibitory activity reported,in terms of cellular activities.Meanwhile,based on our work,we have conducted a preliminary summary and discussion of the structure activity relationships,and are carrying out further crystallographic studies to provide an abundant factual proof and theory foundations for the rational design and structural optimization of RIPK3 small molecule inhibitors.In summary,the discovery of this novel lead compounds of RIPK3 will lay the foundation for the further development of small molecule inhibitors of RIPK3 for basic research and clinical applications for necroptosis.Part Ⅱ: Rhodium(III)-catalyzed C-H Functionalization for The Construction of Chiral Dihydrobenzofuran DerivativesChiral 3,3-disubstituted-2,3-dihydrobenzofuran derivatives have a dominant backbone of six-membered fused five-membered heterocyclic dihydrobenzofuran,which are widely found in a number of biologically active compounds and natural products and have very significant physiological activity,biological functions and application value.Although some elegant progress has been made in the construction of chiral dihydrobenzofuran derivatives,there remains many limitations:(1)most methods require time-consuming and tedious pre-activated substrates;(2)these asymmetric annulative protocols remain limited to one-component hydroarylation,and the types of bifunctionalization reactions are very limited,which largely restricts the complexity and diversity of chiral dihydrobenzofuran derivatives;(3)the currently developed methods are unable to achieve enantioselective control to generate a single chiral 2,3-dihydrobenzofuran derivatives.It is particularly indispensable to explore concise and efficient one-step methods for the direct construction of chiral 2,3-dihydrobenzofuran derivatives and further modification and derivatization.In Chapter 4 of this paper,we ingeniously exploit the strategy of C-H bifunctionalization of olefins,using O-tethered-alkenes derivatives and 1,4,2-dioxazol-5-one derivatives as substrates.Through the screening of chiral cyclopentadiene ligands and further rational design,we have developed a class of chiral rhodium complexcatalyzed enantioselective C-H functionalization reactions of olefins,allowing the onestep direct construction of various chiral 3,3-disubstituted-2,3-dihydrobenzofuranamide derivatives.The experimental results indicates that such reactions have many features:(1)the construction of both C-C and C-N bonds through a one-step synthesis reaction catalyzed by transition metal rhodium(III)catalysts,and the chiral 3,3-disubstituted-2,3-dihydrobenzofuranamide derivatives possess potential application value;(2)the rational design of chiral cyclopentadiene ligands achieved the high enantioselectivity for the β-position quaternary of amide;(3)the mild reaction conditions,wide range of substrate applicability and high functional group tolerance indicate the excellent applicability of this class of reactions;(4)this class of reactions is extremely practical,and derivatization and diversification can be achieved by simple further synthetic modifications,and the substrate chirality can be maintained.(5)the synthetic method enriches the diversity of chiral dihydrobenzofuran derivatives in,and allows the rapid and efficient construction of a library of chiral 3,3-disubstituted-2,3-dihydrobenzofuran derivatives,which is of great importance for the further screening and the development of lead compounds and new drugs.In conclusion,our rational design and optimization of chiral rhodium catalysts with cyclopentadiene ligands that can enantioselectively catalyze the bifunctionalization of C-H of O-tethered-alkenes derivatives has enabled the construction of a library of chiral 3,3-disubstituted-2,3-dihydrobenzofuranamide derivatives.Based on our developed methodology,we have constructed a higher throughput library of chiral dihydrobenzofuran small molecule compounds and are currently testing and screening potential drug targets such as RIPK3 and other target in necroptosis pathway,which is of great importance for the discovery of lead compounds with potential inhibitory activity against necroptosis and other kinase inhibitors for the development of new drugs.