Design,Synthesis And Bioactivity Evaluation Of Novel Indazole PI3Kδ Inhibitor&Hydrogen Functionalization Of Olefins

PI3K/AKT/mTOR signaling pathway is closely related to the occurrence of tumors.It has been proved that PI3Ks is an effective drug therapy target.As an important member of PI3Ks protein family,PI3Kδ is specifically distributed in hematopoietic cells and immune cells.With the in-depth study of PI3Kδ structure and function,PI3Kδ has become an important target for the treatment of chronic lymphocytic leukemia(CLL),acute lymphoblastic leukemia(ALL),non-Hodgkin lymphoma(NHL)and other malignant tumors.Recently,it has also been proved to be an effective target for the treatment of inflammation and immune diseases.In this thesis,a new type of indazole PI3Kδ inhibitor was designed and synthesized and their biological activity was evaluated preliminarily.Olefins are cheap and easily available feedstocks.As the basic chemicals,the efficient transformation of olefins is importing and interesting.In this thesis,we developed the method of Fe(Ⅲ)catalyzed hydroformylation of olefins.Under the Fe(acac)3/PhSiH3 system,non-activated olefins undergo hydrogen transfer reaction to form alkyl radicals,which are added to Morita-Baylis-Hillman(MBH)acetate and unsaturated imines respectively to obtain a variety of functionalized(E)-cinnamate compounds and benzofuran derivatives.In addition,this thesis also carried out the addition of α-oxy radicals formed by alkyl alcohol to(p-QMs)under free-metal catalysis to realize the construction of α-hydroxy C(spr)-C(sp3),und synthesized phenol compounds rapidly and efficiently.The main contents of this paper include three aspects:(1)Based on the binding mode of PI3Kδ inhibitors to PI3Kδ kinase and inspired by the structure of Idelalisib,26 compounds were designed and synthesized by replacing quinazolinone with indazole.The biological evaluation PI3Kδ in vitro show that most compounds ex hibit nanomolar-level PI3Kδ kinase inhibitory activity.In the MV-4-11 cell line proliferation assay,most of the compounds showed stronger inhibitory activity than Idelalisib.Moreover 2-16.2-27,2-32,2-33,and 2-34 have good PI3Kδ subtype selectivity,Their PI3Kδ kinase activity is 30～300 times that of other PI3K subtypes.Finally,compound 2-27 and 2-34 were selected for PK evaluation to show good PK properties.2-27 and 2-34 showed good PK properties with oral bioavailability of 30.2%and 21.3%respectively,which are of value for further research.(2)Alkyl radicals formed by olefins under Fe(acac)3/PhSiH3 system react with MBH carbonate and azadiene compounds respectively to realize the hydroallylation of olefins and obtain(E)-cinnamate compounds and benzofuran derivatives.(3)The 1,6-radical addition of α-hydroxy carbon radical to p-QMs from alkyl alcohol initiated by di-tert-butyl peroxide(DTBP)was carried out,this protocol not only represents a facile C(sp3)-C(sp3)bond formation,but also completes construction ofα-hydroxy C(sp3)-C(sp3)and converts p-QMs to phenol derivatives.