Design,Synthesis And Biological Activity Evaluat-ion Of Novel Quinazoline And Piperidopyri-midine Based KRAS^G12C Covalent Inhibitors

As a small GTPase,RAS mediates multiple cell signaling pathways,and has many biological functions,such as regulating cell adhesion,promoting cell apoptosis,inhibiting cell movement,and regulating cell morphology,As abnormally activated RAS often leads to cancer,RAS is considered to be one of the important targets in oncology.KRAS mutations accounted for about 85%of all RAS mutations.KRAS^G12C is a 12 glycine to cysteine mutation on KRAS,which hinders the binding of KRAS^G12C to GTP hydrolase activating protein and leads to the continuous activation of downstream pathway,becoming an important carcinogen.AMG-510 was the first drug to act on this target and was first put into clinical trials;then the compound of ARS-1620 and MRTX849 appeared.In this study,a series of KRAS^G12Cinhibitors were designed and synthesized based on the structure-activity relationship analysis of the two compounds.Through the activity screening at the proteinlevel,new KRAS inhibitors with good inhibitory effect were obtained.In this thesis,using compounds ARS-1620 and MRTX849 as lead compounds,two types of KRAS^G12C inhibitors with 20 new structures based on quinazoline and piperidinopyrimidine as the core were designed and synthesized.Among them,the type I compounds are based on ARS-1620 to obtain IA-01～07 through group exchange;the aromatic system with different group substitutions at the C7 position is connected to obtain IB-01～06,which is obtained by the quinazoline nucleus.Connecting different piperazine structures at position C4 gives compound IC-01.Class II compounds connect different substituted aromatic groups at the N7 position of the piperidinopyrimidine to obtain IIA-01～03;connect the methyl substituted piperazine at the C4 position on the pyrimidine ring to obtain IIB-01,in the piperidinopyrimidine ring The basic side chain is connected to the C2 position of the pyrimidine structure to obtain compounds IIC-01～02.All target compounds have not been reported in the literature,and the structures of the synthesized compounds have been confirmed by mass spectrometry and proton nuclear magnetic resonance spectroscopy..In this thesis,the synthesized target compound was tested for KRAS^G12C protein inhibitory activity in vitro at 500 n M.The experimental results show that:Class II compounds generally exhibit stronger in vitro inhibitory activity than Class I compounds,and Class I compounds have poorer overall in vitro inhibitory activity.Among the IA series compounds,the inhibition rate of IA-06 is 46.8±7.6%.Well,among the IB and IC compound series,only the 68.3±8.8%in vitro inhibition rate of IB-02 showed stronger inhibitory activity than the IA series.Among the IIA compounds,when the N7 position of the piperidine ring of the IIA compound is connected to the naphthalene ring compound with a hydrophobic group such as IIA-03,it exhibits good in vitro inhibitory activity,while the C4pyrimidine ring of the IIB compound is connected to the methyl group.The activity of the piperazine ring substituted by the group was increased from 45.8%of IIA-03 to 85.7%;the inhibitory rate of IIC-02 series compounds on KRAS^G12C protein reached 91.6±4.7%,showing a better inhibitory rate than the positive compounds.In this paper,the modification of the parent nuclei of quinazolineand piperidopyrimidine provides new candidate compounds and theoretical basis for the further development of small molecule KRAS^G12C inhibitors.