Background:　The　epidermal　growth　factor　receptor　(EGFR)　protein　has　been　intensively　studied　as　a　therapeutic　target　for　non-small　cell　lung　cancer　(NSCLC).　The　aminobenzimidazole　derivatives　as　the　fourth-generation　EGFR　inhibitors　have　achieved　promising　results　and　overcame　EGFR　mutations　at　C797S,　del19　and　T790M　in　NSCLC.　Objective:　In　order　to　understand　the　quantitative　structure-activity　relationship　(QSAR)　of　amino-benzimidazole　derivatives　as　EGFRdel19　T790M　C797S　inhibitors,　the　four-dimensional　QSAR　(4D-QSAR)　and　multivariate　image　analysis　(MIA-QSAR)　have　been　performed　on　the　data　of　45　known　aminobenzimidazole　derivatives.　Methods:　The　4D-QSAR　descriptors　were　acquired　by　calculating　the　association　energies　between　probes　and　aligned　conformational　ensemble　profiles　(CEP),　and　the　regression　models　were　established　by　partial　least　squares　(PLS).　In　order　to　further　understand　and　verify　the　4D-QSAR　model,　MIA-QSAR　was　constructed　by　using　chemical　structure　pictures　to　generate　descriptors　and　PLS　regression.　Furthermore,　the　molecular　docking　and　averaged　noncovalent　interactions　(aNCI)　analysis　were　also　performed　to　further　understand　the　interactions　between　ligands　and　the　EGFR　targets,　which　was　in　good　agreement　with　the　4D-QSAR　model.　Results:　The　established　4D-QSAR　and　MIA-QSAR　models　have　strong　stability　and　good　external　prediction　ability.　Conclusion:　These　results　will　provide　theoretical　guidance　for　the　research　and　development　of　aminobenzimidazole　derivatives　as　new　EGFRdel19　T790M　C797S　inhibitors.　©　2024　Bentham　Science　Publishers.