The　FMS-like　tyrosine　kinase　3-internal　tandem　duplication　(FLT3-ITD)　mutation　is　a　key　target　for　acute　myeloid　leukemia　(AML)　treatment.　The　second-generation　inhibitors　such　as　Gilteritinib　still　present　off-target　effects　and　associated　side　effects.　Therefore,　identifying　novel　FLT3-ITD　inhibitors　has　become　a　promising　strategy　for　AML　treatment.　In　this　study,　a　4D-QSAR　model　was　developed　based　on　Gilteritinib　and　its　analogues,　and　it　was　found　that　introducing　hydrophobic　bulky　groups　at　the　piperazine　or　piperidine　of　Gilteritinib　would　enhance　the　binding　affinity　to　FLT3-ITD.　So,　three　series　of　targeted　compounds　(A1-A5,　B1-B5　and　C1-C5)　were　designed　and　synthesized.　The　antiproliferative　activity　against　MOLM-13　cells　was　evaluated　in　vitro.　Compound　A1　(IC50　=　25.65　nM),　with　a　cubane　group　at　the　piperazine　position;　Compounds　B2　(IC50　=　63.38　nM)　and　C2　(IC50　=　54.96　nM),　with　a　norbornene　group　at　the　piperidine　position,　showed　the　strongest　inhibition　in　their　series.　Their　IC50　values　were　comparable　to　that　of　the　positive　control　Gilteritinib　(IC50　=　22.37　nM).　FLT3-ITD　was　confirmed　as　the　degradation　target　through　a　kinase　inhibition　assay,　where　the　IC50　values　were　2.12　nM　(Compound　A1),　1.29　nM　(Compound　B2),　and　3.06　nM　(Compound　C2),　which　were　comparable　to　that　of　Gilteritinib　(IC50　=　0.43　nM).　Additionally,　molecular　docking　and　molecular　dynamics　(MD)　simulations　showed　that　Compounds　A1,　B2,　and　C2　had　similar　binding　modes　to　that　of　Gilteritinib　with　more　stable　affinities.　Overall,　these　results　demonstrated　that　Compounds　A1,　B2,　and　C2　were　promising　inhibitors　for　targeting　AML　with　FLT3-ITD　mutation.