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Background: FMS-like tyrosine kinase-3 (FLT3) belongs to the class III Receptor Tyrosine Kinase (RTK) family. FLT3 is involved in normal hematopoiesis and is generally expressed in early hematopoietic progenitor cells. Mutations either with an internal tandem duplication of FMS-like tyrosine kinase-3 (FLT3-ITD) or point mutation at the activation loop leads to the Acute Myeloid Leukemia (AML), a highly heterogeneous disease. Thus, FLT3 is an important therapeutic target for AML. Method: In the present work, docking and 3D-QSAR techniques were performed on a series of diaminopyrimidine derivatives as FLT3 kinase antagonists. Results: Docking study recognized important active site residues such as Leu616, Gly617, Val624, Ala642, Phe830, Tyr693, Cys694, Cys695, Tyr696 and Gly697 that participate in the inhibition of FLT3 kinase. Receptor-based CoMFA, RF-CoMFA and CoMSIA models were developed. RFCoMFA model revealed relatively better statistical results compared to other models. Furthermore, the selected RF-CoMFA model was evaluated using various validation techniques. Contour maps of the RF-CoMFA illustrated that steric and electronegative substitutions were favored at R1 position whereas steric and electropositive substitutions were favored at R2 position to enhance the potency. Conclusion: Based on the designed strategy, we derived from the contour map analysis, 14 novel FLT3 inhibitors were designed and their activities were predicted. These designed inhibitors exhibited more potent activity than the most active compounds of the dataset.