Acute Myeloid Leukemia represent only 1.1% of all cancer diseases in the United States, on the contrary though, has one of the highest estimated mortality rates for the year 2025, where near 50% of affected patient will face unfavourable outcome [1]. While Feline McDonough Sarcoma-like tyrosine kinase 3 was identified as a primary deregulated target, Quizartinib had been developed to specifically inhibit the inactive conformation of the kinase, nevertheless is facing tolerance due to point mutation in the Kinase Domain and Internal Tandem Duplication mutations, accountable for the modified length of the juxta-membrane domain [2]. In this study we used an in-silico approach to build a novel series with different heterocyclic-based compounds, more likely to form stronger acceptor-donor interaction than Quizartinib with Cys694 in the hinge, while a novelty covalent bond in the region of the pocket where the point mutation occurs has been investigated. Pyrazine-based compounds covalently bound via cyano-moiety, showed an unreported pose in the binding pocket, enhanced by a stabilizing interaction with Asp829 in the activation-loop. Hence theoretically, the series seems to be unaffected by F691L mutation. Molecular Dynamics simulation will be crucial to monitor the activation-loop flexibility and the impact of the novel pose in the binding pocket, while stability of the complexes and binding-unbinding processes will be studied. Synthesis and the in-vitro testing will serve for data collecting and biologically validation of the series.