AbstractSomatic mutations in JAK2 have been reported to cause myeloproliferative neoplasms, autoimmune disorders, rheumatoid arthritis, and inflammation. JAK2 protein with PDB id 3FUP was selected for docking analysis via cross‐docking. Molecular docking of JAK2 with ATP and crystal ligand revealed their binding affinities and interactions. 3D QSAR models with R2=0.997 and Q2=0.984 having high stability and predictivity were generated. The biological activity of the hit compound obtained from virtual screening, LAS 26879206, was predicted to be 4.21 using the 3D QSAR model. Modification of LAS 26879206 utilizing 3D QSAR contours for modulating its JAK2 inhibitory potential yielded two novel inhibitors with a 2‐aminopyrimidine core – ACP1 and ACPM1. Molecular docking, molecular dynamics simulations, and ADMET analysis indicated improvements in the efficiency of these compounds compared to the hit compound. Synthesis of these compounds was carried out using a two‐step reaction‐ first Buchwald – Hartwig coupling reaction to yield an intermediate ACB1 which was then coupled with appropriate boronic acids via Suzuki reaction to get ACP1 and ACPM1. The effects of these designed compounds as anticancer agents were analyzed in hCT‐116 (human colorectal carcinoma), HeLa (cervical carcinoma), A549 (human lung adenocarcinoma), and A375 (human melanoma) cell lines. ACPM1 was found to be active in all the cell lines with a pIC50 of 5 which was in concordance with the in silico studies. Western blot analysis validated the JAK2 inhibitory property of ACPM1 which can be further ensured by in vivo studies.