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Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight <b>11b</b>, which showed higher potency against Bcr-Abl (IC₅₀ = 0.015 μM) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI₅₀ = 0.7–1.3 μM). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-Abl^T315I, Bcr-Abl^E255K, and Bcr-Abl^Y253H point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-Abl^T315I (GI₅₀ > 20 μM) compared to <b>11b</b>–<b>f</b> (GI₅₀ = 6.4–11.5 μM). Molecular docking studies explained the structure–activity relationship of these purines in Bcr-Abl^WT and Bcr-Abl^T315I. Finally, cell cycle cytometry assays and immunodetection showed that <b>11b</b> arrested the cells in G1 phase, and that <b>11b</b> downregulated the protein levels downstream of Bcr-Abl in these cells.