The anaplastic lymphoma kinase (ALK) was initially identified in 1994 and belongs to the tyrosine kinase of the insulin receptor superfamily. These potential therapeutic targets showed several gene fusions that promote and differentiate cell development in various kinds of cancer. Therefore, the ALK (anaplastic lymphoma kinase) inhibitors have become a plausible option for cancer therapy for lung and associated cancer types. However, despite several FDA-approved molecules, there are resistance and mutations. Therefore, there is an imminent need for the design of new ALK inhibitors.

New and novel molecules were designed through generated pharmacophores using computational techniques. The designed scaffold includes the 2-aminopyrimidine substituent derivatives with the heteroaromatic moieties, providing appropriate target binding with ALK. The aliphatic amine portion was considered the hinge region of the structure and shows interaction with the M1199 protein residue of ALK, which is necessary for the pharmacological activity.

For the synthesis, the acetophenone derivatives were used as starting material for the reductive amination using the reducing agents, sodium cyanoborohydride (NaBH3CN) to get the secondary amine product. In the second step, the nucleophilic substitution reaction was performed with 2,4-dichloro pyrimidine moiety to obtain the intermediate product for further synthesis. The final third step involved the palladium-catalyzed organometallic reaction, where the Suzuki coupling was performed for C-C coupling between the heteroaromatic boronic acid and aromatic halides. The substitution of five-membered heterocyclic rings with pyrimidine moiety was performed by the palladium catalyzed, Suzuki coupling reactions to obtain the final compounds. The synthesized final compound was characterized by LCMS and 1H-NMR spectroscopy methods.

In the future, derivatives with different functional groups/analogs will be designed and we will perform in vitro and in vivo anticancer activities to reveal its therapeutic efficacy.

Keywords: ALK Inhibitor, Lung cancer, NSCLC