Design, synthesis and pharmacological evaluation of 2-(thiazol-2-amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors

• ALK has been recognized as an emergent therapeutic target for cancer treatment.
• New 2,4-diarylaminopyrimidines bearing an 2-aminothiazole motif was developed.
• Compound 5i showed highest potency of 12.4 nM against ALK.
• Compound 5i also showed 24.1 nM against ALK gatekeeper mutation L1196M.
• 5i dose-dependently inhibited phosphorylation of ALK and its down-stream pathways.

A series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) was developed by incorporation of a substituted 2-aminothiazole component as the C-2 substituent of the center pyrimidine core. Compound 5i showed highest potency of 12.4 nM against ALK and 24.1 nM against ALK gatekeeper mutation L1196M. Although only having moderate cellular potency in the SUP-M2 cells harboring NPM-ALK, compound 5i showed good kinase selectivity and dose-dependently inhibited phosphorylation of ALK and its down-stream signaling pathways.

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