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A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction. [ABSTRACT FROM AUTHOR]