Discovery of orally available 1H-pyrazolo [3, 4-d] pyrimidin-4-amine derivative as a novel BTK inhibitor

Abstract

Bruton’s tyrosine kinase (BTK) is a key protein in B cell antigen receptor (BCR) signaling pathway, and is a research hotspot in the clinical treatment of B cell tumors and B cell immune diseases. In this article, based on the structure of Ibrutinib, a series of novel irreversible BTK inhibitors with the scaffolding of 1H-pyrazolo [3, 4-d] pyrimidin-4-amine were designed and synthesized. All the compounds showed a moderate to potent inhibitory activity against BTK. Among them, compound 6b showed the best BTK kinase inhibitory activity with the IC50 value of 1.2 nM. The ADME/T properties performed by pkCSM demonstrated that compound 6b possesses a good druglikeness. Further druggability evaluation showed that 6b exhibited good water solubility and acceptable pharmacokinetic properties. Therefore, compound 6b provided a promising lead compound for developing novel irreversible BTK inhibitors.

Keywords

• Bruton’s tyrosine kinase
• Irreversible inhibitor
• Design
• Synthesis
• Druglikeness