Discovery of Imidazo[1,2-b]pyridazine Derivatives as Potent and Highly Selective Irreversible Bruton’s Tyrosine Kinase (BTK) Inhibitors

Bruton’s tyrosine kinase (BTK) is a crucial enzyme in the B cell receptor signaling pathway. It plays a central role in B cell development, maturation, and signaling. This role extends to the survival, proliferation, and migration of malignant B cells, making BTK an intriguing target in the search for therapeutics against B cell malignancies. Our research focused on the discovery of a covalent inhibitor of BTK with good selectivity and potency and a favorable safety profile. We identified compound 22, an imidazo[1,2-b]pyridazine derivative, exhibiting potent BTK inhibition (IC50 1.3 nM) with excellent selectivity across 310 kinases. Compound 22 demonstrated favorable pharmacokinetics and a robust safety profile. In a xenograft model, it significantly inhibited tumor growth, achieving complete tumor regression in 7 out of 10 mice at a dose of 15 mg/kg. This promising preclinical data led to the advancement of compound 22, named TM471-1, into Phase I clinical trials (CXHL2300956).