Design, synthesis, and biological evaluation of pyrrolopyrimidine derivatives as novel Bruton's tyrosine kinase (BTK) inhibitors.

Developing Bruton's tyrosine kinase (BTK) inhibitors has become a significant focus in recent years because BTK inhibition is an effective approach for the treatment of B-cell malignancies. For covalent BTK inhibitors, low oral bioavailability and low kinase selectivity remain unaddressed issues; thus, more diverse inhibitors with both novel structures and selective on target binding profiles are still needed. Here, four key regions where inhibitors bind to BTK were identified by analyzing the existing crystal structures of BTK complexes. Then, a scaffold-based molecular design work flow was established by integrating fragment-growing method, deep learning-based framework XGraphBoost and molecular docking, leading to four compounds that showed potency against BTK. Optimization of compounds 1 and 2 led to the discovery of the potent BTK inhibitor compound 42 by using in vitro potency and pharmacokinetic (PK) studies to prioritize the compounds. Compound 42 exhibited great BTK inhibition activity (IC = 0.7 nM) along with high oral absorption. Moreover, 42 demonstrated excellent kinase selectivity, especially over EGFR kinase, and low toxicity. In a TMD8 xenograft model, 42 significantly inhibited tumor growth (TGI = 104%) at a dosage of 50 mg/kg, indicating its potential as a novel therapeutic option for B-cell lymphomas.