Discovery of 5-fluoro-aminopyrimidine derivatives as dual BTK/FLT3 inhibitors for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a severe autoimmune disease characterized by dysregulated functions of multiple immune cells such as phagocytes, lymphocytes, and dendritic cells. Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) play critical roles in RA pathogenesis, regulating B-cell survival, myeloid cell differentiation, and dendritic cell activation. Starting from the lead compound CC-292, a series of novel 5-fluoro-aminopyrimidine derivatives were designed and synthesized as dual BTK/FLT3 inhibitors for potential RA therapy. Our in vitro screening revealed that compounds 7a, 7b, and 7c are potent dual inhibitors, demonstrating potent activity with IC50 values in the low nanomolar range. Among them, 7b demonstrated particularly strong dual-target activity (BTK IC50 = 18 nM; FLT3 IC50 = 10 nM), along with high plasma stability and hepatic microsomal metabolic stability. In collagen-induced arthritis model, 7b administration produced dose-dependent reductions in joint swelling and significantly mitigated cartilage degradation and bone erosion, as confirmed by histopathological evaluation. Acute toxicity tests revealed no obvious adverse effects at a dose of 1000 mg/kg, indicating a promising safety profile. This work presents not only a promising lead compound but also a strategic framework for developing next-generation RA therapies.