AVL-292

Spebrutinib (AVL-292; CC-292) is a covalent, orally active, and highly selective with an IC50 of 0.5 nM.

A solution of 6 (309 mg, 0.84 mmol) in THF (10 mL) was cooled in a water/ice- MeOH bath (-10 In a 50 mL 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube and thermo pocket was charged N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2, 4-diamine (0.40 g) in dry DCM (10 mL) and was cooled to −30° C. An acryloyl chloride solution in DCM (0.107 g in 5.0 mL DCM) was added slowly and the reaction mixture was stirred at −30° C. for approx. 40 minutes. The reaction was monitored on TLC using chloroform:methanol (9.6:0.4) as mobile phase. The reaction mixture was poured into water (100 mL) and basified using sodium bicarbonate. The reaction mixture was extracted with MDC (2×25 mL) and the combined organic layer was washed with 50 mL brine solution. The organic layer was dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Obtained solid was purified by triturating with diethyl ether (2×10 mL) and dried under vacuum to give 0.28 g N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide.In a 50 mL 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube and thermo pocket was charged N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxyl)phenyl)pyrimidine-2, 4-diamine (0.40 g) in dry DCM (10 mL) and was cooled to -30° C.

Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase involved in signal transduction pathways regulating the proliferation, activation, and differentiation of B cells. AVL-292 is an orally available, selective, and irreversible inhibitor of BTK (IC50 = 0.5 nM in vitro in B cell lymphoma cell lines) that targets and covalently binds to BTK at cysteine-481, thereby preventing its activity. AVL-292 has been shown to inhibit osteoclast function and to reduce osteoclast-stimulated proliferation of multiple myeloma cells in animal models of rheumatoid arthritis and multiple sclerosis, both of which are diseases where B cells play an important role. In clinical trials, AVL-292 has demonstrated therapeutic significance in the treatment of both B cell-related cancers (e.g., non-Hodgkin’s lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis).[Cayman Chemical]