Six-membered heteroaryl groups are often used to replace aryl moiety to improve a drug´s physical properties and metabolic stability. However, these heteroaryl cores remain susceptible to metabolism at either the carbon atoms or the heteroatoms . Compound 5a, featuring a pyridine ring, showed moderate CLint and t1/2, similar to 7-PhO-THA. On the other hand, compound 5e, which contains a pyrimidine ring, demonstrated higher microsomal stability (t1/2 = 93.65 min) similar to THA (t1/2 = 108.28 min), indicating lower metabolic turnover by liver enzymes and improved stability against enzymatic degradation. Collectively, these results suggest that adding an extra nitrogen atom to the ring reduces its metabolic susceptibility by lowering the LogD7.4 (Table ) and decreasing the susceptibility to interact with the CYP450 system . Generally, for all four tested compounds (5a, 5e, 5i, 5m), the amount of formed 7-OH-THA was reduced to 49-61% in comparison to THA, which means that THA (hetero)aryl substituted derivatives could partially prevent from the formation of toxic quinone methide.