*3.1.1.2 2,4-Disubstitited pyrimidines: a heterocyclic core with privileged regioisomers*

An increased number of 2,4-disubstituted pyrimidine derivatives that are endowed with bioactivities indicated high number of research articles and patent application shown in the literature (**Figure 2**). Though most of the reported activities of 2,4-disubstituted pyrimidines were related to antitumor due to ability to exert antiproliferative effect like inhibitors of KDR [50] and Aurora kinase [51], ERα/VEGFR-2 [52], T790M-EGFR [53] and L858R/T790M-EGFR double mutant [54] inhibitors, bioactivities of high significance of some 2,4-disubstituted pyrimidines such as antibacterial [55], anti-neuronal nitric oxide synthase [56], anticholinesterases [57] actions were also disclosed [58].

In the following section synthetic methods of four FDA approved drugs Pazopanib (21), Spebrutinib (51), Dabrafenib (60) and Rilpivirine (62) will be presented and discussed in details.
