*3.1.3.1 Methods to synthesized* N*-2,4,6-trisubstituted (at C2, C4 and C6 respectively) pyrimidine derivatives*

One of the early identified S-2-*N*-4,6-trisubstituted pyrimidine aurora kinase inhibitor is the compound VX-680 (**Figure 22**). Luo et al. reported the synthesis of a group of N-2,4,6-trisubstituted pyrimidine derivatives and evaluated their action as

**Figure 19.** *Synthesis of unsymmetrical trisubstituted pyrimidines.*

**Figure 20.** *Possible linkages between the substituents and pyrimidine heterocyclic core.*

*Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

**Figure 21.** *Possible derivatives of trisubstituted pyrimidine heterocyclic core.*

**Figure 22.** *Examples of bioactive trisubstituted pyrimidine.*

selective aurora A kinase inhibitors [91]. Luo et al. reported synthesis of Ntrisubstituted pyrmidines starting from 2,4,6-trichloropyrimidine (109).

Starting from 2,4,6-trichloropyrimidine (109), and in a sequential nucleophilic substitution the three substrates were introduced at sites 4-, 2- and 6- of the pyrimidine core. Aminopirazole 5-methyl-1H-pyrazol-3-amine (119) was allowed to react with 2,4,6-trichloropyrimidine (109) under basic conditions at cold temperature and afforded the 4-substitited pyrimidine (120) in high yield. The acid facilitated second amination was performed under elevated temperature afforded the 2,4-diaminated intermediate (121). The third amination afforded the final 2,4,6-trisubstituted product (122) took place under microwave assisted and elevated temperatures (1,4-dioxane, under microwave, 150–180°C) (**Figure 23**) [91].
