N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized and evaluated in vitro for their potential use as inhibitors of Bcr-Abl. The design is based on the bioisosterism between the 1,2,3-triazole ring and the amide group. The synthesis involves a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as the key step, with the exclusive production of anti-(1,4)-triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line.

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A synthetic equivalent of the Nazarov reagent, the silyl derivative 2, able to undergo base-catalyzed double Michael addition reactions with α α α α,β β β β-unsaturated carbonyl compounds, has been developed. The new reagent satisfactorily reacts with unsaturated indolo[2,3-a]quinolizidine lactams to give pentacyclic yohimbinone-type derivatives.The Nazarov reagent (methyl or ethyl 3-oxo-4-pentenoate) 1 is a well-known annelating agent that has been extensively used in terpene and alkaloid syntheses. Its usefulness and synthetic versatility stem from its dense functionalization, with a nucleophilic acidic carbon in the β-keto ester moiety and an electrophilic carbon included in an α,β-unsaturated ketone fragment (Scheme 1). The Nazarov reagent (1) (1) (a) First reported by: Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch. Khim. 1953Khim. , 23, 1703 Engl. Transl. 1953, 23, 1793 Chem. Abstr. 1954, 48:13667h

Abstract:The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 is studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind-unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen bears a Boc substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarovderived adducts is demonstrated by their conversion to allo and epiallo yohimbine-type targets.