Discovery of (7-aryl-1,5-naphthyridin-2-yl)ureas as dual inhibitors of ERK2 and Aurora B kinases with antiproliferative activity against cancer cells

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

“…Likewise, m -NO 2 PhSO 3 Na was used as an oxidant for the preparation of 1,5-naphthyridines 2 ( Scheme 1 ), which displayed a higher yield (45–50%) and a better reproducibility than I 2 [ 8 ]. Additionally, the 3-bromo-1,5-naphthyridine 2b [ 9 ], was reached through a modified Skraup reaction using m -NO 2 PhSO 3 Na [ 10 ]. 2-Methyl- [ 11 ] and 3-methoxy-4-methyl-1,5-naphthyridines 2c – 2e [ 12 , 13 , 14 ] ( Scheme 1 ) were also reported.…”

“…Selective amination by substitution of chlorine atom in 1,5-naphthyridine 82 (R 1 = Br, R 2 = H), was performed in the presence of ammonium hydroxide in sealed tube at 140 °C to synthesize the corresponding amines 83 ( Scheme 30 ) [ 10 ]. Azidation of 82 with NaN 3 followed by reduction with SnCl 2 , the 1,5-naphthyridine 83 (R 1 = 1-methyl-1 H -pyrazol-4-yl, R 2 = OMe) scaffold was also obtained in 63% ( Scheme 30 ) [ 9 ].…”

“…N -oxides 116 were easily prepared from differently substituted 1,5-naphthyridines 2a , 2b (previously prepared, vide supra, Scheme 1 ), 82a (previously prepared, vide supra, Scheme 30 ) and 117 ( Scheme 43 ). In this way, standard reaction conditions (3-chloroperbenzoic acid, m-CPBA) to obtain the corresponding N -oxides 106b – d were used to synthesize valuable intermediates for the construction of biologically active molecules [ 9 , 10 , 53 ]. Alternatively, 1,5-naphthyridines 2a (previously prepared, vide supra, Scheme 1 ) were transformed to the corresponding N -oxide 118 , at high conversion yields, by a monooxygenase PmlABCDEF recombinantly expressed in Escherichia coli as biocatalyst ( Scheme 43 ).…”

“…For example, during the synthesis of (7-aryl-1,5-naphthyridin-2-yl)ureas 149 aromatic moieties were introduced at position 7 of compound 147 under a palladium-catalyzed Suzuki–Miyaura type reaction, using boronic acids or esters 148 . The target compounds 149 were obtained in low to good yields ( Scheme 64 ) [ 10 ].…”

“…In the synthesis of 1,5-naphthyridin-2-yl ureas 222 and 223 , azaheterocyclic amines 220 were reacted with various isocyanates 221 , in pyridine at reflux or in two steps in the presence of triphosgene, trimethylamine and then adding the desired amine ( Scheme 90 ) [ 10 , 32 ].…”