Design and synthesis of novel substituted naphthyridines as potential c-Met kinase inhibitors based on MK-2461

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.…”

“…Bromination of 1,5-naphthyridine 2a are often carried out to obtain valuable intermediates for further functionalization. As an example, bromination with bromine in acetic acid ( Scheme 17 ) was used in the synthesis of 1,5-naphthyridine derivative 2b (previously prepared, vide supra, Scheme 1 ) [ 9 ].…”

“…Other halogenation reactions were carried out in the preparation of fluorine intermediates (compounds 74 and 75 , Figure 2 ) [ 26 ]. In this sense, the reaction was applied for the synthesis of 1,5-naphthyridine-based polymers, new functional materials for electronics (compound 76 , Figure 2 ) [ 40 ], active naphthyridine derivatives for the development of novel anti-Ebola virus pharmacophore (compound 77 , Figure 2 ) [ 27 ], a series of naphthyridine derivatives as bromo domain inibitors (compound 72a , Figure 2 ) [ 24 ], for the development of some novel 1,5-naphthyridines as c-Met kinase inhibitors (compound 78 , Figure 2 ) [ 9 ], for the synthesis of a 1,5-naphthyridine analogues of a first in class Rpn 11-selective proteasome inhibitor (compound 79 , Figure 2 ) [ 34 ] or for the synthesis of 1,5-naphthyridine-based DYRK1A inhibitors (compound 80 , Figure 2 ) [ 21 ].…”

“…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 ).…”