Synthesis and structure-activity relationships of 7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2 (1H)-ones as selective inhibitors of pp60(c-src)

7-Substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H) are potent inhi bitors of protein tyrosine kinases, with some selectivity for c-Src. The co mpounds were prepared by condensing 4,6-diaminonicotinaldehyde with 2,6-dic hlorophenylacetonitrile and selectively converting the 2- and 7-amino group s of the product to hydroxy and fluoro groups, respectively, by prolonged d iazotization in 50% aqueous fluoboric acid. N-Methylation, followed by trea tment with aliphatic diamines, aromatic amines, or their derived lithium an ions, gave the desired compounds. Selected isomeric 1,8-naphthyridin-2(1H)- ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)ones to th e inhibitory activity. The compounds were evaluated for their ability to pr event phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PD GF-beta receptor enzymes. Overall, there was a high degree of correlation o f the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1,6-Naphthyridin-2(1H)one analogu es bearing basic aliphatic side chains [7-NH(CH2)(n)NRR, 7-NHPhO(CH2)(n)NRR , or 7-NHPhN(CH2)(4)NMe] were the most potent against c-Src (IC(50)s of 10- 80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but le ss with respect to FGFR.. The 1,6-naphthyridin-2(1H)-ones showed broadly si milar activity to the analogous pyrido[2,3-d]pyrimidin-7(8H)-ones, whereas the 1,8-naphthyridin-2(1H)-ones were at least 10(3)-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2,3-d]pyrimidin-7(8H )-ones is mandatory, whereas the 1-aza atom is not, support the published b inding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), w here the 3-aza and 2-NH atoms form a bidentate H-bond donor-acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific b inding interactions.