Ready access to 7,8-dihydro- and 1,2,3,4-tetrahydro-1,6-naphthyridine-5(6H)-ones from simple pyridine precursors

Benzamides and nicotinamides represent classes of drugs that have experienced an unusually broad spectrum of clinical development in a number of therapeutic areas [1]. One of their principal targets is the nuclear DNAbinding protein poly(ADP-ribose) polymerase-1 (PARP1), which is activated by nicks in DNA during inflammation, ischemia, neurodegeneration, and cancer therapy. When over-activated, PARP can cause extensive polymerization of ADP-ribose, leading to the depletion of NAD and subsequently a decrease in the level of intracellular ATP. Such decreases can culminate in cell dysfunction and cell death through a necrotic pathway [2]. As part of a broad program to design bicyclic rigid analogues of these chemical classes as PARP inhibitors, we were interested in synthesizing aza-congeners of our 5-substituted-3,4-dihydro-1(2H)-isoquinolinone inhibitor leads [3]. This led us to explore synthetic pathways toward analogues of rigid nicotinamides, specifically compounds of the 7,8-dihydro-1,6-naphthyridine-5(6H)one ring system. Furthermore, we were interested in extending our studies to the synthesis of the isomeric 4,6dihydro-1,6-naphthyridin-5(1H)-ones, and/or more highly reduced congeners, the 1,2,3,4-tetrahydro-1,6-naphthyridine-5(6H)-ones (Chart 1). Previous reports describing the synthesis of reduced 1,6-naphthyridine-5(6H)-ones are relatively sparse. Within the 7,8-dihydro-1,6-naphthyridine-5(6H)-one ring system, Russian investigators [4a] have described an approach toward the synthesis of 6,7-diaryl substituted congeners via acid-catalyzed cyclization of 2-styrylnicotinamides, and German investigators [4b] have reported a synthesis in which an appropriately 3substituted 4amino-5,6-dihydro-2(1H)-pyridinone was annulated to the requisite bicyclic system. Neither synthesis is highyielding nor general for the types of target molecules we