The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.

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f l -D i~~~~~d i N~o~~~5 ( 4 H ) -o x a z o l o n e s2 were prepared by arylation of the corresponding 5(4H)-oxazolones 1 under phase-transfer conditions with the corresponding l-halo-2,4-dinitrobenzenes.2,4-Diaryl-4-(3,5-dinitro-2-pyridyl)-5(4H)-oxa-. zolones 5 were obtained similarly from the corresponding 1 and 2-chloro-3,5-dinitropyridine. On reaction with methanol and ptoluenesulfonic acid, oxazolones 2 rearranged to the corresponding 1-hydroxy-1 If-indazole derivatives 8. Under the same conditions oxazolones 5 afforded a mixture of the correspondingly substituted 1 H-pyrazolo[4,3-b]pyridines 7 and substituted imidazo[1,5-a]pyridines 12. In all cases the solvolysis reaction, yielding substituted glycine esters 9 and 11, was competitive with the rearrangement. Reaction paths are discussed.Recently we described an alkylation method of 2,4-disubstituted 5(4H)-oxazolones under phase-transfer conditions '). An example of arylation was also reported. In the course of our research program on the use of 5-oxazolones in the synthesis of heterocyclic compounds, we extended the above procedure to a series of 4-(2-nitroaryl)-substituted 5(4H)-oxazolones aiming to explore their reactivity. We now report that these thermally stable oxazolones can be rearranged to indazoles under acidic catalysis. Synthesis of OxazolonesThe reaction of compounds 1 a, b, d -f with l-fluoro-2,4-dinitrobenzene in dichloromethane solution with an aqueous solution of sodium carbonate containing tetrabutylammonium bromide as phase-transfer catalyst at room temperature resulted in the formation of substituted 5(4H)-oxazolones 2a, b, f, g, h. Products 2a, b, f, h were easily purified by column chromatography, but 2g partially rearranged when contacted with silica gel yielding 8f as discussed later. Under analogous phase-transfer conditions 1 a and 2,4,6-trinitrochlorobenzene yielded oxazolone 2c. From 1 b and 2-nitrobenzyl chloride product 3 was similarly obtained. When oxazolone 1 c was treated with l-fluoro-2,4-dinitrobenzene under phase-transfer catalysis a mixture of 2e and the isomeric 5(2H)-oxazolone derivative 4 was formed. This outcome exactly parallels the results obtained in homogeneous phase in the presence of triethylamine2). As further example of arylating reagent, 2-chloro-3,5-dinitropyridine afforded 5 a and 5b from l a and I f under PTC conditions. They behaved similarly to 2g, showing a very high rearran- gement rate in the presence of silica gel which prevented the purification by chromatography. 5a could be purified by crystallization and fully characterized. 5 b was identified by its IR data and studied without further purification. 1 a and methyl 2-chloro-3,5-dinitrobenzoate afforded 2d and a byproduct which was recognized as deriving from 1 a and two mol of the aromatic chloride with C 0 2 elimination (M = 643). This compound was not studied further.The oxazolones were identified on the basis of their analytical and/or spectroscopical data, mainly from the characteristic IR absorption in the ranges of 1800-1820 cm-' (C=O). Th...