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The use of fragments with low binding affinity for their targets as starting points has received much attention recently. Screening of fragment libraries has been the most common method to find attractive starting points. Herein, we describe a unique, alternative approach to generating fragment leads. A binding model was developed and a set of guidelines were then selected to use this model to design fragments, enabling our discovery of a novel fragment with high LE.

A facile synthesis of a series of 1-alkoxyisoquinolines and (2H)-isoquinolones by an intramolecular 6-endo-dig cyclization of ortho-alkynylbenzonitriles in the presence of a catalytic amount of hydrido(dimethylphosphinous acid-κP)[hydrogen bis(dimethylphosphinito-κP)]platinum(II) in various alcohols at 65–90 °C is described for the first time.

An expedient enantioselective synthesis of the Δ(4)-oxocene cores present in (+)-laurencin and (+)-prelaureatin was accomplished in eight steps via a novel one-pot regio- and stereoselective ring cyclization-fragmentation-expansion cascade from the tetrahydrofuran precursors which were prepared by stereocontrolled cyclization from vinylsilanes. This process is highlighted by an intramolecular oxo-carbenoid insertion and a β-silyl fragmentation sequence.

Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.

A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.

A one-pot synthesis of phthalides via an intramolecular 5- exo-dig cyclization of ortho -alkynylbenzaldehydes under mild NaClO 2 oxidation conditions is described.

Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Towards those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition which has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.

The synthesis of radiolabeled C60/C70 for potential biochemical tracer studies was carried out. Vaporization under plasma are conditions (~3000C) of graphite rods impregnated with the 14C labeled steroid progesterone generates the expected C60/C70 mixture. Isolation and characterization of the 14C-C60 is reported. Interestingly, the C70 had more radioactivity than the C60.

1-Alkoxyisoquinolines as major products can be easily converted into isoquinolines by dealkylation with HBr in acetic acid.

The optimized conditions provide a broad spectrum of benzofuran derivatives and the pyridine analogue (X) in good yields.