Regioselective Synthesis of Substituted 4‑Alkylamino and 4‑Arylaminophthalazin-1(2<i>H</i>)‑ones

An efficient regioselective synthesis of substituted 4-alkylamino and 4-arylaminophthalazin-1­(1<i>H</i>)-ones <b>5</b> is described. This new method features the formation of substituted phthalazin-1­(1<i>H</i>)-ones <b>3</b> by the reaction of 2-formylbenzoic acids <b>1</b> or 3-hydroxyisobenzofuran-1­(3<i>H</i>)-ones <b>2</b> with hydrazine to generate phthalazin-1­(2<i>H</i>)-ones <b>3</b>. Subsequent regioselective bromination of phthalazin-1­(2<i>H</i>)-ones <b>3</b> with benzyltrimethylammonium tribromide (BTMA-Br₃) followed by mixed copper–copper oxide-catalyzed amination of 4-bromophthalazin-1­(2<i>H</i>)-ones <b>4</b> with primary amines generates aminophthalazin-1­(2<i>H</i>)-ones in good overall yields

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid <b>4</b>, the known benzofuran analogue <b>5</b>, and the benzothiadiazine derivative <b>6</b>, an optimization process utilizing the simple benzofuran template <b>7</b> as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (<b>37</b>), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of <b>37</b> were better than anticipated and suggest promising potential for QD administration