Hepatitis C (HCV) belongs to the Flaviviridae family of positivesense, single-stranded RNA viruses. The HCV genome encodes a polyprotein, comprised of 3000 amino acid residues, which is processed into both structural and nonstructural proteins. [1] HCV infection is a significant global health issue; the World Health Organization estimates that over 170 million people carry the HCV [2] infection, which can ultimately result in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. These complications are responsible for about 10 000-20 000 deaths annually in the U.S. alone. [3] HCV is the leading cause of advanced liver disease and liver transplantation. [4] Current therapies for HCV infection rely on the combination of the nonspecific antiviral medication, ribavirin, and interferon-a (IFN). [4] Not only does this treatment regimen cause undesirable side effects such as leucopenia, thrombocytopenia, and hemolytic anemia, but only ~40 % of patients achieve a sustained viral response. [4b, 5, 6] Recently, several pegylated forms of IFN, including Pegasys and PEG-INTRON, have been approved for HCV treatment, which, in combination with low-dose ribavirin, has resulted in improved viral response rates (> 50 %) and reduced side effects. [7] In 2000, Bartenschlager described a cell-based replication model (replicon) that contains all of the enzymes necessary for efficient HCV replication but lacks the structural proteins required for virion packaging, and hence transmission. [1, 8] In 2001, a chimeric mouse model (SCID/Alb-uPA) was developed to study HCV infection in vivo using human liver explants. [9] The results obtained from this murine infection model have been consistent with observed clinical outcomes. [10] Most recently, a robust cell culture model for HCV infection has been developed, which promises to allow a greater understanding of the early steps in viral transmission. [11] These recent advances in the screening and evaluation of new chemical entities promise to accelerate the discovery and development of anti-HCV treatments. In fact, several inhibitors of HCV NS3/4A protease have advanced into clinical trials as monotherapies, or as combination therapies with pegylated IFNs. [12] Another structural protein essential for viral replication is NS5B RNA-dependent RNA polymerase (RdRp). [12e, 13, 14] Allosteric inhibition of reverse transcriptase has proven affective in the treatment of HIV-1; for this reason allosteric inhibition of HCV NS5B is considered a promising strategy and, as such, has received considerable attention from the pharmaceutical industry. [12d, 14, 15] In 2004, Gopalsamy et al. reported the synthesis and biological evaluation of a series of tetrahydropyranoA C H T U N G T R E N N U N G [3,4b]indole-based allosteric inhibitors of HCV NS5B. [16] This work resulted in the identification and clinical evaluation of HCV-371 (1). [17] Pyranoindole 1 selectively inhibits HCV NS5B (IC 50 = 0.3-1.4 mm for 90 % of HCV genotypes) and displays activity in the subgenomic HCV replicon assay (EC 50 = 4.8 AE 0.5 mm). Acceptable safety and tolerability of 1 were observed in Phase I clinical trials. Disappointingly, compound 1 did not demonstrate significant antiviral activity in a Phase Ib efficacy study. Retrospective evaluation of 1 using the SCID/Alb-uPA mouse model also failed to afford a significant antiviral effect. [10]