We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.

Materials and Methods.Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen using anhydrous solvents (either freshly distilled or passed through activated alumina columns). All commercially obtained reagents were used as received. Reaction temperatures were controlled using an IKAmag temperature modulator. Thinlayer chromatography (TLC) was conducted with E. Merck silica gel 60 F254 pre-coated plates, (0.25 mm) and visualized using a combination of UV, anisaldehyde, ceric ammonium molybdate, and potassium permanganate staining. ICN silica gel (particle size 0.032-0.063 mm) was used for flash column chromatography. Disposable Sep-Pak C 18 Vac Cartridges were purchased from Waters and used for all reversed-phase filtrations. HPLC analysis was performed on a Beckman Gold system using a Rainin C 18 , Microsorb MV, 5µm, 300 x 4.6 mm reversed-phased column in 0.1% (w/v) TFA with acetonitrile as eluent and a flow rate of 1.0 mL/min, gradient elution of 1.25% acetonitrile/min. Preparatory reversed-phase HPLC was performed on a Beckman HPLC with a Waters DeltaPak 25 x 100 mm, 100 µm C 18 column equipped with a guard, 0.1% (w/v) TFA with acetonitrile as eluent, and gradient elution of 0.50% acetonitrile/min. For all reversed-phase purifications, water (18MΩ) was obtained from a Millipore MiliQ water purification system and TFA from Halocarbon, Inc.

No abstract

Materials and Methods.Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen using anhydrous solvents (either freshly distilled or passed through activated alumina columns). All commercially obtained reagents were used as received. Reaction temperatures were controlled using an IKAmag temperature modulator, and unless stated otherwise, reactions were performed at 23 °C. Thin-layer chromatography (TLC) was conducted with E. Merck silica gel 60 F254 pre-coated plates, (0.25 mm) and visualized using a combination of UV, anisaldehyde, ceric ammonium molybdate, and potassium permanganate staining. ICN silica gel (particle size 0.032-0.063 mm) was used for flash column chromatography.

The palladium-catalyzed aerobic oxidative kinetic resolution of key pharmaceutical building blocks is described. Substrates investigated are relevant to the enantioselective preparation of Prozac ¾ , Singulair ¾ , and the promising hNK-1 receptor antagonist from Merck. The latter provides the most selective aerobic oxidative kinetic resolution yet described.