The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

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Optically active b-amino acids have become increasingly prevalent features in small-molecule chemotherapeutic agents [1] and are integral components of peptidic materials that have unique structural properties. [2] As a result, efficient and economical preparation of enantiomerically enriched b-amino acids has become the focus of numerous synthesis studies. [3,4] The amine-mediated S N 2 ring opening of blactones presents an especially attractive and straightforward entry to compounds that contain b-amino carbonyl functionalities [Eq. (1)]. [5, 6] However, the evolution of this strategy as a general asymmetric synthesis of b-amino acids has been limited by the availability of the requisite optically active blactone electrophiles. [7] Herein we describe the union of catalytic asymmetric acyl halide ± aldehyde cyclocondensation reactions with azide-or sulfonamide-anion-mediated ring opening of the derived enantiomerically enriched b-lactones as an economical and efficient asymmetric synthesis of N-protected b-amino acids.Catalyzed enantioselective acyl halide ± aldehyde cyclocondensation (AAC) reactions have recently been reported to provide convenient access to b-lactones with high enantiomeric purities [Eq. (2)]. [8] We envisioned that integrating the catalytic asymmetric AAC reaction technology with the reactivity of nitrogen-based nucleophiles toward b-lactones would represent a general asymmetric synthesis of b-amino acid derivatives. Thus, a series of enantiomerically enriched blactones 1 were prepared by the asymmetric cyclocondensation of acetyl bromide and a variety of aldehyde electrophiles 2 catalyzed by the Al III triamine complex 3 (Table 1). Based on pioneering observations by the groups of Vederas and Seebach, [5a±c] azide ion was evaluated initially as a suitable nucleophile for effecting the desired S N 2 mode of 2-oxetanone ring opening. Reacting the optically active b-lactones 1 a ± f with sodium azide (2.0 equiv) in DMSO (50 8C) promoted efficient S N 2 lactone ring opening to directly afford the bazido acids 4 a ± f in 78 ± 95 % yield [Eq. (3)]. [9] Azide-induced ring opening was insensitive to the structure of the lactone alkyl substituent; lactones bearing aliphatic unbranched, alkoxy-substituted, a-branched, [10] and b-branched alkyl sub-[6] Reviews: a) H. P. Boehm, Carbon 1994, 32, 759 ± 769; b) H. P. Boehm,

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