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.

We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.

The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.

Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC.In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)–low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway–activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments.In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7–7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2–8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81–1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway–activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively.Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed.ClinicalTrials.gov (NCT01896531).

Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.

1. The compound of the formula:! ! and its enantiomers and salts, in which:! G is phenyl, naphthalene, 5-6 membered heteroaryl or 9-10 membered bicyclic heteroaryl, in which phenyl, naphthalene, 5-6 membered heteroaryl or 9-10 membered bicyclic heteroaryl is optionally substituted with one to four Ra in groups; ! R1 and R1a are independently selected from H, Me, Et, —CH = CH2, —CH2OH, CF3, CHF2 or CH2F; ! R2 represents H, —OH, —OMe or F; ! R2a represents H, Me or F, or! R2 and R2a are oxo; ! R3 is H, Me, Et or CF3; ! R4 is H, a 4-6 membered heterocycle, cyclopropylmethyl or C1-C4 alkyl optionally substituted with F, -OH or -O (C1-C3 alkyl); ! R5 and R5a are independently selected from H and C1-C4 alkyl, or R5 and R5a together with the atom to which they are attached form a carbonyl group, a 5-6 membered cycloalkyl or a 5-6 membered heterocycle in which the heterocycle has a heteroatom oxygen; ! each Ra is independently halogen, C1-C6-alkyl, C3-C6-cycloalkyl, -O- (C1-C6-alkyl), CF3, -OCF3, S (C1-C6-alkyl), CN, phenyl, -OCH2 -phenyl, NH2, -NO2, -NH- (C1-C6-alkyl), -N- (C1-C6-alkyl) 2, piperidine, pyrrolidine, pyrazole, pyridine, 2-aminopyridine, CH2F, CHF2, -OCH2F, -OCHF2, -OH, -SO2 (C1-C6-alkyl), C (O) NH2, C (O) NH (C1-C6-alkyl), and C (O) N (C1-C6-alkyl) 2; and! j represents 1 or 2; and when j is a 2, j-ring carbon atom opposite to NR4, may be substituted with an O heteroatom! 2. The compound according to claim 1, in which:! G is phenyl optionally substituted with one to four Ra groups, or 5-6 membered heteroaryl optionally substituted with halogen; ! R1 and R1a are independently selected from H, Me, Et, —CH = CH2, —CH2OH, CF3, CHF2 or CH2F; ! R2 represents H, —OH, —OMe or

An enantioselective synthesis of rhizoxin D, isolated from the plant pathogenic fungus Rhizopus chinensis, is described. The overall strategy is based on elaboration of the delta-lactone-substituted vinyl stannane and the phosphonate-substituted vinyl iodide, followed by their coupling to the core 16-membered macrolide via a sequential intermolecular Horner-Wadsworth-Emmons olefination, leading to (50), and by an intramolecular Stille reaction. The triene oxazole-containing side chain in rhizoxin D is then introduced using the phosphine oxide in an E-selective Horner-Wittig reaction with the macrolide aldehyde.

A new and convergent synthesis of the antitumour macrolide rhizoxin D 2 is described. The synthesis features a Wadsworth–Emmons olefination and a facile intramolecular Stille reaction to elaborate the 16-membered macrocyclic core 5 from the vinyl iodide 3 and the vinyl stannane 4 as key steps.

Treatment of terminal triisopropylsilyl propargyl anilines with methanesulfonic acid resulted in cyclization to give a 3-methylindole derivative.

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The cyclic hemithioacetal sulfoxide 15 readily undergoes the Pummerer reaction in the presence of carbon nucleophiles to give substituted benzylic sulfides in excellent yields.

Reaction of MCl2 (M = Pd, Pt) with PCy2H in EtOH under dinitrogen yielded the unusual tris-secondary phosphine complexes [MCl(PCy2H)3]X (X− = Cl−, BF−4, PF−6) in high yield as stable products. Retention of the secondary phosphine protons in these complexes has been confirmed by 1H, 31P and 195Pt NMR spectroscopic studies. These results confirm that the PH bond in coordinated PCy2H is stronger than in coordinated PPh2H. Similar reaction of NiCl2 · 6H2O with PCy2H yields the bis-secondary phosphine complex [NiCl2(PCy2H)2] as reported previously (R. A. Palmer, H. F. Giles and D. R. Whitcomb, J. Chem. Soc., Dalton Trans. 1978, 1671 ; R. A. Palmer and D. R. Whitcombe, J. Mag. Res. 1980, 39, 371). Variable temperature 31P NMR spectroscopy confirms that the cis isomer exists exclusively in CH2Cl2 solution, while the trans isomer is the dominant form in benzene solution. Addition of excess PCy2H leads to species with higher phosphine : metal ratios at low temperature as seen by 31P NMR spectroscopy and FAB mass spectrometry.