Synthesis and asymmetric hydrogenation of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methylidene]piperidine-2,6-dione

The synthesis of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methylidene]piperidine-2,6-dione 4 from N-benzylglutarimide was achieved in three steps. The asymmetric hydrogenation of 4 gave either the product of partial reduction (10) or full reduction (13), depending on the catalyst which was employed, in high ee in each case. Attempts at asymmetric transfer hydrogenation (ATH) of 4 resulted in formation of a racemic product

Data for Synthesis and reduction reactions of pyridones and 5-acyl-2-methoxypyridines

The synthesis of a series of pyridones, from their 2-hydroxypyridine or 2-methoxypyridine precursors, is described, along with studies into their reductions to saturated heterocycles. A number of 5-acylpyridones were prepared and were evaluated as substrates for asymmetric transfer hydrogenation prior to conversion to saturated heterocycles. The enantioselective reduction of 5-acetyl-1-benzylpyrimidine-2,4(1H,3H)-dione is also described

Synthesis and asymmetric hydrogenation of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methylidene]piperidine-2,6-dione

The synthesis of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methylidene]piperidine-2,6-dione 4 from N-benzylglutarimide was achieved in three steps. The asymmetric hydrogenation of 4 gave either the product of partial reduction (10) or full reduction (13), depending on the catalyst which was employed, in high ee in each case. Attempts at asymmetric transfer hydrogenation (ATH) of 4 resulted in formation of a racemic product

Synthesis and reduction reactions of pyridones and 5-acyl-2-methoxypyridines

The synthesis of a series of pyridones, from their 2-hydroxypyridine or 2-methoxypyridine precursors, is described, along with studies into their reductions to saturated heterocycles. A number of 5-acylpyridones were prepared and were evaluated as substrates for asymmetric transfer hydrogenation prior to conversion to saturated heterocycles. The enantioselective reduction of 5-acetyl-1-benzylpyrimidine-2,4(1H,3H)-dione is also described

The Osmium-Catalyzed Asymmetric Dihydroxylation of <i>cis</i>-Fused Cyclopenteno-1,2,4-trioxanes

Submission of racemic, cis-fused cyclopenteno-1,2,4-trioxanes (1 and 1-ent) to catalytic amounts of K₂OsO₄ and (DHQD)₂PHAL and 1.2 equivalents of N-methylmorpholine N-oxide in aqueous acetone at 20°C (hybrid AD-mix-β) for 2 h gave the (-)-enantiomer, 1-ent (ee 95%) in 30% yield. The same reaction, but with (DHQ)₂PHAL, (hybrid AD-mix-α) afforded the (+)-enantiomer, 1 (ee 95%) in 25% yield after 2.7 h reaction. Similar, efficient kinetic resolution of the racemic di-p-fluoro analogues (2 and 2-ent) was also achieved with the same reagents

Synthesis of Functionalized Cyanopyrazoles via Magnesium Bases

4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles

Discovery of Novel 3‑Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (<b>4</b>), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1<i>R</i>)-1-(tetrahydro-2<i>H</i>-pyran-4-yl)­ethyl]­amino}-3-quinolinecarboxamide (<b>72</b>) and 7-fluoro-6-[6-(methoxymethyl)­pyridin-3-yl]-4-{[(1<i>S</i>)-1-(1-methyl-1<i>H</i>-pyrazol-3-yl)­ethyl]­amino}­quinoline-3-carboxamide (<b>74</b>) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. <b>72</b> and <b>74</b> constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model

Discovery of a Series of 3‑Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound <b>21</b>, a highly potent ATM inhibitor (ATM cell IC₅₀ 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. <i>In vivo</i>, <b>21</b> in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound <b>21</b> was selected for preclinical evaluation alongside AZD0156