Palladium-Catalyzed α‑Arylation of Sultams with Aryl and Heteroaryl Iodides

Palladium­(0)-catalyzed conditions for the α-arylation of sultams with aryl and heteroaryl iodides have been developed. Arylation of 3-substituted 1,3-propanesultams gave rise to high yields and high diastereomeric ratios, leading to the thermodynamically favored <i>cis</i> product. The arylation was broadly applicable to various electron-rich and electron-poor (hetero)­aromatic iodides

Experimental and Computational Studies of the Diastereoselective Alkylations of 3‑Substituted γ‑Sultams

We report that chiral 3-substituted γ-sultam α-carbanions undergo diastereoselective alkylation reactions with alkyl halides to predominantly produce <i>trans</i>-3,5-disubstituted γ-sultam products. Quantum mechanical calculations provided a stereoelectronic rationale for the observed diastereoselectivity

Palladium-Catalyzed Ring Expansion of Spirocyclopropanes to Form Caprolactams and Azepanes

A palladium(0)-catalyzed rearrangement of piperidones and piperidines bearing a spirocyclopropane ring was developed. The ring expansion reaction led to a variety of functionalized caprolactam and azepane products in good to excellent yields. Experimental and computational mechanistic studies revealed an initial oxidative addition of the distal carbon–carbon bond of a cyclopropane ring to the palladium(0) catalyst and the relief of ring strain as a driving force for product formation

Discovery of 1‑{4-[3-Fluoro-4-((3<i>S</i>,6<i>R</i>)‑3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C (RORc or RORγ) Inverse Agonist

Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide <b>1</b> as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (<b>27</b>, 1-{4-[3-fluoro-4-((3<i>S</i>,6<i>R</i>)-3-methyl-1,1-dioxo-6-phenyl-[1,2]­thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of <b>27</b> in preclinical studies

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice

A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC₅₀ in a MiaPaca2 cell line. Optimization of the series led to <b>29</b>, a potent cell active molecule (MiaPaca2 IC₅₀ = 0.67 μM) that also possessed good exposure when dosed orally to mice