A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.

We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke.

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.

Synthesis of N-Substituted 3-Amino-2-pyridones.

Pyridones are versatile building blocks in organic synthesis and a privileged motif in drug discovery. However, N-substituted 2-pyridones bearing an α-tertiary carbon, cyclopropyl, or heterocycle off of the pyridone nitrogen atom remain challenging to prepare. Herein, we describe the efficient synthesis of a large variety of N-substituted 2-pyridones from ethyl nitroacetate and readily available primary amine building blocks, which can be utilized on a large scale and in parallel medicinal chemistry applications.

Total Syntheses of Xiamycins†A, C, F, H and Oridamycin†A and Preliminary Evaluation of their Anti-Fungal Properties.

Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)-carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late-stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one-pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti-fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.

The Rhazinilam-Leuconoxine-Mersicarpine Triad of Monoterpenoid Indole Alkaloids.

The rhazinilam-leuconoxine-mersicarpine triad of monoterpenoid indole alkaloids comprises a variety of diverse natural products with unprecedented structural features and intriguing biological activities. This subfamily of Aspidosperma alkaloids has drawn significant attention from the synthetic community which is reflected by over 20 syntheses within the last 5years. Numerous transformations and strategies have been developed to access the different key structural motifs such as the tetrahydroindolizine, α,ß-unsaturated carbinolamide, diaza[5.5.6.6]fenestrane, and tetrahydro-2H-azepine frameworks. The present contribution comprehensively covers the abundant literature on this natural product class up to the end of May 2016, providing a detailed account of the formal and total syntheses which is complemented by an overview of their biosynthesis, spectroscopy, and pharmacology.

Synthesis of Indolophanes by Photochemical Macrocyclization.

Herein, we report the synthetically practical, short, and general access to novel indolophane architectures by means of a photochemical C-H activation process-the Witkop cyclization. These highly strained scaffolds were obtained by photoinduced ring closure and feature atropisomerism as well as aromatic ring current effects, which both have been investigated. The prevailing regioselectivity of theWitkop cyclization reaction was completely reversed by the presence of a quaternary carbon center, exerting a strong Thorpe-Ingold effect on the system for which experimental-evidence is provided.

The Diaza[5.5.6.6]fenestrane Skeleton-Synthesis of Leuconoxine Alkaloids.

Among the Aspidosperma-derived monoterpene indole alkaloids, the leuconoxine subgroup has drawn significant attention from the synthetic community during the past few years. This Minireview summarizes the hitherto six completed total syntheses of leuconoxines emphasizing the different strategies for assembling the key structural motif, an unprecedented diaza[5.5.6.6]fenestrane skeleton. In addition, the proposed biogenetic relationships within the group of these alkaloids are described.

A photoinduced cyclization cascade-total synthesis of (-)-leuconoxine.

A protecting-group-free and enantioselective total synthesis of the monoterpenoid indole alkaloid (-)-leuconoxine was accomplished. The key step comprises a novel photoinduced domino macrocyclization/transannular cyclization involving the Witkop cyclization, for which additional mechanistic evidence is provided. This process furnishes a diaza[5.5.6.6]fenestrane skeleton, which is a hitherto unprecedented structure element.

Propargyltrimethylsilanes as allene equivalents in transition metal-catalyzed [5 + 2] cycloadditions.

Conventional allenes have not been effective π-reactive 2-carbon components in many intermolecular cycloadditions including metal-catalyzed [5 + 2] cycloadditions. We report herein that rhodium-catalyzed [5 + 2] cycloadditions of propargyltrimethylsilanes and vinylcyclopropanes provide, after in situ protodesilylation, a highly efficient route to formal allene cycloadducts. Propargyltrimethylsilanes function as safe, easily handled synthetic equivalents of gaseous allenes and hard-to-access monosubstituted allenes. In this one-flask procedure, they provide cycloadducts of what is formally addition to the more sterically encumbered allene double bond.

Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents.

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions--the homologous Diels-Alder and Diels-Alder cycloadditions--through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

The Witkop cyclization: a photoinduced C-H activation of the indole system.

Investigations of excited-state redox processes have an exceptional impact on the field of organic photochemistry and its application to the synthesis of complex target molecules. In such a photochemical process a single-electron transfer takes place to produce ion-radical intermediates, if the reduction and oxidation potentials, as well as excited-state energies of electron donors and acceptors are chosen appropriately. The Witkop cyclization constitutes an intramolecular variant of such a process, typically with an indole heterocycle as an electron donor. The specific synthetic value of this reaction lies in a CC bond formation without requiring any prefunctionalization of the indole system. Although this photoreaction has been applied to the total synthesis of natural products, it has still not been used to its full capacity. The following review details synthetic efforts using the Witkop cyclization, and aims to incite further applications of reaction in the synthesis of complex molecular architectures.