Synthesis of Highly Functionalized 4-Iodo-7-azaindazoles via Condensation/Diels-Alder/Retro-Diels-Alder Cyclization of Iodoalkynones and 2-Hydrazineylpyrimidines.

A method for the preparation of highly functionalized 4-iodo-7-azaindazoles is reported. These valuable heterocycles are synthesized via condensation of 2-hydrazineylpyrimidines with various iodoalkynones followed by Diels-Alder/retro-Diels-Alder cyclization. The method is general to the formation of products with a variety of C3, C5, and C6 substituents while preserving the C4 iodide functional handle for further late-stage functionalization. The utility of this transformation is demonstrated through the rapid synthesis of several bioactive azaindazole targets.

Blue Light-Mediated, Photocatalyst-Free Decarboxylative Alkylation of Heteroaryl Sulfinimines.

We report a diastereoselective, photocatalyst-free decarboxylative alkylation of (hetero)aryl sulfinimines using redox-active esters under blue light. High yields and diastereoselectivities can be achieved under mild conditions, and we demonstrate its utility as a synthetic method, especially for medicinal chemists.

Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793.

The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.

Design, Synthesis, and Preclinical Evaluation of 3-Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders.

Selective inhibitors of the GluN2B subunit of N-methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound 12. Compound 12 was found to have robust target engagement in rat with an ED70 of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate 12 for progression into advanced good laboratory practice studies.

Lead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8.

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead 4 was optimized for potency and brain penetration to provide benzimidazolone 3, JNJ-55511118.1 Replacement of the benzimidazolone core in 3 with an oxindole mitigated reactive metabolite formation and led to the identification of 18 (GluA1/γ-8 pIC50 = 9.7). Following oral dosing in rats, 18 demonstrated robust target engagement in hippocampus as assessed by ex vivo autoradiography (ED50 = 0.6 mg/kg, plasma EC50 = 9 ng/mL).

Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate.

The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.

Synthesis of a histamine H(3) receptor antagonist-manipulation of hydroxyproline stereochemistry, desymmetrization of homopiperazine, and nonextractive sodium triacetoxyborohydride reaction workup.

We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.

Reactions between Weinreb amides and 2-magnesiated oxazoles: a simple and efficient preparation of 2-acyl oxazoles.

Treatment of oxazole or 5-aryl oxazoles with i-PrMgCl smoothly generates the corresponding 2-Grignard reagents, which react with Weinreb amides to provide exclusively 2-acyl oxazole products.

Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis.

In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.

Mechanism of electrophilic chlorination: experimental determination of a geometrical requirement for chlorine transfer by the endocyclic restriction test.

An endocyclic restriction test for acid-catalyzed transfer of chlorine from a protonated chloroamine to an aromatic ring provides data that are consistent with a transition structure with a large bond angle between the entering and leaving groups around chlorine. These results rule out a dissociative mechanism or a mechanism that has an oblique angle between the entering and leaving groups.

Solid-State Structural Investigation of an Organolithium (-)-Sparteine Complex: η3 -N-Boc-N-(p-methoxyphenyl)-3-phenylallyllithium⋠(-)-Sparteine.

A η3 monomeric alkyllithium⋅(-)-sparteine complex has been isolated and characterized in the solid state (see picture). Determination of the absolute configuration of this key intermediate in asymmetric metalation/substitution sequences of N-tert-butoxycarbonyl-N-(p-methoxyphenyl)cinnamylamine allows definitive assignment of the stereochemical course of its electrophile-dependent substitution reactions.