Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings.

Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)-C(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Highly Diastereoselective Synthesis of a HCV NS5B Nucleoside Polymerase Inhibitor.

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.

Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions.

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions.

Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*·PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(ii) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings.

Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase.

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N Coupling with Chiral Bisphosphine Mono-oxides.

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

A highly efficient asymmetric synthesis of vernakalant.

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

Enantioselective synthesis of a dual orexin receptor antagonist.

A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.

A mild Negishi cross-coupling of 2-heterocyclic organozinc reagents and aryl chlorides.

A mild Negishi cross-coupling of 2-heterocyclic organozinc reagents and aryl chlorides is described. The use of Pd(2)(dba)(3) and X-Phos as a ligand provides high yields for many examples. An efficient method to generate the organozinc reagents at room temperature is also demonstrated.

A cascade approach to cyclic aminonitrones: reaction discovery, mechanism, and scope.

Treatment of omega-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further selective elaboration.

One-pot iodination of hydroxypyridines.

A one-pot, high-yielding iodination of hydroxypyridines and hydroxyquinolines is described. The iodination proceeds under mild conditions, and the products are obtained in high yield without the need for chromatographic purification. In addition, the iodination works on both 2- and 4-hydroxypyridines and -hydroxyquinolines.

A general and efficient 2-amination of pyridines and quinolines.

Pyridine N-oxides were converted to 2-aminopyridines in a one-pot fashion using Ts2O-t-BuNH2 followed by in situ deprotection with TFA. The amination proceeded in high yields, excellent 2-/4-selectivity, and with good functional group compatibility. 2-Amino (iso)quinolines were also obtained in the same manner. Combined with the simple oxidation of pyridines to pyridine N-oxides, this method provides a general and efficient way for amination of 2-unsubstituted pyridines.

The enantiomeric scaffold approach to highly functionalized 1-oxadecalines: enantio- and regiocontrolled [4 + 2] cycloadditions of 5-alkenyl-eta3-pyranylmolybdenum complexes.

TpMo(CO)2(5-alkenyl-eta-2,3,4-pyranyl) diene complexes function as excellent chiral scaffolds for the efficient regio- and enantiocontrolled synthesis of highly functionalized 1-oxadecaline derivatives through a novel transition metal-mediated Diels-Alder reaction. Very good to excellent yields and excellent levels of endo selectivity are obtained, and the reaction gives products with complete retention of enantiomeric purity when carried out with chiral, nonracemic scaffolds. A subtle structural modification on the diene (replacement of an H by a trans-CH3 group) leads to a complete change of regiochemistry, which is discussed from a mechanistic point of view. The role of the eta3-coordinated TpMo(CO)2 moiety is also critical to the further functionalization of the [4 + 2] cycloadducts, as illustrated by the preparation of 20 variously functionalized 1-oxadecaline derivatives (>98% ee when carried out with high enantiopurity scaffolds).

Highly diastereoselective catalytic Meerwein-Ponndorf-Verley reductions.

[reaction: see text] Very practical synthesis of ephedrine analogues in high yields and enantiopurity was realized by a highly diastereoselective Meerwein-Ponndorf-Verley (MPV) reduction of protected alpha-amino aromatic ketones using catalytic aluminum isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminum. In contrast, high syn selectivity was obtained with alpha-alkoxy ketones and other compounds via Felkin-Ahn control.

Direct and convenient conversion of alcohols to fluorides.

[reaction: see text] Directly mixing primary, secondary, and tertiary alcohols with nC(4)F(9)SO(2)F-NR(3)(HF)(3)-NR(3) in THF or MeCN results in convenient conversion to the corresponding fluorides in high yields. The readily available reagents are easy to handle, and the mild, almost neutral reaction conditions allow for excellent functional group compatibility. A NR(3)(HF)(3)/NR(3) ratio of

Pd-catalyzed N-arylation of heteroarylamines.

The palladium-catalyzed N-(hetero)arylation of a number of heteroarylamines including 2-aminopyridines, 2-aminothiazoles, and their analogues has been realized using Xantphos as the ligand. Weak bases such as Cs(2)CO(3), Na(2)CO(3), and K(3)PO(4) were used in most cases to allow for the introduction of functional groups. Choice of the base and solvent was critical for the success of these reactions. [reaction: see text]

Pd-catalyzed intermolecular amidation of aryl halides: the discovery that xantphos can be trans-chelating in a palladium complex.

A general method for the intermolecular coupling of aryl halides and amides using a Xantphos/Pd catalyst is described. This system displays good functional group compatibility, and the desired C-N bond forming process proceeds in good to excellent yields with 1-4 mol % of the Pd catalyst. Additionally, the arylation of sulfonamides, oxazolidinones, and ureas is reported. The efficiency of these transformations was found to be highly dependent on reaction concentrations and catalyst loadings. A Pd complex resulting from oxidative addition of 4-bromobenzonitrile, (Xantphos)Pd(4-cyanophenyl)(Br) (II), was prepared in one step from Xantphos, Pd(2)(dba)(3), and the aryl bromide. Complex II proved to be an active catalyst for the coupling between 4-bromobenzonitrile and benzamide. X-ray crystallographic analysis of II revealed a rare trans-chelating bisphosphine-Pd(II) structure with a large bite angle of 150.7 degrees.