A Three-Step Method for the Preparation of -Substituted 3,4-Dihydroisoquinolin-1(2)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1)-ones from 2-Bromobenzoate Precursors.

We demonstrate a general method for the preparation of diverse -substituted 3,4-dihydroisoquinolin-1(2)-one compounds through an overall three-step cross-coupling/cyclization/-deprotection/-alkylation sequence. In the first step, ethyl 2-bromobenzoates and 2-bromo-1-carboxyethyl heterocycles are cross-coupled with commercially available potassium (2-((-butoxycarbonyl)amino)ethyl)trifluoroborate to produce (hetero)aryl-substituted 3-[(-Boc-2-carboxyethyl)phenyl]ethylamines. In a subsequent two-stage process, these (hetero)arylethylamines undergo base-mediated ring closure followed by -deprotection and -alkylation to produce -substituted 3,4-dihydroisoquinolin-1(2)-ones and heteroaryl-fused -benzyl 3,4-dihydropyridin-2(1)-ones.

Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators.

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target.

Phenotypic Optimization of Urea-Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss.

Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC) concentration conferred by 1 is 3.

Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme.

The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility.

Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4.

IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity.

Bioavailable pyrrolo-benzo-1,4-diazines as Na(v)1.7 sodium channel blockers for the treatment of pain.

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.

Discovery of pyrrolo-benzo-1,4-diazines as potent Na(v)1.7 sodium channel blockers.

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5.

The optimization of pyridazinone series of glucan synthase inhibitors.

A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.

Lead optimization of a sulfonylurea-based piperazine pyridazinone series of glucan synthase inhibitors.

The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.

Discovery of a novel class of orally active antifungal beta-1,3-D-glucan synthase inhibitors.

The echinocandins are a class of semisynthetic natural products that target β-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally.

SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors.

A novel series of pyridazinone analogs has been developed as potent β-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.

Concise enantiospecific, stereoselective syntheses of (+)-crispine A and its (-)-antipode.

An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.

Palladium-catalyzed preparation of Weinreb amides from boronic acids and N-methyl-N-methoxycarbamoyl chloride.

A simple protocol for the synthesis of Weinreb benzamides and alpha,beta-unsaturated Weinreb amides through a palladium-catalyzed cross-coupling reaction between organoboronic acids and N-methoxy-N-methylcarbamoyl chloride has been developed. The method is also applicable to the use of potassium organotrifluoroborates.

A concise palladium-catalyzed carboamination route to (+/-)-tylophorine.

A total synthesis of the racemic natural product tylophorine [(+/-)-1] has been demonstrated using the palladium-catalyzed carboamination method developed by Wolfe and co-workers. In this case, an electron-rich aryl bromide 18 was prepared in four steps and subjected to palladium-catalyzed Wolfe carboamination conditions with olefinic carbamate 7 to provide the racemic 2-(arylmethyl)pyrrolidine (+/-)-19 in good yield and was further elaborated to racemic tylophorine. This application of the Wolfe carboamination protocol as a key step to construct a natural product provides further evidence of the utility of the method.

Heterobiaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part II.

C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).

Efficient N-arylation/dealkylation of electron deficient heteroaryl chlorides and bicyclic tertiary amines under microwave irradiation.

A highly efficient procedure was developed for the microwave-assisted synthesis of N-heteroaryl-4-(2-chloroethyl)piperazines and N-heteroaryl-4-(2-chloroethyl)piperidines. Microwave irradiation of electron deficient heteroaryl chlorides with 1,4-diazabicyclo[2.2.

Generation of 3-pyridyl biaryl systems via palladium-catalyzed Suzuki cross-couplings of aryl halides with 3-pyridylboroxin.

The synthesis of 3-pyridyl biaryl systems can be readily achieved by means of palladium-catalyzed Suzuki cross-coupling reactions between aryl halides and 3-pyridylboroxin. A series of cross-couplings were conducted in order to investigate the scope and limitations of this protocol.

The diazo ketone approach to the isoprostanes.

A general synthetic approach to the isoprostanes has been established, based on intermolecular aldol condensation of a diazo ketone with an unsaturated aldehyde, followed by cyclization of the resulting diazo ketone to the cyclopropane. Subsequent kinetic opening with thiophenol followed by further elaboration then leads to the isoprostane. The history of this approach and the details of its development are discussed.

Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor.

The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency.

5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods.

5-Substituted-1H-tetrazoles (RCN4H) are often used as metabolism-resistant isosteric replacements for carboxylic acids (RCO2H) in SAR-driven medicinal chemistry analogue syntheses. This review provides a brief summary of the medicinal chemistry of tetrazolic acids and highlights some examples of tetrazole-containing drug substances in the current literature. A survey of representative literature procedures for the preparation of 5-substituted-1H-tetrazoles, focusing on preparations from aryl and alkyl nitriles, is presented in sections by generalized synthetic methods.

Preparation of 8-substituted xanthine CVT-124 precursor by late stage pyrimidine ring closure.

To develop a novel route for the scaleable synthesis of the chiral xanthine CVT-124 (1, aka. BG9719), a method for the late stage pyrimidine ring closure of the nitrogen-protected endo 2-norbornenyl imidazole 3 was developed. The three-component coupling of benzylamine, 2-cyanoglycine ethyl ester (4), and methyl 5-norbornene-2-carboximidate hydrochloride (5) was demonstrated to achieve 3 in 23-46% isolated yields.

Diastereoselective Synthesis of an Isoprostane: (+/-)-8-epi-PGF(2)(alpha) Ethyl Ester.

A total synthesis of the isoprostane (+/-)-8-epi-PGF(2)(alpha) ethyl ester (5) is described, based on the diastereoselective cyclization of alpha-diazo ketone 7. This ketone is assembled by aldol condensation between alpha-diazo ketone 8 and aldehyde 9. The sequential alpha-diazo ketone aldol/insertion described here offers a powerful new approach to cycloalkane construction.