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HETEROARYL COMPOUNDS AND METHODS OF USE THEREOF

Provided herein are heteroaryl compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. In one embodiment, the compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and metabolic disorders, including, but not limited to, e.g., neurological disorders, psychosis, schizophrenia, obesity, and diabetes

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PHOTOLYTIC RING-EXPANSIONS OF 4-AZIDOQUINOLINES AND 6-AZIDODIAZINES: SOME UNEXPECTED AZEPINE RING-OPENING REACTIONS

Photolysis of 6-azidoquinazoline in MeOH-KOMe-dioxan yields 8,9-dihydro-5,7-dimethoxy-5H-pyrimido<5,4-c>azepine (5) which on acid hydrolysis ring-opens to the pyrimidine-carbaldehyde (7).The mechanism of formation of this unexpected dimethoxypyrimido-azepine is discussed and related to previous similar results involving 6-azido-2,3-dihydrofuro- and 6-azido-2,3-dihydrothieno<2,3-b>quinolines. In contrast, 6-azidoquinoxaline and 6-azido-2-chloro-4-methylquinoline on photolysis under similar conditions undergo ring expansion to the expected pyrazino<2,3-c>– and pyrido<3,2-c>azepines (22a) and (17) respectively.However, photolysis of the latter azide in MeOH-dioxan yields the 3-(2-pyridyl)propenonitrile derivative (18) in a reaction analogous to that undergone by 6-azidophenazine.

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Pressure Effects on the Thermal Decomposition of Nitramines, Nitrosamines, and Nitrate Esters

Solutions of nitramine and nitrate ester explosives and model compounds were thermolyzed at various hydrostatic pressures and their rates of decomposition were measured.The effects of pressure on their rates were used to infer the mechanism of their initial decomposition steps.Most nitramines, including the explosive octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), appear to undergo homolysis of the N-NO2 bond, because their reaction rates decrease with increasing pressure.Exceptions are hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and the model compound, 6-nitro-1,2-dinitroso-1,2,3,4-tetrahydroquinoxaline, which react faster with increasing pressure.These two compounds can aromatize by elimination of HNO2 and HNO, respectively.Secondary nitrate esters shift their major decomposition pathway from homolysis of the O-NO2 bond to elimination of HNO3 in the pressure range of 0.4 to 0.8 GPa.The elimination reaction resembles carboxylate ester pyrolysis with E1 character.

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Synthesis and characterization of novel fluorescent compounds derived from 1,4-diethyl-1,2,3,4-tetrahydro-6-nitroquinoxaline

(Chemical Equation Presented) 1,4-Diethyl-1,2,3,4-tetrahydro-6- nitroquinoxaline 4 was synthesized by alkylative reduction of 6-nitroquinoxaline. Catalytic reduction of 4 followed by cyclocondensation with heterocyclic malondialdehydes afforded novel 8-(heteroaryl)-1,4-diethyl-1,2,3,4- tetrahydropyrido[2,3-g]quinoxalines. The solutions of these novel compounds having 1,4-diethyl-1,2,3,4-tetrahydroquinoxaline framework as an electron releasing system showed absorption in the range of 424-426 nm in the visible region and exhibited brilliant bluish-green fluorescence. The thermogravimetric curve obtained by thermogravimetric analysis displayed that these fluorophores possess excellent thermal stability with one-step thermal decomposition.

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Aqueous hydrofluoric acid catalyzed facile synthesis of 2,3,6-substituted quinoxalines

A versatile synthetic route for the preparation of 2,3,6-trisubstituted quinoxalines in excellent yield is developed from theta-diamines and 1,2-dicarbonyl compounds in which aqueous hydrofluoric acid was employed as the medium and catalyst. Other salient features of this protocol include milder conditions, absence of coupling agents, and easy workup procedures.

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Biomass into chemicals: One-pot two- and three-step synthesis of quinoxalines from biomass-derived glycols and 1,2-dinitrobenzene derivatives using supported gold nanoparticles as catalysts

An efficient and selective one-pot two-step method, for the synthesis of quinoxalines by oxidative coupling of vicinal diols with 1,2-phenylenediamine derivatives, has been developed by using gold nanoparticles supported on nanoparticulated ceria (Au/CeO2) or hydrotalcite (Au/HT) as catalysts and air as oxidant, in the absence of any homogeneous base. Reaction kinetics shows that the reaction controlling step is the oxidation of the diol to alpha-hydroxycarbonyl compound. Furthermore, a one-pot three-step synthesis of 2-methylquinoxaline starting from 1,2-dinitrobenzene and 1,2-propanediol has been successfully carried out with 98% conversion and 83% global yield to the final product.

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Investigation on the photoreactions of nitrate and nitrite ions with selected azaarenes in water

The photoreactions of selected azaarenes with nitrate and nitrite ions were investigated under irradiation at lambda = 313 nm. The excitation of both anions leads to several photochemical reactions forming mainly hydroxyl radicals and nitrogen oxides. The purification capability of natural waters i.e. the oxidation of inorganic and organic substances results from the formation of hydroxyl radicals. Nitrated isomers of azaarenes were found among the main products of the investigated photoreactions. The nitrogen oxides were responsible for the production of nitrated derivatives which possess a high toxic potential. Their formation was explained by the parallel occurance of two mechanism, a molecular and a radical one. The molecular mechanism became more important with increasing ionisation potentials of the azaarenes. The spectrum of oxidized products corresponded to the one got in the photoreactions of azaarenes with hydrogen peroxide. The formation of several oxidation and nitration products of the pyridine ring with its low electron density was explained by the reaction of excited states of azaarenes. The photoreactions with nitrite ions only led to the formation of oxidized and nitrated products. Nitroso products were not formed. The reactivity of nitrogen monoxide is too low for its reaction with the azaarenes.

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Reactions of Organic Anions, 177. Vicarious Nucleophilic Substitution of Hydrogen, Bisannulation and Competitive Reactions of alpha-Haloalkyl Carbanions with Bicyclic Azaaromatic Compounds

Carbanions of alpha-haloalkyl aryl sulfones, sulfonates, and sulfonamides react with bicyclic heteroaromatic compounds (quinoxalines, naphthyridines, and 5-azaquinoxalines) according to two general pathways: vicarious nucleophilic substitution of hydrogen and/or bisannulation.In some cases other competitive reactions such as SNAr are observed.Factors governing the direction of these reactions are discussed in terms of the charge distribution in the anionic ? adducts and the reaction conditions.

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Fluorescent sensing of anions using a bis-quinoxaline amidothiourea based supramolecular cleft; an example of an anion-induced deprotonation event

The quinoxaline 1, possessing a 2,6-pyridyl-based amidothiourea moiety, with the view of forming a pre-organised molecular cleft, was developed as a fluorescent anion sensor. The sensing ability of 1 was evaluated in organic solution where both the ground and the excited state of 1 was affected upon recognition of anions such as acetate [as tetrabutylammonium salt (TBAAc) solution] at the amiodothiourea moieties in MeCN. The fluorescence of 1, with lambdamax at 477 nm, was, on all occasions quenched, upon anion recognition. Using TBAOH, we also show that the same anion-induced changes occurred; demonstrating that for this particular sensor, the anion-sensing takes place via a deprotonation mechanism. This anion-induced deprotonation event was further investigated by carrying out 1H NMR titrations on 1, using both AcO- and OH- in DMSO-d6.

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Novel nitroheterocyclic hypoxic markers for solid tumor: Synthesis and biological evaluation

Based on the principle that the nitro-group can quench the fluorescence and can be reduced under hypoxic conditions, several novel nitroheterocyclic compounds without 2-nitroimidazole as potential hypoxic markers were prepared. Although they were synthesized from the same matrix, nitrosubstituted acenaphtho[1,2-b]quinoxaline, these compounds exhibited quite different fluorescence changes when they were differently nitrosubstituted. Their evaluation for imaging tumor hypoxia was carried out in V79 cells in vitro by Fluorescence Microplate Reader. After 3.5 h, the hypoxic-oxic fluorescence differential incubated with A1, A4, and A5 in V79 cells could reach 6, 9, and 11 times differential fluorescence between oxic and hypoxic cells separately, which are suitable for further evaluation as probes for hypoxic cells in tumors in vivo.

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