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The molar standard enthalpy of formation in condensed and gas phases of indazole, 1H-indazole-3-carboxylic acid, 1H-indazole-5-carboxylic acid, 1H-indazole-6-carboxylic acid and 1-methyl-1H-indazole-6-carboxylic methyl ester is reported. These properties were obtained indirectly from experimental determinations of the compounds using isoperibolic calorimetry and thermogravimetry. The values obtained for enthalpy of formation in the gas phase were compared with the computational results by means of the auxiliary density functional theory using deMon2k. The influence of the carbonyl and acetate groups on this type of compounds is analyzed energetically and structurally. The results obtained were compared and discussed with the data found in the literature.

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Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

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A simple, efficient, regioselective, and scalable palladium-catalyzed hydroxycarbonylation of heteroaryl halides to corresponding carboxylic acids using acetic-formic anhydride in presence of Pd(OAc)2, dppf, and diisopropylethyl amine in dimethyl formamide at 80-90 C in excellent yields. Taylor & Francis Group, LLC.

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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.

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The present teachings provide a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. Also described are a pharmaceutical composition and method of use thereof.

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The invention relates to acyl sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new acyl sulfonamide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein U, V, W, X, Y, R and R1 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.

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The invention relates to novel substituted condensed pyrimidine compounds of general formula (I) in which the chemical groupings, substituents and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.

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Fused compounds of Formula (I) and Formula (II), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions. Wherein R1, R2, R2a, R3, R3a, R4, and R4a are defined herein.

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This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4- dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl] -5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.

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Embodiments of the invention are directed to compounds that are positive allosteric modulators of AMP A receptors.

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