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A urea class of high affinity niacin receptor agonists was discovered. Compound 1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound 1q demonstrated equal affinity to GPR109A as niacin.

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The scope and limitations of SNAr substitution reactions of metalated 4-cyanopiperidines with heterocyclic halides were explored. These facile reactions provide rapid access to a wide range of 4-heteroaryl-4-cyanopiperidines and have resulted in improved yields, faster reaction times, and lower temperatures than previously published synthetic methods.

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We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.

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Disulfide Tethering was applied to the active site of human caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker.

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Imaging agents of formula (I) and methods for detecting neurological disorders comprising administering to a patient in need compounds of formula (I) capable of binding to tau proteins and beta-amyloid peptides are presented herein. The invention also relates to methods of imaging Abeta and tau aggregates comprising introducing a detectable quantity of pharmaceutical formulation comprising a radiolabeled compound of formula (I) and detecting the labeled compound associated with amyloid deposits and/or tau proteins in a patient. These methods and compositions enable preclinical diagnosis and monitoring progression of AD and other neurological disorders.

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Disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia

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An efficient method for the cross-coupling reaction of primary trialkybismuth reagents with 2-haloazines and diazines is reported. The reaction functions with pyridines, pyrimidines, pyridazines and pyrazines and tolerates many functional groups. This method gives access to 2-alkylazines and diazines, a class of compounds which is important in medicinal chemistry.

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Dialkylamino acetonitrile derivatives were utilized as alternative to cyanohydrin synthons for preparation of the corresponding heteroaryl dialkyl amides via a strategy of sequential base-mediated coupling and oxidation. The most advantageous oxidant, NiO2-H2O, can readily oxidize 2-substituted aminoacetonitriles to the corresponding amides under both basic and neutral conditions by forming cyanohydrins in situ.

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Facile synthesis of quinoxalinyl-2-oxyphenols are described.The condensation of 2-chloroquinoxalines with three molar equivalent of dihydroxybenzene in basic medium gave preferentially quinoxalinyl-2-oxyphenols, which involves nucleophilic cleavage of the initially formed bis(quinoxalinyl-2-oxy)benzenes by an excess of dihydroxybenzene.

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Heterocyclic thiols (thiones) are conveniently synthesized in good yields by the reaction of heterocyclic halides with sodium thiosulfate.The reaction requires the presence of acid, either added or liberated during the reaction, to hydrolyze the intermediate thiosulfate to thiol.

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