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This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a piperidinyl-benzoimidazole structure which function as antagonists of small ubiquitin like modifier (SUMO) related modification (SUMOylation) of collapsin response mediator protein 2 (CRMP2), and their use as therapeutics for the treatment of voltage gated sodium channel 1.7 (Nav1.7) related itch, anosmia, migraine event, and/or pain (e.g., neuropathic pain).

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We report the first electrochemical strategy to synthesize functionalized naphthalene derivatives through [4+2] annulation?rearrangement?aromatization from styrenes under mild conditions. The electrolysis does not require metals, oxidants and high valence substrates, indicating the atom and step-economy ideals. The dehydrodimer produced through [4+2] cycloaddition of 4-methoxy alpha-methyl styrene is isolated and proved to be the key intermediate for the following oxydehydrogenation to form carbon cation, which undergoes rearrangement?aromatization to afford the final products. This reaction represents a powerful access to construct multi-substituted naphthalene blocks in a single step.

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The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6 and R7 are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

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The invention relates to processes for preparing isoindolin-1-one derivatives, and in particular processes for preparing (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1- (oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid. The invention also relates to crystalline forms of the compound (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4- chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H- isoindol-2-yl]-2-methylpropanoic acid and its salts.

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The synthesis of a new series of 4-acylaminopyrazolo[3,4-d]pyrimidines active on the sigma-1 receptor (sigma1R) is reported. Compounds were efficiently prepared using a two to three step process starting from commercially available 1H-pyrazolo[3,4-d]pyrimidin-4-amine. A SAR study shows that the sigma1R requires the presence of relatively highly lipophilic substituents at opposite sides of the central scaffold, while selectivity versus the sigma2R can be improved by shortening the distance of the basic nitrogen to it. Compound 9a was among the most active and selective in vitro derivatives and exhibited potent antinociceptive properties in several pain models in mice, indicating its antagonistic behaviour.

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The attachment of a tethering group from the basic nitrogen atom to the arene ligand of a ruthenium(II) catalyst greatly improves its ability to catalyze asymmetric transfer hydrogenation (ATH) reactions. In this paper, we describe further applications of this versatile system to an extended substrate range.

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A straightforward method for preparing 3,6-disubstituted-1,2,4-triazines through a redox-efficient cyclodehydration of beta-keto-N-acylsulfonamides with hydrazine salts is described. Two approaches for synthesizing the requisite beta-keto-N-acylsulfonamides are presented, which allow for the late stage incorporation of either the C3 or C6 substituent in a flexible manner from acid chlorides or alpha-bromoketones, respectively. The scope of this methodology includes primary and secondary sp3-linked substituents at both the C3 and C6 positions, and the mild reaction conditions tolerate a variety of sensitive functionalities.

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Based on a hit cluster of compounds inhibiting interleukin-2 inducible T-cell kinase (ITK) in the submicromolar range a series of ITK inhibitor libraries were synthesized. Through iterative design cycles including kinase crystal structure information, indolylindazole libraries were identified which showed low nanomolar activity in enzymatic and cellular assays. The potential of these novel lead series was confirmed through in vivo tests in an anti-CD3-IL2 mouse model. The intravenous administration of highly potent ITK inhibitor 11o resulted in dose-dependent, efficient suppression of IL-2.

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The present invention relates to Bicyclic Heterocycle Derivatives of formula (I), compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR119 in a patient

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