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The present invention is a method for the treatment of pain comprising administering to a subject in need thereof a therapeutically effective amount of one or more novel benzo-heteroaryl sulfamide derivatives of formula (I) as herein defined. The present invention is further directed to methods for the treatment of pain comprising co-therapy with analgesic agent(s) and a compound of formula (I) as described herein.

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The synthesis and transition temperatures are reported for several 2-(4-alkyl- and 4-alkoxy-phenyl)-5-cyano-1-benzofurans, 2-(4?-alkylbiphenyl-4-yl)-5-cyano- and 5-(4?-alkylbiphenyl-4-yl)-2-cyano-1-benzofurans, and for compounds with other combinations of terminal alkyl and cyano groups in 2,5-disubstituted-1-benzofurans containing two phenyl units, some isolated examples of related cyclohexane systems are also presented. The mesogenic behaviour of these compounds and several intermediates (e.g. amides, acids and esters) is discussed and the transition temperatures are rationalised on the following basis (a) 1-benzofuran is a superior core unit to benzene, (b) 2,5-disubstitution in 1-benzofuran gives a bent core which adversely affects mesogenicity, to an extent which depends on its position in the core, (c) antiparallel associations in terminal cyano compounds can eliminate the disadvantage of a bent core structure, (d) 2-aryl-1-benzofurans have negligible inter-annular twist but 5-aryl-1-benzofurans have similar inter-annular twist to that in biphenyls.

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A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones via palladium-catalyzed direct C(sp3)-H arylation of indole-3-ones with aryl halides has been developed. Various 2-monoarylated indole-3-ones were readily obtained with yields up to 95%. As a class of important nucleophilic intermediates, 2-monoarylated indole-3-ones can be used for the construction of C2-quaternary indolin-3-one skeletons.

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Enantio- and diastereoselective conjunctive cross-coupling of beta-substituted alkenylboron “ate” complexes is studied. Whereas beta-substitution shifts the chemoselectivity of the catalytic reaction in favor of the Suzuki-Miyaura product, use of a boronic ester ligand derived from acenaphthoquinone allows the process to favor the conjunctive product, even with substituted substrates.

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The low loading combination of the complex [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] (Xantphos)copper(I) iodide and simple ligand-free palladium(II) acetate was found to be efficient for the domino synthesis of diarylalkynes by the reaction of aryl halides with trimethylsilylethynylene or bis(trimethylsilyl)acetylene in a single-step procedure. The unsymmetrical diarylalkynes can be obtained through a one-pot two-step approach. The reactions of aryl bromides with 1,4-bis(trimethylsilyl)butadiyne also furnished the corresponding 1,4-diaryl-1,3-diynes in a similar fashion. This route to diarylalkynes and 1,4-diaryl-1,3-diynes is complementary to previously reported synthetic procedures. (Figure presented.).

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An efficient Ph2PMe-catalyzed dearomative (3 + 2) annulation of 2-nitrobenzofurans, 2-nitrobenzothiophenes, and 3-nitrobenzothiophenes with allenoates has been developed. With the developed protocol, a series of structurally important cyclopenta[b]benzofurans and cyclopenta[b]benzothiophenes were obtained in good to excellent yields (up to 98%) under mild conditions. In addition, preparative-scale experiments and transformations were conducted to exemplify the synthetic utility. The asymmetric version of this dearomative (3 + 2) annulation reaction was tentatively investigated by using chiral phosphine catalysts.

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1,1?-Bi(hetero)aryl 2-sulfonamide scaffolds have been widely used as a privileged structure in drug discovery. Herein, we report an efficient rhodium-catalyzed oxidative C-H/C-H cross-coupling between a (hetero)aromatic sulfonamide and a (hetero)arene to afford ortho-sulfonamido bi(hetero)aryls. This methodology features broad substrate scope, good functional group tolerance, and relatively inexpensive catalyst (without the use of RhCp). A wide range of (hetero)arenes such as thiophenes, benzothiophenes, pyrroles, furans, benzofuran, indolizine, and simple arenes can engage in this transformation. This protocol also provides a facile route to bi(hetero)aryl sultams and dibenzo[b,d]thiophene 5,5-dioxides through further intramolecular cyclization, indicating its potential application in materials exploitation.

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We report an extensive ?heteroarene scan? of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate pi-stacking on the peptide amide bond Gly67?Gly68 at the entrance of the S3 pocket. This heteroarene???peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nm) and benzothiazolyl (Ki=17 nm) ligands was enhanced by intermolecular C?S???O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.

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A transition-metal-free method has been developed for the boryl substitution of functionalized aryl-, heteroaryl- and alkenyl halides with a silylborane in the presence of an alkali-metal alkoxide. The base-mediated boryl substitution of organohalides with a silylborane was recently reported to provide the corresponding borylated products in good to high yields, and exhibit good functional group compatibility and high tolerance to steric hindrance. In this study, the scope of this transformation has been extended significantly to include a wide variety of functionalized aryl-, heteroaryl- and alkenyl halides. In particular, the boryl substitution of (E)- and (Z)-alkenyl halides proceeded smoothly to afford the corresponding alkenyl boronates in good to high yields with retention of the configuration using modified reaction conditions. The results of the mechanistic studies suggest that this boryl substitution proceeds via a carbanion-mediated mechanism.

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A novel method to access 1,1-diarylalkanes from readily available, nonactivated alkyl bromides and aryl bromides via visible-light-driven nickel and iridium dual catalysis, wherein diisopropylamine (iPr2NH) is used as the terminal stoichiometric reductant, is reported. Both primary and secondary alkyl bromides can be successfully transformed into the migratory benzylic arylation products with good selectivity. Additionally, this method showcases tolerance toward a wide array of functional groups and the presence of bases.

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