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Analogues of dibenzodiazepines, in which the seven-membered nitrogen heterocycle is replaced by a 9?12-membered ring, were made by an unactivated Smiles rearrangement of five- to eight-membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron-withdrawing activating groups, and provides a method for n?n+4 ring expansion. The medium-ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.

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Wnt proteins are secreted morphogens that play critical roles in embryonic development and tissue remodeling in adult organisms. Aberrant Wnt signaling contributes to diseases such as cancer. Wnts are modified by an unusual O-fatty acylation event (O-linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. O-Palmitoleoylation of Wnts is introduced by the porcupine (PORCN) acyltransferase and removed by the serine hydrolase NOTUM. PORCN inhibitors are under development for oncology, while NOTUM inhibitors have potential for treating degenerative diseases. Here, we describe the use of activity-based protein profiling (ABPP) to discover and advance a class of N-hydroxyhydantoin (NHH) carbamates that potently and selectively inhibit NOTUM. An optimized NHH carbamate inhibitor, ABC99, preserves Wnt-mediated cell signaling in the presence of NOTUM and was also converted into an ABPP probe for visualizing NOTUM in native biological systems.

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The synthesis of dihydrobenzo[1,4]oxazines has been accomplished efficiently by copper catalyzed intramolecular cyclization of the adducts formed by the treatment of 1,2-cyclic sulfamidates with 2-halo phenols. The products (except two) are new and their yields are high. The catalyst is easily available and less expensive.

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Starting from 11beta-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11beta-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

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New Advances in Chemical Research, May 2021. Catalysts allow a reaction to proceed via a pathway that has a lower activation energy than the uncatalyzed reaction.Application of 887590-25-2, In a article, mentioned the application of 887590-25-2, Name is tert-Butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate, molecular formula is C13H18N2O2

The present invention is related to a compound of formula (I): wherein i, j, n, o, p, q, r, R1a, R1b, R1c, R1d, R2a, R2b, R2c, R2d, R3a, R3b and R4 are as defined herein, or an addition salt with an acid thereof, or a hydrate or solvate thereof, its preparation, pharmaceutical composition, and uses for treating a disease in which the enzyme 11beta-HSD1 is involved.

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The invention relates to compounds of formula (I), where: A is a bond, an oxygen atom, or an -CH2? group; Ar1 is a phenyl or heteroaryl group; Ar2 is a phenyl, heteroaryl, or heterocycloalkyl group; R1a,b,c and R2a,b,c are a hydrogen or halogen atom, or an alkyl, cycloalkyl, or lkyl-cycloalkyl group optionally substituted by one or more halogen atoms, or an ?OR5 (hydroxy or alkoxy), hydroxy-alkyl, alkoxy-alkyl, alkoxy-alkoxy, halogenoalkyl, ?O-halogenoalkyl, oxo, ?CO-alkyl, ?CO-alkyl-NR6R7, ?CO-halogenoalkyl, ?COOR5, alkyl-COOR5, ?O-alkyl-COOR5, ?SO2-alkyl, ?SO2-cycloalkyl, ?SO2-alkyl-cycloalkyl, ?SO2-alkyl-OR5, ?SO2-alkyl-COOR5, ?SO2-alkyl-NR6R7, ?SO2-halogenoalkyl, alkyl-SO2-alkyl, ?SO2?NR6R7, ?SO2-alkyl-O-alkyl-OR5, ?CONR6R7, -alkyl-CONR6R7, or -alkyl-NR6R7 group, or further R1a, R1b, and R1c are bonded to R2a, R2b, R2c, respectively, as well as to the carbon atom having same, and are -alkyl-O?; R3 is a hydrogen atom or an alkyl group; R4 is a ONR6R7 group, a hydroxyalkyl group substituted by a halogenoalkyl group, or an lkyl-NH?SO2-alkyl, NH?SO2-alkyl, ?O?SO2?NR6R7, -alkyl-CO?NR6R7, ?O-alkyl-CO?NR6R7, -alkyl-NR6R7, ?O?CO?NR6R7, -alkyl-heteroaryl, a heteroaryl group optionally substituted by an alkyl, alkoxy-imino, or ?NH?NH?CO-alkyl group, with the proviso that R4 is in the cis position when it is the ONR6R7 group and that R6 and R7 are each hydrogen, or an lkyl or lkyl-phenyl group; R5 is hydrogen, an lkyl group, or lkyl-phenyl; R6 and R7, identical or different, are each a hydrogen atom, an alkyl group, alkoxy, or an alkyl-phenyl group; and R8 is a hydrogen atom or an O2-alkyl group, or a group of formula -Het, where B can be absent or be a bond, an oxygen atom, or a O? or O2?(CH2)n group, with n being equal to 0, 1, or 2, and where Het is a heteroaryl or heterocycloaryl optionally substituted by the alkyl, ?SO2-alkyl, and ?COOR5 groups. The invention also relates to a method for preparing same to the therapeutic use thereof.

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The present invention relates to tetrahydroquinoxaline urea derivatives, to their preparation and to their therapeutic application.

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Compounds of Formula la or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof are provided, which are useful for the treatment of hyperproliferative diseases in the view of their ability to inhibit SHP2. Methods of using compounds of Formula I or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

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The present invention provides compounds having excellent 11-HSD1 inhibitory activity. A compound represented by the following formula (I): [wherein X 1 represents an oxygen atom, or the formula -(CR 11 R 12 ) p -, etc., Y 1 represents a hydrogen atom, a hydroxyl group, etc., Z 1 represents an oxygen atom or the formula -(NR 14 )-, R 1 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-4 alkyl group, a C 1-4 alkyl group substituted with 1 to 3 halogen atoms, a C 1-4 alkoxy group, a C 1-4 alkoxycarbonyl group, a carboxyl group, a carbamoyl group, or an amino group, and m represents an integer of 1 or 2, and R 2 represents a hydrogen atom or a C 1-4 alkyl group, and n represents an integer of 1 or 2]

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Disclosed are substituted aromatic N-heterocyclic compounds. The disclosed compounds typically exhibit kinase inhibition activity, for example, and inhibit Mnk1 kinase and/or Mnk2 kinase. The disclosed compounds may be used in pharmaceutical compositions and methods for treating diseases or disorders associated with Mnk1 kinase activity and/or Mnk2 kinase activity, such as cancers, diabetes, autism, and fragile X syndrome.

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