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To a stirred solution compound 40 (3 g, 23.25 mmol) in CH2Cl2 (60 mL) under inert atmosphere were added EDCI.HCl (4.9 g, 25.58 mmol), DMAP (2.8 g, 23.25 mmol), N- methylmorpholine (7.65 mL, 69.76 mmol) and N, O-dimethylhydroxylamine hydrochloride (2.72 g, 27.90 mmol) at 0 oC, followed by warming to room temperature and stirring for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with CH2Cl2. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 40-45% EtOAc/ hexanes to afford compound 41 (2.5 g, 63%) as brown syrup. TLC: 40% EtOAc/ hexanes (Rf: 0.5); 1H NMR (400 MHz, DMSO-d6): delta 9.15 (d, J = 4.8 Hz, 1H), 7.63 (d, J = 4.4 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H); LCMS Calculated for C6H7NOS: 141.02; Observed: 142.0 (M+1)+.LC-MS: 98.67%; 172.9 (M+1)+.

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Reference£º
Patent; ASSEMBLY BIOSCIENCES, INC.; TURNER, William, W., Jr.; LI, Leping; HAYDAR, Simon, Nicolas; BURES, Mark, G.; RAI, Roopa; FRANCIS, Samson; ARNOLD, Lee, Daniel; (0 pag.)WO2018/160878; (2018); A1;,
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To a stirred suspension of isothiazole-3-carboxylic acid (10.02 g, 77.6 mmol) in anhydrous te/f-butanol (80 ml_) and anhydrous toluene (120 ml_) was slowly added triethylamine (13.0 ml_, 93.12 mmol). The mixture was stirred at ambient temperature for 5 minutes and then diphenyl phosphoryl azide (18.42 ml_, 85.36 mmol) was added dropwise to it. The reaction mixture was stirred at ambient temperature for 1 h, gradually warmed to 85 C over 1 h, and then heated at 85 C with stirring for 7 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (150 ml_) and saturated aqueous sodium bicarbonate (150 ml_). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 c 100 ml_). The combined organic layers were washed with water (150 ml_), brine (150 ml_), dried over magnesium sulfate, and filtered. Concentration of the filtrate in vacuo provided a residue, which was purified by column chromatography, eluting with a gradient of 0 to 10% of ethyl acetate in heptane. Further purification by column chromatography, eluting with a gradient of 0 to 10% of ethyl acetate in dichloromethane, afforded the title compound as a colorless solid (10.33 g, 66% yield): 1H NMR (400 MHz, CDCI3) d 8.56 (dd, J = 4.9, 0.6 Hz, 1 H), 8.11 (s, 1 H), 7.66 (d, J = 4.9 Hz, 1 H), 1.53 (s, 9H); MS (ES+) m/z 201.1 (M + 1).

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Reference£º
Patent; XENON PHARMACEUTICALS INC.; FOCKEN, Thilo; BURFORD, Kristen Nicole; LOFSTRAND, Verner Alexander; WILSON, Michael Scott; ZENOVA, Alla Yurevna; (121 pag.)WO2019/241533; (2019); A1;,
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CYCLIC SULFAMIDE COMPOUNDS AND METHODS OF USING SAME

The present disclosure provides, in part, cyclic sulfamide compounds, and pharmaceutical compositions thereof, useful as modulators of Hepatitis B (HBV) core protein, and methods of treating Hepatitis B (HBV) infection.

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HETEROARYL-SUBSTITUTED SULFONAMIDE COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS

This invention is directed to pyridine- and thiophene-sulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy and/ or epileptic seizure disorders.

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3-Aryl-5-isothiazolecarboxylic acids and related compounds used to lower uric acid levels

3-Phenyl (or meta or para-substituted phenyl)-4-permissibly substituted-5-isothiazolecarboxylic acids, salts, esters and simple amides, used to lower uric acid levels in mammals.

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Herbicidal benzoylisothiazoles

4-Benzoylisothiazoles of the formula 1 STR1 wherein x is oxygen or sulfur; R1 is hydrogen, alkyl, alkenyl, alkynyl; or is optionally substituted alkoxycarbonyl, aryl, heterocyclyl or hetaryl; R2 is hydrogen, halogen, cyano, nitro, alkylsulfonyl or alkoxycarbonyl; or is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylthio, alkylamino, arylamino, hetaryl or heterocyclyl; R3 is optionally substituted alkyl, cycloalkyl or aryl, or their salts, their manufacture and herbicidal compositions containing them.

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Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson’s disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.

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BENZENESULFONAMIDE COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS

This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels (Na v 1.6), such as epilepsy and/or epileptic seizure disorders.

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HALOGEN-SUBSTITUTED HETEROCYCLIC COMPOUND

A novel alpha-halogen-substituted thiophene compound or a pharmacologically acceptable salt thereof, which has a potent LPA receptor-antagonist activity and is useful as a medicament is provided. A compound represented by the general formula (I) wherein A represents, a phenyl ring, a thiophene ring, or an isothiazole ring; R1 is the same or different, and represents a halogen atom, or a C1-C3 alkyl group; R2 represents a hydrogen atom, or a C1-C6 alkyl group; p represents an integer of 0 to 5; V represents CR3 wherein R3 represents a hydrogen atom, an amino group, a nitro group, or a C1-C3 alkoxy group, or V represents a nitrogen atom; and X represents a halogen atom, or a salt thereof.

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PYRAZOLE DERIVATIVES AS SGC STIMULATORS

There are described imidazole and pyrazole derivatives which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

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