- Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators
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The G protein-gated inwardly-rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent Kp > 0.6).
- Wieting, Joshua M.,Vadukoot, Anish K.,Sharma, Swagat,Abney, Kristopher K.,Bridges, Thomas M.,Daniels, J. Scott,Morrison, Ryan D.,Wickman, Kevin,Weaver, C. David,Hopkins, Corey R.
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p. 1873 - 1879
(2017/09/25)
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- IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE DERIVATIVES AS KINASE JAK-2 INHIBITORS
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A compound represented by the general formula (I) wherein R1represents H or C1-C4 alkyl; R2 represents phenyl substituted with one or two substituents selected from the group consisting of halogen atom and OCsu
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Page/Page column 14
(2014/02/16)
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- 5 - BENZYLAMINOMETHYL - 6 - AMINOPYRAZOLO [3, 4 -B] PYRIDINE DERIVATIVES AS CHOLESTERYL ESTER -TRANSFER PROTEIN (CETP) INHIBITORS USEFUL FOR THE TREATMENT OF ATHEROSCLEROSIS
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The present application relates to a series of substituted pyra- zolopyridin-6-amines having the general formula (I), including their stereoisomers and/or their pharmaceutically acceptable salts. Wherein R, R1, R2, Ra, Rs
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Page/Page column 21
(2013/04/13)
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- Development and a practical synthesis of the JAK2 inhibitor LY2784544
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The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon-carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert-butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C-C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.
- Mitchell, David,Cole, Kevin P.,Pollock, Patrick M.,Coppert, David M.,Burkholder, Timothy P.,Clayton, Joshua R.
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experimental part
p. 70 - 81
(2012/05/31)
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- Approach to the library of fused pyridine-4-carboxylic acids by combes-type reaction of acyl pyruvates and electron-rich amino heterocycles
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A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.
- Volochnyuk, Dmitriy M.,Ryabukhin, Sergey V.,Plaskon, Andrey S.,Dmytriv, Yuri V.,Grygorenko, Oleksandr O.,Mykhailiuk, Pavel K.,Krotko, Dmitriy G.,Pushechnikov, Alexei,Tolmachev, Andrey A.
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scheme or table
p. 510 - 517
(2010/09/05)
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- Composition for dyeing keratin fibers which contain at least one diaminopyrazole, dyeing process, novel diaminopyrazoles and process for their preparation
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The invention relates to novel compositions for the oxidation dyeing of keratin fibers, comprising at least one specific diaminopyrazole derivative, to the dyeing process using this composition, to novel diaminopyrazole derivatives and to a process for their preparation.
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Page column 21
(2008/06/13)
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- A new procedure for the synthesis of 4H-pyrazolo[1,5-c][1,3,5]thiadiazine-4-thiones
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Thiation of N-(1-tert-butyl-3-methylpyrazol-5-yl)carboxamides 2 with the Lawesson reagent afforded the corresponding thiocarboxamides 3. Heating of 3 in formic acid gave the N-dealkylated thiocarboxamides 4 which were cyclized into 4H-pyrazolo[1,5-c][1,3,
- Vicentini,Veronese,Guarneri,Manfrini,Giori,Guccione
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p. 1477 - 1480
(2007/10/02)
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