10199-69-6Relevant articles and documents
Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen
Adeniji-Popoola, Olajumoke,Aherne, Wynne,Blagg, Julian,Box, Gary,Clarke, Paul A.,Court, William,Crumpler, Simon,Dale, Trevor,De Haven Brandon, Alexis,Eccles, Suzanne A.,Esdar, Christina,Georgi, Katrin,Henley, Alan T.,Hobbs, Steve,Leuthner, Birgitta,Mallinger, Aurlie,Ortiz-Ruiz, Maria-Jesus,Pichowicz, Mark,Poeschke, Oliver,Raynaud, Florence,Rohdich, Felix,Schiemann, Kai,Smith, Elizabeth,Stieber, Frank,Stubbs, Mark,Tepoele, Robert,Thai, Ching,Valenti, Melanie,Waalboer, Dennis,Wienke, Dirk,Wood, Bozena,Workman, Paul
, p. 1717 - 1735 (2015)
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
Organocatalytic synthesis of (Het)biaryl scaffoldsviaphotoinduced intra/intermolecular C(sp2)-H arylation by 2-pyridone derivatives
Das, Tapas Kumar,Kundu, Mrinalkanti,Mondal, Biswajit,Ghosh, Prasanjit,Das, Sajal
, p. 208 - 218 (2021/12/29)
A uniqueN,O-bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp2)-H (intra/intermolecular) arylation of unactivated arenes has been developed to expedite access to (Het)biaryl scaffolds under UV-irradiation at room temperature. The protocol tolerated diverse functional groups and substitution patterns, affording the target products in moderate to excellent yields. Mechanistic investigations were also carried out to better understand the reaction pathway. Furthermore, the synthetic applicability of this unified approach has been showcasedviathe construction of biologically relevant 4-quinolone, tricyclic lactam and sultam derivatives.
Five-membered heteroaromatic ring derivative as well as preparation method and application thereof
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Paragraph 0144-0147, (2021/09/26)
The invention discloses a five-membered heteroaromatic ring derivative and a preparation method and application thereof, and the compound has obvious inhibition on DHODH. The blocking effect can be used as DHODH specific inhibitor, can be used for preparing medicines for treating diseases caused by fungal infection, can be used for preparing agricultural fungicides, and has wide application prospects.
Regioselective Synthesis of C3-Hydroxyarylated Pyrazoles
Brownsey, Duncan K.,Derksen, Darren J.,Gelfand, Benjamin S.,Gorobets, Evgueni,O'Sullivan, Leonie,Patel, Ketul V.,Rowley, Ben C.,Van Humbeck, Jeffrey F.
supporting information, (2021/12/27)
Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not requir
Visible-Light-Induced [4+2] Annulation of Thiophenes and Alkynes to Construct Benzene Rings
Song, Chunlan,Dong, Xin,Wang, Zhongjie,Liu, Kun,Chiang, Chien-Wei,Lei, Aiwen
supporting information, p. 12206 - 12210 (2019/07/31)
The [4+2] annulation represents an elegant and versatile synthetic protocol for the construction of benzene rings. Herein, a strategy for visible-light induced [4+2] annulation of thiophenes and alkynes, to afford benzene rings, is presented. Under simple and mild reaction conditions, the ready availability and structural diversity of thiophenes and alkynes permit the facile synthesis of several substituted aromatic rings. Valuable drugs and amino acids are also well tolerated. Moreover, DFT calculations explain the high regioselectivity of the reaction.
Decarboxylative Suzuki-Miyaura coupling of (hetero)aromatic carboxylic acids using iodine as the terminal oxidant
Quibell, Jacob M.,Duan, Guojian,Perry, Gregory J.P.,Larrosa, Igor
supporting information, p. 6445 - 6448 (2019/06/07)
A novel methodology for the decarboxylative Suzuki-Miyaura-type coupling has been established. This process uses iodine or a bromine source as both the decarboxylation mediator and the terminal oxidant, thus avoiding the need for stoichiometric amounts of transition metal salts previously required. Our new protocol allows for the construction of valuable biaryl architectures through the coupling of (hetero)aromatic carboxylic acids with arylboronic acids. The scope of this decarboxylative Suzuki reaction has been greatly diversified, allowing for previously inaccessible non-ortho-substituted aromatic acids to undergo this transformation. The procedure also benefits from low catalyst loadings and the absence of stoichiometric transition metal additives.
Efficient synthesis of 4-substituted pyrazole via microwave-promoted Suzuki cross-coupling reaction
Cheng, Hua,Wu, Qiong-You,Han, Fan,Yang, Guang-Fu
, p. 705 - 709 (2014/06/09)
Pyrazoles and their derivatives are important heterocycles found in nature and present in numerous bioactive compounds. In contrast to 3 or 5-aryl pyrazole, the preparation of 4-aryl pyrazole is fairly rare. Utilizing microwave irradiation, the synthesis of 4-substituted-arylpyrazole via Suzuki cross-coupling has been developed with a wide range of substrates. The remarkable advantages of this method are mild reaction conditions, simple operation, high yield, and short reaction time. Product structures were identified by MS, 1H NMR, 13C NMR, and elemental analysis.
Enhanced heterogeneously catalyzed Suzuki-Miyaura reaction over SiliaCat Pd(0)
Pandarus, Valerica,Desplantier-Giscard, Delphine,Gingras, Genevieve,Ciriminna, Rosaria,Demma Carà, Piera,Béland, Fran?ois,Pagliaro, Mario
, p. 4712 - 4716 (2013/08/23)
The SiliaCat Pd(0) solid catalyst can be efficiently employed in the Suzuki-Miyaura cross-coupling of an ample variety of haloarenes, including economically viable chloroarenes. The catalyst can be extensively recycled without loss of activity and with low leaching of valued palladium, opening the route to widespread utilization of the method to afford high yields of biaryls devoid of contaminating by-products.
Selective methylation of NH-containing heterocycles and sulfonamides using n, N -dimethylformamide dimethylacetal based on calculated pKa Measurements
Fairley, Gary,Hall, Catherine,Greenwood, Ryan
, p. 570 - 574 (2013/04/10)
The use of N,N-dimethylformamide dimethylacetal (DMF-DMA) as a suitable methylating agent for the methylation of NH-containing groups and heterocycles has been investigated. Use of ReactArray and calculated pKa measurements have allowed additional helpful information to be collated to determine optimum reaction conditions for a variety of substrates.
A general method for Suzuki-Miyaura coupling reactions using lithium triisopropyl borates
Oberli, Matthias A.,Buchwald, Stephen L.
supporting information, p. 4606 - 4609 (2012/10/30)
Conditions for the Suzuki-Miyaura coupling of lithium triisopropyl borates are reported, as well as a procedure for a one-pot lithiation, borylation, and subsequent Suzuki-Miyaura coupling of various heterocycles with aryl halides. These borate species are much more stable toward protodeboronation than the corresponding boronic acids and can conveniently be stored on benchtop at room temperature.
