- Palladium-Catalyzed Migratory Insertion of Carbenes and C-C Cleavage of Cycloalkanecarboxamides
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A palladium catalyzed reaction of cycloalkanecarboxamides and diazomalonates or bis(phenylsulfonyl)diazomethane has been developed. The reaction proceeds via carbene migratory insertion and cascade C-C cleavage pathways. Cycloalkanecarboxamides with four to seven membered rings are applicable in the transformation. A series of ring opening products were prepared with moderate yields. The finding provides valuable clues for the development of new reactions involving carbene migratory insertion and the cleavage of unstrained C(sp3)-C(sp3) bonds.
- Zhang, Peng,Zeng, Jia,Pan, Ping,Zhang, Xue-Jing,Yan, Ming
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supporting information
p. 536 - 541
(2022/01/20)
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- Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles
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The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or al
- Court, John J.,Poisson, Carl,Ardzinski, Andrzej,Bilimoria, Darius,Chan, Laval,Chandupatla, Kishan,Chauret, Nathalie,Collier, Philip N.,Das, Sanjoy Kumar,Denis, Francois,Dorsch, Warren,Iyer, Ganesh,Lauffer, David,L'Heureux, Lucille,Li, Pan,Luisi, Brian S.,Mani, Nagraj,Nanthakumar, Suganthi,Nicolas, Olivier,Rao, B. Govinda,Ronkin, Steven,Selliah, Subajini,Shawgo, Rebecca S.,Tang, Qing,Waal, Nathan D.,Yannopoulos, Constantin G.,Green, Jeremy
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p. 6293 - 6302
(2016/07/26)
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- γ,δ,ε-C(sp3)-H Functionalization through Directed Radical H-Abstraction
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Aliphatic amides are selectively functionalized at the γ- and δ-positions through directed radical 1,5 and 1,6 H-abstractions, respectively. The initially formed γ- or δ-lactams are intercepted by N-iodosuccinimide and trimethylsilyl azide, leading to double and triple C-H functionalizations at the γ-, δ-, and ε-positions. This new reactivity is exploited to convert alkyls into amino alcohols and allylic amines.
- Liu, Tao,Mei, Tian-Sheng,Yu, Jin-Quan
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supporting information
p. 5871 - 5874
(2015/05/27)
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- Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection
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Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.
- Lazerwith, Scott E.,Lew, Willard,Zhang, Jennifer,Morganelli, Philip,Liu, Qi,Canales, Eda,Clarke, Michael O.,Doerffler, Edward,Byun, Daniel,Mertzman, Michael,Ye, Hong,Chong, Lee,Xu, Lianhong,Appleby, Todd,Chen, Xiaowu,Fenaux, Martijn,Hashash, Ahmad,Leavitt, Stephanie A.,Mabery, Eric,Matles, Mike,Mwangi, Judy W.,Tian, Yang,Lee, Yu-Jen,Zhang, Jingyu,Zhu, Christine,Murray, Bernard P.,Watkins, William J.
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supporting information
p. 1893 - 1901
(2014/04/03)
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- Discovery of dual death-associated protein related apoptosis inducing protein kinase 1 and 2 inhibitors by a scaffold hopping approach
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DRAK2 emerged as a promising drug target for the treatment of autoimmune diseases and to prevent graft rejection after organ transplantation. Screening of a compound library in a DRAK2 binding assay led to the identification of an isothiazolo[5,4-b]pyridine derivative as a novel ligand for DRAK2, displaying a Kdvalue of 1.6 μM. Subsequent medicinal chemistry work led to the discovery of a thieno[2,3-b]pyridine derivative with strong DRAK2 binding affinity (Kd= 9 nM). Moreover, this compound also behaves as a functional inhibitor of DRAK2 enzymatic activity, displaying an IC50value of 0.82 μM, although lacking selectivity, when tested against DRAK1. This paper describes for the first time functionally active dual DRAK1 and DRAK2 inhibitors that can be used as starting point for the synthesis of chemical tool compounds to study DRAK1 and DRAK2 biology, or they can be considered as hit compounds for hit-to-lead optimization campaigns in drug discovery programs.
- Gao, Ling-Jie,Kovackova, Sona,?ála, Michal,Ramadori, Anna Teresa,De Jonghe, Steven,Herdewijn, Piet
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p. 7624 - 7643
(2015/01/08)
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- THIOPHENE COMPOUNDS
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Polymorph Forms M, H, P, X, and ZA of Compound (1) represented by the following structural formula: are described. A method of preparing polymorph Form M of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes isopro
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Paragraph 00125
(2013/03/26)
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- IMIDAZOPYRROLIDINONE COMPOUNDS
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The invention relates to compounds of formula (I): (I) as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.
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Page/Page column 220
(2013/08/15)
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- VIRAL POLYMERASE INHIBITORS
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Compounds of formula I: wherein X, R2, R3, R3a, R3b,R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.
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Page/Page column 53-55
(2009/07/18)
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- Viral Polymerase Inhibitors
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Compounds of formula I: wherein X, R2, R3, R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.
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Page/Page column 26-27
(2008/06/13)
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- VIRAL POLYMERASE INHIBITORS
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Compounds of formula (I): wherein X, R2, R3, R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.
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Page/Page column 70
(2010/11/28)
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- COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS
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Compounds represented by formula (I) : or pharmaceutically acceptable salts and solvates thereof, wherein R1, X, Y, Y1, and Z are as defined herein, are useful for treating flavivi?dae viral infections Said viral infection is Hepatitis C virus (HCV), bovme viral diarrhea virus (BVDV), hog cholera virus, dengue fever virus, Japanese encephalitis virus or yellow fever virus
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Page/Page column 60; 61
(2008/06/13)
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- Improved synthesis of trans-4-alkylcyclohexane carboxylic acids
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Several stereomerically pure amino acid derivatives containing the N-terminal trans-4-alkylcyclohexanoyl fragment were obtained. Hydrogenation of 4-alkylbenzoic acids in the presence of a special Ru-Ni/C catalytic system and isomerization of the resulting mixture of trans- and cis-isomers of 4-alkylcyclohexanecarboxylic acids were used as the key steps. The stereomeric configuration of all compounds was confirmed by 1H NMR spectroscopy. The compounds obtained possess a broad biological activity potential and are useful intermediates in the synthesis of stereomerically pure modified peptides.
- Bazurin, Alexey A.,Krasnikov, Sergey V.,Obuchova, Tatiana A.,Danilova, Angelina S.,Balakin, Konstantin V.
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p. 6669 - 6672
(2007/10/03)
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- THERAPEUTIC AGENT FOR DIABETES
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A therapeutic agent for diabetes, which comprises a compound of the formula [I] wherein Xis a group of the formula wherein R4and R5are the same or different and each is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, and R6is a hydrogen atom or an amino-protecting group; R1is an optionally substituted alkyl having 1 to 5 carbon atoms, an optionally substituted alkenyl having 2 to 6 carbon atoms and the like, R2is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, R2' is a hydrogen atom, and R3is an optionally substituted alkyl having 1 to 5 carbon atoms and the like, a prodrug thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof. The compound of the present invention shows superior blood sugar decreasing action on the state of hyperglycemia, but does not affect the blood sugar when it is in the normal range or in the hypoglycemic state, which means that it is free of serious side effects such as hypoglycemia. Therefore, the compound of the present invention is useful as a therapeutic drug for diabetes and also useful as a preventive of the chronic complications of diabetes.
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- 1-(TRANS-4 prime -N-ALKYLCYCLOHEXYL)-2-(4 double prime -CYANOPHENYL)ETHANES - A NEW SERIES OF STABLE NEMATOGENS OF POSITIVE DIELECTRIC ANISOTROPY.
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The synthesis and some important properties of the 1-(trans-4 prime -n-alkylcyclohexyl)-2-(4 double prime -cyanophenyl)ethanes - where n-alkyl equals C//1 to C//7 - are described.
- Carr,Gray,McDonnell
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- The Synthesis and Liquid Crystal Properties of Some Laterally Fluorinated trans-Cyclohexane-1-carboxylate and Benzoate Esters
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A large number of laterally fluorinated 4-n-alkyl- and -alkoxy-phenyl 4'-n-alkyl- and -alkoxy-bezoates and 4-n-alkylphenyl trans-4'-n-alkyl- and -alkoxy-cyclohexane-1-carboxylates were synthesised.In these compounds, the lateral fluoro-substituent was situated in either the phenol or the carboxylic acid moiety of the molecules for the benzoate esters, but only in the phenol moiety for the trans-cyclohexane-1-carboxylate esters.The nematic thermal stabilities for the fluorophenyl bezoate and trans-cyclohexane-1-carboxylate esters and the fluorobenzoate esters were compared with those for the corresponding non-fluorinated analogues.A nematic thermal efficiency order was derived for the 4-n-alkyl-fluorophenyl 4-n-alkylbezoate and trans-4-n-alkylcyclohexane-1-carboxylate esters, but only in the case of the latter esters, which were extensively examined, was the smectic tendency of the system investigated.Explanations are given for the observed nematic and smectic thermal stabilities of the titled esters, and some of their physical properties are discussed.
- Gray, G. W.,Hogg, C.,Lacey, D.
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