- Polycyclic amide derivative as CDK9 inhibitor, and preparation method and application thereof
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The invention belongs to the technical field of polycyclic amide derivatives, and particularly relates to a polycyclic amide derivative as a CDK9 inhibitor, and a preparation method and application thereof. The polycyclic amide derivative shows excellent CDK9 enzyme inhibitory activity, and can be used for preparing drugs for treating cancers, especially hematologic cancers including acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, follicular lymphoma and the like and solid tumors, such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia and follicular lymphoma, including breast cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, kidney cancer, stomach cancer, colorectal cancer, lung cancer and the like.
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- DIHYDROPYRIMIDINE DERIVATIVES AND USES THEREOF IN THE TREATMENT OF HBV INFECTION OR OF HBV-INDUCED DISEASES
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Provided herein are dihydropyrimidine derivatives which are useful in the treatment of HBV infection or HBV-induced diseases, as well as pharmaceutical or medical applications thereof.
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Page/Page column 66
(2019/11/28)
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- A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
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Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance - and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.
- Tran, Kim T.,Pallesen, Jakob S.,Solbak, Sara M.,Narayanan, Dilip,Baig, Amina,Zang, Jie,Aguayo-Orozco, Alejandro,Carmona, Rosa M. C.,Garcia, Anthony D.,Bach, Anders
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p. 8028 - 8052
(2019/10/11)
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- Identification and Implementation of Biocatalytic Transformations in Route Discovery: Synthesis of Chiral 1,3-Substituted Cyclohexanone Building Blocks
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Several biocatalytic approaches for the preparation of optically pure methyl 3-oxocyclohexanecarboxylates (S)-, (R)-1 and 3-oxocyclohexanecarbonitriles (S)-, (R)-2 have been successfully demonstrated. Screening of reaction-focused enzyme collections was used to identify initial hits using three enzymatic strategies. Reaction optimization and scale-up enabled the production of chiral intermediates for route scouting efforts on scales of up to 100 g. The enzymes applied in these processes (lipases, enoate reductases, and nitrilases) have been shown to be robust catalysts for drug manufacturing and represent a green alternative to conventional methods to access these chiral cyclohexanone building blocks.
- Hadi, Timin,D?az-Rodr?guez, Alba,Khan, Diluar,Morrison, James P.,Kaplan, Justin M.,Gallagher, Kathleen T.,Schober, Markus,Webb, Michael R.,Brown, Kristin K.,Fuerst, Douglas,Snajdrova, Radka,Roiban, Gheorghe-Doru
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p. 871 - 879
(2018/07/05)
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- IRAK INHIBITORS AND USES THEREOF
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The present invention provides arylo-fused thienopyrimidine compounds, compositions thereof, and methods of using the same.
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Paragraph 00282-00283
(2014/02/15)
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- FLT3 INHIBITORS AND USES THEREOF
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The present invention provides methods of using compounds of formula I: or compositions thereof for the inhibition of FLT3, and the treatment of FLT3-mediated disorders.
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Paragraph 00353; 00355
(2014/12/12)
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- A catalytic enantioselective conjugate addition of cyanide to enones
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The first synthetically useful catalytic enantioselective conjugate addition of cyanide to enones is described. The optimized conditions involved a Gd catalyst (5 or 10 mol %) derived from ligands 3 or 4 and a 1:1 ratio of TBSCN and 2,6-dimethylphenol. Th
- Tanaka, Yuta,Kanai, Motomu,Shibasaki, Masakatsu
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p. 6072 - 6073
(2008/12/20)
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- Formaldehyde dialkylhydrazones as neutral formyl anion and cyanide equivalents: Nucleophilic addition to conjugated enones
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A versatile methodology for the nucleophihc formylation and cyanation of conjugated enones is reported. The procedure is based on the use of formaldehyde dimethylhydrazone, which, acting as a neutral formyl anion equivalent, adds to preformed trialkylsilyl-enone complexes. Both 4-(silyl- oxy)-3-enal hydrazones 3 or deprotected 4-oxo aldehyde monohydrazones 4 can be obtained at products depending on quenching conditions. In full analogy, an asymmetric version of the reaction using chiral formaldehyde SAMP- hydrazone as a neutral synthon of the chiral formyl anion has been developed, giving rise to the corresponding adducts 5 and 6 in good yields and with excellent diastereoselectivities (de 85-≤98%). Ozonolysis or HCl-mediated hydrolysis of adducts 4 and 6 readily affords racemic and optically enriched 4-oxo aldehydes 7, respectively. Additionally, high-yielding MMPP-oxidative cleavage of 4-oxo hydrazones 4 and 6 has been performed to obtain 4-oxo nitriles 8 in racemic and optically enriched forms, respectively. In this way, interesting chiral bifunctional building blocks, some of them bearing newly created stereogenic quaternary centers, have been efficiently synthesized.
- Diez,Fernandez,Gasch,Lassaletta,Llera,Martin-Zamora,Vazquez
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p. 5144 - 5155
(2007/10/03)
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- 2,3-Donor-Acceptor-Substituted 1,3-Butadienes. Synthesis by SO2-Extrusion from 3-Sulfolenes and Diels-Alder Reactions
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The thermal extrusion of SO2 from disubstituted 3-sulfolenes 3 leads to 2,3-donor-acceptor-substituted 1,3-butadienes 4.These dienes react with acrylic acid ester and ethyl vinyl ether to the corresponding Diels-Alder adducts 5 and 6 and with themseleves
- Hoffmann, Ralf,Mattay, Jochen,Banning, Anja,Rodewald, Ute,Moeller, Manfred M.
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p. 343 - 349
(2007/10/02)
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- Synthesis and resolution of DHCGA, a new conformationally rigid 3,4-dehydroglutamic acid analogue
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(±)-1-amino-2-cyclohexene-1,3-dicarboxylic acid (DHCGA),an unsaturated cyclic analogue of glutamic acid, was prepared from 3-carboxy-4-cyclohexenone by a Bucherer-Bergs reaction. Resolution was performed through coupling with L-leucine and separation of the resulting diastereoisomeric dipeptides. Spectral data, including optical rotation and circular dichroism of both enantiomers of DHCGA are reported.
- Trigalo, Francois,Acher, Francine,Azerad, Robert
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p. 5203 - 5212
(2007/10/02)
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- Electrocarboxylation de composes carbonyles aliphatiques, aromatiques et vinyliques: interet de l'utilisation d'une anode consommable en magnesium
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In the presence of carbon dioxide in DMF, the electroreduction of carbonyl compounds or α,β-ketoalkenes at high concentration yields respectively α-hydroxyacids and β-ketoacids.The use of a sacrificial magnesium anode allows constant current electrolyses in a diaphragmless cell.
- Mcharek, Slah,Heintz, Monique,Troupel, Michel,Perichon, Jacques
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- SPECIFITY OF E. COLI SHIKIMATE DEHYDROGENASE TOWARDS ANALOGUES OF 3-DEHYDROSHIKIMIC ACID
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Analogues of 3-dehydroshikimic acid which lack the C-4 and C-5 hydroxyl groups have been synthesised and assayed as substrates for shikimate dehydrogenase.The presence of the C-4 hydroxyl group is found to be very important for specificity, whereas the C-5 hydroxyl group is not.The enzyme exhibits enantioselectivity at C-1 and C-4 of the racemic substrate analogues.
- Bugg, Timothy D. H.,Abell, Chris,Coggins, John R.
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p. 6779 - 6782
(2007/10/02)
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- ELECTROCHEMICAL CARBOXYLATION OF alpha , beta -UNSATURATED KETONES WITH CARBON DIOXIDE.
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Several aromatic and aliphatic alpha , beta -unsaturated ketones were converted to the corresponding gamma -keto acids by the electrochemical reduction in acetonitrile in the presence of CO//2. The yields of the keto acid were 73-82% when the enones have at least one aromatic substituent. In the case of aliphatic enones, the yields of the carboxylation reaction were 67% for 2-cyclohexen-1-one and 44% for 3-buten-2-one.
- Harada,Sakakibara,Kunai,Sasaki
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p. 611 - 612
(2007/10/02)
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- Reactions of Cyanide Ions with α,β-Unsaturated Esters, IV. - Reactions to Carbocycles
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Sodium cyanide reacts with diethyl 2-methylenealkanedioates 1a-c and 8a-h to give simple or alkylated ethyl 2-cyano-3-oxo-1-cycloalkanecarboxylates 5a-c and 9a-h, respectively.From these the 3-oxo-1-cycloalkanecarboxylic acids 6a-c and 10a-h, respectively
- Stetter, Hermann,Marten, Klaus
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p. 240 - 249
(2007/10/02)
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