- Heterocyclic compound and preparation and application thereof
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The invention relates to bromodomain inhibitors, and provides a compound represented by a general formula I, a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method thereof, a pharmaceutical composition containing the same, and applicationthereof in pharmacy.
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Paragraph 0288-0290; 0412-0414; 0421-0423; 0430-0432; 0439
(2020/07/24)
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- A Next-Generation Air-Stable Palladium(I) Dimer Enables Olefin Migration and Selective C?C Coupling in Air
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We report a new air-stable PdI dimer, [Pd(μ-I)(PCy2tBu)]2, which triggers E-selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C?C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion of aromatic C?Br, C?OTf/OFs, and C?Cl bonds in poly(pseudo)halogenated arenes, displaying superior activity over previous PdI dimer generations for substrates that bear substituents ortho to C?OTf.
- Kundu, Gourab,Rissanen, Kari,Schoenebeck, Franziska,Sperger, Theresa
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supporting information
p. 21930 - 21934
(2020/10/02)
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- Palladium-Catalyzed Electrochemical C-H Bromination Using NH4Br as the Brominating Reagent
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The palladium-catalyzed electrochemical C-H bromination of benzamide derivatives under divided cells is developed, in which NH4Br serves as a brominating reagent and electrolyte. The protocol avoids the use of chemical oxidants and provides an alternative method for the synthesis of aryl bromides.
- Yang, Qi-Liang,Wang, Xiang-Yang,Wang, Tong-Lin,Yang, Xiang,Liu, Dong,Tong, Xiaofeng,Wu, Xin-Yan,Mei, Tian-Sheng
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supporting information
p. 2645 - 2649
(2019/04/17)
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- Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)
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Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and noncatalyt
- Chessum, Nicola E. A.,Sharp, Swee Y.,Caldwell, John J.,Pasqua, A. Elisa,Wilding, Birgit,Colombano, Giampiero,Collins, Ian,Ozer, Bugra,Richards, Meirion,Rowlands, Martin,Stubbs, Mark,Burke, Rosemary,McAndrew, P. Craig,Clarke, Paul A.,Workman, Paul,Cheeseman, Matthew D.,Jones, Keith
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supporting information
p. 918 - 933
(2018/02/17)
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- Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen
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Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.
- Cheeseman, Matthew D.,Chessum, Nicola E. A.,Rye, Carl S.,Pasqua, A. Elisa,Tucker, Michael J.,Wilding, Birgit,Evans, Lindsay E.,Lepri, Susan,Richards, Meirion,Sharp, Swee Y.,Ali, Salyha,Rowlands, Martin,O’Fee, Lisa,Miah, Asadh,Hayes, Angela,Henley, Alan T.,Powers, Marissa,Te Poele, Robert,De Billy, Emmanuel,Pellegrino, Loredana,Raynaud, Florence,Burke, Rosemary,Van Montfort, Rob L. M.,Eccles, Suzanne A.,Workman, Paul,Jones, Keith
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p. 180 - 201
(2017/04/26)
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- Cobalt-Catalyzed C(sp2)?H Methylation by using Dicumyl Peroxide as both the Methylating Reagent and Hydrogen Acceptor
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The first cobalt-catalyzed direct methylation of a C(sp2)?H bond using dicumyl peroxide (DCP) as both the methylating reagent and hydrogen acceptor has been established. The reaction proceeded without the use of any additives, and was proven to be applicable to various amides bearing a 2-pyridinylisopropyl (PIP) directing group, providing an efficient access to o-methyl aryl amides with high functional-group tolerance. Preliminary mechanistic studies suggest a radical process would be involved in the catalytic process.
- Li, Qun,Li, Yanrong,Hu, Weipeng,Hu, Renjian,Li, Guigen,Lu, Hongjian
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supporting information
p. 12286 - 12289
(2016/08/24)
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- Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity
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A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC 50 value of 3.11 μM and Hela with IC50 value of 2.54 μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50 = 0.45 μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.
- Duan, Yong-Tao,Yao, Yong-Fang,Huang, Wei,Makawana, Jigar A.,Teraiya, Shashikant B.,Thumar, Nilesh J.,Tang, Dan-Jie,Tao, Xiang-Xiang,Wang, Zhong-Chang,Jiang, Ai-Qin,Zhu, Hai-Liang
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p. 2947 - 2954
(2014/05/20)
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- Discovery of agonists of cannabinoid receptor 1 with restricted central nervous system penetration aimed for treatment of gastroesophageal reflux disease
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Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.
- Plowright, Alleyn T.,Nilsson, Karolina,Antonsson, Madeleine,Amin, Kosrat,Broddefalk, Johan,Jensen, J?rgen,Lehmann, Anders,Jin, Shujuan,St-Onge, Stephane,Tomaszewski, Miros?aw J.,Tremblay, Maxime,Walpole, Christopher,Wei, Zhongyong,Yang, Hua,Ulander, Johan
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p. 220 - 240
(2013/02/25)
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- Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors
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It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.
- Li, Dong-Dong,Fang, Fei,Li, Jing-Ran,Du, Qian-Ru,Sun, Jian,Gong, Hai-Bin,Zhu, Hai-Liang
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supporting information
p. 5870 - 5875
(2012/11/13)
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- Synthesis, crystal structures, insecticidal activities, and structure-activity relationships of novel N ′- Tert -Butyl- N ′-substituted-benzoyl- N -[di(octa)hydro]benzofuran{(2,3-dihydro)benzo[1, 3]([1,4])dioxine}carbohydrazide derivatives
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Several series of novel N′-tert-butyl-N′-substituted-benzoyl-N- [di(octa)hydro]benzofuran{(2,3-dihydro)benzo[1,3]([1,4])dioxine}carbohydrazide derivatives Ia, Ib, IIa-IIg, IIIa, IIIb, and Va-Vc were designed and synthesized. Their structures were confirmed by 1H NMR spectra, HRMS, and X-ray single-crystal structures. The larvicidal activities against oriental armyworm, beet armyworm, diamond-back moth, and corn borer of these compounds were evaluated and contrasted with those of RH-2485, JS-118, and ANS-118. The larvicidal activities against oriental armyworm indicate that monosubstituent or multisubstituents and the substituting group position cannot promote increasing activities and that the cycle region in the general structure of IIa-IIg is much more sensitive to activity than that in the general structure of Ia and Ib. The space volume of the A ring in the structure of Va cannot be too large; if it is, the activity will be decreased significantly. Stomach toxicities against beet armyworm, diamond-back moth, and corn borer of compounds Ia, Ib and IIg indicate that benzoheterocyclic analogues of N-tert-butyl-N,N′- diacylhydrazines show significant selectivities to different lepidopterous pests.
- Huang, Zhiqiang,Liu, Yuxiu,Li, Yongqiang,Xiong, Lixia,Cui, Zhipeng,Song, Hongjian,Liu, Hongli,Zhao, Qiqi,Wang, Qingmin
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experimental part
p. 635 - 644
(2011/10/02)
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- N-PHENYL HYDRAZIDES AS MODULATORS OF THE GHRELIN RECEPTOR
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The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: each R1 is independently selected from the group consisting of Cl, Br, CH3 and CF3; X is carbon or nitrogen; R1a is H or a straight C1-3 alkyl group; R2a is H or a methyl group R2 is selected from the group consisting of C1-3alkyl, H and -(CH2)n-, wherein n is 3 or 4 and the terminal carbon of the chain is bonded to the carbon atom adjacent to the nitrogen bearing the R2 group, such that a fused 6,5 or 6,6-bicyclic ring is formed. Y is selected from the group consisting of: phenyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of C1-3alkyl, C1-3alkoxy, halogen, C1-3alkyl substituted by 1 to 7 fluoro atoms and C1-3alkoxy substituted by 1 to 7 fluoro atoms; pyridyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of C1-3alkyl, OCH3, CF3, CN, and halogen; naphthyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of F and OCH3; pyrimidinyl; imidazo[1,2-a]pyridine-6-yl; benzothiophen-2-yl; benzothiophen-5-yl; benzofuran-2-yl; dibenzo[b,d]furan-3-yl; dibenzo[b,d]thiophen-2-yl; dibenzo[b,d]thiophen-4-yl; 1,3- benzodioxol-5-yl; 2,3-dihydro-1,4-benzodioxin-5-yl; 2,3-dihydro-1,4-benzodioxin-6-yl; 2,3- dihydro-1-benzofuran-4-yl; 2,2-difluoro-1,3-benzodiox-4-yl; pyridazinyl; imidazolyl; oxazolyl; pyrazolyl; thiazolyl; and triazolyl; with the proviso that when Y is 2,3-dihydro-1,4-benzodioxin-6-yl, R1 is not Cl; processes for their preparation, intermediates useble in these processes, pharmaceutical compositions containing them and their use in therapy, for example as modulators of of the growth hormone secretagogue receptor (also referred to as the ghrelin receptor or GHSR1a receptor) and/or for the treatment and/or prophylaxis of a disorder mediated by the ghrelin receptor.
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Page/Page column 73-74
(2009/01/24)
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- Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues
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New sildenafil analogues containing an ether ring fused into the phenyl moiety, 6a-d and 7a-d, were efficiently synthesized from the readily available starting materials, 1a-d and 2, in five steps. Ab initio calculations indicated that introduction of a cyclic ether to the phenyl group might enhance the co-planarity of the molecule. The torsional angles were calculated to be 2-3° for the 5-membered cyclic ether derivatives, 6a, 6c, 7a, and 7c, and 12-16° for the 6-membered ones, 6b, 6d, 7b, and 7d. On the other hand, sildenafil showed the least co-planarity with the torsional angle of 23° compared with the target compounds, 6a-d and 7a-d. in the enzyme assay, however, the in vitro PDE 5 inhibitory activity was found out to be inversely related to the degree of co-planarity. In other words, the least planar sildenafil showed the highest actiivty, and the most planar 5-membered cyclic ether derivatives were least active by 100-200-fold compared with sildenafil. Our study clearly demonstrated that the open chain 2'-alkoxy group of the phenyl ring, although less effective for inducing the co-planarity, seemed to act as a much better lipophilic requirement than the cyclic alkoxy moiety. Copyright
- Kim, Dae-Kee,Lee, Namkyu,Lee, Ju Young,Ryu, Do Hyun,Kim, Jae-Sun,Lee, Suk-Ho,Choi, Jin-Young,Chang, Kieyoung,Kim, Young-Woo,Im, Guang-Jin,Choi, Won-Son,Kim, Tae-Kon,Ryu, Je-Ho,Kim, Nam-Ho,Lee, Kyoungrim
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p. 1609 - 1616
(2007/10/03)
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- Compounds of N-benzoylpyroline
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Compounds of the general formula (I): STR1 where A, R1, R2, R3, R4, R5 and R6 are defined in the description. Medicinal products.
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