- 2-chloro-3-fluoro-4-(trifluoromethyl) benzaldehyde and synthesis method thereof
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The invention belongs to the technical field of pesticide intermediates, and particularly relates to 2-chloro-3-fluoro-4-(trifluoromethyl) benzaldehyde. The invention discloses unreported 2-chloro-3-fluoro-4-(trifluoromethyl) benzaldehyde and a synthetic method thereof. In the synthesis process, the product is formed through reaction under normal pressure, the process is simple, industrial application is facilitated, reaction conditions are mild, operation is easy, and the industrial production requirement is met; the 2-chloro-3-fluoro-4-(trifluoromethyl) benzaldehyde disclosed by the invention can be widely applied to a pesticide synthesis process, such as synthesis of pesticides such as herbicides and the like, and is relatively high in synthesis yield and relatively high in purity.
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Paragraph 0018-0019; 0030-0031
(2021/04/10)
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- A Dipolar Cycloaddition Reaction to Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate
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A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relati
- Chrovian, Christa C.,Soyode-Johnson, Akinola,Peterson, Alexander A.,Gelin, Christine F.,Deng, Xiaohu,Dvorak, Curt A.,Carruthers, Nicholas I.,Lord, Brian,Fraser, Ian,Aluisio, Leah,Coe, Kevin J.,Scott, Brian,Koudriakova, Tatiana,Schoetens, Freddy,Sepassi, Kia,Gallacher, David J.,Bhattacharya, Anindya,Letavic, Michael A.
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supporting information
p. 207 - 223
(2018/02/10)
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- Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors
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A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.
- Hou, Weijie,Ren, Yan,Zhang, Zhenhua,Sun, Huan,Ma, Yongfen,Yan, Bo
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p. 1740 - 1750
(2018/03/12)
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- From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer
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Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.
- Zhang, Chun-Hui,Chen, Kai,Jiao, Yan,Li, Lin-Li,Li, Ya-Ping,Zhang, Rong-Jie,Zheng, Ming-Wu,Zhong, Lei,Huang, Shen-Zhen,Song, Chun-Li,Lin, Wan-Ting,Yang, Jiao,Xiang, Rong,Peng, Bing,Han, Jun-Hong,Lu, Guang-Wen,Wei, Yu-Quan,Yang, Sheng-Yong
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supporting information
p. 9788 - 9805
(2016/11/19)
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- P2X7 MODULATORS
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The present invention is directed to a compound of Formula (I) The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.
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Paragraph 0403; 0404
(2014/09/30)
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- P2X7 MODULATORS
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The present invention is directed to compounds of Formulas (I, IIa and IIb): The invention also relates to pharmaceutical compositions comprising compounds of Formulas (I, IIa and IIb). Methods of making and using the compounds of Formulas (I, IIa and IIb) are also within the scope of the invention.
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Paragraph 0284; 0285
(2014/09/29)
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- Biarylether amide quinolines as liver X receptor agonists
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A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide
- Bernotas, Ronald C.,Singhaus, Robert R.,Kaufman, David H.,Ullrich, John,Fletcher III, Horace,Quinet, Elaine,Nambi, Ponnal,Unwalla, Rayomand,Wilhelmsson, Anna,Goos-Nilsson, Annika,Farnegardh, Mathias,Wrobel, Jay
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experimental part
p. 1663 - 1670
(2009/08/08)
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- Discovery and SAR of cinnolines/quinolines as liver X receptor (LXR) agonists with binding selectivity for LXRβ
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A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2′,3′ or 2′,5′-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRβ over LXRα. The LXRβ binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRα Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.
- Hu, Baihua,Unwalla, Raymound,Collini, Michael,Quinet, Elaine,Feingold, Irene,Goos-Nilsson, Annika,Wihelmsson, Anna,Nambi, Ponnal,Wrobel, Jay
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experimental part
p. 3519 - 3527
(2009/10/17)
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- A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors
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Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationshi
- Shen, Hong C.,Ding, Fa-Xiang,Deng, Qiaolin,Xu, Suoyu,Tong, Xinchun,Zhang, Xiaoping,Chen, Yuli,Zhou, Gaochao,Pai, Lee-Yuh,Alonso-Galicia, Magdalena,Roy, Sophie,Zhang, Bei,Tata, James R.,Berger, Joel P.,Colletti, Steven L.
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experimental part
p. 5716 - 5721
(2010/04/30)
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- Synthesis and structural characterization of new phosphinooxazoline complexes of iron
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The first phosphinooxazoline chelate complexes of iron were synthesized, and their structural and electronic properties were studied. The known phosphinooxazolines 2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole (7a), 2-(2-(diphenylphosphino)phenyl)-4,
- Sedinkin, Sergey L.,Rath, Nigam P.,Bauer, Eike B.
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p. 3081 - 3091
(2008/12/22)
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- Indazole-based Liver X Receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis
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A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRα than on LXRβ. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.
- Wrobel, Jay,Steffan, Robert,Bowen, S. Marc,Magolda, Ronald,Matelan, Edward,Unwalla, Rayomand,Basso, Michael,Clerin, Valerie,Gardell, Stephen J.,Nambi, Ponnal,Quinet, Elaine,Reminick, Jason I.,Vlasuk, George P.,Wang, Shuguang,Feingold, Irene,Huselton, Christine,Bonn, Tomas,Farnegardh, Mathias,Hansson, Tomas,Nilsson, Annika Goos,Wilhelmsson, Anna,Zamaratski, Edouard,Evans, Mark J.
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experimental part
p. 7161 - 7168
(2009/11/30)
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