- Aryl imidazole derivative and application thereof
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The invention relates to an aryl imidazole derivative and application thereof. The aryl imidazole derivative is a compound shown as a formula (I) in the description or pharmaceutically acceptable salt thereof. The invention also discloses application of the aryl imidazole derivative in preparation of drugs for treating cancers. The invention further discloses application of the aryl imidazole derivative in preparation of drugs for treating diseases caused by EGFR mutation.
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Paragraph 0534-0537
(2021/06/23)
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- Compound with dual inhibitory activity TDO, IDOO1 and application of compound for treating neurodegenerative disease (by machine translation)
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The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which can selectively inhibit TDO, IDOO1, which has a significant inhibitory effect on TDO and/or IDOO1. In addition, the prepared compound has a remarkable anti-tumor effect, has a certain treatment effect on's disease and's disease, and has a good application prospect in the field of medicine preparation. (by machine translation)
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Paragraph 0149; 0241-0244
(2020/10/06)
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- Development of a late-stage diversification strategy for the 4- And 5-Positions of 4,5,6-trisubstituted indazoles
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Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.
- Barber, Joyann S.,Burtea, Alexander,Collins, Michael R.,Tran-Dube, Michelle,Patman, Ryan L.,Scales, Stephanie,Smith, Graham,Spangler, Jillian E.,Wang, Fen,Wang, Wei,Yang, Shouliang,Zhu, JinJiang,Patrick Montgomery
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supporting information
p. 9047 - 9052
(2020/11/30)
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- Inhibiting effect of trisubstituted pyrimidine derivative on protein kinase
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The invention discloses a trisubstituted pyrimidine derivative with a structure shown as general formula (I), and pharmaceutically acceptable salt, ester or solvent compound thereof. The derivative isa protein kinase inhibitor, can be used individually or in combination with other drugs for cancer treatment, and has tremendous clinical application value. General formula (I) is shown as the specification.
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- AMINO PYRIMIDINE COMPOUND FOR INHIBITING PROTEIN TYROSINE KINASE ACTIVITY
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An amino pyrimidine compound for inhibiting protein tyrosine kinase activity, a pharmaceutical composition thereof, preparation therefor, and an application thereof. Specifically, an amino pyrimidine compound represented by formula (I), R1, R2, L, Y, R6, W, A, m, and n being defined in the specification, and a pharmaceutically acceptable salt, a stereoisomer, a solvent compound, a hydrate, a polymorphism, a prodrug, or an isotope variant thereof. The compound can be used for treating and/or preventing protein tyrosine kinase-related diseases such as cell proliferative diseases, cancers, and immune diseases.
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Paragraph 0354; 0355
(2019/06/07)
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- Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability
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Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.
- Wang, Xiaojing,Kolesnikov, Aleksandr,Tay, Suzanne,Chan, Grace,Chao, Qi,Do, Steven,Drummond, Jason,Ebens, Allen J.,Liu, Ning,Ly, Justin,Harstad, Eric,Hu, Huiyong,Moffat, John,Munugalavadla, Veerendra,Murray, Jeremy,Slaga, Dionysos,Tsui, Vickie,Volgraf, Matthew,Wallweber, Heidi,Chang, Jae H.
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p. 4458 - 4473
(2017/06/05)
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- Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy
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GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.
- McCoull, William,Bailey, Andrew,Barton, Peter,Birch, Alan M.,Brown, Alastair J. H.,Butler, Hayley S.,Boyd, Scott,Butlin, Roger J.,Chappell, Ben,Clarkson, Paul,Collins, Shelley,Davies, Robert M. D.,Ertan, Anne,Hammond, Clare D.,Holmes, Jane L.,Lenaghan, Carol,Midha, Anita,Morentin-Gutierrez, Pablo,Moore, Jane E.,Raubo, Piotr,Robb, Graeme
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supporting information
p. 3187 - 3197
(2017/04/19)
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- Discovery and preliminary structure–activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties
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Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50value of 5.3 μM. The structure–activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
- Qian, Shan,He, Tao,Wang, Wei,He, Yanying,Zhang, Man,Yang, Lingling,Li, Guobo,Wang, Zhouyu
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p. 6194 - 6205
(2016/12/06)
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- ANTAGONISTS OF PROSTAGLANDIN EP3 RECEPTOR
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Provided herein are antagonists of prostaglandin EP3 receptor, processes to make said antagonists, and methods comprising administering said antagonists to a mammal in need thereof.
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Paragraph 0225; 0226
(2015/04/15)
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- N-ALKYLATED INDOLE AND INDAZOLE COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
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The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts or solvates thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.
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Paragraph 0262
(2015/08/04)
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- N-ALKYLATED INDOLE AND INDAZOLE COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
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The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts or solvates thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.
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Page/Page column 51
(2014/03/22)
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