- Indazole derivative, preparation method and application thereof
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The invention relates to an indazole derivative, a preparation method and application thereof, and belongs to the field of chemical medicines. The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof. The invention also provides a preparation method and application of the compound. Biological experiments show that the compounds show an obvious inhibition effect on FGFR1, and part of the compounds can effectively inhibit breast cancer cells, colorectal cancer cells, lung cancer cells and other cancer cells under the condition of single use, so that the compounds have a broad-spectrum anti-cancer effect; besides, the compound also has an obvious inhibiting effect on proliferation of fibroblasts and human hepatic stellate cells, the effect of resisting bleomycin-induced pulmonary fibrosis in an animal body is equivalent to that of a current clinical drug nintedanib for treating pulmonary fibrosis, and the anti-fibrosis curative effect is remarkable. The invention provides a new choice for development and application of anti-cancer and anti-fibrosis drugs.
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Paragraph 0104-0106
(2021/04/26)
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- Synthesis and biological evaluation of indazole derivatives as anti-cancer agents
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Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC50 = 0.23-1.15 μM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.
- Wei, Wei,Liu, Zhihao,Wu, Xiuli,Gan, Cailing,Su, Xingping,Liu, Hongyao,Que, Hanyun,Zhang, Qianyu,Xue, Qiang,Yue, Lin,Yu, Luoting,Ye, Tinghong
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p. 15675 - 15687
(2021/05/19)
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- PROTEIN TYROSINE PHOSPHATASE DEGRADERS AND METHODS OF USE THEREOF
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Provided herein are compounds, compositions, and methods useful for degrading protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and/or protein tyrosine phosphatase non-receptor type 1 (PTPN1), and for treating related diseases favorably responsive to PTPN1 or PTPN2 inhibitor treatment, e.g., a cancer 5 or a metabolic disease.
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Page/Page column 270-271
(2021/06/26)
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- Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors
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Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 μM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 μM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.
- Wang, Xing-Rong,Wang, Shuai,Li, Wen-Bo,Xu, Kai-Yan,Qiao, Xue-Peng,Jing, Xue-Li,Wang, Zi-Xiao,Yang, Chang-jiang,Chen, Shi-Wu
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supporting information
(2021/01/26)
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- Design, synthesis and structure–activity relationship of indolylindazoles as potent and selective covalent inhibitors of interleukin-2 inducible T-cell kinase (ITK)
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Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays an important role in T cell signaling downstream of the T-cell receptor (TCR). Herein we report the discovery of a series of indolylindazole based covalent ITK inhibitors with nanomolar inhibitory potency against ITK, good kinase selectivity and potent inhibition of the phosphorylation of PLCγ1 and ERK1/2 in living cells. A computational study provided insight into the interactions between inhibitors and Phe437 at the ATP binding pocket of ITK, suggesting that both edge-to-face π-π interaction and the dihedral torsion angle contribute to inhibitors’ potency. Compounds 43 and 55 stood out as selective covalent inhibitors with potent cellular activity, which could be used as chemical tools for further study of ITK functions.
- Wang, Xueying,Xue, Gang,Pan, Zhengying
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- Indazole derivatives as well as preparation method and application thereof
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The invention relates to indazole derivatives as well as a preparation method and application thereof, and belongs to the field of chemical medicine. The invention provides the compounds represented by a formula I shown in the description. Experimental results show that the compounds provided by the invention can significantly inhibit proliferation of various tumor cells such as lung cancer cells,breast cancer cells, liver cancer cells and colorectal cancer cells, and provides a novel drug selection for clinical treatment of cancers.
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Paragraph 0121; 0125-0126
(2019/11/28)
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- PESTICIDAL COMPOUNDS
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The present invention relates to the compounds of formula (I), and the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof wherein the variables are defined according to the description, formula (I). The compounds of formula (I), as well as the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof, are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
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Page/Page column 86
(2019/07/13)
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- Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors
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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC50 values of 0.55 μM, 0.86 μM and 0.80 μM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC50 values of 0.19 μM, 0.32 μM and 0.12 μM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.
- Rong, Juan,Feng, Zhan-Zhan,Shi, Yao-Jie,Ren, Jing,Xu, Ying,Wang, Ning-Yu,Xue, Qiang,Liu, Kun-Lin,Zhou, Shu-Yan,Wei, Wei,Yu, Luo-Ting
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.
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Paragraph 00479
(2019/01/08)
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- PHARMACEUTICAL COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
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Complement Factor D inhibitors, pharmaceutical compositions, and uses thereof, as well as processes for their manufacture are provided. The compounds provided include Formula I, Formula II, Formula III, and Formula IV or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade.
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Page/Page column 548-549
(2018/09/21)
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- INDAZOLE INHIBITORS OF FRUCTOKINASE (KHK) AND METHODS OF USE IN TREATING KHK-MEDIATED DISORDERS OR DISEASES
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Disclosed herein are novel indazole-based compounds that inhibit fructokinase (aka ketohexokinase) and the downstream metabolic effects mediated by fructose metabolism. Fructokinase inhibitors specifically block the metabolism of both dietary and endogenous fructose metabolism and have a host of potential metabolic benefits. These benefits including blocking sugar craving and sugar induced metabolic syndrome and diabetes, but also blocking fructose metabolism can benefit the rare orphan disease Hereditary Fructose Intolerance, obesity, insulin resistance, metabolic syndrome, fatty liver, hypertension, cardiac injury from ischemia, certain cancers (including hepatocellular and pancreas), acute kidney injury from ischemia, heat stress, rhabdomyolysis or radiocontrast, and chronic diabetic and nondiabetic renal disease.
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Page/Page column 60; 61
(2018/10/19)
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- Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor
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The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds. These inhibitors are conformationally less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M, and covalently alkylate Cys797. Western blot analysis, as well as characterization of the binding kinetics and kinase selectivity profiling, substantiates our approach of targeting drug-resistant EGFR-L858R/T790M with inhibitors incorporating the indazole as hinge binder.
- Tomassi, Stefano,Lategahn, Jonas,Engel, Julian,Keul, Marina,Tumbrink, Hannah L.,Ketzer, Julia,Mühlenberg, Thomas,Baumann, Matthias,Schultz-Fademrecht, Carsten,Bauer, Sebastian,Rauh, Daniel
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supporting information
p. 2361 - 2372
(2017/04/03)
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- NOVEL 2,5-SUBSTITUTED PYRIMIDINES AS PDE4 INHIBITORS
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The invention relates to novel substituted condensed pyrimidine compounds of general formula (I) in which the chemical groupings, substituents and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.
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Page/Page column 59
(2016/02/10)
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- HEPARAN SULFATE BIOSYNTHESIS INHIBITORS FOR THE TREATMENT OF DISEASES
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Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions in need of inhibition of heparan sulfate biosynthesis.
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Paragraph 000178; 000231; 000468
(2016/05/02)
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- DIFLUOROMETHYLENE COMPOUND
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The present invention relates to a compound having an URAT1 inhibitory activity, and to an URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition containing the compound. More specifically, the present invention relates to a compound represented by the formula (I): wherein R1 is -Q1-A1 or the like; R2 is a hydrogen atom, a halogen atom, a lower alkyl group or the like; W1, W2, W3 and W4 are each independently a nitrogen atom or a methine group optionally having substituents, or the like; X and Y are each a single bond, an oxygen atom or the like; Z is a hydroxyl group or COOR3 or the like.
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Paragraph 0532-0534
(2015/06/16)
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- A novel series of indazole-/indole-based glucagon receptor antagonists
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A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.
- Lin, Songnian,Zhang, Fengqi,Jiang, Guoqiang,Qureshi, Sajjad A.,Yang, Xiaodong,Chicchi, Gary G.,Tota, Laurie,Bansal, Alka,Brady, Edward,Trujillo, Maria,Salituro, Gino,Miller, Corey,Tata, James R.,Zhang, Bei B.,Parmee, Emma R.
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p. 4143 - 4147
(2015/11/03)
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- 4-HETEROARYL SUBSTITUTED BENZOIC ACID COMPOUNDS AS RORGAMMAT INHIBITORS AND USES THEREOF
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Provided are compounds according to Formula I or a pharmaceutically acceptable salt or solvate thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.
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Page/Page column 61
(2014/03/22)
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- 4-HETEROARYL SUBSTITUTED BENZOIC ACID COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
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The present invention relates to compounds according to Formula I (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 63
(2014/03/22)
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- INDAZOLE INHIBITORS OF KINASE
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A1, A2, A3 and L are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as aurora and KDR.
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Page/Page column 19
(2011/11/30)
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- 3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6
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The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC50 = 0.30 nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.
- Fraley, Mark E.,Steen, Justin T.,Brnardic, Edward J.,Arrington, Kenneth L.,Spencer, Keith L.,Hanney, Barbara A.,Kim, Yuntae,Hartman, George D.,Stirdivant, Steven M.,Drakas, Bob A.,Rickert, Keith,Walsh, Eileen S.,Hamilton, Kelly,Buser, Carolyn A.,Hardwick, James,Tao, Weikang,Beck, Stephen C.,Mao, Xianzhi,Lobell, Robert B.,Sepp-Lorenzino, Laura,Yan, Youwei,Ikuta, Mari,Munshi, Sanjeev K.,Kuo, Lawrence C.,Kreatsoulas, Constantine
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p. 6049 - 6053
(2007/10/03)
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