- Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3
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Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell-fate determination. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and specific inhibitors of a single Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A "clickable" version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3's role in various biological processes and disease contribution.
- Kung, Alvin,Chen, Ying-Chu,Schimpl, Marianne,Ni, Feng,Zhu, Jianfa,Turner, Maurice,Molina, Henrik,Overman, Ross,Zhang, Chao
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Read Online
- Photo-Triggered Self-Induced Homolytic Dechlorinative Sulfonylation/Cyclization of Unactivated Alkenes: Synthesis of Quinazolinones Containing a Sulfonyl Group
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A self-photocatalyzed sulfonylation/cyclization of quinazolinones containing unactivated alkenes with various sulfonyl chlorides was developed. The protocol provides access to sulfonyl radicals via energy transfer from the quinazolinone skeleton to the sulfonyl chloride. Notably, the transformations proceeded without any external photocatalysts, additives, or oxidants, providing an alternative method for fabricating sulfonylated compounds.
- Sun, Bin,Ding, Hao,Tian, Hai-Xia,Huang, Pan-Yi,Jin, Can,Wu, Chun-Lei,Shen, Run-Pu
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supporting information
p. 766 - 772
(2021/12/22)
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- Electrosynthesis of CF3-Substituted Polycyclic Quinazolinones via Cascade Trifluoromethylation/Cyclization of Unactivated Alkene
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An atom and step economy cascade trifluoromethylation/cyclization of unactivated alkene with Langlois reagent as a CF3 source is described. A variety of polycyclic quinazolinones were successfully synthesized in 52–81% yields under transition metal- and oxidant-free conditions. The Langlois reagent used in this strategy as a CF3 reagent possesses the advantages of bench-stablity, cost-effectivity and high-efficiency. Additionally, gram-scale reaction, broad substrate scope and good functional group tolerance demonstrated the synthetic usefulness of this protocol.
- He, Jiaying,Ling, Fei,Liu, Lei,Xu, Chao,Xu, Zhenhui,Yang, Zehui,Zhang, Wangqin,Zhong, Weihui
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supporting information
(2022/03/15)
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- Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents
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In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure–activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.
- Dung, Do T. M.,Park, Eun J.,Anh, Duong T.,Hai, Pham-The,Huy, Le D.,Jun, Hye W.,Kwon, Joo-Hee,Young Ji,Kang, Jong S.,Tung, Truong T.,Dung, Phan T. P.,Han, Sang-Bae,Nam, Nguyen-Hai
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- Visible-Light Photosynthesis of CHF2/CClF2/CBrF2-Substituted Ring-fused Quinazolinones in Dimethyl Carbonate
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With eco-friendly and sustainable CO2-derived dimethyl carbonate as the sole solvent, the visible-light-induced cascade radical reactions have been established as a green and efficient tool for constructing various CHF2/CClF2/CBrF2-substituted ring-fused quinazolinones.
- Gui, Qing-Wen,He, Wei-Min,Huang, Wen-Jie,Lu, Zi-Qin,Ouyang, Wen-Tao,Teng, Fan,Xun, Changping,Yang, Hao,Zhu, Meng-Xue
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- Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model
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Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.
- Chang, Chun-Yu,Chen, Chiung-Tong,Chou, Ling-Hui,Hsieh, Hsing-Pang,Huang, Yu-Chen,Lai, You-Liang,Lee, Kun-Hung,Lin, Wen-Hsing,Shih, Chuan,Su, Yu-Chieh,Wang, Pei-Chen,Wu, Cai-Syuan,Yang, Chen-Ming,Yeh, Teng-Kuang,Yen, Wan-Ching
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supporting information
p. 14477 - 14497
(2021/10/20)
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- Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors
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Recent research has indicated that the abnormal expression of the deubiquitinase USP7 induces tumorigenesis via multiple cell pathways, and in particular, the p53-MDM2-USP7 pathway is well understood. USP7 is emerging as a promising target for cancer therapy. However, there are limited reports on USP7 inhibitors. Here we report design, synthesis and biological evaluation of novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors. Our results indicated that the compounds C9 and C19 exhibited the greatest potency against the USP7 catalytic domain, with IC50 values of 4.86 μM and 1.537 μM, respectively. Ub-AMC assays further confirmed IC50 values of 5.048 μM for C9 and 0.595 μM for C19. MTT assays indicated that gastric cancer MGC-803 cells were more sensitive to these compounds than BGC-823 cells. Flow cytometry analysis revealed that C9 restricted cancer cell growth at the G0/G1 and S phases and inhibited the proliferation and clone formation of MGC-803 cells. Further biochemical experiments indicated that C9 decreased the MDM2 protein level and increased the levels of the tumour suppressors p53 and p21 in a dose-dependent manner. Docking studies predicted that solvent exposure of the side chains of C9 and C19 would uniquely form hydrogen bonds with Met407 of USP7. Additionally, C9 exhibited a remarkable anticancer effect in a zebrafish gastric cancer MGC-803 cell model. Our results demonstrated that quinazolin-4(3H)-one derivatives were suitable as leads for the development of novel USP7 inhibitors and especially for anti-gastric cancer drugs.
- Li, Peng,Liu, Ying,Yang, Hua,Liu, Hong-Min
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- Self-catalyzed phototandem perfluoroalkylation/cyclization of unactivated alkenes: Synthesis of perfluoroalkyl-substituted quinazolinones
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A novel visible-light-induced radical tandem trifluoromethylation/cyclization of unactivated alkenes with sodium perfluoroalkanesulfinates (Rf = CF3, C3F7, C4F9, C6F13, C8F17) under air atmosphere has been developed. A range of quinazolinones containing unactivated alkene moiety and sodium perfluoroalkanesulfinates were compatible with this transformation, leading to a variety of perfluoroalkyl-substituted quinazoline alkaloids. Remarkably, the experiment can be carried out without any metal catalyst, strong oxidant, or external photosensitizer.
- Sun, Bin,Huang, Panyi,Yan, Zhiyang,Shi, Xiayue,Tang, Xiaoli,Yang, Jin,Jin, Can
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supporting information
p. 1026 - 1031
(2021/02/06)
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- Photoinduced homolytic decarboxylative acylation/cyclization of unactivated alkenes with α-keto acid under external oxidant and photocatalyst free conditions: access to quinazolinone derivatives
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A novel and green strategy for the synthesis of acylated quinazolinone derivativesviaphoto-induced decarboxylative cascade radical acylation/cyclization of quinazolinone bearing unactivated alkenes has been developed. The protocol provides a novel route to access acyl radicals from α-keto acids through a self-catalyzed energy transfer process. Most importantly, the reaction proceeded smoothly without any external photocatalyst, additive or oxidant, and could be easily scaled-up in flow conditions with sunlight irradiation.
- Sun, Bin,Shi, Rongcheng,Zhang, Kesheng,Tang, Xiaoli,Shi, Xiayue,Xu, Jiayun,Yang, Jin,Jin, Can
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supporting information
p. 6050 - 6053
(2021/06/21)
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- Photo-triggered self-catalyzed fluoroalkylation/cyclization of unactivated alkenes: Synthesis of quinazolinones containing the CF2R group
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A novel photo-triggered self-catalyzed fluoroalkylation/cyclization of quinazolinones containing unactivated alkenes with various fluoroalkyl bromides has been developed. This transformation exhibits excellent substrate generality with respect to both the coupling partners. Of note is that this is the first example describing the Csp3-Br bond homolysis of alkyl bromides via a substrate (quinazolinones) induced energy transfer process. Additionally, the mild conditions, tolerance to a wide range of functional groups and operational simplicity make this protocol practical for the synthesis of fluorine-containing ring-fused quinazolinones. This journal is
- Yang, Jin,Sun, Bin,Ding, Hao,Huang, Pan-Yi,Tang, Xiao-Li,Shi, Rong-Cheng,Yan, Zhi-Yang,Yu, Chuan-Ming,Jin, Can
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supporting information
p. 575 - 581
(2021/01/28)
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- Visible-Light-Induced Radical Difluoromethylation/Cyclization of Unactivated Alkenes: Access to CF2H-Substituted Quinazolinones
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A mild and efficient visible-light-induced radical difluoromethylation/cyclization of unactivated alkenes toward the synthesis of substituted quinazolinones with easily accessible difluoromethyltriphenylphosphonium bromide has been developed. The transformation has the advantages of wide functional group compatibility, a broad substrate scope, and operational simplicity. The benign protocol offers a facile access to pharmaceutically valuable difluoromethylated polycyclic quinazolinones.
- Chen, Xiaoyu,Liu, Bo,Pei, Congcong,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
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supporting information
p. 7787 - 7791
(2021/10/20)
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- As neuroprotective agents of pharmaceutical compounds
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The invention discloses a medicinal compound as a neuroprotective agent. The medicinal compound is a neuronal nitric oxide synthase-postsynaptic density protein 95 (nNOS-PSD95) decoupling agent. The medicinal compound is a benzene ring derivative shown in the general formula (I) or its pharmaceutically acceptable salt. The invention further discloses a preparation method of the medicinal compound and a use of the medicinal compound in prevention and treatment on neuronal damage influence-caused diseases.
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Paragraph 0561; 0562; 0563; 0564
(2019/06/26)
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- A Scaffold-Hopping Strategy toward the Identification of Inhibitors of Cyclin G Associated Kinase
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We recently reported the discovery of isothiazolo[4,3-b]pyridine-based inhibitors of cyclin G associated kinase (GAK) displaying low nanomolar binding affinity for GAK and demonstrating broad-spectrum antiviral activity. To come up with novel core structures that act as GAK inhibitors, a scaffold-hopping approach was applied starting from two different isothiazolo[4,3-b]pyridines. In total, 13 novel 5,6- and 6,6-fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with Kd values in the low micromolar range that can serve as chemical starting points for the discovery of GAK inhibitors based on a different scaffold.
- Wouters, Randy,Tian, Junjun,Herdewijn, Piet,De Jonghe, Steven
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p. 237 - 254
(2019/01/08)
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- Quinazolinone-containing diaryl urea compound and preparation method and application thereof
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The invention provides a quinazolinone-containing diaryl urea compound and a preparation method and application thereof. The quinazolinone-containing diaryl urea compound can obviously inhibit LAD2 cells from releasing beta-hexosaminidase, shows obvious dosage association, can be used for preparing an antiallergic medicament, and particularly can be used for preparing a medicament for antagonizingLAD2 cells from releasing beta-hexosaminidase so as to reduce pain and a load of a patient. The preparation method provided by the invention is easy in obtaining of raw material sources, mild in reaction condition, simple in operation in the reaction process and cheap in used reagent.
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Paragraph 0064-0065
(2018/05/16)
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- Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof
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The invention relates to compounds capable of inhibiting ErbB/HDAC and a preparation method thereof, and a pharmaceutical composition comprising the compounds and application thereof. The compounds are disclosed as Formula 1. The compounds or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, or the pharmaceutical composition comprising the compounds can be used for preparing ErbB kinases and HDAC activity inhibitors and also preparing ErbB-kinase/HDAC-activated mediated disease curatives.
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Paragraph 0070; 0071; 0072; 0073; 0074; 0364-0367
(2017/07/31)
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- Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors
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VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.
- Sun, Ying,Shan, Yuanyuan,Li, Chuansheng,Si, Ru,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
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p. 373 - 385
(2017/10/16)
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- Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4
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Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a ‘triplet’ inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.
- Li, Chuansheng,Shan, Yuanyuan,Sun, Ying,Si, Ru,Liang, Liyuan,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
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p. 506 - 518
(2017/11/14)
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- Method of synthesizing quinazolinone derivative by using methanol as raw material
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The invention discloses a method of synthesizing a quinazolinone derivative by using methanol as a raw material. The method comprises adding an anthranilamide derivative II, methanol III and an iridium metal complex in a reaction container; performing a reaction on the reaction mixture in a microwave reactor or under magnetic stirring at a temperature of 130 +/- 10 DEG C for 2 hours or more; performing cooling to a room temperature; removing a solvent in a spin drying manner; and performing column separation to obtain a target compound. The method provided by the invention adopts nontoxic and renewable methanol as a raw material, and the by-products in the reaction are hydrogen gas and water, thus the method does not pollute the environment and meet the requirements of green chemistry, so that the method has a wide development prospect.
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Paragraph 0085; 0086; 0087; 0088
(2017/12/06)
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- Cyclobutane-diamide compound with antitumor activity and preparation method and application thereof
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The invention provides a cyclobutane-diamide compound with antitumor activity and a preparation method and application thereof. The structure formula of the compound is shown in the description, wherein R1 and R2 are hydrogen, alkane groups or halogen groups. The compound has very good inhibitory activity for VEGFR-2 kinase and can cut off an inductive signal channel of the VEGFR-2 kinase and restrain hyperplasia and migration of tumor cells by restraining the activity of the VEGFR-2 kinase, and therefore the compound can be applied to preparation of antitumor drugs. The preparation method of the compound has the advantages that raw materials are easy to get, reaction conditions are mild, operation is easy in the reaction process, and adopted reagents are low in price.
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Paragraph 0036; 0037
(2017/04/25)
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- A microwave catalysis in the aqueous phase a method of preparing Quinazolinone compounds
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The invention discloses a method for preparing quinazolinone in water phase through microwave catalysis. The method comprises the step: by utilizing a water-soluble coordination compound (such as 8-hydroxyquinoline) as a catalyst, carrying out high-efficiency microwave catalysis on the reaction of 2-halogenated benzaldehyde and amidine salts in pure water phase. The invention relates to a method for preparing a quinazolinone compound, which is environment-friendly, simple and convenient to operate, safe and low-cost, and high-efficiency. Compared with the prior art, the method not only can be applicable to a great deal of functional groups, high in yield, fewer in side products, but also is simple and safe to operate, low in cost, and environment-friendly.
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Paragraph 0059
(2017/02/09)
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- joint phenyl-urea containing quinazolinones compounds and its preparation method and application (by machine translation)
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The present invention provides a compound joint phenyl-urea containing quinazolinones and its preparation method and application, the structural formula of the compound is Wherein R 1, R 2 is hydrogen, isopropyl or halogen group. To
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Paragraph 0033; 0036; 0037
(2016/12/01)
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- ALKYNE SUBSTITUTED QUINAZOLINE COMPOUND AND METHODS OF USE
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The invention provides alkyne substituted quinazoline compounds, such as compounds of the formula (I), which are irreversible ErbB kinase inhibitors. The compounds are useful in the treatment of diseases and disorders where ErbB kinase activity is implicated such as a hyperproliferative disorder (e.g., cancer).
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Paragraph 0110; 0111
(2016/02/21)
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- Acceptorless Dehydrogenative Coupling of o-Aminobenzamides with the Activation of Methanol as a C1 Source for the Construction of Quinazolinones
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A strategy for the synthesis of quinazolinones via acceptorless coupling of o-aminobenzamides with methanol has been accomplished in the presence of the metal-ligand bifunctional catalyst [Cp?Ir(2,2′-bpyO)(H2O)]. Notably, this research exhibited the potential of transition-metal-catalyzed activation of methanol as a C1 source for the construction of heterocycles.
- Li, Feng,Lu, Lei,Liu, Pengcheng
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supporting information
p. 2580 - 2583
(2016/06/15)
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- Novel synthesis of angular thiazolo[5,4-f] and [4,5-h]quinazolines, preparation of their linear thiazolo[4,5-g] and [5,4-g]quinazoline analogs
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Synthesis of 9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carbonitrile (1) or 6-oxo-6,7-dihydrothiazolo[4,5-h]quinazoline-2-carbonitrile (2) was reinvestigated with the ambition of varying the position of the thiazole ring linked to the quinazolin-4-one
- Hédou, Damien,Guillon, Rémi,Lecointe, Charlotte,Logé, Cédric,Chosson, Elizabeth,Besson, Thierry
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p. 3182 - 3191
(2013/04/24)
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- Discovery of a novel broad-spectrum antifungal agent derived from albaconazole
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Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed preliminary in vivo antifungal efficacy in a mice model of systemic candidiasis.
- Guillon, Rémi,Pagniez, Fabrice,Picot, Carine,Hédou, Damien,Tonnerre, Alain,Chosson, Elizabeth,Duflos, Muriel,Besson, Thierry,Logé, Cédric,Le Pape, Patrice
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supporting information
p. 288 - 292
(2013/03/29)
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- Morpholinylquinazolines
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The invention relates to compounds of the formulae (I), (II) and (III) in which R1, R2, R3, R4, Y, W1, W2, L, A, Alk, Cyc, Ar, Het1, Het2, Hal and n have the meaning indicated in claim 1, and/or physiologically acceptable salts, tautomers and stereo-isomers thereof, including mixtures thereof in all ratios. The compounds of the formula (I) can be used for the inhibition of serine/threonine protein kinases and for the sensitisation of cancer cells to anticancer agents and/or ionising radiation. The invention also relates to the use of the compounds of the formula (I) in the prophylaxis, therapy or progress control of cancer, tumours, metastases or angiogenesis disorders, in combination with radiotherapy and/or an anticancer agent. The invention furthermore relates to a process for the preparation of the compounds of the formula (I) by reaction of compounds of the formulae (II) and (III) and optionally conversion of a base or acid of the compounds of the formula (I) into one of their salts.
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Paragraph 0182
(2013/03/26)
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- QUINAZOLINE DERIVATIVES AS HISTAMINE H4-RECEPT0R INHIBITORS FOR USE IN THE TREATMENT OF INFLAMMATORY DISORDERS
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Compounds that modulate the histamine H4 receptor, and which may be useful for treating or preventing disorders and conditions mediated by the histamine H4 receptor, e.g. inflammation, are of Formula (I):
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Page/Page column 16
(2010/12/31)
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- AURORA KINASE INHIBITORS
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Disclosed herein are Aurora kinase Inhibitors represented by Structural Formula (I): Values for the variables in Structural Formula (I) are defined herein.
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Page/Page column 52
(2009/10/22)
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- 2-METHYLMORPHOLINE PYRIDO-, PYRAZO- AND PYRIMIDO-PYRIMIDINE DERIVATIVES AS MTOR INHIBITORS
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There is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula (1), and the use of a compound of Formula (1) as a medicament and in the treatment of cancer
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Page/Page column 119-120
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound of the formula (I) or a salt, solvate, tautomer or N-oxide thereof for use in the treatment or prophylaxis of a disease state or condition mediated by protein kinase A and/or protein kinase B, wherein the ring Q is a benzene ring; J2-J1 is N=CR7 or R1aN-CO; G is OH or NR5R6; E is CONR7, NR7CO, C(R8)=C(R8) or (X)m(CR8R8a)n where X is O, S or NR7; provided that when J2-J1 is R1aN-CO, E is other than NR7CO; m and n are each 0 or 1, where m + n = 1 or 2; A is a bond and R4 and R4a are absent, or A is a saturated optionally substituted C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between E and G, one carbon atom in the linker group A being optionally replaced by O or N; R1,Rla, R2, and R3 are each H; halogen; C1-6 hydrocarbyl optionally substituted by halogen, OH or C1-2 alkoxy; CN; CONHR8; NH2; NHCOR10 or NHCONHR10; R4 is H or C1-4 alkyl; R4a is H, C1-4 alkyl or a group R9; R5 and R6 are each selected from H, R9 and C1-4 hydrocarbyl optionally substituted by halogen, C1-2 alkoxy or R9;or NR5R6 forms a saturated 4-7 membered monocyclic heterocyclic group; R7 is H or C1-4 alkyl; R8 and R8a each H or saturated C1-4 hydrocarbyl optionally substituted by fluorine; R9is a monocyclic or bicyclic carbocyclic or heterocyclic group containing up to 3 ring heteroatoms selected from N, O and S; or R4, R4a and A together form a saturated monocyclic 4-7 membered heterocycle; or NR5R6, R4 and A form a saturated 4-7 membered monocyclic heterocycle; or R4,together with R7 or R8 and A and E form a 4-7 membered saturated monocyclic heterocycle; or NR5R6 and R7 or R8 together with A and E form a 4-7 membered saturated monocyclic heterocycle; and R10 is optionally substituted phenyl or benzyl.
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Page/Page column 111-112; 144-145
(2010/11/30)
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- P-38 kinase inhibitors
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Compounds and compositions for modulating the activity of p38 kinases are provided, including p38α and p38β kinase. Methods for treating, preventing or ameliorating one or more symptoms of a p38 kinase mediated disease or disorder are also provided.
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Page/Page column 23
(2008/06/13)
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- Quinazoline derivatives
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A compound of the formula (I) or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof has a superior tyrosine-specific protein kinase inhibitory activity and is useful as a pharmaceutical agent, particularly as an agent for the prophylaxis or treatment of various cancers, psoriasis or diseases caused by arteriosclerosis, and the like.
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Page/Page column 32
(2010/02/07)
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- Quinazoline compounds
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The invention concerns quinazoline compounds of the formula I STR1 wherein Q 1 is a 5- or 6-membered heteroaryl moiety and Q 1 optionally bears up to 3 substituents;wherein m is 1 or 2 and each R 1 may be a group such as hydrogen, halogeno and trifluorome
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