- Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors
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Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.
- Zhao, Bingbing,Xiao, Zhen,Qi, Jianguo,Luo, Rong,Lan, Zhou,Zhang, Yanzhuo,Hu, Xiaohan,Tang, Qidong,Zheng, Pengwu,Xu, Shan,Zhu, Wufu
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Read Online
- Synthesis and structure-activity relationship analysis of 5-HT7 receptor antagonists: Piperazin-1-yl substituted unfused heterobiaryls
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A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl)pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT7 /5-HT2A R ligand, and 13 as a multi-receptor (5-HT7 , 5-HT2A , 5-HT6 and D2 ) agent.
- Strekowski, Lucjan,Saczewski, Jaros?aw,Raux, Elizabeth A.,Fernando, Nilmi T.,Klenc, Jeff,Paranjpe, Shirish,Raszkiewicz, Aldona,Blake, Ava L.,Ehalt, Adam J.,Barnes, Samuel,Baranowski, Timothy C.,Sullivan, Shannon M.,Sata?a, Grzegorz,Bojarski, Andrzej J.
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- A novel and efficient synthesis of anti-cancer agent, mereletinib
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A convenient route for the synthesis of a third-generation epidermal growth factor receptor inhibitor, mereletinib (AZD9291) using starting materials that are commercially available has been achieved through reactions that are readily conducted under mild conditions. Importantly, a 5 g scale synthesis was also accomplished and this method could therefore be useful in the synthesis of similar drugs.
- Liu, Haidong,Lv, Yongfeng,Li, Yuan,Cai, Jin,Chen, Junqing,Qin, Yu,Ji, Min
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- Discovery of N-(4-(3-isopropyl-2-methyl-2 H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies
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Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.
- Huang, Jianhang,Wang, Xinren,Dong, Ruinan,Liu, Xiaoyue,Li, Hongmei,Zhang, Tianyi,Xu, Junyu,Liu, Chenhe,Zhang, Yanmin,Hou, Shaohua,Tang, Weifang,Lu, Tao,Chen, Yadong
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- Discovery of highly potent and selective EGFRT790M/L858R TKIs against NSCLC based on molecular dynamic simulation
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Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). There have been three generation drugs developed to treat of NSCLC. The third-generation EGFR tyrosine kinase inhibitors (TKIs)
- Yang, Tingting,Zhang, Wenjuan,Cao, Shengjie,Sun, Shiyang,Cai, Xu,Xu, Lei,Li, Pengyun,Zheng, Zhibing,Li, Song
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- Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFRL858R/T790M kinase inhibitors
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On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities aga
- Chen, Ye,Ding, Shi,Dong, Xiaoyong,Duan, Wenwen,Gao, Ziye,Ji, Jingchao,Li, Min,Liu, Fang,Liu, Ju,Shen, Jiwei,Song, Wenshan,Wu, Shuang,Zhang, Mingjuan,Zheng, Xiangshan
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- Design, synthesis and biological evaluation of 2-aminopyrimidine-based LSD1 inhibitors
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AZD9291, with excellent pharmaceutical properties, has been reported to have certain LSD1 inhibitory activity. Therefore, we carried out structural optimization based on the AZD9291 skeleton to increase the LSD1 inhibitory potential of the compound. Then, a series of 2-aminopyrimidine derivatives were designed and synthesized as LSD1 inhibitors, and their structure–activity relationships were studied. The most promising compound, X43, with an IC50 of 0.89 μM showed remarkable LSD1 selectivity not only to EGFRwt (>100-fold) but also to MAO-A/B (>50-fold). Further studies showed that X43 inhibited LSD1 activity and induced the apoptosis of A549 cells in a dose-dependent manner. Meanwhile, compound X43 showed a superior ability to inhibit the proliferation of A549 and THP-1 cells, with IC50 values of 1.62 μM and 1.21 μM, respectively. Then, analyses of the stability of human liver microsomes, CYP inhibition and in vivo pharmacokinetics in rats showed that X43 had favorable profiles in vitro and in vivo and the potential for further study. Our findings suggested that a 2-aminopyrimidine-based LSD1 inhibitor deserves further investigation as a treatment for LSD1-overexpressing cancer.
- Cheng, Maosheng,Wang, Jiming,Wang, Xinran,Zhang, Cai,Zhang, Xiangyu,Zhao, Dongmei,Zhao, Liyu
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- Refinement of covalent EGFR inhibitor AZD9291 to eliminate off-target activity
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Non-small-cell lung cancer (NSCLC) is a major disease that accounts for 85% of all lung cancer cases which claimed around 1.8 billion lives worldwide in 2020. Tyrosine kinase inhibitors (TKIs) that target EGFR have been used for the treatment of NSCLC, but often develop drug resistance, and the covalent inhibitor AZD9291 has been developed to tackle the problem of drug resistance mediated by the T790M EGFR mutation; however, there is a side effect of hyperglycemia that may be due to off-target activity. This study examines analogs of AZD9291 by chemical proteomics, identifying analogs that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.
- Bouffard, Elise,Cravatt, Benjamin,Dix, Melissa M.,Wong, Chi-Huey,Zaro, Balyn W.
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supporting information
(2021/05/29)
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- P-phenylenediamine LSD1 inhibitor and preparation method thereof
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Disclosed are a p-phenylenediamine derivative as represented by general formula I, a pharmaceutically acceptable salt, and a stereoisomer thereof. The p-phenylenediamine derivative as represented by general formula I, the pharmaceutically acceptable salt thereof and the stereoisomer thereof can be used alone or in combination as lysine-specific demethylase-1 (LSD1) inhibitors.
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Paragraph 0112-0115
(2021/09/08)
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- Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury
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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti-ALI activity of these compounds was evaluated. Compounds 6c and 6h showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, respectively. Furthermore, most of compounds had no significant cytotoxicity in vitro. The infiltration of inflammatory cells into lung tissue significantly reduced by using compound 6h (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound 6h through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound 6h showed good anti-inflammatory activity in vitro and in vivo, which was expected to become a leading compound for the treatment of ALI.
- Chen, Tianpeng,Wei, Yingying,Zhang, Xingxian,Zhao, Huajun,Zhu, Gaoyang
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- Compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase and application thereof
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The invention discloses a compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase, and is characterized in that the structural formula is as follows. Among them: Substituent R1 . One of: Substituent R2 . One of: The substituent X is H or Cl. Substituent R3 To H. One of the following.
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Paragraph 0039-0042; 0049-0051
(2021/09/15)
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- EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs
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The invention discloses an EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs, the EGFR kinase inhibitor can effectively improve EGFRTKI acquired drug resistance caused by SQSTM1 accumulati
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Paragraph 0284-0285
(2020/11/23)
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- Design, synthesis and SAR study of 2-aminopyrimidines with diverse Michael addition acceptors for chemically tuning the potency against EGFRL858R/T790M
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The covalent binding nature of irreversible kinase inhibitors potentially increases the severity of “off-target” toxicity. Based on our continual strategy of chemically tuning the Michael addition acceptors, herein, we further explore the relationship amo
- Chen, Wenteng,Liu, Shuangrong,Liu, Xingyu,Pan, Youlu,Shao, Jiaan
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- Pyrimidine bis-aromatic ring derivative epidermal growth factor inhibitor, and preparation method and application thereof
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The invention relates to a pyrimidine double-aromatic-ring derivative epidermal growth factor inhibitor, and a preparation method and application thereof. The invention discloses a selective inhibitorfor a clinical mutant of EGFR protein tyrosine kinase.
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Paragraph 0031-0035
(2020/09/09)
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- Deuterated pyrimidine derivative and application thereof
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The invention discloses a deuterated pyrimidine derivative and application thereof, and belongs to the field of medicines. The deuterated pyrimidine derivative and a pharmaceutically acceptable salt thereof have good activity of selectively inhibiting an
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Paragraph 0089-0092
(2020/07/15)
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- Compound, containing conjugated dienamide structure, preparation method, pharmaceutical composition and application thereof
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The invention relates to a compound containing a conjugated allene amide structure and a preparation method, a medicine composition and application thereof, in particular to a compound containing a conjugated allene amide structure shown in a formula (I), and a preparation method, a medicine composition and application thereof in preparation of an EGFR (epidermal growth factor receptor) inhibitoror a medicine for preventing and/or treating EGFR-related diseases, especially cancers. (The formula (I) is shown in the description.).
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- Synthetic method of osimertinib AZD9291
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The invention provides a synthetic method of osimertinib AZD9291; an intermediate (III) is synthesized by adopting CoCl2/SoCl2 to catalyze; an intermediate (VIII) is synthesized by adopting CoSO4.7H2Oto carry out catalytic reduction; in the preparation of an intermediate (X), sodium carbonate is used as an acid binding agent; and the intermediate (X) and methane sulfonic acid are adopted for salification in a mixed solvent of ethyl alcohol and isopropyl alcohol to prepare the AZD9291. The synthetic method provided by the invention is high in yield, mild in reaction condition, simple in after-treatment and suitable for industrial production.
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Paragraph 0025-0037
(2019/01/23)
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- Novel epidermal growth factor receptor inhibitor and application thereof (by machine translation)
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The invention discloses a novel epidermal growth factor receptor inhibitor and application thereof. The compounds of the general formula (I) shown in the general 2 formula 3 - d (I), and the pharmaceutically acceptable salts, prodrugs or solvates thereof
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Paragraph 0038; 0058-0061
(2019/10/10)
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- A phenyl acrylamide structure containing substituted pyrimidine compound and use thereof (by machine translation)
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The invention discloses a containing substituted phenyl acrylamide structure of the pyridine compound, its geometric isomer and its pharmaceutically acceptable salt, hydrate, solvate or prodrug. The invention containing substituted phenyl acrylamide structure of pyrimidines, and its pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, with a pharmaceutically acceptable carrier or excipient mixed preparation composition in, and prepared into a clinically acceptable dosage form. The compounds of the invention in preparing and treating and/or preventing proliferative disorders application of the medicament, for treating and/or preventing cancer of application of the medicament, for treating and/or preventing lung cancer, prostate cancer, breast cancer and applied in the medicine of cervical cancer. (by machine translation)
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Paragraph 0054; 0085; 0086
(2019/02/10)
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- FLUORINE- AND/OR DEUTERIUM-CONTAINING COMPOUNDS FOR TREATING NON-SMALL CELL LUNG CANCER AND RELATED DISEASES
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Novel fluoride and/or deuterium-containing chemical, compounds useful for treating cancer or a related disease or disorder thereof, and pharmaceutical compositions and methods of preparation and use thereof.
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- 2-(2,4,5-substituted aniline) pyrimidine derivative
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The invention discloses a compound shown as a formula (I) or a salt acceptable to a drug thereof, a method for preparing the compound shown as the formula (I) or the salt acceptable to the drug thereof, a pharmaceutical composition containing the compound shown as the formula (I) or the salt acceptable to the drug thereof and applications for the compound shown as the formula (I) or the salt acceptable to the drug thereof. The structural formula of the compound is shown as the description, wherein R1, R2 and R3 are defined as the invention.
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Paragraph 0218-0219
(2019/01/06)
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- EGFR PROTEOLYSIS TARGETING CHIMERIC MOLECULES AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00890; 00891
(2018/07/29)
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- 2,4-disubstituted benzene-1,5-diamine derivative used as EGFR (epidermal growth factor receptor) inhibitor and application of derivative
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The invention discloses a 2,4-disubstituted benzene-1,5-diamine derivative shown in a formula I as well as pharmaceutically acceptable salt, a stereoisomer, a solvate or a predrug of the derivative, with symbols defined in claims. The 2,4-disubstituted benzene-1,5-diamine derivative can inhibit activation or resistant mutation of one or more EGFRs (epidermal growth factor receptors), can be used for treating EGFR sensitive mutation cancer, can be applied to cases with secondary drug resistance in EGFR-TKI treatment at present and is an ideal treatment drug for diseases caused by EGFR mutation.
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Paragraph 0095; 0097; 0099
(2018/09/28)
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- Phenyl sulfonamide compound with anti-tumor activity and preparation and application thereof
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The invention discloses a novel phenyl sulfonamide compound and a preparation method and application thereof. The structure of the novel phenyl sulfonamide compound is shown in a formula (I), whereinR1 is selected from one of H, CH3 and CH2CH3; R2 is selected from one of H, F, Cl, Br, CH3, CF3, NO2, OCH3, naphthyl, tertiary butyl, 2,4-difluoro, and 3,5-difluoro; R3 is selected from one of CH3, OCH3, CF3 and OCF3; R4 and R5 are selected from one of H or CH3. The preparation method comprises the following steps of dissolving a phenyl pyrimidinamine derivative shown in a structural formula (II)in a certain solvent; adding a certain amount of benzenesulfonyl azide compound shown in a structural formula (III) or homologous series thereof, catalyzing by a rhodium reagent and a silver additive,reacting at proper temperature, post-treating after reaction is finished, and re-crystallizing by methyl alcohol, so as to obtain the product. The novel phenyl sulfonamide compound has the advantagesthat the inhibiting function is realized in resistance of tumor cells, and the certain application prospect is realized. The structural formula (I), the structural formula (II) and the structural formula (III) are shown in the description.
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Paragraph 0017; 0021; 0023
(2018/11/03)
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- EGFR INHIBITOR COMPOUNDS
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Disclosed herein are nitrogen-containing bicyclic compounds, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
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Paragraph 0138
(2017/12/29)
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- Preparation method for graphene-supported FeCl3 catalyst and application of graphene-supported FeCl3 catalyst to preparation of anticancer drug intermediate
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The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method for a graphene-supported FeC13 catalyst and application of the graphene-supported FeC13 catalyst to preparation of an anticancer drug intermediate. The preparation method comprises the following steps: modifying graphene by taking ammonium nitrate and ammonium dihydrogen phosphate as modifiers; meanwhile, supporting FeCl3 with the graphene to prepare the graphene-supported FeCl3 catalyst. The obtained catalyst is used for catalyzing to prepare the anticancer drug intermediate, namely, 3-(2-chloro-pyrimidine-4-yl)-1-methylindole, so that the raw material converting rate and product selectivity are improved greatly; moreover, the catalyst can be recycled, the production cost is lowered, and wastewater is not produced during production; an environment-friendly production process is provided.
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Paragraph 0013
(2017/08/31)
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- 2-(2,4,5-SUBSTITUTED ANILINE) PYRIMIDINE DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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Disclosed are a 2-(2,4,5-substituted aniline) pyrimidine derivative, a pharmaceutical composition and a use thereof. The pharmaceutical composition comprises a therapeutically effective amount of the 2-(2,4,5-substituted aniline) pyrimidine derivative, a solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also disclosed is a use of the 2-(2,4,5-substituted aniline) pyrimidine derivative, a solvate, or a pharmaceutically acceptable salt thereof in the preparation of drugs for treating cancers. The compounds of the present invention have a relatively high solubility in water and a relatively high permeability, and/or a relatively low binding ability to plasma proteins, and at the same time have a relatively low toxicity characteristic and a relatively high anti-tumor activity.
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Paragraph 0048
(2017/07/14)
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- EGFR INHIBITOR, AND PREPARATION AND APPLICATION THEREOF
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A 4-substituted-2-(N-(5-substituted allyl amide)phenyl)amino)pyrimidine derivative as represented by formula (I), and a preparation and application thereof as an EGFR inhibitor. The compound has activity of inhibiting the L858R EGFR mutant, the T790M EGFR mutant and the exon 19 deletion activating mutant, may be used to treat diseases mediated alone or in part by EGFR mutant activity, and has a wide application in drugs preventing and treating cancers, particularly non-small cell lung cancer.
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Paragraph 0119; 0120
(2017/09/02)
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- PYRIDINE AMIDOPYRIMIDINE DERIVATIVE, PREPARATION METHOD AND USE THEREOF
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The present invention relates to pyridinylaminopyrimidine derivatives represented by the following formula (I), and pharmaceutically acceptable salts, preparation process and use thereof, wherein R1, R2, R3, R4,
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Paragraph 0131; 0132; 0133
(2017/07/14)
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- PYRIMIDINE OR PYRIDINE COMPOUNDS, PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USES THEREOF
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The present invention disclosed a class of pyrimidine or pyridine compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, preparation method therefor and pharmaceutical compositions and pharmaceutical uses thereof. The compounds can inhibit the variants of EGFR (Epidermis Growth Factor Receptor) proteinases, and therefore can inhibit the growth of a variety of tumor cells effectively. The compounds can be used to prepare antitumor drugs, used for the treatment, combined therapy or prevention of various different cancers. The compounds can overcome the drug resistance induced by the existing first-generation EGFR inhibitors such as gefitinib, erlotinib and so on. Particularly, the compounds can be used to prepare drugs for treating or preventing diseases, disturbances, disorders or conditions mediated by epidermis growth factor receptor variants (such as L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants).
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Paragraph 0097-0099
(2017/09/19)
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- 2-(2,4,5-substituted aniline) pyrimidine derivative
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The invention discloses a compound as shown in a formula (I) or pharmaceutically acceptable salt thereof, a method for preparing the compound as shown in the formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound as shown in the formula (I) or pharmaceutically acceptable salt thereof, and an application of the compound as shown in the formula (I) or pharmaceutically acceptable salt thereof (as shown in the specification), wherein R1 to R7 are as defined in the invention.
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Paragraph 0403; 0404; 0405; 0406
(2017/09/01)
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- DEUTERATED COMPOUNDS FOR TREATING CANCER AND RELATED DISEASES AND CONDITIONS, AND COMPOSITIONS AND METHODS THEREOF
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The invention provides novel chemical compounds useful for treating cancer or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.
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- Preparation method of 3-(2-chloro-pyrimidine-4-yl)-1-methylindole
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The invention relates to a preparation method of 3-(2-chloro-pyrimidine-4-yl)-1-methylindole. According to the method, formaldehyde is adopted as a reaction material, the reaction technology is simple and convenient, the security is high, the yield is high and the mass production can be carried out.
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Paragraph 0018-0020
(2017/07/07)
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- Pentadeuteropyridine compounds, and preparation method, pharmaceutical compositions and uses thereof
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The invention relates to pentadeuteropyridine compounds represented by the following formula (I) and pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, and a preparation method, pharmaceutical compositions and uses thereof. The compounds can generate an inhibitory effect on variation forms of epidermal growth factor receptor (EGFR) protein kinase, thereby effectively inhibiting the growth of a variety of tumor cells; the compounds can be used for preparation of antitumor drugs, are used for treatment or prevention of a plenty of different cancers, and moreover, can overcome the drug resistance induced by conventional drugs gefitinib, erlotinib and other first-generation EGFR inhibitors. More specifically, the compounds can be used for preparation of drugs for treatment or prevention of diseases, obstacles, disorders or illness conditions mediated by certain variation-form epidermal growth factor receptors (such as L858R activated mutants, Exon19 deletion activated mutants, and T790M resistance mutants).
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Paragraph 0185; 0186; 0187
(2016/10/07)
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- Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor
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Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
- Finlay, M. Raymond V.,Anderton, Mark,Ashton, Susan,Ballard, Peter,Bethel, Paul A.,Box, Matthew R.,Bradbury, Robert H.,Brown, Simon J.,Butterworth, Sam,Campbell, Andrew,Chorley, Christopher,Colclough, Nicola,Cross, Darren A. E.,Currie, Gordon S.,Grist, Matthew,Hassall, Lorraine,Hill, George B.,James, Daniel,James, Michael,Kemmitt, Paul,Klinowska, Teresa,Lamont, Gillian,Lamont, Scott G.,Martin, Nathaniel,McFarland, Heather L.,Mellor, Martine J.,Orme, Jonathon P.,Perkins, David,Perkins, Paula,Richmond, Graham,Smith, Peter,Ward, Richard A.,Waring, Michael J.,Whittaker, David,Wells, Stuart,Wrigley, Gail L.
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p. 8249 - 8267
(2014/12/11)
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- 2 - (2, 4, 5 - SUBSTITUTED -ANILINO) PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATING CANCER
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The present invention relates to certain 2-(2,4,5-substituted-anilino) pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exonl9 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.
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Page/Page column 160
(2013/03/26)
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- JNK modulators
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Compounds of formula I modulate JNK: wherein the variables are as defined herein.
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Page/Page column 111; 112
(2008/12/06)
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