- FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
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The present disclosure relates to a class of fused pyrimidine compounds of Formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to a process of preparation of these fused pyrimidine compounds, and to pharmaceutical compositions containing them.
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- Pyrido[2,3-d]pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient
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The present invention relates to: a pyrido[2,3-d]pyrimidine derivative; a method for manufacturing the same; and a pharmaceutical composition for preventing or treating cancer containing the same as an active component. The derivative exhibits inhibitory
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- Pyrimidinone compound and composition prepared from pyrimidinone compound
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The invention relates to the technical field of chemical medicine, and particularly discloses a pyrimidinone compound, a pharmaceutical composition prepared from the pyrimidinone compound and application of the pyrimidinone compound. The structural formula of the pyrimidinone compound is as follows: the pyrimidinone compound disclosed by the invention can serve as a protease inhibitor and furtherinhibit multiple kinds of tumor cells from growth effectively, generates an inhibiting effect on the protease of EGFR and Her families such as EGFR L858R/T790M and EGFR E745_A750/T790, can be used forpreparing antitumor drugs and overcome drug resistance induced by current drugs. The compound, to which the invention is related, and a pharmaceutically acceptable composition of the compound can beused for preparing the antitumor drugs for mankind and other mammals.
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- Novel pyrimido-heterocyclic compound and preparation method and application thereof
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The invention discloses a novel pyrimido-heterocyclic compound and a preparation method and application thereof. The structure of the pyrimido-heterocyclic compound disclosed by the invention is as shown in a general formula I, and the definitions of all substituents are described in the specification and claims. The pyrimido-heterocyclic compound disclosed by the invention has much better inhibitory activity and selectivity for double-mutant EGFR kinase than the existing AZD-9291, can be used for preparing anti-tumor drugs, and overcomes the defect of drug tolerance of the first generation ofEGFR inhibitor.
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- INHIBITORS OF EGFR AND/OR HER2 AND METHODS OF USE
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The application relates to a compound having Formula X: which modulates the activity of HER2 and/or a mutant thereof, and/or EGFR and/or a mutant thereof, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disea
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- Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
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In nonsmall cell lung cancer (NSCLC), the threonine790-methionine790 (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFRL858R,T790M with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFRL858R,T790M driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.
- Wurz, Ryan P.,Pettus, Liping H.,Ashton, Kate,Brown, James,Chen, Jian Jeffrey,Herberich, Brad,Hong, Fang-Tsao,Hu-Harrington, Essa,Nguyen, Tom,St. Jean, David J.,Tadesse, Seifu,Bauer, David,Kubryk, Michele,Zhan, Jinghui,Cooke, Keegan,Mitchell, Petia,Andrews, Kristin L.,Hsieh, Faye,Hickman, Dean,Kalyanaraman, Nataraj,Wu, Tian,Reid, Darren L.,Lobenhofer, Edward K.,Andrews, Dina A.,Everds, Nancy,Guzman, Roberto,Parsons, Andrew T.,Hedley, Simon J.,Tedrow, Jason,Thiel, Oliver R.,Potter, Matthew,Radinsky, Robert,Beltran, Pedro J.,Tasker, Andrew S.
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p. 987 - 992
(2015/09/22)
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- PYRIMIDOPYRIMIDONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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A compound of formula (I) or (II) and use of the compound in the preparation of drugs for treating cancer are disclosed. The study shows that the compounds can inhibit the growth of many kinds of tumor cells, can be used for targeting epidermal growth factor receptor (EGFR), and particularly can inhibit tumor cells with single or multiple mutations of EGFR (T790M). Therefore, the compound can be used as EGFR inhibitor to treat cancer and has a relatively large application value.
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- Substituted 7-Oxo-Pyrido[2,3-d]Pyrimidines and Methods of Use
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The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer.
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- PYRIMIDO[4,5-D]PYRIMIDINYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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A compound of formula (I) or (II) and use of the compound in the preparation of drugs for treating cancer are disclosed. The study shows that the compounds can inhibit the growth of many kinds of tumor cells, can be used for targeting epidermal growth factor receptor (EGFR), and particularly can inhibit tumor cells with single or multiple mutations of EGFR (T790M). Therefore, the compound can be used as EGFR inhibitor to treat cancer and has a relatively large application value.
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- Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine 790 → methionine790 mutant
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The EGFRT790M mutant contributes approximately 50% to clinically acquired resistance against gefitinib or erlotinib. However, almost all the single agent clinical trials of the second generation irreversible EGFR inhibitors appear inadequate to overcome the EGFRT790M-related resistance. We have designed and synthesized a series of 2-oxo-3,4- dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors. The most potent compounds, 2q and 2s, inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC50 values in subnanomolar ranges, including the T790M mutants. The kinase inhibitory efficiencies of the compounds were further validated by Western blot analysis of the activation of EGFR and downstream signaling in cancer cells harboring different mutants of EGFR. The compounds also strongly inhibited the proliferation of H1975 non small cell lung cancer cells bearing EGFRL858R/T790M, while being significantly less toxic to normal cells. Moreover, 2s displayed promising anticancer efficacy in a human NSCLC (H1975) xenograft nude mouse model.
- Chang, Shaohua,Zhang, Lianwen,Xu, Shilin,Luo, Jinfeng,Lu, Xiaoyun,Zhang, Zhang,Xu, Tianfeng,Liu, Yingxue,Tu, Zhengchao,Xu, Yong,Ren, Xiaomei,Geng, Meiyu,Ding, Jian,Pei, Duanqing,Ding, Ke
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p. 2711 - 2723
(2012/06/04)
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