- Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents
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Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer.
- Wu, Feng,Yao, Han,Li, Wei,Zhang, Niuniu,Fan, Yangyang,Chan, Albert S.C.,Li, Xingshu,An, Baijiao
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- N2,N4-DIPHENYLPYRIMIDINE-2,4-DIAMINE DERIVATIVE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT FOR PREVENTION OR TREATMENT OF CANCER
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The present invention relates to a N2,N4-diphenylpyrimidin-2,4-diamine derivative, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of cancer, containing the same as an active ingredient. The derivative sho
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Paragraph 0125; 0126
(2020/05/07)
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- PYRIMIDINE DERIVATIVE AND USE THEREOF
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The present invention provides a pyrimidine derivative and a use thereof. The pyrimidine derivative is the compound shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein, R1, R2, R3, R4 and R5 are, for example, as defined in the specification. The compound can act as an ALK inhibitor, and is for preparing an anti-tumor medicament for suppressing an anaplastic lymphoma kinase.
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Paragraph 0261; 0262; 0263
(2018/09/27)
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- 2,4-dibasic miazines compound
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The invention belongs to the field of medical chemistry, relates to a 2,4-dibasic miazines compound and specifically relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof, a drug compound thereof and an application thereof in treating EGFR or/and ALK mediated diseases.
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- NOVEL CHEMICAL COMPOUNDS (VARIANTS) AND THE USE THEREOF TO TREAT ONCOLOGICAL DISEASES
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The invention relates to novel chemical compounds of general formula I, in which L A , L B , L C , ring A, ring B, R A , R B , R C ,R D ,R E and R F have are defined in the description, and which are protein kinases inhibitors. The invention also relates
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Paragraph 0304; 0305
(2016/10/08)
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- Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase
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In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
- Huang, Wei-Sheng,Liu, Shuangying,Zou, Dong,Thomas, Mathew,Wang, Yihan,Zhou, Tianjun,Romero, Jan,Kohlmann, Anna,Li, Feng,Qi, Jiwei,Cai, Lisi,Dwight, Timothy A.,Xu, Yongjin,Xu, Rongsong,Dodd, Rory,Toms, Angela,Parillon, Lois,Lu, Xiaohui,Anjum, Rana,Zhang, Sen,Wang, Frank,Keats, Jeffrey,Wardwell, Scott D.,Ning, Yaoyu,Xu, Qihong,Moran, Lauren E.,Mohemmad, Qurish K.,Jang, Hyun Gyung,Clackson, Tim,Narasimhan, Narayana I.,Rivera, Victor M.,Zhu, Xiaotian,Dalgarno, David,Shakespeare, William C.
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p. 4948 - 4964
(2016/06/13)
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- CHEMICAL COMPOUNDS
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The present invention relates to compounds of Formula (I) and/or Formula (Ia): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds inhibit ALK kinase activity, and thus may be used for the tr
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Page/Page column 26
(2012/02/06)
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- PYRIMIDINE INHIBITORS OF KINASE ACTIVITY
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Described herein are compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein G1, L1, R2, R3, n, p, Ar1, and Ar2 are defined in the description. Methods of making said compounds, and compositions comprising said compounds which are useful for inhibiting kinases such as IGF-IR are also disclosed.
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Page/Page column 81-82
(2010/12/26)
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- PYRIMIDINE INHIBITORS OF KINASE ACTIVITY
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Described herein are compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein L1, R1, R2, R3, R4, R5, and m are defined in the description. Methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as IGF-IR are also disclosed.
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Page/Page column 58
(2010/12/26)
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- PYRIMIDINE INHIBITORS OF KINASE ACTIVITY
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein G1, R2, R3, R4, R5, n, p, q, Ar1, and Ar2 are defined in the description. The present invention relates also to methods of making said compounds, and compositions comprising said compounds which are useful for inhibiting kinases such as IGF-IR.
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Page/Page column 76
(2010/12/26)
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- Imidazopyridine Kinase Inhibitors
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The present invention provides imidazopyridine compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 86
(2009/01/20)
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