- DIMETHYLPHOSPHINE OXIDE COMPOUND
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Disclosed is an application of a series of dimethylphosphine oxide compounds in the preparation of an LRRK2 kinase activity inhibitor-related drug, specifically an application of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an LRRK2 kinase activity inhibitor-related drug.
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Paragraph 0048
(2021/02/25)
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- Preparation method of intermediate (2-aminophenyl)dimethyl phosphine oxide of Brigatinib
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The invention provides a preparation method of an intermediate (2-aminophenyl)dimethyl phosphine oxide of Brigatinib, and belongs to the technical field of organic synthesis. The method comprises thefollowing steps: (1) reacting an intermediate I-1 with an intermediate I-2 in the presence of a catalyst at a certain temperature to obtain an intermediate I-3; (2) reacting the intermediate I-3 witha methyl Grignard reagent in a first solvent at a low temperature to obtain an intermediate I crude product; (3) reacting the intermediate I crude product with an acid in a second solvent to form a salt of the intermediate I, and performing recrystallization to obtain a pure product of the salt of the intermediate I; and (4) carrying out alkaline hydrolysis on the pure product of the salt of the intermediate I, and performing extraction with a third solvent to obtain the intermediate I pure product. In the first step, the coupling reaction conditions are mild, the formed intermediate is directly subjected to the next step of reaction without separation and purification, the obtained crude product is salified with a proper amount of acid to form a good solid, the solid is recrystallized toobtain the intermediate with very high purity, and the intermediate I pure product is obtained through free extraction under the alkaline condition. The cost is reduced by 50% or above compared with the prior art.
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Paragraph 0100; 0106-0112
(2020/02/14)
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- Polymorphism of novel spiroarylphosphine oxide
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The invention relates to a polymorphic substance of a compound (2-((5-chloro-2-((2-methoxyl-4-(9-methyl-3,9-diaza-sprio[5.5]hendecane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)dimethyl phosphineoxide (compound I). The invention further relates to a m
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Paragraph 0114; 0118-0120
(2019/11/20)
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- 2-aminopyrimidine compound and application thereof
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The invention relates to a 2-aminopyrimidine compound and application thereof. The structure of the 2-aminopyrimidine compound is shown as I. The compound can effectively inhibit the activity of EGFRprotein kinase resistance mutants (such as EGFRT790M and
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Paragraph 0165-0172
(2019/10/17)
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- TYK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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Paragraph 001166; 001167
(2018/05/15)
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- TYK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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Paragraph 00662; 00664
(2018/04/27)
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- Preparation method, intermediate and crystal form of spironolamine arylphosphine oxide
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The invention discloses a preparation method and a crystal form of high-purity spironolamine arylphosphine oxide. The invention further discloses a method for preparing a compound shown as a formula (I) and an intermediate compound.
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Paragraph 0097-0099
(2017/08/30)
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- Homogeneous-phase 'one-pot' preparation method of Brigatinib key intermediate
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The invention belongs to the technical field of drug synthesis, and particularly relates to a homogeneous-phase 'one-pot' preparation method of a Brigatinib key intermediate (II). The preparation method includes the steps: performing coupling reaction on 2-iodoaniline and dimethyl phosphine oxide under the action of catalysts and acid-binding agents; directly performing substitution reaction on reactants and 2, 4, 5-trichloropyrimidine without separation; performing extraction, washing, drying, filtration and concentration to obtain a crude product; performing recrystallization on the crude product to obtain a (2-((2,5-dichloropyrimidine-4-group) amidogen) phenyl) dimethyl phosphine oxide (II). According to the method, two-step reaction is replaced by a homogeneous-phase 'one-pot' method, separation and purification are omitted, steps are decreased, operation is simplified, yield is improved as compared with the prior art, recrystallization replaces column chromatography purification, solvent consumption and emission of 'waste gas, waste water and solid waste' are reduced, and the preparation method is suitable for industrial production.
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Paragraph 0022; 0023; 0025; 0027; 0029; 0031; 0033
(2018/01/19)
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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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- Spiro aryl phosphorus oxide or sulfide
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The invention discloses a spiro aryl phosphorus oxide or sulfide as ALK inhibitor, and in particular discloses a compound shown in a formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof.
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Paragraph 0192; 0193; 0194; 0195
(2016/10/08)
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- CRYSTALLINE FORMS OF 5-CHLORO-N4-[-2-(DIMETHYLPHOSPHORYL) PHENYL]-N2-{2-METHOXY-4-[4-(4-METHYLPIPERAZIN-1-YL) PIPERIDIN-1-YL] PYRIMIDINE-2,4-DIAMINE
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Crystalline forms of brigatinib, pharmaceutical compositions comprising the same, and methods of their preparation and use of the same are disclosed herein.
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Paragraph 00366; 00367; 00368
(2016/05/24)
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- PHOSPHOROUS DERIVATIVES AS KINASE INHIBITORS
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The invention features compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use.
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Paragraph 0791-0792
(2015/09/22)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula (I), wherein the variables are as defined herein.
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Page/Page column 41-42
(2013/12/03)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of formula (I), wherein the variables are as defined herein.
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Page/Page column 37
(2012/11/14)
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