- Improvements in the Synthesis of the Third-Generation EGFR Inhibitor Osimertinib
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Osimertinib, a third generation potent and specific EGFR inhibitor is an important drug against many forms of cancer. It was synthesized by an improved and highly efficient protocol, revisiting the classical synthetic process and modifying parameters, such as solvents, temperature, reagents, and reaction time. A cost-effective, environmentally friendly methodology for the synthesis of osimertinib was established, which gave shorter reaction times, saved labor by eliminating purification steps through column chromatography, and enhanced yields. Four of the seven steps in total, were proceeded quantitatively or almost quantitatively (ca. 98 %). This synthetic protocol provides a very high overall yield, up to 68 %. In addition, the entire approach enables the preparation of osimertinib analogues and could be extended in the synthesis of other structurally similar bioactive compounds.
- Alivertis, Dimitrios,Skobridis, Konstantinos,Voulgari, Pinelopi
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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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- 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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- 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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- Preparation method of osimertinib mesylate
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The invention discloses a preparation method of osimertinib mesylate. 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole are subjected to a condensation reaction and then subjected to a nucleophilic substitution reaction with N, N-dimethylethylenediamine, a high-purity compound shown in the formula (6) is obtained through Eschweiler-Clarke amine reductive alkylation, water serves as a solvent, acetic acid and the like serve as a cosolvent, catalytic hydrogenation is performed, amidation reaction with acryloyl chloride is carried out to obtain high-purity osimertinib and salifying with methanesulfonic acid is carried out to obtain osimertinib mesylate, and compared with the patent CN103702990B, the method is simple and convenient to operate, less in environmental pollution, high in yield, low in cost, good in product quality and more suitable for industrial production.
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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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- 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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Paragraph 0110
(2019/06/14)
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- 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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p. 367 - 380
(2018/12/13)
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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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- 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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- Osimertinib intermediate and preparation method thereof
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The invention belongs to the field of medicine synthesis and particularly relates to an osimertinib intermediate and a preparation method thereof. The provided osimertinib intermediate is a compound in a formula C and has a structural formula in the description, wherein R is alkyl or aryl; R1 is alkyl, more preferably, methyl. After the compound in the formula C is hydrolyzed, the compound and a compound in a formula E are subjected to a condensation reaction, a compound in a formula F is prepared, wherein R is alkyl or aryl; R1 is alkyl, more preferably, methyl.
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- Pyrimidine heterocyclic compounds, preparation method and application thereof
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The present invention relates to compounds of a formula (I) shown in the description, and pharmaceutically acceptable salts, prodrugs and solvates thereof, and the compounds are useful for treating cancer and inflammation in mammals. The invention also discloses a preparation method for the compounds of the formula (I) and a pharmaceutical composition containing the compound.
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- Osimertinib preparation method
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The present invention relates to an osimertinib preparation method, which comprises: (1) carrying out a nucleophilic substitution reaction on 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole and 4-fluoro-2-methoxy-5-nitroaniline to prepare a compound 1; (2) carrying out a substitution reaction on the compound 1 and N,N,N-trimethylethylenediamine in the presence of an organic alkali to prepare a compound 2; (3) reducing the compound 2 in the presence of a reducing agent to prepare a compound 3; (4) carrying out condensation on the compound 3 and 3-chloropropionyl chloride in the presence of an alkali to obtain a compound 4; (5) carrying out a heat elimination reaction on the compound 4 through heating in the presence of an alkali to prepare a compound 5; and (6) carrying out salification on the compound 5 and methanesulfonic acid under a heating condition to obtain osimertinib. According to the present invention, the osimertinib synthesis process has characteristics of stability, controllability, no high-toxicity solvent is used, energy saving and environmental protection.
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- Preparation method of AZD9291
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The invention relates to the technical field of organic synthesis and bulk drug preparation and concretely relates to a preparation method of an antineoplastic drug AZD9291. 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine and N, N, N'-trimethylethylenediamine undergo a reaction to produce 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine, the 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine and 1-(1-methylindolyl-3-yl)-3-(dimethylamino)-2-acrylketone undergo a reaction to produce N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methylindolyl-3-yl)pyrimidin-2-yl)-2-nitrophenyl-1, 4-diamine, the N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methylindolyl-3-yl)pyrimidin-2-yl)-2-nitrophenyl-1, 4-diamine is hydrogenated until a nitro group is reduced to form an amino group, and the hydrogenated product and acryloyl chloride undergo a reaction to produce AZD9291.
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- New and Convergent Synthesis of Osimertinib
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New and convergent synthetic route of osimertinib is described on a dozen of grams scale. A key cyclization of 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine and 3-(dimethylamino)-1-(1-methyl-1H-indol-3-yl)prop-2-en-1-one is adopted to give the 4-(1H-indol-3-yl)-N-phenylpyrimidin-2-amine structure. Osimertinib is prepared in 40.4% yield over six steps and 99.1% purity (HPLC). Purification methods of the intermediates involved in the route are also given.
- Zhu, Guoqing,Wang, Xingyan,Wang, Feng,Mao, Yongjun,Wang, Han
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p. 2898 - 2901
(2017/09/26)
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- Intermediate used for AZD9291 preparation, and preparation method and application thereof
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The invention relates to the technical field of organic synthesis and raw medicine preparation, and concretely relates to an organic intermediate used for antitumor medicine AZD9291 preparation, and a preparation method and an application thereof. The intermediate is 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine. The preparation method of the intermediate comprises the following steps: 1, reacting 2-methoxy-4-fluoro-5-nitroaniline with cyanamide to obtain 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine; and 2, carrying out a nucleophilic substitution reaction on the 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine and N,N,N'-trimethylethylenediamine to prepare the 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine. The preparation method of the intermediate has the advantages of easily available raw materials, mild reaction conditions, simplicity and convenience in post-treatment, suitableness for amplified preparation, and high yield.
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Paragraph 0071; 0072; 0073; 0074; 0076; 0077
(2017/02/28)
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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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- 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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- Design, synthesis, SAR discussion, in?vitro and in?vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants
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Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in?vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.
- Zhang, Haoyang,Wu, Wenkui,Feng, Chao,Liu, Zhaogang,Bai, Enhe,Wang, Xueyuan,Lei, Meng,Cheng, Hao,Feng, Huayun,Shi, Jingmiao,Wang, Jia,Zhang, Zhao,Jin, Tao,Chen, Shanshan,Hu, Shihe,Zhu, Yongqiang
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- Method for preparing AZD9291
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The invention discloses a method for preparing AZD9291, and belongs to the technical field of medicine preparation. The method comprises the following steps: by taking 3-(2-chloro-pyrimidine-4-yl)-1-methylindole as a raw material, firstly, performing substitution reaction with 4-fluorine-2-methoxy-5-nitroaniline so as to generate 3-[2-[(4-fluorine-2-methoxy-5-nitro)aniline]pyrimidine-4-yl]-1-methylindole (3); secondly, under the action of a catalyst, performing substitution on the compound 3 with N,N,N'-trimethyl quadrol so as to generate 3-[2-[(4-(N,N,N'-trimethylethylenediamine)-2-methoxy-5-nitro)aniline]pyrimidine-4-yl]-1-methylindole (5); performing reduction of nitro and amidation of amino on the compound 5, and performing synthesis by using a 'one-pot method', thereby obtaining AZD9291. The method is concise in process, environmentally friendly, low in cost and applicable to industrial production.
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- Method for preparing osimertinib mesylate
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The invention discloses a method for preparing Osimertinib mesylate. The method comprises the steps that after 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with 4-fluorine-2-methoxy-5-nitroaniline, 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with N,N,N'-trimethyl-ethylenediamine, nitro is restored after catalytic hydrogenation, then 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to coupling reaction with 3-chloropropionyl-chloride, osimertinib is obtained after elimination with sodium hydroxide, and osimertinib reacts with salt mesylate in acetone and water to obtain osimertinib mesylate, wherein a catalyst for restoring nitro by the catalytic hydrogenation is raney nickel, palladium carbon or palladium-carbon hydroxide. The method for preparing osimertinib mesylate is low in cost, high in yield, little in environmental pollution, simple and easy in production process operation and suitable for industrialized production.
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- Preparation method of antitumor drug AZD9291
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The invention discloses a preparation method of antitumor drug AZD9291. The method is as follows: reaction of 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-pyrimidine-4-yl)-1-methylindole to obtain an intermediate 1; reaction of the intermediate 1 and N, N, N '-trimethylethylenediamine to obtain a compound intermediate 2; hydrogenation reduction of the intermediate 2 to obtain a compound intermediate 3, further introduction of acryloyl group into the intermediate 3 to obtain the AZD9291, and the method is characterized in that activator cuprous bromide is added into the preparing process of the intermediate 2; palladium carbon is used for catalytic hydrogenation reduction, and a mixed anhydride solution of acrylic acid is used for introduction of the acryloyl group of the AZD9291. The method effectively reduces waste solid generation, and improves the purity and the yield of the product.
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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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