- Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib
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The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro-2-methoxy-5-nitroaniline, a key building block in the synthesis of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is used for the treatment of nonsmall-cell lung carcinomas carrying EGFR-TKI sensitizing and EGFR T790M resistance mutations. The hazards associated with nitration of organic compounds, such as thermal runaway and explosivity of intermediates, make it difficult to scale up nitrations to industrial quantities, particularly within large-scale batch reactors. In this study, we investigated an acetic acid/aqueous nitric acid mixture as a predominantly kinetically controlled nitration regime and a water-free mixture of acetic acid, fuming nitric acid, and fuming sulfuric acid (oleum) as a mass-transfer-limited nitration regime. A modular microreactor platform with in-line temperature measurement was utilized for the nitration. Furthermore, we identified that it was necessary to protect the amine functionality through acetylation to avoid side reactions. The process parameters and equipment configuration were optimized at laboratory scale for the acetylation and nitration to improve the product yield and purity. The two steps could be successfully telescoped, and the laboratory-scale flow process was operated for 80 min to afford the target molecule in 82% isolated yield over two steps, corresponding to a throughput of 25 mmol/h. The developed flow process was then transferred to an industrial partner for commercial implementation and scaled up by the use of higher flow rates and sizing-up of the microreactor platform to pilot scale to afford the product in 83% isolated yield, corresponding to a throughput of 2 mol/h (0.46 kg/h).
- K?ckinger, Manuel,Wyler, Benjamin,Aellig, Christof,Roberge, Dominique M.,Hone, Christopher A.,Kappe, C. Oliver
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Read Online
- 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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Read Online
- Synthesis method of osimertinib intermediate
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The invention relates to a synthesis method of an osimertinib intermediate. The synthesis method comprises the following steps: 1, with 3-fluoroanisole as an initial raw material, adding 3-fluoroanisole into concentrated sulfuric acid, dropwise adding the concentrated nitric acid in a low-temperature environment, carrying out primary heating and stirring after completion of the addition, injectingthe formed system into ice water for quenching, carrying out secondary heating and stirring, and carrying out filtering to obtain a product, namely 3-fluoro-4, 6-dinitroanisole; and 2, adding the compound 3-fluoro-4,6-dinitroanisole obtained in the step 1 into water, adding alkali, conducting heating, adding a weak reducing agent in batches, performing stirring while keeping the temperature untila reaction endpoint is reached, carrying out filtering to obtain a crude product, and successively conducting washing, recrystallizing with methanol, crystallizing and filtering at a low temperatureand drying to finally obtain 4-fluoro-2-methoxy-5-nitroaniline. The method of the invention solves the problems that raw materials are expensive and hardly-available in the market, process is complexand yield is low in conventional synthesis methods of the osimertinib intermediate.
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Paragraph 0045; 0048-0050; 0053-0055; 0060; 0063-0065; 0068
(2021/02/10)
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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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- BENZIMIDAZOLE DERIVATIVES
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The invention relates to benzimidazoles of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1 to R6 are as defined in the description; to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes. The benzimidazoles of Formula (I) are ITK inhibitors and are therefore potentially useful in the treatment of a wide range of disorders including, atopic dermatitis.
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Page/Page column 53; 93
(2021/06/26)
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- 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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- Novel crystal form of deuterated AZD9291 compound and application thereof (by machine translation)
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The invention belongs to the technical field of medicines, and particularly discloses a preparation method AZD9291 of a novel crystal form, and of deuterated . and application AZD9291 of the deuterated, crystal form is stable in crystal form, crystal form stability compared with crystal form DVS by combining suspension experiment with acceleration stability study, at normal temperature and accelerated stability. AZD9291. The present invention further discloses the crystal form A of a deuterated C . crystal form. (by machine translation)
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- The therapeutic effect of the anticancer agent for predicting alternative (by machine translation)
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[Problem] non-small cell lung cells resistant to various epidermal growth factor receptor gene mutation appears when, for selecting alternative anticancer effects, minimally invasive or non-invasive diagnosis of a genetic therapeutic effect of anticancer agent can be labeled with radioactive alternative predicted. The therapeutic effect of the anticancer agent is predicted [solution] alternatively, the anticancer drug is selected to be labeled with a radioactive isotope which alternate, the anticancer drug resistance should be selected to be an alternative to the anticancer agent is preferably labeled with a radioactive isotope as an alternative. The therapeutic effect of the anticancer agent is an alternative prediction, wherein the anticancer agent is an anticancer agent are alternative, epidermal growth factor receptor due to genetic drug resistance, epidermal growth factor receptor tyrosine kinase inhibitors is that. [Drawing] no (by machine translation)
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- Purine compounds and application thereof
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The invention relates to purine derivatives represented as the general formula I and pharmaceutically acceptable salts, hydrates or prodrugs of the purine derivatives. Substituent groups X, R1, R1', R2, R3, R4 and Ar have the meaning given in the description. The invention further relates to a function of the compounds represented as the general formula I in inhibition of EGFR (epidermal growth factor receptor) kinase and mutants of EGFR kinase, in particular to an application of the compounds and the pharmaceutically acceptable salts, hydrates or prodrugs thereof to preparation of drugs for treating diseases related to EGFR kinase activity, especially an application to preparation of drugs for treating and/or preventing cancer.
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Paragraph 0090-0092
(2019/09/17)
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- 2-(2, 4, 5-substituted aniline) pyrimidine derivative
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The invention relates to a 2-(2, 4, 5-substituted aniline) pyrimidine derivative, and more specifically discloses a compound represented by formula I or a pharmaceutically acceptable salt thereof, anda preparation method and applications of the compound represented by formula I and the pharmaceutically acceptable salt of the compound, wherein R1 to R9 are used for representing groups defined in the invention.
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Paragraph 0393-0396
(2019/11/21)
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- A PROCESS FOR THE PREPARATION OF 4-FLUORO-2-METHOXY-5-NITROANILINE
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The present invention is directed towards a process for the preparation of 4- fluoro-2-methoxy-5-nitroaniline (I) or salts thereof, wherein, 4-fluoro-2-methoxy aniline (III) is protected to obtain N-protected-(4-fiuoro-2-methoxy)aniline (VI), which is nitrated to obtain N-protected-(4-fluoro-2-methoxy-5-nitro)aniline (VII) and finally deprotected to obtain 4-fluoro-2-methoxy-5-nitroaniline (I) or salt thereof.
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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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- FUSED-RING OR TRICYCLIC ARYL PYRIMIDINE COMPOUND USED AS KINASE INHIBITOR
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Disclosed is a fused-ring or tricyclic aryl pyrimidine compound used as a mutation selectivity EGFR inhibitor. Specifically, disclosed is a compound represented by formula (I) and used as an EGFR inhibitor or a pharmaceutically acceptable salt thereof.
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- 2, 4-DI-(NITROGEN CONTAINING GROUP) SUBSTITUTED PYRIMIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF
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Provided are a 2, 4-di-(nitrogen containing group) substituted pyrimidine compound represented by a general formula (I), a pharmaceutically acceptable salt and a stereoisomer thereof, a preparation method thereof, and a use thereof in preparation of anti-tumor drugs. The compound having a structural feature shown in the general formula (I) can selectively suppress activity of mutant epidermal growth factor receptors (EGFR), including single-mutant EGFR (T790M) and double-mutant EGFR (including L858R/T790M and ex19del/T790M), and can suppress activity of single gain-of-function mutant EGFR (including L858R and ex19del) as well. The compound has a weak suppression effect on wild-type EFGR and a very high selectivity, and thus it has a potential to be used in preparation of drugs for treating EGFR mutant tumors, especially non-small cell lung cancer (NSCLC) comprising a T790M EGFR mutation.
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- A deuterated AZD9291 crystalline form, preparation method and use thereof (by machine translation)
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The invention belongs to the field of medical technology, specifically discloses a deuterated AZD9291 crystalline form, and the crystal preparation method and use thereof. The states the deuterium generation AZD9291 crystalline form using Cu - Kα ray measuring the obtained X-ray powder diffraction in the 2 θ angle is: 7.1 ± 0.2, 8.5 ± 0.2, 9.4 ± 0.2, 10.3 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 18.7 ± 0.2, 22.0 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2 with at the peak. The invention also discloses the deuterated AZD9291 crystalline form for the preparation of a medicament for the treatment of cancer in the use thereof. The present invention provides of the deuterated AZD9291 crystalline form of physical and chemical properties are stable, metabolic stability is good, its in vivo blood medicine concentration and the concentration of the brain is remarkably improved, and can achieve better curative effect. (by machine translation)
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- Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold
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Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.
- Hu, Jinxing,Han, Yufei,Wang, Jingtao,Liu, Yue,Zhao, Yanfang,Liu, Yajing,Gong, Ping
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p. 1810 - 1822
(2018/03/01)
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- Substituted pyrimidine derivative and preparation method and pharmaceutical application thereof
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The invention relates to a piperazine substituted pyridylamino derivative and an optical isomer, a pharmaceutically acceptable salt or eutectic thereof, and a preparation method and purposes during preparing antitumor drugs. The structure of the derivative is shown in the description.
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Paragraph 0081-0085
(2018/10/11)
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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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- 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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- 2,4-DISUBSTITUTED PHENYLENE-1,5-DIAMINE DERIVATIVES AND APPLICATIONS THEREOF, AND PHARMACEUTICAL COMPOSITIONS AND PHARMACEUTICALLY ACCEPTABLE COMPOSITIONS PREPARED THEREFROM
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The present invention provides a class of 2,4-substituted phenylene-1,5-diamine derivatives, having an inhibiting effect on EGFR tyrosine kinases, and pharmaceutically acceptable salt, stereoisomer, solvate or prodrug of said derivatives. See the description for the definition of each group in the formula. In addition, the present invention also discloses pharmaceutical compositions, pharmaceutically acceptable compositions and applications thereof.
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- 2,3,4,6-TETRA-SUBSTITUTED BENZENE-1,5-DIAMINE DERIVATIVES, PREPARATION METHOD THEREFOR AND MEDICINAL USE THEREOF
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The present invention relates to 2,3,4,6-tetra-substituted benzene-1,5-diamine derivatives, a preparation method therefor and a medicinal use thereof. Specifically, disclosed are compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, preparation method therefor and application thereof. Definition of each group in the formula can be found in the specification for details.
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- 2,4-DISUBSTITUTED 7H-PYRROLO[2,3-D]PYRIMIDINE DERIVATIVE, PREPARATION METHOD AND MEDICINAL USE THEREOF
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The present invention relates to a 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, a preparation method and a medicinal use thereof. In particular, the present invention discloses a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a preparation method and use thereof. For the definition of each group in formula (I), see the description for details.
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- SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF THE EGFR TYROSINE KINASE
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The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and/or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell proliferative disorders, such as cancer, wherein A, R2, R3, R10, E1, E2, E3, Y, and Z are as defined herein.
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Page/Page column 340
(2017/08/01)
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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 0411; 0412; 0413; 0414
(2017/09/01)
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- 2-(2,4,5-substituted aniline) pyrimidine derivative
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Disclosed is a 2-(2,4,5-substituted aniline) pyrimidine derivative. Disclosed are a compound shown in the formula (I) or pharmaceutically-acceptable salt thereof, a preparation method of the compound shown in the formula (I) or the pharmaceutically-acceptable salt thereof, a pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically-acceptable salt thereof, and an application of the compound shown in the formula (I) or the pharmaceutically-acceptable salt thereof. In the formula (I), R1 to R6 are defined as shown in the application.
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Paragraph 0305-0308
(2017/09/01)
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- Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC
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Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFRT790M secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three-step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFRT790M-driven NSCLC.
- Chen, Lingfeng,Fu, Weitao,Feng, Chen,Qu, Rong,Tong, Linjiang,Zheng, Lulu,Fang, Bo,Qiu, Yinda,Hu, Jie,Cai, Yuepiao,Feng, Jianpeng,Xie, Hua,Ding, Jian,Liu, Zhiguo,Liang, Guang
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p. 510 - 527
(2017/10/10)
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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 0052-0053
(2017/09/19)
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- Pyrimidine compound as well as preparation method and medical application of pyrimidine compound
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The invention discloses a pyrimidine compound, a pharmaceutically-acceptable salt, a stereoisomer, a prodrug and a solvate thereof, as well as a preparation method, a pharmaceutical composition and medical application of the pyrimidine compound. This type of compound can generate an inhibitory effect on variant forms of EGFR (epidermal growth factor receptor) protease, so that the compound can effectively inhibit the growth of various tumor cells, can be used for preparing antitumor drugs, can be applied to treatment, combined treatment or prevention of many different cancers, and can overcome drug tolerance induced by first-generation EGFR inhibitors including existing drugs of gefitinib, erlotinib and the like. More particularly, this type of compound can be used for preparing medicines for treating or preventing diseases, obstacles, disorders or illness states mediated by certain epidermal growth-factor receptors with variant forms (for example, L858R active mutants, Exon19 deletion active mutants, and T790M resistant mutants).
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Paragraph 0120; 0121; 0122; 0123
(2017/08/28)
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- Azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof
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The invention relates to azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof. Specifically, the invention discloses compounds represented by a formula (I), or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof. The invention also provides preparation methods of the derivatives, and applications of the derivatives in EGFR inhibitors. The definitions of the groups in the formula are defined in the specifications.
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- Heterocyclic derivate tyrosine kinase inhibitor
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The invention belongs to the technical field of medicine and particularly relates to a heterocyclic derivate tyrosine kinase inhibitor shown in the formula (I), a pharmaceutically acceptable salt and ester thereof and stereoisomers thereof, wherein Y, W, Q m, L, R1, R2, R3, R4, R5, R6, R7, R7', R8 and R8' are defined in the specification. The invention further relates to a preparation method of the compounds and a pharmaceutical preparation and pharmaceutical compositions containing the compounds, and application of the compounds as the tyrosine kinase inhibitor for preparing medicine for preventing and/or treating cancer diseases caused by EGFR mutation and drug resistance diseases caused by EGFR T790M mutation.
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- HETEROARYL COMPOUNDS FOR KINASE INHIBITION
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Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFRand mutant HER2 activity, are described herein.
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- Pyrimidine compound, EGFR inhibitor and application of EGFR inhibitor
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The invention discloses a pyrimidine compound, an EGFR inhibitor and application of the EGFR inhibitor. The pyrimidine compound is prepared from a compound shown in the formula I or pharmaceutically acceptable salt thereof, a stereoisomer, and a solvate or prodrug. The EGFR inhibitor contains the pyrimidine compound. The pyrimidine compound can inhibit activated or resistant mutation of one or more kinds of EGFRs, can inhibit proliferation of the EGFR T790M/L858R double-mutant enzyme in the nanomolar concentration, but has a weak inhibiting effect on the wild EGFR enzyme; the pyrimidine compound is applicable to treatment of the EGFR-sensitive mutations cancer and also suitable for cases with secondary dug resistance in present EGFR-TKI treatment; meanwhile, toxic and side effects caused by inhibition on the wild EGFR are greatly reduced due to the mutation selectivity of the pyrimidine compound, and the pyrimidine compound is an ideal treatment drug for diseases caused by EGFR mutation.
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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 0065; 0066; 0067
(2016/10/07)
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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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p. 318 - 320
(2015/08/18)
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- HETEROARYL COMPOUNDS FOR KINASE INHIBITION
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Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFRand mutant HER2 activity, are described herein.
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- HETEROARYL COMPOUNDS FOR KINASE INHIBITION
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Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFRand mutant HER2 activity, are described herein.
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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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- 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 93
(2013/03/26)
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- Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR)
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A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
- Ward, Richard A.,Anderton, Mark J.,Ashton, Susan,Bethel, Paul A.,Box, Matthew,Butterworth, Sam,Colclough, Nicola,Chorley, Christopher G.,Chuaqui, Claudio,Cross, Darren A.E.,Dakin, Les A.,Debreczeni, Judit é.,Eberlein, Cath,Finlay, M. Raymond V.,Hill, George B.,Grist, Matthew,Klinowska, Teresa C.M.,Lane, Clare,Martin, Scott,Orme, Jonathon P.,Smith, Peter,Wang, Fengjiang,Waring, Michael J.
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p. 7025 - 7048
(2013/10/01)
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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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- FUSED HETEROCYCLIC DERIVATIVE, PHARMACEUTICAL COMPOSITION COMPRISING THE DERIVATIVE, AND USE OF THE COMPOSITION FOR MEDICAL PURPOSES
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The present invention provides compounds useful as agents for the prevention or treatment of a sex hormone-dependent disease or the like. That is, the present invention provides fused heterocyclic derivatives represented by the following general formula (I) which has a GnRH antagonistic activity, pharmaceutical compositions containing the same, medicinal uses thereof and the like. In the formula (I), rings A is 5-membered cyclic unsaturated hydrocarbon or 5-membered heteroaryl; RA is halogen, alkyl, alkenyl, alkynyl, carboxy, alkoxy, carbamoyl, alkylcarbamoyl, etc.; ring B is aryl or heteroaryl; RB is halogen, alkyl, carboxy, alkoxy, carbamoyl, alkylcarbamoyl, etc.; E1 and E2 are oxygen atom, etc.; Q is hydrogen atom, alkyl, alkylsulfonyl, acyl, etc.; X is -(alkylene)-Z, -CO-Y, -SO2-Y, etc. (in which Y is Z or amino, etc.; Z is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.
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Page/Page column 16
(2010/02/17)
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