- Process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine
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The invention discloses a process method suitable for amplification preparation of 4-(6-aminopyridin-3-yl) substituted piperidine, and belongs to the synthesis field of a medicine intermediate. N-substituted piperidone, aryl sulfohydrazide and 2-amino-5-bromopyridine are subjected to a coupling reaction under a palladium catalyst, and then are subjected to a hydrogenation to obtain 4-(6-aminopyridin-3-yl) substituted piperidine. According to the process, the raw materials in pyridine do not need to be protected; the condensation and the coupling are carried out in the same reaction kettle, sothat the operation cost is reduced, the steps of performing protection at first and then performing protection removal as in documents can be avoided, and production cost of the existing biological, medicine and chemical intermediates is greatly reduced; and the process is subjected to amplification verification in kilogram-scale, and the verification proves that the yield and the product purity are basically equal to those of gram-scale, so that the method can be used as a process for industrial scale production.
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Paragraph 0040; 0041; 0044; 0045; 0046
(2019/12/25)
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- SUBSTITUTED PYRROLOPYRIMIDINE CDK INHIBITOR, PHARMACEUTICAL COMPOSITION CONTAINING SAME AND USE THEREOF
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The present invention belongs to the field of pharmaceutical chemistry, and relates to a substituted pyrrolopyrimidine CDK inhibitor, in particular to a compound as shown in formula I or a pharmaceutically acceptable salt or solvate thereof, as well as a preparation method thereof and a pharmaceutical composition thereof. The present invention also relates to the use of the compound and the pharmaceutical composition thereof in the preparation of a drug for treating diseases associated with CDK inhibition. The compound according to the present invention has a marked inhibitory effect on CDK, excellent drug absorption and significantly superior oral absorption effect.
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Paragraph 0096; 0097
(2019/02/09)
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- PYRIDINE CARBONYL DERIVATIVES AND THERAPEUTIC USES THEREOF AS TRPC6 INHIBITORS
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The invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein R1 to R7, A, Y and L are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 50
(2019/05/15)
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- PYRAZOLO-TRIAZINE AND/OR PYRAZOLO-PYRIMIDINE DERIVATIVES AS SELECTIVE INHIBITOR OF CYCLIN DEPENDENT KINASE
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The present invention relates to pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[l,5-a]pyrimidine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases. Furthermore, the present invention is directed towards pharmaceutical compositions containing at least one of the pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives and/or pharmaceutically acceptable salts thereof.
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Page/Page column 50; 54
(2019/11/04)
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- Streamlined Synthesis of Diaminopyridines by Pd-Catalyzed Ammonia Coupling with Deactivated Amino-Chloropyridines
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An efficient and cost-effective two-step synthesis of diaminopyridines, fundamental building blocks of biologically active compounds, is reported. The advantages over previously reported routes include cost and wider availability of the bromo-chloropyridine starting materials and the straightforward accessibility to an extended array of diaminopyridine regioisomers. The key enabler of this synthetic strategy is the development of an unprecedented palladium-catalyzed coupling reaction of ammonia with chloropyridines deactivated by the presence of an alkylamino substituent. The coupling reaction was accomplished with very low catalyst loadings under remarkably mild reaction conditions, making the system particularly suitable for both academic and industrial applications. The utility of this methodology is exemplified by the application to the synthesis of highly relevant scaffolds, including the synthetic intermediates of the marketed drugs Ribociclib and Palbociclib.
- Bourriquen, Florian,Bruneau-Voisine, Antoine,Jeandin, Aliénor,Stihle, Etienne,Fantasia, Serena
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p. 9006 - 9011
(2019/06/24)
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- Preparation method and intermediate of pyridinopyrimidine derivative
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The invention relates to a preparation method and an intermediate of a pyridinopyrimidine derivative. Specifically, the invention provides a compound as shown in a formula I which is described in thespecification and a method for preparing the pyridinopyr
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- INHIBITORS OF TRPC6
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The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts therefore, wherein R1 to R6, A, U, V, W, X, Y, and Z are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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- Preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate
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The invention discloses a preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate. The method is characterized in that 2-fluoro-5-bromopyridine, N-t-butyloxycarboryl-4-piperidone, raney nickel, etc. are used as the raw materials and subjected to three-step reaction to prepare the target product that is 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate. The method is simple, convenient and stable in process and operation; the product obtained in each step is easily separated and high in yield; the environment is protected; the rawmaterials are low in price and easy to obtain, so that the production cost of existing biological, medical and chemical intermediates can be greatly decreased; and the method is beneficial for industrial massive production.
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Paragraph 0100; 0103; 0104
(2018/03/24)
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- Preparation method of 4-(6-aminopyridine-3-radical) piperidine-1-tert-butyl formate
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The invention discloses a preparation method of 4-(6-aminopyridine-3-radical) piperidine-1-tert-butyl formate. The target product 4-(6-aminopyridine-3-radical) piperidine-1-tert-butyl formate is obtained by three steps of reactions by taking N-(5-bromine-piperidine-2-)-2, 2-dimethylacrylamide, N-t-butyloxycarboryl-4-piperidone, raney nickel and the like as raw materials. The preparation method issimple, convenient and stable in process operation, and a product in each step is easy to separate, high in yield and environmentally friendly; the comprehensive yield is 82 percent or above; comparedwith the yield of 42 percent of the existing process, the yield is obviously increased; furthermore, the raw materials are low in cost and readily available, so that the production costs of existingbiological, medical and chemical intermediates are substantially reduced; industrial large-scale production is facilitated.
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Paragraph 0074; 0075
(2018/05/16)
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- PYRIDO[3,4-d]PYRIMIDINE DERIVATIVE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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The purpose of the present invention is to provide a compound having an excellent CDK4/6 inhibiting activity. The present invention is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.
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- PROTEIN KINASE INHIBITOR, PREPARATION METHOD AND MEDICAL USE THEREOF
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The present invention provides compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R1 to R7 are as defined in the description. The present invention also provides a preparation method and a medical use of the compounds, The compounds of the present invention have an activity superior or equivalent to the candidate drug LY283521 9 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of the present invention thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.
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- A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy
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Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM.
- Yin, Lei,Li, Heng,Liu, Wenjian,Yao, Zhenglin,Cheng, Zhenzhen,Zhang, Huabei,Zou, Hui
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- SUBSTITUTED 2-HYDROGEN-PYRAZOLE DERIVATIVE SERVING AS ANTICANCER DRUG
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Disclosed is a substituted 2H-pyrazole derivative serving as a selective CDK4/6 inhibitor. Specifically, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof which serves as a selective CDK4/6 inhibitor.
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- PYRIMIDINE OR PYRIDOPYRIDONE COMPOUND AND APPLICATION THEREOF
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The present invention discloses a pyrimidine or pyridopyridone compound as shown in formula (I) and an application thereof relating to the technical field of medicament preparation. The compound can selectively suppress cyclin-dependent kinases (Cdks) CDK
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- Protein kinase inhibitor and its preparation method and medical application
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The invention provides a compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture, or a pharmaceutically acceptable salt or solvate of the compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture. The ring A, R1, R2, R3 and R4 are defined in the specification. The invention also provides a preparation method of the compound shown in the structural formula I and a use of the compound in preparation of a drug for treating cell proliferative disorder.
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- Aminoheteroaryl benzamides as kinase inhibitors
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The present invention provides a compound of Formula (I) or a salt thereof; and therapeutic uses of these compounds. The present invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent.
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Page/Page column 59; 60; 61
(2016/02/15)
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- Pyrimidine or pyridine pyridine ketone compound and its preparation method and application (by machine translation)
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The invention discloses a kind of type I of the pyrimidine or pyridine pyridine ketone compound and its preparation and application, which belongs to the technical field of pharmaceutical preparation. The compounds have high-efficient and selectively inhibit the cell cycle dependent kinases (Cdks) CDK4 and CDK6 active, and then by inhibiting CDK4/CDK6 prevent tumor cell division. Therefore, the compounds of this invention can be used for CDK4 and CDK6 the involved in cell cycle control disorders result in various diseases, especially suitable for the treatment of malignant tumors. (by machine translation)
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- Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors
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A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo.
- Zhao, Xinge,Xin, Minhang,Huang, Wei,Ren, Yanliang,Jin, Qiu,Tang, Feng,Jiang, Hailong,Wang, Yazhou,Yang, Jie,Mo, Shifu,Xiang, Hua
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p. 348 - 364
(2015/02/05)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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This application discloses the Btk inhibitor compounds 6-tert-Butyl-8-fluoro-2-{3- hydroxymethyl-4-[1-methyl-5-(1'-methyl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino)- 6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-2H-phthalazin-1-one, 2-(2-{3-[5-(5-Azetidin-1- ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2- hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile, and 6-tert-Butyl-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridin-2- ylamino}-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one, formulations thereof, and methods of treatment of asthma, as described herein.
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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This application discloses compounds according to generic Formula I: wherein the variables are defined as described herein, and which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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This application discloses compounds according to generic Formula I: wherein the variables are defined as described herein, and which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with
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- GLYCINE COMPOUND
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[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that a compound of the present invention or a salt thereof exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. The present invention further relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound of the present invention or a salt thereof, and an excipient.
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Page/Page column 24; 75; 87
(2012/07/28)
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- Inhibitors of Bruton's Tyrosine Kinase
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This application discloses 6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivatives according to generic Formula I: wherein, variables X, R, and Y4, are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation, such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.
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- 4-(pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6
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Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.
- Cho, Young Shin,Borland, Maria,Brain, Christopher,Chen, Christine H.-T.,Cheng, Hong,Chopra, Rajiv,Chung, Kristy,Groarke, James,He, Guo,Hou, Ying,Kim, Sunkyu,Kovats, Steven,Lu, Yipin,O'Reilly, Marc,Shen, Junqing,Smith, Troy,Trakshel, Gary,V?gtle, Markus,Xu, Mei,Xu, Ming,Sung, Moo Je
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experimental part
p. 7938 - 7957
(2011/03/19)
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- PROTEIN KINASE INHIBITORS
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The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof which is useful in the treatment of cell proliferative diseases.
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Page/Page column 8-9
(2010/07/04)
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- Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors
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A structure-activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure-activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of 288 kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor.
- Qiao, Lixin,Choi, Sungwoon,Case, April,Gainer, Thomas G.,Seyb, Kathleen,Glicksman, Marcie A.,Lo, Donald C.,Stein, Ross L.,Cuny, Gregory D.
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supporting information; experimental part
p. 6122 - 6126
(2010/06/16)
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