- Synthesis method of copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate
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The invention provides a synthetic method of a copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate, which comprises the following specific reaction steps: reacting sodium methoxide, ethyl formate and methyl 3,3-dimethoxypropionate in a methanol solvent at room temperature for 5 hours, then adding guanidine hydrochloride, conducting reacting at 50-55 DEG C for 2 hours, conducting cooling to room temperature after the reaction is completed, and conducting filtering and drying to obtain methyl 2-aminopyrimidine-5-carboxylate. The invention solves the problems of tedious reaction, high-risk raw material need, much waste liquid and waste water generated in the production process and the like in the existing reaction of the copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate, and provides a novel synthetic method of the copanlisib intermeidate methyl 2-aminopyrimidine-5-carboxylate, and the preparation method is simple, safe and controllable in reaction process, cheap and easily available in raw materials, high in yield, less in generated three wastes and the like.
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Paragraph 0016; 0022-0029
(2021/05/12)
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- Simple preparation method of 2-aminopyrimidine-5-formate
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The invention provides a simple preparation method of 2-aminopyrimidine-5-formate. The preparation method comprises: carrying out a substitution reaction on 2-methacrylate as a raw material and a halogenating reagent 1, carrying out an addition reaction with a halogenating reagent 2 to obtain 2,3,3-trihalogenated-2-halogenated methyl propionate, and condensing the obtained 2,3,3-trihalogenated-2-halogenated methyl propionate and a guanidine salt to prepare 2-aminopyrimidine-5-formate. According to the invention, the raw materials used in the method are cheap, easy to obtain and low in cost; and the preparation method has characteristics of simpleness, easily achieved conditions, good operation safety, little wastewater generation, environmental protection, high target product yield and high target product purity, and is suitable for industrial production.
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- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
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The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a PD-1 signaling inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and the PD-1 signaling inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a PD-1 signaling inhibitor and a pharmaceutically acceptable carrier or excipient.
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Paragraph 0088; 0094
(2020/04/09)
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- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
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The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a BCL-2 inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and a BCL-2 inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a BCL-2 inhibitor and a pharmaceutically acceptable carrier or excipient.
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Page/Page column 26; 28
(2018/05/24)
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- New tetrahydropyrido pyrimidinecarboxylic compound or salt thereof
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To provide a compound having an inhibitory activity for an androgen receptor. A tetrahydropyridopyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable thereof (in the formula, X and R are as defined in the specification).
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Paragraph 0171
(2016/10/08)
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- Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
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The invention provides a compound of Formula I, Pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.
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Page/Page column 35
(2016/02/26)
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- Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)
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The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.
- Scott, William J.,Hentemann, Martin F.,Rowley, R. Bruce,Bull, Cathy O.,Jenkins, Susan,Bullion, Ann M.,Johnson, Jeffrey,Redman, Anikó,Robbins, Arthur H.,Esler, William,Fracasso, R. Paul,Garrison, Timothy,Hamilton, Mark,Michels, Martin,Wood, Jill E.,Wilkie, Dean P.,Xiao, Hong,Levy, Joan,Stasik, Enrico,Liu, Ningshu,Schaefer, Martina,Brands, Michael,Lefranc, Julien
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p. 1517 - 1530
(2016/08/27)
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- Identification and optimization of new dual inhibitors of B-Raf and epidermal growth factor receptor kinases for overcoming resistance against vemurafenib
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Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-RafV600E inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-RafV600E mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC 50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf V600E dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-RafV600E inhibitor therapy.
- Cheng, Huimin,Chang, Yu,Zhang, Lianwen,Luo, Jinfeng,Tu, Zhengchao,Lu, Xiaoyun,Zhang, Qingwen,Lu, Jibu,Ren, Xiaomei,Ding, Ke
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p. 2692 - 2703
(2014/04/17)
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- HEDGEHOG ANTAGONISTS HAVING ZINC BINDING MOIETIES
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The present invention provides compounds which antagonize hedgehog signaling and inhibit HDAC activity. The com-pounds can be used in methods of treating proliferative dis-eases and disorders such as cancer
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Paragraph 0178
(2014/02/16)
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- AMIDO SPIROCYCLIC AMIDE AND SULFONAMIDE DERIVATIVES
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Provided are amido spirocyclic amide and sulfonamide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 144
(2013/09/12)
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- AMIDO-BENZYL SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment of an NAMPT-mediated disease or condition in a subject, selected from solid or liquid tumor, rheumat
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Paragraph 0175
(2013/09/12)
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- PYRIDINYL AND PYRIMIDINYL SULFOXIDE AND SULFONE DERIVATIVES
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Disclosed are certain pyridinyl and pyrimidinyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds and methods of treatment using such compounds.
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Page/Page column 82
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
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Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
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Page/Page column 60
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 131
(2013/09/12)
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- ALKYL-AND DI-SUBSTITUTED AMIDO-BENZYL SULFONAMIDE DERIVATIVES
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The present invention relates to certain alkyl- and di-substituted amido-benzyl sulfonamide compounds, pharmaceutical compositions comprising such compounds, and to methods of treatment of NAMPT-mediated disorders, such as diabetes, rheumatoid arthritis,
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Paragraph 0183
(2013/09/12)
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- AMINOALCOHOL SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
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This invention relates to novel 2,3-dihydroimidazo[1,2 -c]quinazoline compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition and treating diseases associated with phosphotidylinositol-3-kinase (PI3K) activity, in particular treating hyper-proliferative and/ or angiogenesis disorders, as a sole agent or in combination with other active ingredients
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Page/Page column 53
(2012/05/31)
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- ARYLAMINOALCOHOL-SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINOLINES
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The present invention relates to substituted phenoxypyridine compounds of general foumula (I); in which R1, R2 and R3 are as defined in the claims, to methods of preparing said compounds, to intermediates for the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and /or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 57
(2012/05/31)
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- ALKOXY-SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES
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The present invention relates to alkoxy-substituted 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (I) in which R1, R2 and R3 are as defined in the claims, to methods of preparing said compounds, to intermediates for the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 58
(2012/05/31)
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- FUSED HETEROCYCLYC INHIBITOR COMPOUNDS
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The present invention provides a compound of general Formula (I) having histone deacetylase (HDAC) and/or Cyclin-dependent kinase (CDK) inhibitory activity, a pharmaceutical composition comprising the compound, and a method useful to treat diseases using the compound
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Page/Page column 123-124
(2010/03/02)
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- SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
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This invention relates to novel 2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition and treating diseases associated with phosphotidylinositol-3-kinase (PI3K) activity, in particular treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.
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Page/Page column 59
(2008/12/06)
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- Process for preparing heterocycles
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Process for the preparation of heterocycles by reacting 2-substituted acetals of malondialdehyde with a reactant selected from hydroxylamines and their salts, hydrazines and their salts, formamid, amidines and their salts, guanidines and their salts, aminoguanidines and their salts, nitroguanidine and their salts, O-alkyl-isoureas and their salts, O-cycloalkyl-isoureas and their salts, O-aralkyl-isoureas and their salts, O-aryl-isoureas and their salts, S-alkyl-isothioureas, S-cycloalkyl-isothioureas, S-aralkyl-isothioureas, S-arylisothioureas, S-alkyl-isothiouronium salts, S-cycloalkyl-isothiouronium salts, S-aralkyl-isothiouronium salts, S-aryl-isothiuronium salts, thiourea and urea.
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