- PROCESSES OF PREPARING A JAK1 INHIBITOR
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The present application provides processes for preparing 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H, 1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, and phosphoric acid salt thereof, which is useful as a selective (Janus kinase 1) JAK1 inhibitor, as well as salt forms and intermediates related thereto.
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- Method for preparing aldehyde or ketone by oxidizing reaction alcohol oxide
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The invention relates to a method for preparing aldehyde or ketone by oxidizing reaction alcohol oxide. The invention belongs to the field of medicine and chemical engineering, and particularly relates to a nitric acid and organic nitrogen oxide composition as a catalyst. The invention is prepared by the oxidation reaction of alcohol, wherein the oxidant is oxygen, and the nitric acid and organic nitrogen oxide composition are used as a catalytic system. The reaction is homogeneous reaction, and the catalytic system is simplified. The method is simple and convenient to operate, high in yield and low in cost. The invention is a very economical and simple method for preparing aldehyde or ketone from alcohol, and is suitable for industrial production.
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Paragraph 0025-0036
(2021/11/03)
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- Synthesis of trisubstituted alkenes by Ni-catalyzed hydroalkylation of internal alkynes with cycloketone oxime esters
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A method for Ni-catalyzed hydroalkylation of internal alkynes with cycloketone oxime esters was developed. The reaction has a broad substrate scope. This hydroalkylation shows excellent regio-and stereo-selectivity. This method enables readily available starting materials to be used to access a range of cyano-substituted single-configuration trisubstituted alkenes. These are valuable feedstock chemicals and are widely used in synthetic and medicinal chemistry.
- Lu, Xiao-Yu,Liu, Chuang-Chuang,Jiang, Run-Chuang,Yan, Lu-Yu,Liu, Qi-Le,Wang, Qing-Qing,Li, Jia-Mei
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supporting information
p. 14191 - 14194
(2020/11/24)
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- Preparation method of medicine intermediate 1 -tert-butoxycarbonyl -3 -azetidinone (by machine translation)
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The invention relates to the technical field of organic chemistry, and concretely relates 1 - tert-butyloxycarbonyl -3 -azetidinone and a preparation method thereof. Wherein R1 Is C1 - C6 Alkyl groups and R2 And R3 Is H or C1 - C6 The alkyl group and the acid are organic acids or inorganic acids. The method is high in relative yield and high in industrial amplification production applicability. (by machine translation)
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Paragraph 0075-0080
(2020/07/15)
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- Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester
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The invention discloses a preparation method of 3-oxaazetidine-1-carboxylic acid tert-butyl ester. The preparation method comprises the following steps: firstly, synthesizing 2,2-bis(bromomethyl)-1,3-dioxolane from 1,3-dibromoacetone and ethylene glycol under the action of an acid, and cyclizing the 2,2-bis(bromomethyl)-1,3-dioxolane and tert-butyl carbamate under the action of an alkali to generate the 3-oxazetidine-1-carboxylic acid tert-butyl ester. The raw materials adopted in the method are cheap and easy to obtain, and the method is simple to operate, mild in reaction conditions, low inequipment requirements and suitable for industrial large-scale production.
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Paragraph 0029; 0033-0035
(2020/07/15)
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- 3-nitrile methylene azetidine-1-tert-butyl carbonate preparation method
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The invention discloses a 3-nitrile methylene azetidine-1-tert-butyl carbonate preparation method, which specifically comprises: 1, synthesizing 1-tert-butyl-3-glycolate; 2, synthesizing N-Boc-3-hydroxy azetidine through the 1-tert-butyl-3-glycolate obtained in the step 1; 3, synthesizing N-Boc-3-azetidinone through the N-Boc-3-hydroxy azetidinone obtained in the step 2; and 4, synthesizing 3-nitrile methylene azetidine-1-tert-butyl carbonate through the N-Boc-3-azetidinone obtained in the step 3. According to the preparation method disclosed by the invention, the existing conventional five-step synthesis process of 3-nitrile methylene azetidine-1-tert-butyl carbonate is reduced into three steps, so that the synthesis time is greatly saved, the emission of three-waste is reduced, and the process cost is reduced.
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Page/Page column 15; 17-19
(2020/02/06)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0111; 0114
(2019/08/22)
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- Preparation method of 2-[1-(ethyl sulfonyl)-3-azacyclic butyl] acetonitrile
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The invention relates to the technical field of medical chemistry, and particularly relates to a preparation method of a baricotinib tetratomic ring intermediate, and also provides green oxidizing reaction performed in a micro-channel reactor. According to the method, the raw materials in the technical route are easily obtained; the method is economic, green, environmentally friendly and suitablefor industrial production.
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Paragraph 0077-0080; 0082-0085
(2018/11/22)
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- Pleuromutilin antibiotics
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The present invention relates to pleuromutilin antibiotics represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R, R, R, R, m, X and Y are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and/or prevention of diseases caused by microorganisms.
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- Novel azetidine-containing TZT-1027 analogues as antitumor agents
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A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of TZT-1027 at the C-terminus. These analogues exhibited moderate to excellent antiproliferative activities, and the most potent compound 1a showed IC50 values of 2.2 nM against A549 and 2.1 nM against HCT116 cell lines, respectively. However, 1a could not achieve effective inhibition at all the dose levels in the A549 xenograft model (up to 5 mg/kg, injection, once a day), which is only 16%-35% inhibition at the end of the experiment.
- Yan, Qi,Wang, Yujie,Zhang, Wei,Li, Yingxia
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS AS TROPOMYOSIN RECEPTOR KINASE A (TRKA) INHIBITORS
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The present application relates to a series of substituted pyrazolo[1,5-a]pyridine compounds, their use as tropomyosin receptor kinase (Trk) family protein kinase inhibitors, method of making and pharmaceutical compositions comprising such compounds.
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- SUBSTITUTED IMIDAZO[1,2-a]PYRIDINE COMPOUNDS AS TROPOMYOSIN RECEPTOR KINASE A (TrkA) INHIBITORS
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The present application relates to a series of substituted imidazo[1,2-a]pyridine compounds of formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, their use as tropomyosin receptor kinase (Trk) family protein kinase inhibitors, method of making and pharmaceutical compositions comprising such compounds.
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- Process Development of CuI/ABNO/NMI-Catalyzed Aerobic Alcohol Oxidation
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An improved Cu/nitroxyl catalyst system for aerobic alcohol oxidation has been developed for the oxidation of functionalized primary and secondary alcohols to aldehydes and ketones, suitable for implementation in batch and flow processes. This catalyst, which has been demonstrated in a >50 g scale batch reaction, addresses a number of process limitations associated with a previously reported (MeObpy)CuI/ABNO/NMI catalyst system (MeObpy = 4,4′-dimethoxy-2,2′-bipyridine, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl, NMI = N-methylimidazole). Important catalyst modifications include the replacement of [Cu(MeCN)4]OTf with a lower-cost Cu source, CuI, reduction of the ABNO loading to 0.05-0.3 mol%, and use of NMI as the only ligand/additive (i.e., without a need for MeObpy). Use of a high flash point solvent, N-methylpyrrolidone, enables safe operation in batch reactions with air as the oxidant. For continuous-flow applications compatible with elevated gas pressures, better performance is observed with acetonitrile as the solvent.
- Steves, Janelle E.,Preger, Yuliya,Martinelli, Joseph R.,Welch, Christopher J.,Root, Thatcher W.,Hawkins, Joel M.,Stahl, Shannon S.
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p. 1548 - 1553
(2015/12/01)
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- JAK1 INHIBITORS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROMES
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This invention relates to JAK1 selective inhibitors, particularly pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine derivatives, and their use in treating myelodysplastic syndromes (MDS).
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Paragraph 0130
(2015/10/05)
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- Design, synthesis, and optimization of balanced dual NK1/NK 3 receptor antagonists
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In connection with a program directed at potent and balanced dual NK 1/NK3 receptor ligands, a focused exploration of an original class of peptidomimetic derivatives was performed. The rational design and molecular hybridization of a novel phenylalanine core series was achieved to maximize the in vitro affinity and antagonism at both human NK1 and NK3 receptors. This study led to the identification of a new potent dual NK1/NK3 antagonist with pKi values of 8.6 and 8.1, respectively.
- Hanessian, Stephen,Jennequin, Thomas,Boyer, Nicolas,Babonneau, Vincent,Soma, Udaykumar,Mannoury La Cour, Clotilde,Millan, Mark J.,De Nanteuil, Guillaume
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supporting information
p. 550 - 555
(2014/06/09)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0156
(2014/09/29)
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- PROCESS FOR THE PREPARATION OF CHIRAL ISOXAZOLINE AZETIDINE DERIVATIVES AS ANTIPARASITIC AGENTS
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The invention recites a chiral process for the synthesis of isoxazoline azetidine phenyl substituted derivatives of Formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, processes for making, and their use as a parasiticide in an animal. The variables *, R1a, R1b, R1c, R2, and R3 are as described herein
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- AZETIDINE DERIVATIVES AS ANTIPARASITIC AGENTS
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This invention recites substituted azetidine derivatives of Formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, and their use as a parasiticide in animals. The substituents A, B, R1a, R1b, R1c, R2, R3, R4, R6, and n are as described herein.
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- Copper(I)/ABNO-catalyzed aerobic alcohol oxidation: Alleviating steric and electronic constraints of Cu/TEMPO catalyst systems
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Cu/TEMPO catalyst systems promote efficient aerobic oxidation of sterically unhindered primary alcohols and electronically activated substrates, but they show reduced reactivity with aliphatic and secondary alcohols. Here, we report a catalyst system, consisting of (MeObpy)CuI(OTf) and ABNO (MeObpy =4,4′-dimethoxy-2,2′-bipyridine; ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl), that mediates aerobic oxidation of all classes of alcohols, including primary and secondary allylic, benzylic, and aliphatic alcohols with nearly equal efficiency. The catalyst exhibits broad functional group compatibility, and most reactions are complete within 1 h at room temperature using ambient air as the source of oxidant.
- Steves, Janelle E.,Stahl, Shannon S.
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supporting information
p. 15742 - 15745
(2013/11/06)
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- BENZOFURAN DERIVATIVES FOR THE TREATMENT OF HEPATITIS C
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The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.
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Page/Page column 23; 24
(2013/10/21)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Page/Page column 27; 28
(2013/03/26)
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- Efficient aerobic oxidation of secondary alcohols at ambient temperature with an ABNO/NOx catalyst system
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New highly practical methods are presented for aerobic oxidation of secondary alcohols with a nitroxyl radical in combination with HNO3, NaNO2, or both as cocatalysts. Diverse nitroxyls are compared, including several novel bicyclic derivatives. Catalyst systems with the readily available nitroxyls, 9-azabicyclo[3.3.1]nonane-N-oxyl (ABNO) and 9-azabicyclo[3.3.1]nonan-3-one-N-oxyl (keto-ABNO), are optimized in acetic acid or acetonitrile as the solvent. The reactions are compatible with substrates bearing diverse functional groups and proceed efficiently under mild conditions at ambient pressure and temperature.
- Lauber, Markus B.,Stahl, Shannon S.
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p. 2612 - 2616
(2013/11/19)
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- Novel carboxamide-based allosteric MEK inhibitors: Discovery and optimization efforts toward XL518 (GDC-0973)
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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S) -piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
- Rice, Kenneth D.,Aay, Naing,Anand, Neel K.,Blazey, Charles M.,Bowles, Owen J.,Bussenius, Joerg,Costanzo, Simona,Curtis, Jeffry K.,Defina, Steven C.,Dubenko, Larisa,Engst, Stefan,Joshi, Anagha A.,Kennedy, Abigail R.,Kim, Angie I.,Koltun, Elena S.,Lougheed, Julie C.,Manalo, Jean-Claire L.,Martini, Jean-Francois,Nuss, John M.,Peto, Csaba J.,Tsang, Tsze H.,Yu, Peiwen,Johnston, Stuart
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p. 416 - 421
(2012/06/30)
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- ISOXAZOLINE DERIVATIVES AS ANTIPARASITIC AGENTS
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This invention recites isoxazoline substituted azetidine derivatives of Formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, and their use as a parasiticide in mammals and birds. R1a, R1b, R1c, R2, R3, R4, R6, and n are as described herein.
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- 10A-AZALIDE COMPOUND HAVING 4-MEMBERED RING STRUCTURE
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A 10a-azalide compound having a 4-membered ring structure crosslinked at the 10a- and 12-positions, which is represented by the formula (I), and is effective on even Haemophilus influenzae, or erythromycin resistant bacteria (e.g., resistant pneumococci and streptococci).
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- PIPERIDIN-4-YL AZETIDINE DERIVATIVES AS JAK1 INHIBITORS
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The present invention provides piperidin-4-yl azetidine derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase 1 (JAK1) and are useful in the treatment of diseases related to the activity of JAK1 including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Page/Page column 36
(2011/10/04)
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- TRIAZOLOPYRIDINE COMPOUNDS AS PIM KINASE INHIBITORS
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Compounds of Formula (I), in which A, B, R1, R1a, R2, R3, R4, R5, R6, and R7 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of immune cell-associated diseases and disorders, such as inflammatory and autoimmune diseases.
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Page/Page column 127
(2010/04/03)
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- 8-Substituted isoquinoline derivative and the use thereof
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The present invention relates to a compound represented by the following formula (1): wherein D1, A1, D2, R1, D3, and R2 each have the same meaning as defined in the present specification or a salt thereof. The compound represented by the formula (1) or a salt thereof has an IKKβ inhibiting activity and the like and is useful for the prevention and/or treatment of IKKβ-associated diseases or symptoms and the like.
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Page/Page column 145; 146
(2010/11/03)
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- INDOLE DERIVATIVES
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The present invention relates to indole derivatives which bind to the MCHl receptor. In separate aspects, the subject invention is directed to uses of said compounds in the preparation of a pharmaceutical composition for the treatment of obesity and CNS related disorders and to methods of treating said disorders comprising administering a therapeutically effective amount of a compound of the invention.
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Page/Page column 35-36
(2009/10/22)
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- The design and discovery of novel amide CCR5 antagonists
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The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
- Pryde, David C.,Corless, Martin,Fenwick, David R.,Mason, Helen J.,Stammen, Blanda C.,Stephenson, Peter T.,Ellis, David,Bachelor, David,Gordon, David,Barber, Christopher G.,Wood, Anthony,Middleton, Donald S.,Blakemore, David C.,Parsons, Gemma C.,Eastwood, Rachel,Platts, Michelle Y.,Statham, Keith,Paradowski, Kerry A.,Burt, Catherine,Klute, Wolfgang
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supporting information; scheme or table
p. 1084 - 1088
(2009/08/07)
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- AZETIDINE AND CYCLOBUTANE DERIVATIVES AS JAK INHIBITORS
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The present invention relates to azetidine and cyclobutane derivatives, as well as their compositions, methods of use, and processes for preparation, which are JAK inhibitors useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.
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Page/Page column 62-63
(2009/09/28)
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- THERAPEUTIC COMPOUNDS
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The present invention relates to pyrazine substituted pyrrolopyridines which are inhibitors of JAK kinases (JAKl, JAK2, JAK3 and/or TYK2) and/or PDKl and are thus useful for the treatment of myeloproliferative disorders or cancer.
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Page/Page column 63
(2009/05/30)
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- METHODS OF USING MEK INHIBITORS
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The present invention provides methods of treating cancer by administering a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments.
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Page/Page column 339
(2008/12/06)
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- METHODS OF USING COMBINATIONS OF MEK AND JAK-2 INHIBITORS
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A method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a MEK compound of Formula I(M), or a pharmaceutical composition comprising a therapeutically effective amount of a MEK compound of Formula I(M) and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a JAK-2 compound of Formula I(J), or a pharmaceutical composition comprising a therapeutically effective amount of a JAK-2 compound of Formula I(J) and a pharmaceutically acceptable carrier, wherein the MEK compound of Formula I(M) and JAK-2 compound of Formula I(J) are as defined in the specification.
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Page/Page column 189
(2008/12/04)
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- AZETIDINE DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Azetidine derivatives of structural formula I are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; liver steatosis; and non-alcoholic steatohepatitis. (I)
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- Cathepsin cysteine protease inhibitors
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This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of Cathepsins K and L. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
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