- COMPOUNDS WITH COPPER- OR ZINC-ACTIVATED TOXICITY AGAINST MICROBIAL INFECTION
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Heterocyclic compounds with a novel pyrazole thioamide-based NNSN structural motif, having highly effective zinc- or copper-activated toxicity against microbial infections at micromolar or nanomolar minimum inhibitory concentrations (MIC), and methods of making and using same.
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- Preparation method of pyraclostrobin intermediate
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The invention discloses a preparation method of pyraclostrobin intermediate 3 - hydroxyl - 1H - pyrazole and 1 - (4 - chlorophenyl) -3 - pyrazol, which comprises: synthesizing 3 - hydroxyl - 1H - pyrazole -4 - carboxylic acid ethyl ester by cyclization re
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Paragraph 0050-0055
(2021/09/15)
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- Nickel-Catalyzed C-O Cross-Coupling Reaction at Low Catalytic Loading with Weak Base Participation
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Herein, we report a nickel-catalyzed crossing-coupling reaction for the synthesis of diaryl ethers. The desired products are achieved by coupling heterocyclic alcohols with aryl bromides bearing strong electron withdrawing nitro group under the catalyst system of NiCl2(PPh3)2 and weak base KHCO3. This mild reaction exhibits a broad functional group tolerance. Compound 4 as an important intermediate is suitable for further structural modification of MALT1 inhibitor MI-2.
- Wu, Fan,Zhu, Kejie,Wu, Guolin,Gao, Yu,Chen, Haijun
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supporting information
p. 519 - 522
(2020/01/30)
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- Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies
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A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
- Barlaam, Bernard,Casella, Robert,Cidado, Justin,Cook, Calum,De Savi, Chris,Dishington, Allan,Donald, Craig S.,Drew, Lisa,Ferguson, Andrew D.,Ferguson, Douglas,Glossop, Steve,Grebe, Tyler,Gu, Chungang,Hande, Sudhir,Hawkins, Janet,Hird, Alexander W.,Holmes, Jane,Horstick, James,Jiang, Yun,Lamb, Michelle L.,McGuire, Thomas M.,Moore, Jane E.,O'Connell, Nichole,Pike, Andy,Pike, Kurt G.,Proia, Theresa,Roberts, Bryan,San Martin, Maryann,Sarkar, Ujjal,Shao, Wenlin,Stead, Darren,Sumner, Neil,Thakur, Kumar,Vasbinder, Melissa M.,Varnes, Jeffrey G.,Wang, Jianyan,Wang, Lei,Wu, Dedong,Wu, Liangwei,Yang, Bin,Yao, Tieguang
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supporting information
p. 15564 - 15590
(2021/01/09)
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- Design, synthesis and biological evaluation of ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors
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We report herein the synthesis of novel ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors and the evaluation of pharmaceutical activity against five cancer cell lines (MDA-MB-231, BXPC-3, NCI-H1975, DU145 and 786O). Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC50 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 μM in comparison with GSK2256098 as a reference. Among them, compound 4o is considered to be the most effective due to high sensitivity in antiproliferation. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain.
- Xie, Hongming,Lin, Xinglong,Zhang, Yingjun,Tan, Fuxing,Chi, Bo,Peng, Zhihong,Dong, Wanrong,An, Delie
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supporting information
(2020/10/06)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH APJ RECEPTOR ACTIVITY
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This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol "APLNR"). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and/or symptoms and/or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.
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Page/Page column 102-103
(2019/09/18)
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- Preparation method of 1-(4-chlorophenyl)-3-hydroxy-1-h-pyrazole
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The invention discloses a preparation method for 1-(4-chlorophenyl)-3-hydroxy-1-h-pyrazole. Hydrazine hydrate and acrylic ester are taken as raw materials to synthesize pyrazol-3-ketone, the pyrazol-3-ketone is oxidized into hydroxypyrazole, and finally,
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Page/Page column 5-11
(2018/11/03)
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- Focal adhesion kinase inhibitor and use
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The invention belongs to the field of medicines, relates to a focal adhesion kinase inhibitor and use, in particular relates to a novel focal adhesion kinase inhibitor compound, or stereoisomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, further relates to the use of the compound and pharmaceutical compositions as medicines, in particular the use of the compound and pharmaceutical compositions in manufacture of medicines for treatment or prevention of cancer, pulmonary hypertension, and pathological angiogenesis-related diseases.
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Paragraph 0455; 0457; 0458
(2019/01/08)
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- PYRAZOLE DERIVATIVES
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Provided herein are compounds of the formula I: as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment or prevention of mGluR5 mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.
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Paragraph 54
(2017/08/01)
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- Chemical Compounds
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Provided are a series of novel pyridine or pyrimidine derivatives which inhibit CDK9 and may be useful for the treatment of hyperproliferative diseases. In particular the compounds are of use in the treatment of proliferative disease such as cancer including hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
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Paragraph 0634
(2017/01/19)
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- TETRAZOLINONE COMPOUND AND USE THEREOF
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A tetrazolinone compound represented by formula (1): wherein Q represents a divalent 5-membred aromatic heterocyclic group optionally having one or more atoms or groups selected from Group P2; A represents a 5- to 10-membered monocyclic or fused ring heterocyclic group optionally having one or more atoms or groups selected from Group P1; R1 and R2 each represents a hydrogen atom, etc.; R3 represents a C1-C6 alkyl group optionally having one or more halogen atoms, etc.; R4, R5, and R6 each represents a hydrogen atom, etc.; and X represents an oxygen atom or a sulfur atom, has excellent control activity against pests.
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Paragraph 0548; 0549; 0550
(2016/07/27)
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- Tetrazolinone compound and use thereof
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A tetrazolinone compound represented by formula (1) [wherein Q represents a bivalent 5-membered aromatic heterocyclic group which may have at least one atom or group selected from the group P2; A represents a 5- to 10-membered monocyclic or condensed-cyclic heterocyclic group which may have at least one atom or group selected from the group P1; R1 and R2 independently represent a hydrogen atom or the like; R3 represents a C1-C6 alkyl group which may have at least one halogen atom or the like; R4, R5 and R6 independently represent a hydrogen atom or the like; and X represents an oxygen atom or a sulfur atom] has an excellent controlling effect on harmful organisms.
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Paragraph 0932; 0933; 0934; 0935; 0936
(2016/10/08)
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- 2-ACYLAMIDOMETHYL AND SULFONYLAMIDOMETHYL BENZOXAZINE CARBAMATES FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE
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The invention provides certain benzoxazine compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, Ra, Rb, Rc, Rd, Rg, and Cy are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds of the Formula (I) or pharmaceutically acceptable salts thereof, and methods of using the compounds of the Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for treating diseases or conditions mediated by RORgammaT.
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Paragraph 0226
(2015/07/07)
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- CARBAMATE BENZOXAXINE PROPIONIC ACIDS AND ACID DERIVATIVES FOR MODULATION OF RORGAMMA ACTIVITY AND THE TREATMENT OF DISEASE
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The invention provides certain benzoxazine compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, Ra1, Ra2, Rb1, Rb2, Rc, Rd, and C
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Paragraph 0223
(2015/07/07)
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- Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
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Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.
- Huang, Huang,Si, Pei,Wang, Lei,Xu, Yong,Xu, Xin,Zhu, Jin,Jiang, Hualiang,Li, Weihua,Chen, Lili,Li, Jian
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p. 1184 - 1199
(2015/07/07)
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- TETRAZOLINONE COMPOUNDS AND ITS USE AS PESTICIDES
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The present invention provides a compound having an excellent efficacy for controlling pests. A tetrazolinone compound of a formula (1): [wherein R1 represents an C6-C16 aryl group, an C1-C12 alkyl group, or a C3-C12 cycloalkyl group, etc., which each optionally be substituted; R2, R3, R4 and R5 represent independently of each other a hydrogen atom, a halogen atom or an C1-C3 alkyl group, etc.; R6 represents an C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen atom, a C1-C6 haloalkyl group, an C2-C6 alkenyl group, an C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, etc.; R7, R8 and R9 represent independently of each other a hydrogen atom, a halogen atom, or an C1-C4 alkyl group, etc.; X represents an oxygen atom or a sulfur atom; and R10 represents an C1-C6 alkyl group, etc.] shows an excellent controlling efficacy on pests.
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Page/Page column 959
(2013/11/18)
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- Optimized scale up of 3-pyrimidinylpyrazolo[1,5-a]pyridine via Suzuki coupling; A general method of accessing a range of 3-(hetero)arylpyrazolo[1,5-a] pyridines
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We have developed an improved synthesis of 3-(hetero)aryl pyrazolo[1,5-a]pyridines (such as 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a] pyridine (8)) via an optimized synthesis and Suzuki coupling of 3-pyrazolo[1,5-a]pyridine boronic ester 10. These conditions are applicable to both high throughput chemistry and large scale synthesis of these medicinally important compounds. The scope of this chemistry has been further extended to include the synthesis and coupling of a novel boronic ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine (43).
- Bethel, Paul A.,Campbell, Andrew D.,Goldberg, Frederick W.,Kemmitt, Paul D.,Lamont, Gillian M.,Suleman, Abid
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experimental part
p. 5434 - 5444
(2012/09/08)
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- PROCESS FOR PREPARING 1-PHENYLPYRAZOLES
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The present invention to a process for preparing 1-phenylpyrazoles of the formula I in which each R1 is independently selected from chlorine, fluorine, alkyl, haloalkyl, alkoxy and haloalkoxy;n is 1, 2 or 3;each R2 is independently selected from cyano, nitro, halogen, alkyl, haloalkyl,alkoxy, haloalkoxy,alkylthio and alkoxycarbonyl; mis 0, 1 or 2;A is alkyl, aryl or aryl-C1-C4-alkyl, where A optionally bears 1, 2, 3 or 4 substituents comprising reacting a phenyl halide of the formula (II) with apyrazole derivative of the formula (III) in which X is chlorine, iodine or bromine; and R1, n, R2, m and A are each as defined above, in the presence of a base and a catalytic system comprising a ligand and a metal compound selected from palladium compounds, iron compounds and copper compounds.
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Page/Page column 25-26
(2011/04/14)
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- Pyrazolo-triazine derivatives as ligands for gaba receptors
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A class of substituted pyrazolo[1,5-d][1,2,4]triazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 7-position, an alkyl group at the 4-position, and a substituted alkoxy moiety at the 2-position, are selective ligands for GABAA receptors, in particular having high affinity for the α2 and/or α3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.
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- Heterocyclic substituted pyrazolones
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The present invention is directed to novel heterocyclic substituted pyrazolones, including pharmaceutical compositions, diagnostic kits, assay standards or reagents containing the same, and methods of using the same as therapeutics. The invention is also directed to intermediates and processes for making these novel compounds.
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- Acetate ester compounds
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The present invention provides an acetate ester compound of formula (III), STR1 a process for synthesizing compound (III), and a process for using that compound to prepare a pyrazolone compound, where the substituent definitions are as defined in the Summary of the Invention.
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- Yellow cationic dyes having flocculating properties
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A flocculating dye reduces bleed between two inks when they are applied side by side. A first ink comprises the flocculating dye which flocculates the dispersant-pigment of the second ink.
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- Process for the preparation of pyrazolones
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A process for the preparation of pyrazolone derivatives represented by the general formula STR1 wherein R is a hydrogen atom, an alkyl group, an allyl group, an aryl group or an aralkyl group, and R1 and R2 are, respectively, a hydrogen atom, an alkyl group or a phenyl group which may have a substituent, comprising reacting a 2,3-dihalocarboxylic acid derivative or a 2-haloacrylic acid derivative with a hydrazine derivative. A pyrazolone or 1-substituted-3-pyrazolones useful as intermediate starting materials for the synthesis of agricultural chemicals, medicine and chemical compounds can be easily and cheaply prepared from widely used industrial starting materials.
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- Polazo reactive dyestuffs
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A polyazo reactive dyestuff of the formula STR1 wherein D=the radical of a diazo component of the formulae STR2 A and A'=H, C1 -C4 -alkyl, C1 -C4 -alkoxy or halogen, R and R'=H, C1 -C4 -alkyl, C1 -C4 -alkoxy, halogen, CO2 H or SO3 H, X=--CH=CH2 or --CH2 --CH2 --Y, wherein Y=a radical which can be eliminated under alkaline conditions and K=the radical of a coupling component of the pyridone, pyrazolone, pyrazolopyridone, acetoacetic acid arylide, N-(3-aminophenyl)acetamide, 3-aminophenylureido, naphthylamine, naphthol or naphtholamine series, it being possible for the radical K to contain further azo groups or radicals containing azo groups and further fibre-reactive radicals.
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- Yellow pyrazolone ester dyes for heat transfer printing
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The application is concerned with new pyrazolone compounds having the structure: STR1 wherein R is hydrogen or halogen (especially fluorine, bromine and chlorine) and R1 and R2 independently of one another are hydrogen or halogen (especially bromine and chlorine) and R3 is lower alkyl (especially methyl, ethyl, propyl and butyl). The compounds are useful in heat transfer printing of polyester fabrics and impart yellow shades thereto. The application discloses a method of making the new compounds and discusses the utilization of the compounds in the heat transfer printing of polyester fabrics, in the preparation of ink formulations, and in making transfer sheets for heat transfer printing.
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- Process for the preparation of 3-anilino-5-pyrazolones
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In accordance with the present invention, it has been found that 3-anilino-5-pyrazolones can be prepared in high yields by a multi-step process using available starting materials. In the first step of the process, an alkyl β-alkoxy-β-iminopropionate salt is reacted with a suitable alkanol to form an orthoester intermediate in situ. The orthoester then is converted in high yields to the corresponding imidic ester by condensation with an aniline while simultaneously removing alkanol from the reaction mixture to drive the equilibrium reaction to completion. In a preferred form of the invention, formation of the imidic ester is carried out in a high boiling solvent whose presence enables the condensation to be carried out effectively at a high temperature, and which facilitates distillation of the more volatile alkanol by-product from the reaction mixture at atmospheric pressure.
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- Cycloalkanapyrazole-3-carbonitrile herbicides
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Herbicidal cycloalkanapyrazoles of the formula: STR1 where N IS 3, 4 OR 5; R1 is hydrogen or methyl; X is fluorine, chlorine, bromine, iodine, cyano, or methoxy; Y is hydrogen, fluorine, or chlorine; Z is hydrogen or fluorine; and V is hydrogen, fluorine, chlorine or methoxy; provided that (a) when n is 3, R1 must be hydrogen; (b) when n is 5, R1 must be hydrogen, Y must be hydrogen or fluorine, Z and V must both be hydrogen, and X must be fluorine, chlorine or bromine; (c) when V is methoxy, X and Y must be chlorine, and Z must be hydrogen; and (d) when V is fluorine or chlorine, X must be fluorine, chlorine or bromine, and Z must be hydrogen.
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- Cycloalkanapyrazole herbicides
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Herbicidal cycloalkanapyrazoles of the formula: STR1 where N IS 3, 4 OR 5; R1 is hydrogen or methyl; Q is fluorine, chlorine, bromine or iodine; X is fluorine, chlorine, bromine, iodine, cyano, methoxy or nitro; Y is hydrogen, fluorine, or chlorine; Z is hydrogen or fluorine; and V is hydrogen, fluorine, chlorine or methoxy with the proviso that A. when n is 5, R1 must be hydrogen, Q must be chlorine or bromine, Z and V must both be hydrogen and Y must be hydrogen or fluorine; B. when n is 3 or 4 and Q is fluorine or iodine, R1, Z and V must be hydrogen and Y must be hydrogen or fluorine; C. when n is 3 and R1 is methyl, Q must be chlorine or bromine, Y must be hydrogen or fluorine and Z and V must both be hydrogen; and, D. when V is other than hydrogen, X must be fluorine, chlorine or bromine and Z must be hydrogen.
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- Process for the preparation of 3-anilino-pyrazolones-(5)
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Preparation of 1-aryl-3-anilino-pyrazolones-(5) by reacting a hydrazine with an ester from the group of dialkoxyacrylic acid ester, trialkoxy propionic acid ester or iminoalkoxy propionic acid ester to produce a β-hydrazine-β-alkoxyacrylic acid ester and then condensing this intermediate product with an aniline to result in the desired anilinopyrazolone. These reactions are carried out in a methanolic solution in the presence of an acetic acid catalyst.
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- Evaporator system comprising a stabilized pesticidal phosphoric acid ester and method for stabilizing such ester enclosed in an evaporator
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An evaporator system adapted for emitting insect killing vapors of an insecticide therefrom and comprising a liquid or solid composition enclosed therein, said insecticide consisting in at least one volatile phosphoric acid ester which is stabilized by at least one diazene compound.
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- Color photographic recording material
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The present invention relates to new compounds having an active methylene group or phenolic hydroxyl group and therefore capable of being used as photographic color couplers. The new compounds contain at least one radical of a phosphoric acid diester, phosphonic acid diester, phosphoric acid diamide, phosphonic acid diamide, phosphoric acid ester-amide or phosphonic acid ester-amide.
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- Process for preparing 3-anilino-pyrazolones-(5)
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Anilinopyrazolone are to be prepared in high yields and with a high degree of purity by reacting a salt particularly hydrochloride of a β-arylamino-β-imino-propionic acid ester of one of the tautomeric formulae which are defined hereinafter with a suitable substituted hydrazine.
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