cas 98948-95-9, 6-BROMO-4-HYDROXYQUINOLINE-3-CARBOXYLIC ACID

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PAPD5 INHIBITORS AND METHODS OF USE THEREOF
The present application provides compounds that are PAPD5 inhibitors and are useful in treating a variety of conditions such as cancer, telomere diseases, and aging-related and other degenerative disorders.
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Page/Page column 155

(2020/11/03)

The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one)
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5-c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Pike, Kurt G.,Barlaam, Bernard,Cadogan, Elaine,Campbell, Andrew,Chen, Yingxue,Colclough, Nicola,Davies, Nichola L.,De-Almeida, Camila,Degorce, Sebastien L.,Didelot, Myriam,Dishington, Allan,Ducray, Richard,Durant, Stephen T.,Hassall, Lorraine A.,Holmes, Jane,Hughes, Gareth D.,Macfaul, Philip A.,Mulholland, Keith R.,McGuire, Thomas M.,Ouvry, Gilles,Pass, Martin,Robb, Graeme,Stratton, Natalie,Wang, Zhenhua,Wilson, Joanne,Zhai, Baochang,Zhao, Kang,Al-Huniti, Nidal
p. 3823 - 3841
(2018/05/14)

6-bromo-4-chloroquinoline preparation method
The invention discloses a 6-bromo-4-chloroquinoline preparation method. 4-bromaniline, ethyl propiolate, phosphorus trichloride and the like are used as raw materials to obtain a target product 6-bromo-4-chloroquinoline through three-step reaction. The 6-bromo-4-chloroquinoline preparation method is convenient and simple in operation and environment friendly, the comprehensive yield is 70% or above and remarkably increased as compared with existing yield which is 26-42%, existing medicine production cost is sharply reduced, and the 6-bromo-4-chloroquinoline preparation method is suitable for industrial mass production.
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(2017/03/28)

Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites
Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously
Devine, William,Thomas, Sarah M.,Erath, Jessey,Bachovchin, Kelly A.,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Sciotti, Richard J.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
p. 350 - 354
(2017/03/17)

Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth.
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(2016/04/26)

COMBINATION OF KINASE INHIBITORS AND USES THEREOF
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or a receptor tyrosine kinase (RTK) in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or an RTK in a subject. In yet another aspect, a method of inhibiting phosphorylation of Akt (S473) in a cell is set forth.
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(2015/02/19)

Indolo[3,2-c]quinoline G-quadruplex stabilizers: A structural analysis of binding to the human telomeric G-quadruplex
A library of 5-methylindolo[3,2-c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G-quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and two weakly basic side chains are potent and selective human telomeric (HT) and gene promoter G4 stabilizers. Spectroscopic studies with HT G4 as a model showed that an IQc stabilizing complex involves the binding of two IQc molecules (2,9-bis{[3-(diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride, 3 d) per G4 unit, in two non-independent but equivalent binding sites. Molecular dynamics studies suggest that end-stacking of 3 d induces a conformational rearrangement in the G4 structure, driving the binding of a second 3 d ligand to a G4 groove. Modeling studies also suggest that 3 d, with two three-carbon side chains, has the appropriate geometry to participate in direct or water-mediated hydrogen bonding to the phosphate backbone and/or G4 loops, assisted by the terminal nitrogen atoms of the side chains. Additionally, antiproliferative studies showed that IQc compounds 2 d (2-{[3-(diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride) and 3 d are 7- to 12-fold more selective for human malignant cell lines than for nonmalignant fibroblasts.
Lavrado, Jo?o,Ohnmacht, Stephan A.,Correia, Isabel,Leit?o, Clara,Pisco, Sílvia,Gunaratnam, Mekala,Moreira, Rui,Neidle, Stephen,Santos, Daniel J.V.A. Dos,Paulo, Alexandra
p. 836 - 849
(2015/05/05)

Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors
Abstract A novel series of 4-alkynyl-quinoline derivatives were designed, synthesized and biologically evaluated for their PI3Kα inhibitory activities and anti-proliferative effects against two cancer cell lines PC-3 and HCT-116. Most of them showed potent PI3Kα inhibitory activities with IC50 values at low nanomolar level and good to excellent anti-proliferative effects against both cell lines. Among them, compound 15d, the most potent one, was selected for further biological evaluation. As a result, 15d displayed strong inhibitory activity against other class I PI3K isoforms (PI3Kβ, PI3Kγ and PI3Kδ) and mTOR with an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that the phosphorylation of Akt, another downstream effector of PI3K, can be remarkably suppressed by 15d at cellular level. All these experimental results suggested that 15d is a potent PI3K/mTOR dual inhibitor and could serve as a promising lead compound for the development of anticancer agents.
Lv, Xiaoqing,Ying, Huazhou,Ma, Xiaodong,Qiu, Ni,Wu, Peng,Yang, Bo,Hu, Yongzhou
p. 36 - 50
(2015/06/08)

HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.
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(2015/11/30)

Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery
Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
Devine, William,Woodring, Jennifer L.,Swaminathan, Uma,Amata, Emanuele,Patel, Gautam,Erath, Jessey,Roncal, Norma E.,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Sciotti, Richard J.,Pollastri, Michael P.
p. 5522 - 5537
(2015/08/03)

IMIDAZO[4,5-C]QUINOLIN-2-ONE COMPOUNDS AND THEIR USE IN TREATING CANCER
The specification generally relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, where Q, R1, R2, R3, R4 and R5 have any of the meanings defined herein. The specification also relates to the use of such compounds and salts thereof to treat or prevent ATM kinase mediated disease, including cancer. The specification further relates to crystalline forms of compounds of imidazo[4,5- c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; intermediates useful in the manufacture of such compounds and salts; and to methods of treating ATM kinase mediated disease, including cancer, using such compounds and salts.
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(2015/11/27)

COMBINATION OF KINASE INHIBITORS AND USES THEREOF
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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(2014/10/04)

HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.
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(2012/09/11)

Use of 2-[18F]fluoroethylazide for the Staudinger ligation - Preparation and characterisation of GABAA receptor binding 4-quinolones
The labelling reagent 2-[18F]fluoroethylazide was used in a traceless Staudinger ligation. This reaction was employed to obtain the GABAA receptor binding 6-benzyl-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid (2-[18F]flu
Gaeta, Alessandra,Woodcraft, John,Plant, Stuart,Goggi, Julian,Jones, Paul,Battle, Mark,Trigg, William,Luthra, Sajinder K.,Glaser, Matthias
supporting information; experimental part
p. 4649 - 4652
(2010/10/02)

IMAGING AGENTS
The invention relates to compounds of formula (I), or a salt or solvate thereof which comprise a detectable label. The compounds have use as radioligands for the GABAA receptor.
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Page/Page column 19-20

(2009/05/29)

Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo
Quinolone-3-carboxamides 11 bearing at position 5, 6, 7, or 8 diverse substituents such as halides, alkyl, aryl, alkoxy, and aryloxy groups differing in their steric/electronic properties, were prepared. The new compounds were tested in vitro for CB1 and
Pasquini, Serena,Botta, Lorenzo,Semeraro, Teresa,Mugnaini, Claudia,Ligresti, Alessia,Palazzo, Enza,Maione, Sabatino,Di Marzo, Vincenzo,Corelli, Federico
supporting information; experimental part
p. 5075 - 5084
(2009/07/25)

Controlled derivatization of polyhalogenated quinolines utilizing selective cross-coupling reactions
Straightforward procedures for the derivatization of tri- and tetrahalogenated quinolines utilizing sequential selective Pd-catalyzed cross-coupling reactions are described. Taking advantage of intrinsic halide reactivity, substrate control, and appropria
Brad Nolt,Zhao, Zhijian,Wolkenberg, Scott E.
p. 3137 - 3141
(2008/09/20)

NOVEL CHEMICAL COMPOUNDS
This invention relates to newly identified compounds for inhibiting hYAK3 proteins and methods for treating diseases associated with hYAK3 activity.
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(2010/11/25)

Evaluation of 3-carboxy-4(1H)-quinolones as inhibitors of human protein kinase CK2
Due to the emerging role of protein kinase CK2 as a molecule that participates not only in the development of some cancers but also in viral infections and inflammatory failures, small organic inhibitors of CK2, besides application in scientific research, may have therapeutic significance. In this paper, we present a new class of CK2 inhibitors-3-carboxy-4(1H)-quinolones. This class of inhibitors has been selected via receptor-based virtual screening of the Otava compound library. It was revealed that the most active compounds, 5,6,8-trichloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7) (IC 50 = 0.3 μM) and 4-oxo-1,4-dihydrobenzo[h]quinoline-3-carboxylic acid (9) (IC50 = 1 μM), are ATP competitive (Ki values are 0.06 and 0.28 μM, respectively). Evaluation of the inhibitors on seven protein kinases shows considerable selectivity toward CK2. According to theoretical calculations and experimental data, a structural model describing the key features of 3-carboxy-4(1H)-quinolones responsible for tight binding to CK2 active site has been developed.
Golub, Andriy G.,Yakovenko, Olexander Ya.,Bdzhola, Volodymyr G.,Sapelkin, Vladislav M.,Zien, Piotr,Yarmoluk, Sergiy M.
p. 6443 - 6450
(2007/10/03)

Thiazolinone 4-monosubstituted quinolines
Thiazolinone monosubstituted quinoline derivatives where the quinoline ring is mono-substituted at the 4 positions which derivatives demonstrates CDK1 antiproliferative activity and are useful as anti-cancer agents.
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Page/Page column 9

(2010/10/20)

4-HYDROXY-2-QUINOLONES. 20. SYNTHESIS AND CHEMICAL CONVERSIONS OF ETHYL ESTERS OF CHLORO-SUBSTITUTED QUINOLINE-3-CARBOXYLIC ACIDS
Preparative methods for the synthesis of ethyl esters of 2,4-dichloro- and 2-oxo-4-chloroquinoline-3-carboxylic acids were developed.The behavior of the compounds indicated was studied under conditions of alkaline and acidic hydrolysis, in reactions with some nucleophilic reagents, as well as in reductive dehalogenation.Results of the study of the antimicrobial and antiinflammatory activity of the synthesized compounds are presented.
Ukrainets, I. V.,Taran, S. G.,Gorokhova, O. V.,Marusenko, N. A.,Kovalenko, S. N.,et al.
p. 167 - 175
(2007/10/03)