- Facile synthesis, antimicrobial evaluation and molecular docking studies of pyrazole-imidazole-triazole hybrids
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A series of eighteen pyrazole-imidazole-triazole hybrid (2-(4-((2-(substituted-1H-pyrazol-1-yl)-4-phenyl-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-(substituted)phenylacetami- de) (6a-6r) are synthesized through click reaction between in situ gener
- Deswal, Laxmi,Kumar, Ashwani,Kumar, Devinder,Punia, Suman,Verma, Vikas
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- Design, synthesis, antimicrobial evaluation and docking studies of urea-triazole-amide hybrids
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A series of urea-1,2,3-triazole-amide hybrids was designed and synthesized via click reaction of urea derivatives containing a propargyl unit with 2-bromo-N-phenylacetamide derivatives and characterized by FTIR, NMR and HRMS data. The antimicrobial evalua
- Kumar, Anil,Kumar, Ashwani,Lal, Kashmiri,Poonia, Nisha,Rani, Poonam
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- Selective carbonic anhydrase inhibitor, synthesis method and application thereof
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The invention discloses a selective carbonic anhydrase inhibitor. The compound adopts acetazolamide as a lead compound, and is designed and synthesized by introducing a side chain for structural modification. The structure comprises a monosubstituted compound and a disubstituted compound; the selective inhibition effect of the compound on carbonic anhydrase is evaluated by esterase method; the neuroprotective effect of the compound is evaluated through a sodium nitroprusside oxidative stress model; and the toxicity of the compound is tested through cytotoxicity experiment. Research results show that in terms of the inhibition effect of the compound on carbonic anhydrase, monosubstitution is superior to disubstitution; the selectivity to carbonic anhydrase II is superior to that of carbonicanhydrase IX; the monosubstituted compound presents certain protective effect on sodium nitroprusside damaged PC12 cells; the IC50 of the optimal compound to carbonic anhydrase II is 16.7nM, the IC50to carbonic anhydrase IX is 4757nM, the selectivity is 285 times, which is remarkably superior to that of acetazolamide; the neuroprotective effect on PC12 is close to that of acetazolamide, and thetoxicity is lower than that of acetazolamide. The compound has the characteristics of good selectivity, effectiveness and safety, and is expected to be applied to drugs for preventing and treating neurological diseases.
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Paragraph 0102; 0104
(2020/03/06)
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- 5-[2-(N-(Substituted phenyl)acetamide)]amino-1,3,4-thiadiazole-2-sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects
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In this study, 22 novel compounds were designed and synthesized by acetamide bridge chains, among which 5 a–5 k were monosubstituted compounds, and 6 a–6 k were disubstituted. A series of biological evaluations was then carried out to determine the carbonic anhydrase inhibitory activity, neuroprotective effects and cytotoxicity of 5 a–5 k and 6 a–6 k. The results showed that some compounds could protect PC12 cells from sodium nitroprusside (SNP)-induced damage. In terms of the neuroprotection and inhibitory activity against carbonic anhydrase II, monosubstituted compounds were better than disubstituted. Compound 5 c exhibited better protective effect in PC12 cells than that of edaravone, and 5 c also showed less cytotoxicity. In addition, compound 5 c was found to be the most effective selective carbonic anhydrase II inhibitor (IC50=16.7 nM, CAI/CAII=54.3), which was similar to the inhibitory effect of acetazolamide. Moreover, the selectivity of compound 5 c was better than that of acetazolamide (IC50=12.0 nM, CAI/CAII=20.8). Molecular docking presented that the binding effect of compound 5 c with carbonic anhydrase II was superior to that of 5 c with carbonic anhydrase I and IX, which was consistent with the inhibitory results. Based on above findings, compound 5 c may be a potential candidate for selective carbonic anhydrase II inhibitor, and it had obviously neuroprotective effect and great advantages in drug safety.
- Jiang, Caibao,Lao, Yaoqiang,Liao, Liping,Liu, Jiayong,Shi, Jinguo,Wang, Yang,Zhang, Jingxia,Zhang, Liantao
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- Synthesis and antidiabetic evaluation of benzimidazole-tethered 1,2,3-triazoles
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Some novel benzimidazole-tethered 1,2,3-triazole derivatives (4a–r) were synthesized by a click reaction between 2-substituted 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole and in situ azide. The structures of the synthesized compounds were confirmed by spectroscopic studies (one- and two-dimensional nuclear magnetic resonance, Fourier transform infrared, and high-resolution mass spectra). The synthesized compounds were evaluated for their antidiabetic activity. Compounds 4a–r exhibited a good-to-moderate α-amylase and α-glucosidase inhibitory activity, with IC50 values ranging from 0.0410 to 0.0916 μmol/ml and 0.0146 to 0.0732 μmol/ml, respectively. Compounds 4e, 4g, and 4n were found to be most active. Furthermore, the binding conformation of the most active compounds was ascertained by docking studies.
- Deswal, Laxmi,Verma, Vikas,Kumar, Devinder,Kaushik, Chander?P.,Kumar, Ashwani,Deswal, Yogesh,Punia, Suman
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- Synthesis, crystal structure and antimicrobial activity of 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives against phytopathogens
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Abstract: A total of eighteen 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives were designed and synthesized, via hybrid pharmacophore approach. Among these compounds, chemical structure of compound 4a was unambiguously confirmed by means of single-crystal X-ray diffraction analysis. All the compounds were evaluated in vitro for their inhibition activity against several important phytopathogenic bacteria and fungi in agriculture. The obtained results indicated that several compounds demonstrated potent antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo). For example, compounds 4c, 4g and 4q had EC50 values of 35.0, 36.5 and 32.4 μg/mL toward this bacterium, respectively, around 1.5 times more active than commercial bactericide bismerthiazol (EC50 = 89.8 μg/mL). Additionally, compounds 4j and 4p were found to display comparable antifungal activity against Gloeosporium fructigenum at 50 μg/mL, to commercial fungicide hymexazol. Finally, the relationships between antibacterial activities and molecular structures of this class of compounds were discussed in detail. Graphical abstract: [Figure not available: see fulltext.].
- Fan, Zhijiang,Shi, Jun,Luo, Na,Bao, Xiaoping
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p. 615 - 624
(2019/08/12)
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- 3-Aminomethyl pyridine chalcone derivatives: Design, synthesis, DNA binding and cytotoxic studies
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Herein we report design, synthesis, and anticancer activity of compounds 6a–h and 11a–j. Compounds 6a–f were designed based on 3-aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g–h it was attached to coumarin moiety. Coumarin containing compounds 6g–h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF-7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a–j were designed as derivatives of 3-aminomethyl pyridine and 4-amino chalcones. A series of chalcone derivatives of 3-aminomethyl pyridine 11a–j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA-binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT-DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA-EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC50 0.0067?±?0.0002?μm, against MCF-7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.
- Durgapal, Sunil Dutt,Soni, Rina,Umar, Shweta,Suresh, Balakrishnan,Soman, Shubhangi S.
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p. 1279 - 1287
(2018/06/29)
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- Synthesis of novel 1,2,4-triazole derivatives containing the quinazolinylpiperidinyl moiety and: N -(substituted phenyl)acetamide group as efficient bactericides against the phytopathogenic bacterium Xanthomonas oryzae pv. oryzae
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A series of novel 1,2,4-triazole derivatives (7a-7p) containing the quinazolinylpiperidinyl moiety and N-(substituted phenyl)acetamide group were designed, synthesized and evaluated for their antimicrobial activities in vitro. These compounds were fully characterized by 1H NMR, 13C NMR, HRMS and IR spectra. Notably, the structure of compound 7p was further confirmed through the single-crystal X-ray diffraction method. The obtained bioassay results indicated that most of these compounds exhibited good to excellent antibacterial activities against the rice bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). For example, compounds 7e, 7g, 7n, 7l, 7i, 7k, 7a and 7h had EC50 (half-maximal effective concentration) values of 34.5, 38.3, 39.0, 46.0, 47.5, 54.6, 55.0 and 58.2 μg mL-1 against the bacterium, respectively, which were significantly lower than the control agent Bismerthiazol (85.6 μg mL-1). Additionally, antifungal experiments demonstrated that all the compounds did possess weak inhibition capabilities against three phytopathogenic fungi at 50 μg mL-1, except in the cases of compounds 7e and 7p against the fungus Gibberella zeae. The above experimental results proved that 1,2,4-triazole derivatives bearing both a quinazolinylpiperidinyl fragment and N-(substituted phenyl)acetamide unit are promising candidates for the development of new agricultural bactericides against the pathogenic bacterium Xoo, deserving further investigation in the future.
- Yang, Lan,Bao, Xiao-Ping
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p. 34005 - 34011
(2017/07/17)
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- Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
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Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.
- Leung, Euphemia,Pilkington, Lisa I.,van Rensburg, Michelle,Jeon, Chae Yeon,Song, Mirae,Arabshahi, Homayon J.,De Zoysa, Gayan Heruka,Sarojini, Vijayalekshmi,Denny, William A.,Reynisson, Jóhannes,Barker, David
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supporting information
p. 1142 - 1154
(2019/05/24)
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- Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives and their cytotoxic activity
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A series of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives 3 and 4 were prepared respectively starting from 6-phenyl-4-(trifluoromethyl)- 1H-pyrazolo[3,4-b]pyridin-3-amine 1 via selective N-propargylation, followed by reaction with divers
- Kurumurthy, Chavva,Veeraswamy, Banda,Sambasiva Rao, Pillalamarri,Santhosh Kumar, Gautham,Shanthan Rao, Pamulaparthy,Loka Reddy, Velaturu,Venkateswara Rao, Janapala,Narsaiah, Banda
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p. 746 - 749
(2014/02/14)
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- Synthesis and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold
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In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1a24, IC50=3.4±0.2μM) of the WNV NS2B-NS3 protease. Molecular docking of 1a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.
- Samanta, Sanjay,Lim, Ting Liang,Lam, Yulin
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supporting information
p. 994 - 1001
(2013/07/27)
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- QUINUCLIDINE DERIVATIVES AS MUSCARINIC M3 RECEPTOR ANTAGONISTS
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The invention provides named compounds of formula (I), wherein R4 is a N-substituted quinuclidine (I) pharmaceutical compositions containing them and a process for preparing the pharmaceutical compositions. Their use in therapy for’ the treatment of conditions mediated by M3 muscarinic receptors, such as chronic obstructive pulmonary disease is also disclosed.
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Page/Page column 16-17
(2011/08/02)
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- Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
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The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.
- Zhang, Xian,He, Yantao,Liu, Sijiu,Yu, Zhihong,Jiang, Zhong-Xing,Yang, Zhenyun,Dong, Yuanshu,Nabinger, Sarah C.,Wu, Li,Gunawan, Andrea M.,Wang, Lina,Chan, Rebecca J.,Zhang, Zhong-Yin
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experimental part
p. 2482 - 2493
(2010/09/03)
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- Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents
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Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.
- Zhou, Bo,He, Yantao,Zhang, Xian,Xu, Jie,Luo, Yong,Wang, Yuehong,Franzblau, Scott G.,Yang, Zhenyun,Chan, Rebecca J.,Liu, Yan,Zheng, Jianyu,Zhang, Zhong-Yin
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scheme or table
p. 4573 - 4578
(2010/10/03)
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- Quinoline derivatives as neurokinin receptor antagonists
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The present invention relates to substituted quinoline hydrazides of Formula (I): wherein R1, R2, R3, R4, R5, X, Y and Z are defined herein, pharmaceutical compositions comprising them and their use in treating diseases mediated by neurokinin-2 and/or neurokinin-3 (NK-3) receptors. These compounds can thus be used in methods of treatment to suppress and treat such disorders.
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Page/Page column 37
(2009/04/24)
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- QUINUCLIDINE DERIVATIVES AS MUSCARINIC M3 RECEPTOR ANTAGONISTS
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The invention provides named compounds of formula (I ), wherein R4 is a N- sustituted quinuclidine ( I ) pharmaceutical compositions containing them and a process for preparing the pharmaceutical compositions. Their use in therapy for' the treatment of conditions mediated by M3 muscarinic receptors, such as chronic obstructive pulmonary disease is also disclosed.
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Page/Page column 45-46
(2009/12/23)
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- SUBSTITUTED CYCLOHEXYL DERIVATIVES AS NK-3 RECEPTOR ANTAGONISTS
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The present invention relates to the compounds of formula (I): wherein A,B, n, X, Y, Z, R1, R2, R3, R4, R5, R6, R7 and R8 are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them and their use in treating diseases mediated by neurokinin-3 (NK-3) receptors. These compounds can thus be used in methods of treatment to suppress and treat such disorders.
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Page/Page column 39
(2010/11/25)
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- Discovery of 3-methyl-N-(1-oxy-3′,4′,5′,6′- tetrahydro-2′H-[2,4′-bipyridine]-1′-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction
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The goal of this study was to identify a structurally distinct D4-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
- Patel, Meena V.,Kolasa, Teodozyj,Mortell, Kathleen,Matulenko, Mark A.,Hakeem, Ahmed A.,Rohde, Jeffrey J.,Nelson, Sherry L.,Cowart, Marlon D.,Nakane, Masaki,Miller, Loan N.,Uchic, Marie E.,Terranova, Marc A.,El-Kouhen, Odile F.,Donnelly-Roberts, Diana L.,Namovic, Marian T.,Hollingsworth, Peter R.,Chang, Renjie,Martino, Brenda R.,Wetter, Jill M.,Marsh, Kennan C.,Martin, Ruth,Darbyshire, John F.,Gintant, Gary,Hsieh, Gin C.,Moreland, Robert B.,Sullivan, James P.,Brioni, Jorge D.,Stewart, Andrew O.
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p. 7450 - 7465
(2007/10/03)
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- (3- ((QUINAZOLIN-4-YL) AMINO )-1H-PYRAZOL-1-YL) ACETAMIDE DERIVATIVES AND RELATED COMPOUNDS AS AURORA KINASE INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES SUCH AS CANCER
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Quinazoline derivatives of formula (I) for use in the treatment of proliferative diseases such as cancer and in the preparation of medicaments for use in the treatment of proliferative diseases, and to processes for their preparation, as well as pharmaceutical compositions containing, them as active ingredient. X is O or NR 6 ;R 5 is aryl or heteroaryl optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, cyano, nitro, amino,C 1-4 alkylamino, bis(C1-4 alkyl)amino, C 1-4 alkyl, C 2-4 alkenyl,C 2-4 alkynyl, C 1-4 alkoxy, C(O)NHR17 , NHC(0)R 18 and S(O) p R 19where p is 0,1 or 2;The other substituents are as defined in claim 1.
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