- EIF4E-INHIBITING 4-OXO-3,4-DIHYDROPYRIDO[3,4-D]PYRIMIDINE COMPOUNDS
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The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds X1, X2, X3, X4, X5, X6, Q, L1, L2, Y, R1, R2, R3, R4, R5, R6, R7, R8 and rings A, B and C are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4e and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
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Paragraph 0311-0312; 0342
(2021/01/23)
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- NITROGEN-CONTAINING FUSED CYCLIC COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF
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The present invention relates to a nitrogen-containing fused ring compound, a preparation method and use thereof. Specifically, the present invention relates to a compound having the structure of Formula (X), a stereoisomer, tautomer or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, or a stable isotope derivative, metabolite or prodrug thereof. The compound of the invention may have the structure of Formula (I) or Formula (II). These compounds are useful for the treatment of an abnormal cell proliferation disease (e.g., cancer). ????????R-L-R3?????(X)
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- Polysubstituted quinolone compounds, and preparation method and use thereof
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The invention provides polysubstituted quinolone compounds, and a preparation method and a use thereof, and concretely provides a polysubstituted quinolone compound represented by formula I, and optical isomers, pharmaceutically acceptable salts or solvates thereof. All groups in the formula I are defined in the description. The quinolone compound has excellent c-Met inhibition activity, and can be used for treating c-Met activity or expression level corrected diseases.
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Paragraph 0265; 0266; 0267
(2017/09/19)
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- Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
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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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Page/Page column 361; 362
(2016/04/26)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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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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Page/Page column 75; 76
(2015/02/19)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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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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Paragraph 00641
(2014/10/04)
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- Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases
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A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC50 values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.
- Claridge, Stephen,Raeppel, Franck,Granger, Marie-Claude,Bernstein, Naomy,Saavedra, Oscar,Zhan, Lijie,Llewellyn, David,Wahhab, Amal,Deziel, Robert,Rahil, Jubrail,Beaulieu, Normand,Nguyen, Hannah,Dupont, Isabelle,Barsalou, Annie,Beaulieu, Carole,Chute, Ian,Gravel, Serge,Robert, Marie-France,Lefebvre, Sylvain,Dubay, Marja,Pascal, Roussen,Gillespie, Jeff,Jin, Zhiyun,Wang, James,Besterman, Jeffrey M.,MacLeod, A. Robert,Vaisburg, Arkadii
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p. 2793 - 2798
(2008/12/21)
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- Heterobicyclic thiophene compounds and methods of use
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Compounds of Formula I and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula I and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
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Page/Page column 52
(2008/06/13)
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- Development of a scalable synthesis to VEGFR inhibitor AG-28262
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The synthesis of N,2-dimethyl-6-(2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2- b]pyridin-7-yloxy)benzo[b]thiophene-3-carboxamide (1, AG-28262) on kilogram scale is described. Initial syntheses of key components 2 and 3 worked well on laboratory scale but had significant drawbacks for larger-scale manufacture. Therefore, new routes to these two key fragments were developed and demonstrated to synthesize kilogram quantities. Key steps involve a two-step thiophenol alkylation/cyclization protocol to synthesize 2 in a convergent manner. A difficult Pd-mediated coupling to produce 3 was replaced with a more scalable stepwise imidazole synthesis. Key rationale for the new routes are discussed.
- Scott, Robert W.,Neville, Scan N.,Urbina, Armando,Camp, David,Stankovic, Nebojsa
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p. 296 - 303
(2012/12/22)
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- Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity
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Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.
- Munchhof, Michael J.,Beebe, Jean S.,Casavant, Jeffery M.,Cooper, Beth A.,Doty, Jonathan L.,Higdon, R. Carla,Hillerman, Stephen M.,Soderstrom, Catherine I.,Knauth, Elisabeth A.,Marx, Matthew A.,Rossi, Ann Marie K.,Sobolov, Susan B.,Sun, Jianmin
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- Cross-coupling methods for the large-scale preparation of an imidazole - Thienopyridine: Synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl] -(2-methyl-1H-indol-5-yl)-amine
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The multihundred-gram synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl] -(2-methyl-1H-indol-5-yl)-amine (1) is described utilizing a Stille cross-coupling of an iodothienopyridine (3) with 5-(tributylstannyl)-1-methylimidazole (11). Several cross-coupling methods were evaluated for the conversion of thienopyridine 3 to imidazole - thienopyridine 2, but only two were effective: the Stille coupling and a Negishi cross-coupling of the organozinc reagent derived from 2-(tertbutyldimethylsilyl)-1-methylimidazole and iodothienopyridine (3). The latter procedure worked well on laboratory scale (50 g), but was capricious upon scale-up. The issues with scale-up of an organostannane reagent are discussed, including control and analysis of organotin levels.
- Ragan,Raggon,Hill,Jones,McDermott,Munchhof,Marx,Casavant,Cooper,Doty,Lu
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p. 676 - 683
(2013/09/05)
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