- A comparative study of the recent most potent small-molecule PD-L1 inhibitors: what can we learn?
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Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have become a “game-changer” in the cancer treatment. However, none of the small molecular inhibitors has been approved yet. To explore the advantages and disadvantages of various scaffolds, di
- Liu, Mei,Zhang, Yu,Guo, Yu,Gao, Jian,Huang, Wenhai,Dong, Xiaowu
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p. 1230 - 1239
(2021/04/26)
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- Compound capable of being used as immunomodulator, and preparation method and application thereof
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The invention relates to a micromolecular immunomodulator and discloses a method for preparing the micromolecular immunomodulator at the same time, and the micromolecular immunomodulator can be used for treating cancers or tumors, infectious diseases, metabolic diseases and other diseases and has great clinical value.
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Paragraph 0094-0098
(2021/10/13)
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- 1,4,6-Trisubstituted imidazo[4,5-c]pyridines as inhibitors of Bruton's tyrosine kinase
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Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.
- Kraj?ovi?ová, Soňa,Jorda, Radek,Vanda, David,Soural, Miroslav,Kry?tof, Vladimír
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- BIARYL DERIVATIVE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL APPLICATION THEREOF
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Disclosed are a biaryl derivative having a structure represented by Formula (I) and inhibitory activity against PD-1/PD-L1 interaction, a preparation method thereof, and a pharmaceutical application thereof. The series of compounds of the present inventio
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Paragraph 0100; 0101
(2020/12/22)
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- Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)
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Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fc receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
- Watterson, Scott H.,Liu, Qingjie,Beaudoin Bertrand, Myra,Batt, Douglas G.,Li, Ling,Pattoli, Mark A.,Skala, Stacey,Cheng, Lihong,Obermeier, Mary T.,Moore, Robin,Yang, Zheng,Vickery, Rodney,Elzinga, Paul A.,Discenza, Lorell,D'Arienzo, Celia,Gillooly, Kathleen M.,Taylor, Tracy L.,Pulicicchio, Claudine,Zhang, Yifan,Heimrich, Elizabeth,McIntyre, Kim W.,Ruan, Qian,Westhouse, Richard A.,Catlett, Ian M.,Zheng, Naiyu,Chaudhry, Charu,Dai, Jun,Galella, Michael A.,Tebben, Andrew J.,Pokross, Matt,Li, Jianqing,Zhao, Rulin,Smith, Daniel,Rampulla, Richard,Allentoff, Alban,Wallace, Michael A.,Mathur, Arvind,Salter-Cid, Luisa,Macor, John E.,Carter, Percy H.,Fura, Aberra,Burke, James R.,Tino, Joseph A.
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- Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)
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Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fc receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
- Watterson, Scott H.,Liu, Qingjie,Beaudoin Bertrand, Myra,Batt, Douglas G.,Li, Ling,Pattoli, Mark A.,Skala, Stacey,Cheng, Lihong,Obermeier, Mary T.,Moore, Robin,Yang, Zheng,Vickery, Rodney,Elzinga, Paul A.,Discenza, Lorell,D'Arienzo, Celia,Gillooly, Kathleen M.,Taylor, Tracy L.,Pulicicchio, Claudine,Zhang, Yifan,Heimrich, Elizabeth,McIntyre, Kim W.,Ruan, Qian,Westhouse, Richard A.,Catlett, Ian M.,Zheng, Naiyu,Chaudhry, Charu,Dai, Jun,Galella, Michael A.,Tebben, Andrew J.,Pokross, Matt,Li, Jianqing,Zhao, Rulin,Smith, Daniel,Rampulla, Richard,Allentoff, Alban,Wallace, Michael A.,Mathur, Arvind,Salter-Cid, Luisa,Macor, John E.,Carter, Percy H.,Fura, Aberra,Burke, James R.,Tino, Joseph A.
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p. 3228 - 3250
(2019/04/17)
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- IMMUNOMODULATORS, COMPOSITIONS AND METHODS THEREOF
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Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or
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Page/Page column 37-38
(2019/10/30)
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- SUBSTITUTED 1,1'-BIPHENYL COMPOUNDS, ANALOGUES THEREOF, AND METHODS USING SAME
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The present invention includes substituted 3,3'-bis(phenoxymethyl)-1,1'-biphenyl compounds, analogues thereof, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a patient.
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Page/Page column 113
(2019/10/23)
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- Highly Potent 17β-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy
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Intracellular elevation of E2 levels in bone by inhibition of 17β hydroxysteroid dehydrogenase type 2 (17β-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17β-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range. Compound 33, comparable to A in terms of inhibitor potency against both human and mouse enzymes, displays high in vitro metabolic stability in human and mouse liver S9 fraction as well as low toxicity and moderate hepatic CYP inhibition. Thus, compound 33 showed a highly improved peroral pharmacokinetic profile in comparison to A, making 33 a promising candidate for further development.
- Siebenbuerger, Lorenz,Hernandez-Olmos, Victor,Abdelsamie, Ahmed S.,Frotscher, Martin,Van Koppen, Chris J.,Marchais-Oberwinkler, Sandrine,Scheuer, Claudia,Laschke, Matthias W.,Menger, Michael D.,Boerger, Carsten,Hartmann, Rolf W.
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supporting information
p. 10724 - 10738
(2019/01/04)
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- N-(SUBSTITUTED-PHENYL)-SULFONAMIDE DERIVATIVES AS KINASE INHIBITORS
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The invention relates to N-(substituted-phenyl)-sulfonamide compounds, which are extremely useful as inhibitors of protein kinases (e.g. PERK kinase) and accordingly can be used for the treatment of cell proliferative disorders, such as cancer, or diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
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Page/Page column 29
(2018/04/11)
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- Small Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)
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Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.
- De Lucca, George V.,Shi, Qing,Liu, Qingjie,Batt, Douglas G.,Beaudoin Bertrand, Myra,Rampulla, Rick,Mathur, Arvind,Discenza, Lorell,D'Arienzo, Celia,Dai, Jun,Obermeier, Mary,Vickery, Rodney,Zhang, Yingru,Yang, Zheng,Marathe, Punit,Tebben, Andrew J.,Muckelbauer, Jodi K.,Chang, Chiehying J.,Zhang, Huiping,Gillooly, Kathleen,Taylor, Tracy,Pattoli, Mark A.,Skala, Stacey,Kukral, Daniel W.,McIntyre, Kim W.,Salter-Cid, Luisa,Fura, Aberra,Burke, James R.,Barrish, Joel C.,Carter, Percy H.,Tino, Joseph A.
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p. 7915 - 7935
(2016/10/12)
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- Inhibitors of 17Beta-Hydroxysteroid Dehydrogenases Type 1 and Type 2
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Provided herein are non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 and type 2 (17β-HSD1 and 17β-HSD2) inhibitors, their production and use, especially for the treatment and for prophylaxis of hormone-related diseases.
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Paragraph 0297
(2016/12/12)
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- Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis
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Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.
- Lou, Yan,Han, Xiaochun,Kuglstatter, Andreas,Kondru, Rama K.,Sweeney, Zachary K.,Soth, Michael,McIntosh, Joel,Litman, Renee,Suh, Judy,Kocer, Buelent,Davis, Dana,Park, Jaehyeon,Frauchiger, Sandra,Dewdney, Nolan,Zecic, Hasim,Taygerly, Joshua P.,Sarma, Keshab,Hong, Junbae,Hill, Ronald J.,Gabriel, Tobias,Goldstein, David M.,Owens, Timothy D.
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p. 512 - 516
(2015/03/03)
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- SUBSTITUTED 1H-PYRROLOPYRIDINONE DERIVATIVES AS KINASE INHIBITORS
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The present invention provides novel substituted 1H-Pyrrolopyridinone derivatives of formula (1) as protein kinase inhibitors, in which R1, R2, R3, R4, R5, R6 and 'p' have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly BTK enzyme. The present invention also provides methods for synthesizing and administering the kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 26
(2014/09/03)
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- METHOD FOR MANUFACTURING A BORONIC ACID ESTER COMPOUND
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The present invention relates to a method for manufacturing a boronic acid ester compound, characterized by reacting an aryl halide compound and a diboron ester compound in the presence of a nitrogen-containing organic base, a nickel catalyst, a phosphine compound and a solvent. According to the manufacturing method of the present invention, even if a nickel catalyst is used as the catalyst, a desired boronic acid ester compound can be obtained in a sufficiently high yield. Furthermore, even if aryl chloride or aryl bromide having relatively low price and low reactivity, was used as the aryl halide compound, a desired boronic acid ester compound can be obtained in a sufficiently high yield.
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Page/Page column 14
(2012/05/21)
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- PYRIDINONES/PYRAZINONES, METHOD OF MAKING, AND METHOD OF USE THEREOF
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Pyridone and pyrazinone compounds of Formula (I) including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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- METHOD FOR MANUFACTURING A BORONIC ACID ESTER COMPOUND
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The present invention relates to a method for manufacturing a boronic acid ester compound, characterized by reacting an aryl halide compound and a diboron ester compound in the presence of a nitrogen-containing organic base, a nickel catalyst, a phosphine compound and a solvent. According to the manufacturing method of the present invention, even if a nickel catalyst is used as the catalyst, a desired boronic acid ester compound can be obtained in a sufficiently high yield. Furthermore, even if aryl chloride or aryl bromide having relatively low price and low reactivity, was used as the aryl halide compound, a desired boronic acid ester compound can be obtained in a sufficiently high yield.
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Page/Page column 47-48
(2010/11/03)
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- SUBSTITUTED AMIDES, METHOD OF MAKING, AND USE AS BTK INHIBITORS
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Compounds of Formula I that inhibit Btk are described herein. Pharmaceutical compositions comprising at least one compound of Formula I, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients. are de
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- CERTAIN SUBSTITUTED AMIDES, METHOD OF MAKING, AND METHOD OF USE THEREOF
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Compounds of Formula I that inhibit Btk are described herein. Pharmaceutical compositions comprising at least one compound of Formula I, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are de
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Page/Page column 24
(2009/04/24)
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- NOVEL IMIDAZO[1,2-A]PYRIDINE AND IMIDAZO[1,2-B]PYRIDAZINE DERIVATIVES
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Imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine derivatives which inhibit Btk and are useful for the treatment of auto-immune and inflammatory diseases caused by aberrant B-cell activation, e.g. arthritis.
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Page/Page column 87
(2009/07/18)
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- KINASE INHIBITORS, AND METHODS OF USING AND IDENTIFYING KINASE INHIBITORS
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Methods of inhibiting BTK activity by inhibiting phosphorylation of Y551 of BTK, methods of treating patients by inhibiting BTK activity by inhibiting phosphorylation of Y551 of BTK, chemical entities that bind to BTK and inhibited complexes are provided.
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- The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer
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Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110α. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
- Folkes, Adrian J.,Ahmadi, Khatereh,Alderton, Wendy K.,Alix, Sonia,Baker, Stewart J.,Box, Gary,Chuckowree, Irina S.,Clarke, Paul A.,Depledge, Paul,Eccles, Suzanne A.,Friedman, Lori S.,Hayes, Angela,Hancox, Timothy C.,Kugendradas, Arumugam,Lensun, Letitia,Moore, Pauline,Olivero, Alan G.,Pang, Jodie,Patel, Sonal,Pergl-Wilson, Giles H.,Raynaud, Florence I.,Robson, Anthony,Saghir, Nahid,Salphati, Laurent,Sohal, Sukhjit,Ultsch, Mark H.,Valenti, Melanie,Wallweber, Heidi J. A.,Nan, Chi Wan,Wiesmann, Christian,Workman, Paul,Zhyvoloup, Alexander,Zvelebil, Marketa J.,Shuttleworth, Stephen J.
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experimental part
p. 5522 - 5532
(2009/09/06)
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- Aryl nitrogen-containing bicyclic compounds and methods of use
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The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation, cancer and related conditions. The compounds have a general Formula I wherein A1, As
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Page/Page column 108
(2010/11/26)
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