- Azaindazole bipyridine derivative myeloid cell proliferation inhibitor as well as preparation method and application thereof in pharmacy
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The invention provides an azaindazole bipyridine derivative myeloid cell proliferation inhibitor shown as a formula I, wherein R1, R2 and R3 have the meanings defined in the specification of the invention. A compound in formula I can significantly inhibit proliferation and related disordersof myeloid cells represented by MOLM-16, HL-60, and MV-4-11. The formula I or salt thereof or the related pharmaceutical composition provided by the invention has excellent in-vivo and in-vitro inhibitory activity, good druggability, high bioavailability and no obvious damage to organs. Therefore, the compound shown in the formula I or the salt thereof and the related drug combination have huge clinical application prospects.
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- Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis
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Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.
- Klug, Dana M.,Mavrogiannaki, Eftychia M.,Forbes, Katherine C.,Silva, Lisseth,Diaz-Gonzalez, Rosario,Pérez-Moreno, Guiomar,Ceballos-Pérez, Gloria,Garcia-Hernández, Raquel,Bosch-Navarrete, Cristina,Cordón-Obras, Carlos,Gómez-Li?án, Claudia,Saura, Andreu,Momper, Jeremiah D.,Martinez-Martinez, Maria Santos,Manzano, Pilar,Syed, Ali,El-Sakkary, Nelly,Caffrey, Conor R.,Gamarro, Francisco,Ruiz-Perez, Luis Miguel,Gonzalez Pacanowska, Dolores,Ferrins, Lori,Navarro, Miguel,Pollastri, Michael P.
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supporting information
p. 9404 - 9430
(2021/07/25)
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- Design and synthesis of 1H-pyrazolo[3,4-b]pyridines targeting mitogen-activated protein kinase kinase 4 (MKK4) - A promising target for liver regeneration
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Currently, the therapeutic options for treatment of liver failure are very limited. As mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified by in vivo RNAi experiments to be a major regulator in hepatocyte regeneration, we pursued the development of a small molecule targeting this protein kinase. Starting from the approved BRAFV600E inhibitor vemurafenib (8), that showed a high off-target affinity to MKK4 in an initial screening, we followed a scaffold-hopping approach, changing the core heterocycle from 1H-pyrrolo[2,3-b]pyridine to 1H-pyrazolo[2,3-b]pyridine (10). Affinity to MKK4 could be conserved while the selectivity against off-target protein kinases was slightly improved. Further modifications led to 58 and 59 showing high affinity to MKK4 in the low nanomolar range and excellent selectivity profile from mandatory multiparameter-optimization for the essential anti-targets (MKK7, JNK1) and off-targets (BRAF, MAP4K5, ZAK) in the MKK4 pathway. Herein we report the first selective MKK4 inhibitors in this class.
- Pfaffenrot, Bent,Kl?vekorn, Philip,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
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- Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors
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As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC50 Values of 3–287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC50 = 3 nM) and cell proliferation inhibitory activity (IC50 = 1.6 μM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.
- Park, Areum,Hwang, Jieon,Lee, Joo-Youn,Heo, Eun Ji,Na, Yoon-Ju,Kang, Sein,Jeong, Kyu-Sung,Kim, Ki Young,Shin, Sang Joon,Lee, Hyuk
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supporting information
(2021/07/06)
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- HETEROARYL-SUBSTITUTED PYRAZOLO-PYRIDINE PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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Page/Page column 20; 21
(2021/02/05)
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- IMIDAZOPIPERAZINE INHIBITORS OF TRANSCRIPTION ACTIVATING PROTEINS
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The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of transcription activating proteins such as CBP and P300 for the treatment or prevention of diseases such as proliferative diseases, inflammatory disorders, autoimmune diseases, and fibrotic diseases.
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Paragraph 0662-0663
(2019/10/17)
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- PROTEIN KINASE MKK4 INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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Page/Page column 51; 64
(2019/08/26)
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- Alkylene phenylsulfonamide type selective ZAK inhibitor and application thereof
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The invention relates to application of an alkylene phenylsulfonamide compound with a structure of formula (I) (shown in the description) or pharmaceutically acceptable salt thereof or stereisomer thereof or a prodrug molecule thereof in preparation of a
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Paragraph 0278; 0279; 0280-0282
(2018/06/16)
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- PYRAZOLO FUSED HETEROCYCLIC COMPOUNDS AS ERK INHIBITORS
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Disclosed herein is a compound of formula (I) and/or a pharmaceutically acceptable salt thereof that can serve as Erk inhibitors. They are potentially useful in the treatment of diseases treatable by inhibition of Erk, such as cancers. Also disclosed here
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Paragraph 0125
(2017/03/14)
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- HETEROCYCLIC COMPOUNDS AS ERK INHIBITORS
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Compounds of Formula (I) and pharmaceutical compositions containing the compounds are disclosed, which are used for treatment of disease, disorder or condition associated with ERK activity.
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Paragraph 065
(2016/03/18)
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- HETEROCYCLIC COMPOUNDS AS ERK INHIBITORS
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Disclosed herein is a compound of formula (I) and/or a pharmaceutically acceptable salt thereof that can serve as Erk inhibitors. They are potentially useful in the treatment of diseases treatable by inhibition of Erk, such as cancers. Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
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Paragraph 0112; 0115; 0116
(2016/12/22)
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- Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors
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Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8 nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329 nM and EBC-1 IC50 of 479 nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization.
- Liu, Na,Wang, Yanfen,Huang, Gongchao,Ji, Conghui,Fan, Wei,Li, Haitao,Cheng, Ying,Tian, Hongqi
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p. 146 - 158
(2016/03/12)
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- As inhibitors of cMet compounds and methods for their preparation and use
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The present invention relates to a substituted 1H-pyrrolo[2,3-b]pyridine compound adopted as a cMet inhibitor and a substituted 1H-pyrazolo[3,4-b]pyridine compound, a preparation method of the compounds, uses of the compounds, a compound represented by a formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof, and a preparation method of the compound represented by the formula (I), wherein X, X, X, X, W, R and R1 are defined in an instruction. The invention further discloses the preparation method of the compound represented by the formula (I) and a drug composition containing the compound represented by the formula (I).
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Paragraph 0342-0344
(2016/11/14)
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- FIVE-MEMBER-HETEROCYCLE FUSED PYRIDINE COMPOUNDS, METHOD OF PRODUCING THE SAME, AND USE THEREOF
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This invention provides a class of five-member-heterocycle fused pyridine compounds as shown below in Formula (X), pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, a method of producing the same, pharmaceutical compositions containing the compound, and use of the compounds in preparing medicament for preventing and/or treating diseases and tumours associated with abnormal protein tyrosine kinase.
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Paragraph 0181; 0182
(2016/06/06)
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- HETEROCYCLIC COMPOUNDS FOR TREATING PSORIASIS
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Disclosed herein is a method of treating psoriasis involving the use of compound of formula I and/or a pharmaceutically acceptable salt thereof
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Paragraph 0118-0119
(2016/12/22)
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- Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b ]pyridines as selective c-met inhibitors
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c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π-π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.
- Ma, Yuchi,Sun, Guangqiang,Chen, Danqi,Peng, Xia,Chen, Yue-Lei,Su, Yi,Ji, Yinchun,Liang, Jin,Wang, Xin,Chen, Lin,Ding, Jian,Xiong, Bing,Ai, Jing,Geng, Meiyu,Shen, Jingkang
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p. 2513 - 2529
(2015/03/30)
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- N-(3-ethynyl-2,4-difluorophenyl)sulfonamide derivatives as selective Raf inhibitors
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A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-RafV600E with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferation of a panel of human cancer cell lines and patient-derived melanoma cells with B-RafV600E mutation while being significantly less potent to the cells with B-RafWT. The compounds also display favorable pharmacokinetic properties with a preferred example (3s) demonstrating significant in vivo antitumor efficacy in a xenograft mouse model of B-RafV600E mutated Colo205 human colorectal cancer cells, supporting it as a promising lead compound for further anticancer drug discovery.
- Li, Yingjun,Cheng, Huimin,Zhang, Zhang,Zhuang, Xiaoxi,Luo, Jinfeng,Long, Huoyou,Zhou, Yang,Xu, Yong,Taghipouran, Rana,Li, Dan,Patterson, Adam,Smaill, Jeff,Tu, Zhengchao,Wu, Donghai,Ren, Xiaomei,Ding, Ke
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supporting information
p. 543 - 547
(2015/05/27)
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- ALKYNYL ALCOHOLS AND METHODS OF USE
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The invention relates to compounds of Formula (0): wherein Q, A1-A8, R4 and R5 and each has the meaning as described herein. Compounds of Formula (0) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over- activation of NF-kB signaling is observed.
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Page/Page column 130
(2015/03/13)
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- Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib
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Bcr-AblT315I mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-AblWT and Bcr-AblT315I with Kd values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC50 values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC 50 values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-AblWT or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-AblT315I. GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.
- Ren, Xiaomei,Pan, Xiaofen,Zhang, Zhang,Wang, Deping,Lu, Xiaoyun,Li, Yupeng,Wen, Donghai,Long, Huoyou,Luo, Jinfeng,Feng, Yubing,Zhuang, Xiaoxi,Zhang, Fengxiang,Liu, Jianqi,Leng, Fang,Lang, Xingfen,Bai, Yang,She, Miaoqin,Tu, Zhengchao,Pan, Jingxuan,Ding, Ke
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supporting information
p. 879 - 894
(2013/03/28)
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- DIAZAINDOLE DERIVATIVES AND THEIR USE IN THE INHIBITION OF C-JUN N-TERMINAL KINASE
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The invention relates to diazaindole derivatives represented by the general formula (I): where A, E, G, R1, R2, R3 and R4 are defined herein, or pharmaceutically acceptable salts thereof, their use in the inhibition of c-Jun N-terminal kinase (JNK) activity, their use in medicine and particularly in the treatment of neurodegenerative disorders, inflammatory diseases, autoimmune diseases and/or organ failure. The invention also provides processes for the manufacture of said diazaindole derivatives and compositions containing them.
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Page/Page column 43
(2010/04/03)
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- PYRAZOLE [3, 4-B] PYRIDINE RAF INHIBITORS
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Compounds of Formula I are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers, tautomers, prodrugs 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 83
(2009/10/22)
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- FUSED RING HETEROCYCLE KINASE MODULATORS
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The present invention provides fused ring heterocycles as kinase modulators, pharmaceutical compositions containing these modulators, and methods of using these modulators to treat diseases mediated by kinase activity.
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Page/Page column 73-74
(2008/12/04)
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- Synthesis of 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor
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The novel compound 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described.
- Huang, Shenlin,Lin, Ronghui,Yu, Yang,Lu, Yanhua,Connolly, Peter J.,Chiu, George,Li, Shengjian,Emanuel, Stuart L.,Middleton, Steven A.
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p. 1243 - 1245
(2007/10/03)
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- 3-BENZOIMIDAZOLYL-PYRAZOLOPYRIDINES USEFUL IN TREATING KINASE DISORDERS
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The present invention is directed to novel 3-benzoimidazolyl-pyrazolopyridine compounds of formula (I): and pharmaceutically acceptable forms thereof and their synthesis and use as inhibitors of serine-threonine protein kinases and tyrosine protein kinases and interactions thereof.
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Page/Page column 86
(2008/06/13)
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- FUSED RING HETEROCYCLE KINASE MODULATORS
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The present invention provides novel fused ring heterocycle kinase modulators and methods of using the novel fused ring heterocycle kinase modulators to treat diseases mediated by kinase activity.
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Page/Page column 59
(2008/06/13)
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