- Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL
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MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.
- Fu, Liqiang,Zhang, Jing,Shen, Bin,Kong, Linglong,Liu, Yingtao,Tu, Wangyang,Wang, Wenqian,Cai, Xin,Wang, Xiaotao,Cheng, Na,Xia, Mingxuan,Zhou, Tianyuan,Liu, Qian,Xu, Yanping,Yang, Jennifer,Gavine, Paul,Philippar, Ulrike,Attar, Ricardo,Edwards, James P.,Venable, Jennifer D.,Dai, Xuedong
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Read Online
- Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance
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EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
- Chen, Jinju,Jiang, Biao,Kong, Ying,Li, Yan,Lin, Haifan,Qiu, Xing,Ren, Chaowei,Song, Xiaoling,Sun, Ning,Yang, Xiaobao,Zhang, Jianshui,Zhong, Hui,Zhou, Yuedong
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Read Online
- Conformational, vibrational and DFT studies of a newly synthesized arylpiperazine-based drug and evaluation of its reactivity towards the human GABA receptor
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This study reports a computational assessment of important biochemical properties and vibrational assignments for the synthesized 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone (MNPE). MNPE is related to the commonly used arylpiperazine-based drugs
- Onawole,Al-Ahmadi,Mary,Panicker,Ullah,Armakovi?,Armakovi?,Van Alsenoy,Al-Saadi
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Read Online
- Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor
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Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure-activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline "tail,"which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC50 = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.
- Groendyke, Brian J.,Nabet, Behnam,Mohardt, Mikaela L.,Zhang, Haisheng,Peng, Ke,Koide, Eriko,Coffey, Calvin R.,Che, Jianwei,Scott, David A.,Bass, Adam J.,Gray, Nathanael S.
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supporting information
p. 30 - 38
(2021/01/11)
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- TYROSINE KINASE NON-RECEPTOR 1 (TNK1) INHIBITORS AND USES THEREOF
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Provided herein is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g, X11, X22, R11, R22, R33, R44, R55, R66, R77, R88, m, n) are as described herein. Compounds of Formula I, pharmaceutically acceptable salts thereof, pharmaceutical compositions of either of the foregoing, and combinations of any of the foregoing can be used to treat tyrosine kinase non- receptor 1 (TNK1)-mediated diseases, disorders and conditions.
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Paragraph 00267; 00277
(2021/01/23)
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- Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity
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TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
- Elsner, Jan,Cashion, Dan,Robinson, Dale,Bahmanyar, Sogole,Tehrani, Lida,Fultz, Kimberly E.,Narla, Rama Krishna,Peng, Xiaohui,Tran, Tam,Apuy, Julius,Lebrun, Laurie,Leftheris, Katerina,Boylan, John F.,Zhu, Dan,Riggs, Jennifer R.
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supporting information
p. 12670 - 12679
(2021/09/13)
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- PROTEIN DEGRADATION TARGETING COMPOUND, ANTI-TUMOR APPLICATION, INTERMEDIATE THEREOF AND USE OF INTERMEDIATE
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The present disclosure relates to compounds of formula (I) and their anti-tumor uses, and their intermediates of formula (III), intermediates of formula (IV), and uses of the intermediates. The compound of formula (I) has a degrading effect on a specific target protein, which is mainly composed of three parts. The first part is a small molecule compound (SMBP, Small Molecules Binding Protein) that can bind to a protein, the second part LIN is a linker, and the three-part ULM is a ubiquitin ligand (ULM, Ubiquitin Ligase Binding Moiety), wherein SMBP is covalently bound to LIN, and LIN is covalently bound to ULM. A series of compounds designed and synthesized in the present disclosure have a wide range of pharmacological activities, including the functions of degrading specific proteins and/or inhibiting activities of specific proteins, and thus can be used in related tumor treatments.
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Paragraph 0371-0372
(2021/02/18)
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- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 1 PROTEINS
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The present invention relates to compounds comprising an interleukin-1 receptor-associated kinase 1 (IRAK1) protein binding moiety and a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety, and associated methods of use. The compounds are useful as modulators of targeted ubiquitination, especially with respect to IRAK1, which is degraded by the compounds according to the invention.
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Page/Page column 51; 52
(2021/02/05)
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- Discovery and structure ? activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors
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Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance- conferring mutations, FLT3D835Y, both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.
- Chen, Yun,Bai, Gang,Li, Yan,Ning, Yi,Cao, Sufen,Zhou, Jinpei,Ding, Jian,Zhang, Huibin,Xie, Hua,Duan, Wenhu
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supporting information
(2021/09/28)
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- Compounds for targeted degradation of focal adhesion kinase and application of the compounds in medicine
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The invention relates to the field of biomedicine and drug synthesis, in particular to compounds for targeted degradation of focal adhesion kinase (FAK) protein, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, preparation methods of the compounds and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs, and application of the compounds as therapeutic agents, especially as FAK degradation agents. The structures of the compounds, and the geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are shown inthe specification. The compounds provided by the invention have a good degradation effect on FAK kinase, and can be used for preventing, treating or adjunctively treating various diseases related tothe expression or activity of FAK kinase.
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Paragraph 0110-0113
(2020/07/06)
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- ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof
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The invention discloses a compound in a formula (I) and an anti-tumor application thereof. The compound in the formula (I) has degradation and inhabitation functions on ALK target protein and mainly comprises four parts, the first part ALK-TKIs is a compound with ALK tyrosine kinase inhabitation activity; the second part LIN is different linkers; the third part ULM (ubiquitin ligase binding moiety) of VHL, CRBN or other protease micromolecular ligand with a ubiquitination function; the fourth part group A is carboxyl or deficiency and covalently binds ALK-TKIs with LIN and covalently binds LINwith ULM. A series of designed and synthesized compounds have wide pharmacological activity, have functions of degrading ALK protein and inhibiting ALK activity and can be applied to related tumor therapy.
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Paragraph 0358; 0359-0360
(2019/07/04)
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- Novel pyrimido-heterocyclic compound and preparation method and application thereof
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The invention discloses a novel pyrimido-heterocyclic compound and a preparation method and application thereof. The structure of the pyrimido-heterocyclic compound disclosed by the invention is as shown in a general formula I, and the definitions of all substituents are described in the specification and claims. The pyrimido-heterocyclic compound disclosed by the invention has much better inhibitory activity and selectivity for double-mutant EGFR kinase than the existing AZD-9291, can be used for preparing anti-tumor drugs, and overcomes the defect of drug tolerance of the first generation ofEGFR inhibitor.
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Paragraph 0070; 0072; 0073; 0074
(2019/02/19)
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- Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy
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Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. P
- Riggs, Jennifer R.,Elsner, Jan,Cashion, Dan,Robinson, Dale,Tehrani, Lida,Nagy, Mark,Fultz, Kimberly E.,Krishna Narla, Rama,Peng, Xiaohui,Tran, Tam,Kulkarni, Ashutosh,Bahmanyar, Sogole,Condroski, Kevin,Pagarigan, Barbra,Fenalti, Gustavo,Lebrun, Laurie,Leftheris, Katerina,Zhu, Dan,Boylan, John F.
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supporting information
p. 4401 - 4410
(2019/05/17)
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- PYRIMIDINE DERIVATIVE AND USE THEREOF
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The present invention provides a pyrimidine derivative and a use thereof. The pyrimidine derivative is the compound shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein, R1, R2, R3, R4 and R5 are, for example, as defined in the specification. The compound can act as an ALK inhibitor, and is for preparing an anti-tumor medicament for suppressing an anaplastic lymphoma kinase.
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Paragraph 0154; 0155; 0156
(2018/09/27)
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- 2,4-dibasic miazines compound
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The invention belongs to the field of medical chemistry, relates to a 2,4-dibasic miazines compound and specifically relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof, a drug compound thereof and an application thereof in treating EGFR or/and ALK mediated diseases.
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Paragraph 0294; 0295; 0296; 0297; 0298
(2017/08/29)
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- Substituted aminopyrimidine derivative, preparation method therefor and pharmaceutical application thereof
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The invention relates to a substituted aminopyrimidine derivative as shown in general formula (I) and (II), an optical isomer, a pharmaceutically acceptable salt or co-crystallization thereof, a preparation method and application in preparation of tumor m
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Paragraph 0369; 0370; 0371; 0372; 0373; 0374
(2016/10/07)
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- Substituted 7-Oxo-Pyrido[2,3-d]Pyrimidines and Methods of Use
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The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer.
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Paragraph 0261; 0262
(2014/09/16)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, Formula (1) wherein R1, R2, R3, X, Y, Z, A, B, G1, m, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Paragraph 0350
(2014/06/25)
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- Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors
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Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
- Kumar, D. Vijay,Hoarau, Christophe,Bursavich, Matthew,Slattum, Paul,Gerrish, David,Yager, Kraig,Saunders, Michael,Shenderovich, Mark,Roth, Bruce L.,McKinnon, Rena,Chan, Ashley,Cimbora, Daniel M.,Bradford, Chad,Reeves, Leslie,Patton, Scott,Papac, Damon I.,Williams, Brandi L.,Carlson, Robert O.
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scheme or table
p. 4377 - 4385
(2012/08/07)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, wherein R1, X, Y, Z, A, B, G1, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Page/Page column 68
(2012/08/07)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, Formula (1) wherein R1, R2, R3, X, Y, Z, A, B, G1, m, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Page/Page column 83-84
(2012/08/07)
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- BICYCLIC CARBOXAMIDE INHIBITORS OF KINASES
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Compounds of formula (I) or pharmaceutical acceptable salts are provided, wherein X1~X5, R1~R3, A, B, Z and n are defined in the description. And compositions containing said compounds, and the uses for inhibitors of kinases such as ALK, and the uses for treating cancer thereof are provided.
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Page/Page column 64
(2012/08/07)
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- EGFR INHIBITORS AND METHODS OF TREATING DISORDERS
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The present invention relates to novel pyrimidine, pyrrolo-pyrimidine, pyrrolo-pyridine, pyridine, purine and triazine compounds which are able to modulate epidermal growth factor receptor (EGFR), including Her-kinases, and the use of such compounds in the treatment of various diseases, disorders or conditions.
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Page/Page column 126
(2010/11/18)
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- 2- [ (2-{PHENYLAMINO}-1H-PYRROLO [2, 3-D] PYRIMIDIN-4-YL) AMINO] BENZAMIDE DERIVATIVES AS IGF-1R INHIBITORS FOR THE TREATMENT OF CANCER
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Novel pyrrolopyrimidines as shown in formula (I) and pharmaceutically acceptable derivatives thereof. The compounds are useful in the inhibition of IGF-1R.
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Page/Page column 102-103
(2009/04/25)
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- Imidazopyridine Kinase Inhibitors
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The present invention provides imidazopyridine compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 97
(2009/01/20)
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