- Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib
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Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.
- Rozema, Michael J.,Bhagavatula, Lakshmi,Christesen, Alan,Dunn, Travis B.,Ickes, Andrew,Kotecki, Brian J.,Marek, James C.,Moschetta, Eric,Morrill, Westin H.,Mulhern, Mathew,Rasmussen, Michael,Reynolds, Troy,Yu, Su
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p. 949 - 962
(2021/10/21)
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- Synthetic method of indole or azabenzopyrrole compound
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The invention relates to a synthetic method of an indole or azabenzopyrrole compound. The synthetic method comprises the following steps: carrying out cyclization reaction on a compound A and disubstituted amine in a solvent, wherein the structural general formula of the disubstituted amine is NH(R2)2, R2 is respectively and independently selected from C1-C6 alkyl, C1-C6 alkyl hydroxyl, C1-C6 alkyl O-C1-C6 alkyl, C1-C6 alkyl NH-C1-C6 alkyl or C1-C6 alkylamino, and the two R2 are connected with each other to form a ring or not form a ring. According to the synthetic method of the indole or azabenzopyrrole compound, the disubstituted amine compound with a specific structural general formula and the terminal alkynyl of the intermediate are subjected to an addition reaction, the rigid structure of the terminal alkynyl is changed, and the structure of alkenyl amine is changed, so that under mild reaction conditions, ring closing of pyrrole groups in indole or azabenzopyrrole compounds is realized, side reactions are few, the product yield is high, and the production cost of the product is reduced from the source.
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Paragraph 0087-0091; 0098-0099; 0103-0105; 0109-0110
(2021/03/31)
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- Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ
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Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγinhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
- Bellenie, Benjamin R.,Hall, Edward,Bruce, Ian,Spendiff, Matthew,Culshaw, Andrew,McDonald, Sarah,Ambarkhane, Ameet,Chinn, Colin,Thomas, Matthew,Rosner, Elisabeth,Bracher, Marguerite,Nicklin, Paul,Marshall, Stephen,Coote, Julie,Cullen, Eva,Tessier, Clemence,Wuersch, Kuno,Lal, Ajay,Wallis, Gillian,Hollingworth, Gregory J.,Neef, James
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p. 12304 - 12321
(2021/09/02)
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- PYRROLIDINE COMPOUNDS, ITS SALT AND USE IN THE PREPARATION OF UPADACITINIB THEREOF
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The present invention relates to process for the preparation of a pyrrolidine compounds useful as key intermediate for the preparation of upadacitinib. More specifically the present invention relates to a process for preparing compound of Formula I, or pharmaceutically acceptable salts, polymorphs, isomers thereof. The present invention further provides a process for the preparation of upadacitinib using compounds of Formula I. Moreover, the present invention provides various crystalline solvates and crystalline hydrates of Upadacitinib or its pharmaceutically acceptable salts thereof.
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Page/Page column 17; 23
(2021/01/29)
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- Influenza virus replication inhibitors and uses thereof (by machine translation)
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The invention provides a compound as an influenza virus replication inhibitor, a method for preparing the same, a pharmaceutical composition containing the compound and application. (by machine translation)
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Paragraph 0415; 0417-0420
(2019/10/01)
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- Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity
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There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3-b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.
- Verdonck, Sven,Pu, Szu-Yuan,Sorrell, Fiona J.,Elkins, Jon M.,Froeyen, Mathy,Gao, Ling-Jie,Prugar, Laura I.,Dorosky, Danielle E.,Brannan, Jennifer M.,Barouch-Bentov, Rina,Knapp, Stefan,Dye, John M.,Herdewijn, Piet,Einav, Shirit,De Jonghe, Steven
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p. 5810 - 5831
(2019/07/04)
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- JAK kinase inhibitor, preparation method thereof, and application in the field of medicines
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The application relates to a JAK kinase inhibitor, a preparation method thereof, and an application in the field of medicines and belongs to the field of medical chemistry. In the application, a series of novel small-molecular JAK inhibitors are provided and are represented as the general formula (II). The compounds have better effects and higher safety in prevention or treatment on JAK-related adaptation diseases.
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Paragraph 0268; 0271-0273
(2019/04/10)
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- INHIBITORS OF INFLUENZA VIRUS REPLICATION AND USES THEREOF
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The invention provides a class of compounds as inhibitors of influenza virus replication, preparation methods thereof, pharmaceutical compositions containing these compounds, and uses of these compounds and pharmaceutical compositions thereof in the treatment of influenza.
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Paragraph 00586
(2018/07/05)
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- Upadacitinib tartrate: Tyrosine-protein kinase JAK1 inhibitor Treatment of autoimmune inflammatory diseases Treatment of rheumatoid arthritis
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Upadacitinib tartrate (ABT-494) is a potent and selective tyrosine-protein kinase JAK1 inhibitor being developed for the treatment of systemic autoimmune inflammatory diseases, including rheumatoid arthritis (RA), Crohn's disease, ulcerative colitis and psoriatic arthritis. In vitro, upadacitinib demonstrated higher selectivity for inhibiting JAK1 over JAK2 and JAK3, suggesting a potentially improved therapeutic profile in treating patients with inflammatory diseases compared to nonselective JAK inhibitors. Upadacitinib has demonstrated safety and efficacy in phase II trials in patients with RA and inflammatory bowel disease, and is currently in phase III development for these indications.
- Gajdosik
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p. 731 - 743
(2018/11/21)
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- Heteroaromatic compound and application thereof to drug
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The invention discloses a heteroaromatic compound and application thereof to drug. In particular, the invention provides a heteroaromatic compound or stereoisomers thereof, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutical composition comprising the compound provided by the invention. The invention also discloses application of the compound provided by the invention or the pharmaceutical composition thereofto preparation of a medicine for reatment of autoimmune diseases or proliferative diseases.
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Paragraph 0540; 0541; 0542
(2017/07/31)
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- Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors
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Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.
- Friedman, Michael,Frank, Kristine E.,Aguirre, Ana,Argiriadi, Maria A.,Davis, Heather,Edmunds, Jeremy J.,George, Dawn M.,George, Jonathan S.,Goedken, Eric,Fiamengo, Bryan,Hyland, Deborah,Li, Bin,Murtaza, Anwar,Morytko, Michael,Somal, Gagandeep,Stewart, Kent,Tarcsa, Edit,Van Epps, Stacy,Voss, Jeffrey,Wang, Lu,Woller, Kevin,Wishart, Neil
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p. 4399 - 4404
(2015/10/12)
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- JAK1 SELECTIVE INHIBITOR AND USES THEREOF
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The invention relates to the use of a JAK1 kinase-selective inhibitor that has minimal inhibitory activity towards Jak2 kinase for treating a disease, such as an inflammatory disease (e.g., moderate to severe Rheumatoid Arthritis) and/or bone loss, either
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Paragraph 0183
(2015/05/05)
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- AMINO PYRAZINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
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The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.
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Page/Page column 327; 328
(2015/12/09)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, a
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Page/Page column
(2014/05/07)
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- MIXED LINEAGE KINASE INHIBITORS FOR HIV/AIDS THERAPIES
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Disclosed are methods for treating an individual infected with a retrovirus that comprise administering to the individual effective amounts of a mixed lineage kinase inhibitor and antiretroviral drug. In further aspects, disclosed are methods for treating an individual infected with a retrovirus that comprises administering an antiretroviral drug formulated into a crystalline nanoparticle comprising a surfactant, and a MLK inhibitor. Still further disclosed are methods for treating an individual infected with a retrovirus that comprises administering a composition comprising both an antiretroviral and MLK inhibitor formulated into a crystalline nanoparticle, which comprises a surfactant. Still further disclosed are compositions that comprise an antiretroviral drug, a MLK inhibitor, and a surfactant, wherein the composition is a crystalline nanoparticle. Compostions comprising MLK inhibitors with other drugs in nanoparticulate form, and methods of there use, are also disclosed.
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Paragraph 0280
(2014/06/23)
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- AZAINDOLE DERIVATIVES AS JAK3 INHIBITORS
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The present disclosure provides compounds that are JAK3 inhibitors and therefore useful for the treatment of diseases treatable by inhibition of JAK3 such as cancer and inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 31-32
(2014/06/11)
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- Design and synthesis of tricyclic cores for kinase inhibition
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Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest.
- Van Epps, Stacy,Fiamengo, Bryan,Edmunds, Jeremy,Ericsson, Anna,Frank, Kristine,Friedman, Michael,George, Dawn,George, Jonathan,Goedken, Eric,Kotecki, Brian,Martinez, Gloria,Merta, Philip,Morytko, Michael,Shekhar, Shashank,Skinner, Barbara,Stewart, Kent,Voss, Jeffrey,Wallace, Grier,Wang, Lu,Wishart, Neil
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p. 693 - 698
(2013/03/13)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, a
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Paragraph 00209
(2013/04/13)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, a
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Paragraph 00178
(2013/04/13)
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- PROCESSES FOR MAKING COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to processes and intermediates for preparing compounds useful as inhibitors of ATR kinase, such as aminopyrazine-isoxazole derivatives and related molecules. The present invention also relates to compounds useful as inhibitors of ATR protein kinase. The invention relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and solid forms of the compounds of this invention. The compounds of this invention have formula (I) or (II) wherein the variables are as defined herein.
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Paragraph 00162
(2013/04/13)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The invention relates to the compound 5-(4-isopropylsulfonylphenyl) -3-[3-[4-[(3R)-morpholin-3-yl]phenyl]isoxazol-5-yl]pyrazine-2-amine and pharmaceutically acceptable salts thereof. The compounds are useful as inhibitors of ATR kinase.
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Paragraph 00178
(2013/04/13)
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- AZAINDOLE DERIVATIVES AS TYROSINE KINASE INHIBITORS
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The present disclosure provides compounds and pharmaceutically acceptable salts that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, JAK3, TEC, Btk, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts and processes for preparing such compounds and pharmaceutically acceptable salts.
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Page/Page column 89-90
(2012/12/13)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula I wherein the variables are as defined herein.
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Page/Page column 69
(2011/12/02)
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- BICYCLIC HETEROARYL KINASE INHIBITORS AND METHODS OF USE
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Provided are compounds having an inhibitory effect on kinases including Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders that comprise the inhibition of Mixed Lineage Kinases.
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Page/Page column 65-66
(2011/12/14)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present disclosure relates to pyrazine compounds of formula (I) wherein L, n, R1, and R2 are as described in the specification. These compounds are useful as inhibitors of ATR protein kinase. The disclosure also relates to pharmaceutically acceptable compositions comprising the compounds of the disclosure; methods of treating of various diseases, disorders, and conditions using the compounds of the disclosure; processes for preparing the compounds of the disclosure; intermediates for the preparation of the compounds of the disclosure; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
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Page/Page column 150-151
(2010/06/11)
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- MLK INHIBITORS AND METHODS OF USE
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Provided are compounds having an inhibitory effect on Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders which comprise the inhibition of Mixed Lineage Kinases.
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Page/Page column 66-67
(2010/07/02)
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- HISTAMINE H3 INVERSE AGONISTS AND ANTAGONISTS AND METHODS OF USE THEREOF
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Provided herein are fused imidazolyl compounds, methods of synthesis, and methods of use thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders and metabolic disorders. Compounds provided herein inhibit the activity of histamine H3 receptors and modulate the release of various neurotransmitters, such as histamine, acetylcholine, norepinephrine, and dopamine (e.g. at the synapse). Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.
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Page/Page column 114
(2010/08/18)
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- Novel Tricyclic Compounds
-
The invention provides a compound of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.
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Page/Page column 61
(2009/12/27)
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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 102
(2008/06/13)
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