- A N-heterocyclic carbene (NHC) platinum complex as pre-catalyst for the intramolecular hydroamination of olefins with secondary alkylamines and oxidative amination of ω-alkenic amines
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A N-heterocyclic carbene (NHC) platinum complex 3 prepared from BINAM was found to be a highly effective pre-catalyst for the intramolecular hydroamination of olefins with secondary alkylamines to give the corresponding intramolecular hydroamination products in excellent yields. The substrate scope has been carefully examined and the plausible reaction mechanism has been also proposed.
- Zhang, Rui,Xu, Qin,Mei, Liang-Yong,Li, Sheng-Ke,Shi, Min
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supporting information; experimental part
p. 3172 - 3178
(2012/06/01)
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- Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors
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Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
- Medina, Jesús R.,Becker, Christopher J.,Blackledge, Charles W.,Duquenne, Celine,Feng, Yanhong,Grant, Seth W.,Heerding, Dirk,Li, William H.,Miller, William H.,Romeril, Stuart P.,Scherzer, Daryl,Shu, Arthur,Bobko, Mark A.,Chadderton, Antony R.,Dumble, Melissa,Gardiner, Christine M.,Gilbert, Seth,Liu, Qi,Rabindran, Sridhar K.,Sudakin, Valery,Xiang, Hong,Brady, Pat G.,Campobasso, Nino,Ward, Paris,Axten, Jeffrey M.
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p. 1871 - 1895
(2011/05/30)
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- CHEMICAL COMPOUNDS
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The invention is directed to 6-(4-pyι?midinyl)-1 H-indazole derivatives. Specifically, the invention is directed to compounds according to Formula (I) wherein R1 - R4 are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of immune and metabolic diseases and disorders characterized by constitutively activated ACG kinases such as cancer and more specifically cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 182
(2010/07/10)
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- CHEMICAL COMPOUNDS
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The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 102
(2010/11/04)
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- 2-AMINOBENZOXAZOLE CARBOXAMIDES AS 5HT3 MODULATORS
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Compounds of formulae I, II and III: are disclosed as 5-HT3 inhibitors. The compounds are useful in treating CINV, IBS-D and other diseases and conditions.
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Page/Page column 21
(2008/12/04)
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- Phthalazine, aza- and diaza-phthalazine 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 and related conditions. The compounds have a general Formula I wherein A1, A2, B, R1, R2, R3 and R4 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammation disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.
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Page/Page column 45
(2008/06/13)
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- SYNTHESIS AND ABSOLUTE CONFIGURATION OF SUBSTITUTED MORPHOLINES
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We studied methods of stereospecific synthesis that enabled us to obtain variously substituted morpholinic compounds and to determine their absolute configuration.From a study of the chiroptical properties of synthetic N-(2-pyridyl-N-oxide) derivatives of optically active morpholines, it was possible to correlate the sign of the Cotton effect with the absolute configuration.This correlation agrees with that previously established for derivatives of the piperidine type.By evaluating the various contributions to the Cotton effect of substituents in positions 2 and 3, we established the absolute configuration of bicyclic compounds condensed in the two positions mentioned above.
- Bettoni, Giancarlo,Franchini, Carlo,Perrone, Roberto,Tortorella, Vincenzo
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p. 409 - 415
(2007/10/02)
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