13076-15-8Relevant articles and documents
Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity
Hansen, Bettina Borreschmidt,Jepsen, Tue Heesgaard,Larsen, Mogens,Sindet, Rikke,Vifian, Thomas,Burhardt, Mia N?rreskov,Larsen, Jens,Seitzberg, Jimmi Gerner,Carnerup, Martin A.,Jerre, Anders,M?lck, Christina,Lovato, Paola,Rai, Sanjay,Nasipireddy, Venkatarathnam Reddy,Ritzén, Andreas
, p. 7008 - 7032 (2020/07/28)
Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.
Directing abilities of alcohol-derived functional groups in the hydroformylation of olefins
Ren, Li,Crudden, Cathleen M.
, p. 1746 - 1750 (2007/10/03)
The hydroformylation of allylic and homoallylic alcohols and their derivatives using cationic and neutral rhodium complexes has been examined. The highest diastereoselectivity (87:13) was observed in the reaction of 1-methoxymethoxy-2-methylenecyclohexane. Higher yields and similar selectivities were obtained in the reaction of the TBDMS-protected alcohol. The major diastereomer results from hydroformylation syn to the functional group, which would suggest a directing effect. However, hydroformylation of 3-methylene-1-cyclohexanol derivatives occurs on the face opposite to the directing group in the major isomer. These data, in addition to the results of hydroformylation of 1-methyl-2-methylenecyclohexane, suggest that inherent conformational preferences are of significant importance in determining the product distribution and that the directing power of simple alcohols and their derivatives is moderate at best under the conditions examined in this study.
SILICON IN SYTHESIS-17 CHLROMETHYL(TRIMETHYLSILYL)LITHIUM-A NEW REAGENT FOR THE DIRECT CONVERSION OF ALDEHYDES AND KETONES INTO α,β-EPOXYTRIMETHYLSILANES
Burford, Clifford,Cooke, Frank,Roy, Glenn,Magnus, Philip
, p. 867 - 876 (2007/10/02)
Treatment of chloromethyltrimethylsilane 1 with sec-BuLi at -78 deg produces chloromethyl(trimethylsilyl)lithium 4.Treatment of 4 with a wide range of aldehydes and ketones gives α,β-epoxytrimethylsilanes 5-28, which on acidic hydrolysis give homologated aldehydes.
