3937-45-9Relevant 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.
Oxidation with the "H2O2 - Manganese(IV) complex - Carboxylic acid" reagent 1. Oxidation of saturated hydrocarbons with peroxy acids and hydrogen peroxide
Shul'pin,Lindsay-Smith
, p. 2379 - 2386 (2007/10/03)
The complex [LMnIV(O)3MnIVL](PF6)2 (1), where L is 1,4,7-trimethyl-1,4,7-triazacyclononane, catalyzes a highly efficient stereoselective oxygenation of saturated hydrocarbons in the presence of H2O2. A carboxylic acid is an obligatory component of the reaction mixture, while acetonitrile or acetone can be used as solvent. The reaction occurs, forming alkyl hydroperoxide, ketone, and alcohol. Substitution at the tertiary carbon atom proceeds more easily than that at the secondary carbon atom, whereas primary C-H bonds are rather inactive. Oxidation of alkanes and alcohols with peroxy acids catalyzed by complex 1 occurs with lower efficiency.
Stereoselectivity in Organoborane Rearrangement: Relationship to the Mechanism of Hydroboration
Wood, Stanley E.,Rickborn, Bruce
, p. 555 - 562 (2007/10/02)
Hydroboration of 1,2-dimethylcyclohexene and subsequent rearrangement of the tertiary to the primary alkylborane occur with substantial (99:1) suprafacial selectivity.Similar though less pronounced behavior is found for the rearrangement of the tertiary to the secondary alkylborane.These results rule out, as the lowest energy pathway, dissociation (dehydroboration) to the free olefins followed by readdition with reversed regiochemistry, since hydroborations of these olefins exhibit little selectivity.The observed stereoselectivity provides strong support for an intra molecular process, most likely involving an intermediate ? complex, which must give rearranged alkylborane faster than dissociated entities.Similar stereochemical results are obtained for the rearrangement in the presence or absence of THF, showing that solvent plays no critical role in the intramolecular migration.As a further mechanistic probe, B2D6 was employed, and the deuterium content was examined in various products.Evidence for an exchange process at the tertiary center β to boron was found.In general, the results are compatible with the proposed ?-complex mechanism.An unusual feature is the incorporation of deuterium at the borane migration terminus, for which a free-radical mechanism is suggested.The rearrangement results are considered in the context of the mechanism of hydroboration.Although a ?-complex intermediate has been suggested for hydroboration, it is concluded that such an intermediate (if it exists) must be fundamentally different from that involved in the rearrangement.This conclusion is surprising considering the close similarities of the two processes.
