A novel palladium migration methodology for the synthesis of complex fused polycycles has been developed. This process involves 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecular Heck reaction providing a very efficient way to synthesize fused ring systems.
HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.
[reaction: see text] 3,4-Disubstituted isoquinolines have been prepared in good yields by the palladium-catalyzed cross-coupling of N-tert-butyl-o-(1-alkynyl)benzaldimines with aryl, allylic, and alkynyl halides.
An electronic density model was developed
and used to identify
a novel pyrrolotriazinone replacement for a quinazolinone, a commonly
used moiety to impart selectivity in inhibitors for PI3Kγ and
PI3Kδ. Guided by molecular docking, this new specificity piece
was then linked to the hinge-binding region of the inhibitor using
a novel cyclic moiety. Further structure–activity relationship
optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ–PI3Kδ
dual inhibitor with favorable drug metabolism and pharmacokinetic
properties in preclinical species.
The palladium-catalyzed cross-coupling of readily available N-tert-butyl-2-(1-alkynyl)benzaldimines and aryl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, provides a valuable new route to 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substituents, respectively, in the 4-position. The reaction appears to require an aryl group on the end of the acetylene furthest from the imine functionality. The reaction conditions have been optimized, and reasonably good yields have been obtained.
A number of 3-substituted 4-aroylisoquinolines have been prepared in good yields by treating N-tert-butyl-2-(1-alkynyl)benzaldimines with aryl halides in the presence of CO and a palladium catalyst. Synthetically the methodology provides a simple and convenient route to isoquinolines containing an aryl, alkyl, or vinylic group at C-3 and an aroyl group at C-4 of the isoquinoline ring. The reaction is believed to proceed via cyclization of the alkyne containing a proximate nucleophilic center promoted by an acylpalladium complex.
The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof-of-concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA.
[reaction: see text] o-(1-Alkynyl)benzaldimines react with aryl iodides and 1 atm of CO in the presence of tri-n-butylamine and a Pd(PPh(3))(4) catalyst to afford good yields of 3-substituted 4-aroylisoquinolines by acylpalladation of the carbon-carbon triple bond and cyclization.
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