A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.

A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.

An efficient synthesis of 2,5-disubstituted-3-cyanoindoles is described. This approach utilizes a highly selective iodination together with the modified Madelung reaction to generate an intermediate which can be readily transformed to more fully elaborated 2,5-disubstituted-3-cyanoindole templates that were previously difficult to access. Detailed examples and utility of this approach are presented herein.

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.

Synthetic approaches are described for the synthesis of 4-alkoxyindole-7-carboxamides and 4-alkoxy-3-cyanoindole-7-carboxamides, which are useful intermediates in medicinal chemistry research. Two strategies were employed, highlighted by a Bartoli indole synthesis or a sequential and regioselective use of chlorosulfonyl isocyanate to install both the 3-cyano and 7-carboxamido groups. These routes are scalable and afford diversely functionalized indoles for further elaboration.

L'invention concerne l'utilisation de derives diaryle acide representes par la formule (I) et de compositions pharmaceutiques comprenant ces derives, en tant que ligands se fixant sur le recepteur PPAR. Ces ligands se fixant sur le recepteur PPAR sont utiles en tant qu'agonistes ou antagonistes du recepteur PPAR. Dans cette formule, (a) et (b) sont independamment l'un de l'autre aryle, arylcycloalcenyle condense, arylcycloalkyle condense, arylheterocyclenyle condense, arylheterocyclyle condense, heteroaryle, heteroarylcycloalcenyle condense, heteroarylcycloalkyle condense, heteroarylheterocyclenyle condense, ou heteroarylheterocyclyle condense ; A est O-, -S-, -SO-, -SO2-, -NR13-, -C(O)-, -N(R14)C(O)-, -C(O)N(R15)-,-N(R14)C(O)N(R15)-, -C(R14)=N, (c), (d), (e), une liaison chimique, (f), ou (g) ; B est O-, -S-, -NR19-, une liaison chimique, -C(O)-, N(R20)C(O)-, ou -C(O)N(R20)- ; Z est R21O2C-, R21OC-, cyclo-imide, -CN, R21O2SHNCO-, R21O2SHN-, (R21)2NCO-, R21O-2,4-thiazolidinedionyle, ou tetrazolyle.