The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action.

AMP deaminase 2 (AMPD2) has been thought to play an important role in energy homeostasis and immuno-oncology, while selective AMPD2 inhibitors are highly demanded to clarify the physiological function of AMPD2. In this report, we describe selective AMPD2 inhibitors inducing allosteric modulation. Based on hypothesis that compounds that exhibit increased inhibition by preincubation would cause conformational change of the enzyme, starting from HTS hit compound 4, we discovered compound 8 through the SAR study. From X-ray structural information of 8, this chemical series has a novel mechanism of action that changes the substrate pocket to prevent AMP from binding. Further elaboration of compound 8 led to the tool compound 21 which exhibited potent inhibitory activity of AMPD2 in ex vivo evaluation of mouse liver.

Palladium-catalyzed intramolecular amidation of C(sp2)-H bonds: synthesis of 4-aryl-2-quinolinones.

A catalytic synthetic approach for the synthesis of 2-quinolinone compounds through a Pd-catalyzed C(sp(2))-H functionalization/intramolecular amidation sequence is described. The cyclization process efficiently proceeds in the presence of a catalytic amount of PdCl(2) and Cu(OAc)(2) under an O(2) atmosphere, providing practical access to a range of variously substituted 4-aryl-2-quinolinones.

Palladium-catalyzed C-H activation/intramolecular amination reaction: a new route to 3-aryl/alkylindazoles.

A method for the catalytic C-H activation of hydrazone compounds followed by intramolecular amination is described. It requires the use of a catalytic amount of Pd(OAc)2 in the presence of Cu(OAc)2 and AgOCOCF3, which efficiently effects the cyclization to afford variously substituted indazoles. The reactions proceed under relatively mild conditions and thus tolerate a variety of functional groups, including alkoxycarbonyl and cyano groups and halogen atoms.