The Application of Microwaves, Ultrasounds, and Their Combination in the Synthesis of Nitrogen-Containing Bicyclic Heterocycles.

The use of alternative energy sources, such as microwaves (MW) or ultrasounds (US), and their mutual cross-combination have been widely described in the literature in the development of new synthetic methodologies in organic and medicinal chemistry. In this review, our attention is focused on representative examples, reported in the literature in the year range 2013-2023 of selected N-containing bicyclic heterocycles, with the aim to highlight the advantages of microwave- and ultrasound-assisted organic synthesis.

Microwave Assisted Reactions of Fluorescent Pyrrolodiazine Building Blocks.

We report here the synthesis and optical spectral properties of several new pyrrolodiazine derivatives. The luminescent heterocycles were synthesized by 1,3-dipolar cycloaddition reactions between N-alkylated pyridazine and methylpropiolate or dimethyl acetylenedicarboxylate (DMAD). The pyrrolopyridazine derivatives are blue emitters with moderate quantum yields (around 25%) in the case of pyrrolopyridazines and negligible yet measurable emission for pyrrolophthalazines. In a subsequent step towards including the pyrrolodiazine moiety, given its spectral properties in various macromolecular frameworks such as biological molecules, a subset of the synthetized compounds has been subjected to α-bromination. A selective and efficient way for α-bromination in heterogeneous catalysis of pyrrolodiazine derivatives under microwave (MW) irradiation is presented. We report substantially higher yields under MW irradiation, whereas the solvent amounts required are at least five-fold less compared to classical heating.

Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.