A simple general synthesis of 1-aryl-6-azaisocytosine-5-carbonitriles 4 is described. This method is based on coupling diazonium salts with cyanoacetylcyanamide 2 and then cyclization of the formed 2-arylhydrazono-2-cyanoacetylcyanamides 3. The 6-azaisocytosines 4 were studied with respect to tautomeric equilibrium and the transformation of functional groups, and used in the synthesis of the condensed heterocyclic compounds: Purine isosteric imidazo[2,1-c]-[1,2,4]triazine 8 and the 1,2,4-triazino[2,3-a]quinazolines 9–12.

Increasing molecular three-dimensionality is a key strategy in drug discovery, yet α-heteroaryl α,α-disubstituted amino acids (HAAs) remain largely unexplored despite their potential to modulate peptide conformation and recognition. Here we report a stereodivergent Truce-Smiles rearrangement that converts enantioenriched heteroaryl sulfonamides into HAA derivatives with predictable control over configuration at Cα. The method exploits memory-of-chirality and cation-dependent conformational bias to deliver either inversion or retention of configuration under complementary conditions (Method A: NaHMDS/18-crown-6/LiCl; Method B: KHMDS/Cu(I)OTf). Both protocols operate under mild conditions (THF, −78 °C) and accommodate diverse heteroaryl motifs, N-substituents, and amino acid backbones, achieving high enantiomeric ratios and good yields. Downstream functionalization demonstrates compatibility with peptide coupling and reveals intrinsic limitations such as decarboxylation of free acids. This stereodivergent approach expands the toolbox for constructing quaternary stereocenters adjacent to nitrogen and provides practical access to conformationally defined scaffolds for peptide engineering and 3D chemical-space exploration.

N6-Adenosine methylation (m6A) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the nucleus of the cell. Here we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor 40 which shows an equilibrium dissociation constant (Kd) of 49 nM. The crystal structure of the complex (1.6-Å resolution) validated the design. Compound 40 is selective against the cytoplasmic m6A-RNA readers YTHDF1-3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO1. For the series of compounds that culminated into ligand 40, the good correlation between the affinity in the biochemical assay and antiproliferative activity in the cellular assay (THP-1) provides evidence of YTHDC1 target engagement in the cell. Thus compound 40 meets chemical probe properties for studying the role of YTHDC1 in AML.