To investigate how different methods predict the similarity of these kind of central bicyclic heterocyclic scaffolds we first generate a dataset of fragments containing the same framework and similar substitution pattern. Thus, the ChEMBL v28 database was queried for compounds including a 9membered bicyclic ring system, with three substituents, using SMARTS matching. For comparison reasons, the substituents were subsequently removed providing 30 different scaffolds, see Figure . In this manner we identified an extensive list of 9membered bicyclic heterocyclic scaffolds present in drug-like molecules that potentially could act as replacements for the pyrazolopyrimidine in compound 1.