With compound 1 at hand, the design question is then "which compound should we make next?". The optimization task usually includes improving molecular properties (e.g., permeability, solubility, clearance, selectivity, etc.) and perhaps also IP related issues. A common scenario then is for the project team, to try to come up with ideas of novel central rings to be introduced as scaffold replacements. In this context, it should be noted that heterocyclic rings are often considered special and typically end up in different patent applications. Also, with regards to calculating molecular properties (e.g. lipophilicity), many 2Dbased methods are not adequately parametrized and have difficulties in assessing heterocyclic compounds accurately. So, how can break-through ideas for novel central rings be generated and which methods can be used to do it? Here, compound 2 (Figure ) is one answer to the question "what to make next?". It is equipotent to compound 1 and importantly, contains a different but related central scaffold. That is, the bicyclic heterocycle in compound 1 (imidazo(1,2-a)pyridine) and compound 2 (pyrazolo(1,5-a)pyridine) are both 9-membered ring-systems with identical substituents.