I’m not aware of specific problems with isoquinolines although the benzenoid ring is potentially vulnerable to CYP-mediated metabolism (as would also be the case for isoquinolines) and, as noted by @JSPEN, the aromatic nitrogen makes the isoquinolines potential substrates for aldehyde oxidase. That said, there may be specific problems associated with the isoquinoline substructure when it is incorporated into one or more of the structural series that form the basis of project MedChem. I believe that there is microsomal stability data available for some project compounds although I’ve not seen any of this and I don’t know whether there are any plans to make the data more widely available.
The IC50 ratios for the matched molecular pair MAT-POS-54c4bf04-3 / ERI-UCB-a0b0dbcb-2 are both below the MSR cutoffs of 3.6 (fluorescence assay) and 3.1 (RapidFire assay) proposed by @Wal-Ward. That said, it’s always good to have options since these give the project team room to manoeuvre. The ‘unmatched’ hydrogen bond donor of the quinolone may weaken affinity and PET-UNK-82544c07-1 has been ordered. The ‘unmatched’ HB donor is absent in this 4-pyridone analog and I’d also expect the the carbonyl oxygen to be a very strong HB acceptor (as discussed in this article). What is not clear right now is how much of the potency benefits of the benzenoid ring of quinolones (and isoquinolines) are due to protein-ligand contact (as opposed to conformational biasing).