The 4 designs in this submission substitute the P1 isoquinoline with MeSO2O (aryl sulfonates are more stable than their alkyl equivalents) and are intended to address metabolism without compromising potency. Although related to sulfonamides, substitution of NH for O results in a profound change in conformational preference (see PDB file associated with the submission) and an MeSO2O at C7 appears to be able to accept a hydrogen bond from the backbone NH of N142. Designs 1/2 substitute isoquinoline C7/C6 (in ADA-UCB-6c2cb422-1) with MeSO2O and Designs 3/4 substitute C6/C7 of Designs 1 /2 with fluoro. I would recommend synthesizing Designs 1 and 2 in the first instance so that the effects on potency of this substitution can be assessed.
Protein-ligand complexes (P0601 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following:  P0601 A chain protein structure  P0601 A chain crystallographic ligand ( EDJ-MED-e4b030d8-11) [3-6] Binding modes for Designs 1-4