[2] In the search for a substance that fit the criteria mentioned, the crystal structure of imatinib bound to Abl was examined.

Attempts to utilize this pocket to increase efficacy led to the addition of various hydrophobic groups including single fluoro, bromo and chloro substituents.

Closer examination of the crystal structure of imatinib-kinase complex revealed Tyr-236 was in close proximity to the pyridine ring of imatinib, suggesting there was little or no room for a larger group there.

With that in mind a more hydrophilic pyrimidine ring was substituted for the pyridine, which was found to increase solubility while leaving efficacy the same or even slightly greater.

Finally to improve the hydrogen bonding of the piperazine ring of imatinib with Ile-360 and His-361, pyrrolidine and azetidine derivatives were introduced.