inhibitor pacitrinib (27), involving compounds virtually identical to 25 and 26 except for the replacement of a secondary amine by an ether, the same increase in ring size from 17 to 18 atoms (compounds 28 and 29) had the opposite effect, causing a ≥30-fold decrease in potency towards CDK2, as well as a 75-fold decrease towards TYK2, both of which were considered off-targets for this discovery program. A particularly interesting example of a ring size effect is provided by the work that led to discovery of the ALK inhibitor lorlatinib (discussed in greater detail below). The authors report that varying the ring size between 12 and 13 atoms, in compound pair 30/31