Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazi n -3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells

We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)- one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.