Several novel series of nitrile-containing fluoroquinolones with weakly basic amines are reported which have reduced potential for hERG (human ether-a-go-go gene) channel inhibition as measured by the dofetilide assay. The new fluoroquinolones are potent against both Gram-positive and fastidious Gram-negative strains, including Methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Streptococcus pneumoniae. Several analogs also showed low potential for human genotoxicity as measured by the clonogenicity test. Compounds 22 and 37 (designated PF-00951966 and PF-02298732, respectively), which had good in vitro activity and in vitro safety profiles, also showed good pharmacokinetic properties in rats.