rna polymerase i is a dedicated polymerase for the transcription of the 47s ribosomal rna precursor subsequently processed into the mature 5 . 8s , 18s and 28s ribosomal rnas and assembled into ribosomes in the nucleolus . pol i activity is commonly deregulated in human cancers . based on the discovery of lead molecule bmh - 21 , a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of pol i and activators of the destruction of rpa194 , the pol i large catalytic subunit protein . the present invention identifies a set of bioactive compounds , including purified stereoisomers , that potently cause rpa194 degradation that function in a tightly constrained chemical space . pharmaceutical compositions comprising these compounds and their uses in cancer and other pol i related diseases is also provided .