Prodrug forms of kinase inhibitors and their use in therapy

Abstract

The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R 1 is a group of the formula —(CH 2 ) n Tr, where Tr is an aromatic nitroheterocyde or aromatic nitrocarbocycle and —(CH 2 ) n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R 2 , R 3 and R 4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R 2 )(R 3 )(R 4 )N, or two of R 2 , R 3 , and R 4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R 2 , R 3 , and R 4 may be absent and two of R 2 , R 3 and R 4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

1 . A compound comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, said compound carrying a positive charge. 
     
     
         2 .- 73 . (canceled) 
     
     
         74 . A method of treating a proliferative disease such as cancer in a mammal, including a human, comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         75 .- 83 . (canceled) 
     
     
         84 . A kinase inhibitor suitable for use in the preparation of a compound according to  claim 1  for use in treating a proliferative disease such as cancer. 
     
     
         85 .- 90 . (canceled)