EGFR Inhibitors and Methods of Treating Disorders

Abstract

The present invention relates to novel pyrimidine, pyrrolo-pyrimidine, pyrrolo-pyridine, pyridine, purine and triazine compounds which are able to modulate epidermal growth factor receptor (EGFR), including Her-kinases, and the use of such compounds in the treatment of various diseases, disorders or conditions.

What is claimed: 
     
         1 . A method for treating a cancer in a subject comprising administering a substituted pyrimidine compound that covalently bonds to Cysteine 797 in epidermal growth factor receptor (EGFR) via an acrylamide functional group, wherein said compound exhibits at least 2-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR.2. 
     
     
         2 . The method of  claim 1 , wherein the compound exhibits at least 3-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         3 . The method of  claim 1 , wherein the compound exhibits at least 10-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         4 . The method of  claim 1 , wherein the compound exhibits at least 50-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         5 . The method of  claim 1 , wherein the drug-resistant EGFR mutant is selected from L858R/T790M EGFR and Exon-19 deletion/T790M EGFR. 
     
     
         6 . A method for modulating epidermal growth factor receptor (EGFR) in a subject comprising administering a substituted pyrimidine compound that covalently bonds to Cysteine 797 in epidermal growth factor receptor (EGFR) via an acrylamide functional group, wherein said compound exhibits at least 2-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         7 . The method of  claim 6 , wherein the compound exhibits at least 3-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         8 . The method of  claim 6 , wherein the compound exhibits at least 10-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         9 . The method of  claim 6 , wherein the compound exhibits at least 50-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         10 . The method of  claim 6 , wherein the drug-resistant EGFR mutant is selected from L858R/T790M EGFR and Exon-19 deletion/T790M EGFR. 
     
     
         11 . A method for inhibiting epidermal growth factor receptor (EGFR) in a subject comprising administering a substituted pyrimidine compound that covalently bonds to Cysteine 797 in epidermal growth factor receptor (EGFR) via an acrylamide functional group, wherein said compound exhibits at least 2-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         12 . The method of  claim 6 , wherein the compound exhibits at least 3-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         13 . The method of  claim 6 , wherein the compound exhibits at least 10-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         14 . The method of  claim 6 , wherein the compound exhibits at least 50-fold greater inhibition of a drug-resistant EGFR mutant relative to wild-type EGFR. 
     
     
         15 . The method of  claim 6 , wherein the drug-resistant EGFR mutant is selected from L858R/T790M EGFR and Exon-19 deletion/T790M EGFR.