Compounds useful as inhibitors of atr kinase

Abstract

The present invention relates to pyrazine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula I: wherein the variables are as defined herein.

1 - 244 . (canceled) 
     
     
         245 . A compound having formula IIA-7: 
       
         
           
           
               
               
           
         
       
     
     
         246 . A pharmaceutical composition comprising the compound of  claim 245  and a pharmaceutically acceptable carrier. 
     
     
         247 . A method of promoting cell death in cancer cells comprising administering to a patient the compound of  claim 245 . 
     
     
         248 . A method of preventing cell repair from DNA damage comprising administering to a patient the compound of  claim 245 . 
     
     
         249 . A method of inhibiting ATR in a biological sample comprising the step of contacting the compound of  claim 245  with said biological sample. 
     
     
         250 . The method of  claim 249 , wherein said biological sample is a cell. 
     
     
         251 . A method of sensitizing cells to DNA damaging agents comprising administering to a patient the compound of  claim 245 . 
     
     
         252 . The method of  claim 251 , wherein said cell is a cancer cell having defects in the ATM signaling cascade. 
     
     
         253 . The method of  claim 252 , wherein said defect is altered expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 and H2AX. 
     
     
         254 . The method of  claim 251 , wherein said cell is a cancer cell expressing DNA damaging oncogenes. 
     
     
         255 . The method of  claim 254 , wherein said cancer cell has altered expression or activity of one or more of the following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A and Rb.