Compounds useful as inhibitors of atr kinase and combination therapies thereof

Abstract

The present invention relates to compounds useful as inhibitors of ATR protein kinase and combination therapies thereof. 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 - 105 . (canceled) 
     
     
         106 . A method of promoting cell death in a cancer cell in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of an ATR inhibitor compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         an agent which inhibits or modulates a base excision repair protein. 
       
     
     
         107 . The method of  claim 106 , wherein said cell is a cancer cell having defects in the ATM signaling cascade. 
     
     
         108 . The method of  claim 107 , wherein said defect is altered expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP, or SMC1. 
     
     
         109 . The method of  claim 108 , wherein said defect is altered expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 or H2AX. 
     
     
         110 . The method of  claim 106 , wherein said cancer cell is a cancer cell expressing DNA damaging oncogenes. 
     
     
         111 . The method of  claim 110 , 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, CDCl4, CDK2, Cyclin E, Cyclin A and Rb. 
     
     
         112 . The method of  claim 106 , wherein said cancer cell has a defect in a base excision repair protein. 
     
     
         113 . The method of  claim 112 , wherein the base excision repair protein is selected from the group consisting of DNA glycosylases; AP endonucleases; a DNA ligases I and III; LIG3 accessory; polynucleotide kinases and phosphatases; poly(ADP-ribose) polymerases; polymerases; endonucleases; and Aprataxin. 
     
     
         114 . The method of  claim 113 , wherein the base excision repair protein is a DNA glycosylase selected from UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEILL NEIL2 and NEIL3; an AP endonuclease selected from APE1 and APEX2; a DNA ligase I or III selected from LIG1 and LIG3; a LIG3 accessory selected from XRCC1; a polynucleotide kinase or phosphatase selected from PNK and PNKP; a Poly(ADP-Ribose) Polymerase selected from PARP1 and PARP2; a polymerase selected from PolB and PolG; an endonuclease selected from FEN1; or Aprataxin. 
     
     
         115 . The method of  claim 114 , wherein the base excision repair protein is PARP1, PARP2, PolB, or XRCC1. 
     
     
         116 . The method of  claim 115 , wherein the base excision repair protein is PARP1 or PARP2. 
     
     
         117 . The method of  claim 106 , wherein said agent is selected from Olaparib, Iniparib, Veliparib, Rucaparib, CEP-9722, INO-1001, MK-4827, E7016, BMN673, and AZD2461. 
     
     
         118 . The method of  claim 117 , wherein said agent is Olaparib. 
     
     
         119 . The method of  claim 106 , wherein the ATR inhibitor is administered sequentially with the agent which inhibits or modulates a base excision repair protein. 
     
     
         120 . The method of  claim 106 , wherein the ATR inhibitor is administered concurrently with the agent which inhibits or modulates a base excision repair protein. 
     
     
         121 . The method of  claim 106 , further comprising administering to the patient a therapeutically effective amount of a DNA damaging agent, wherein the DNA damaging agent is selected from radiation, Cisplatin, Oxaliplatin, Carboplatin, Nedaplatin, Lobaplatin, Triplatin, Tetranitrate, Picoplatin, Satraplatin, ProLindac, Aroplatin, Camptothecin, Topotecan, Irinotecan/SN38, Rubitecan, Belotecan, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin, Teniposide, Aminopterin, Methotrexate, Pemetrexed, Raltitrexed, Pentostatin, Cladribine, Clofarabine, Fludarabine, Thioguanine, Mercaptopurine, Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine, Cytarabine, Gemcitabine, Azacitidine, Hydroxyurea, Mechlorethamine, Cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Melphalan, Prednimustine, Bendamustine, Uramustine, Estramustine, Carmustine, Lomustine, Semustine, Fotemustine, Nimustine, Ranimustine, Streptozocin, Busulfan, Mannosulfan, Treosulfan, Carboquone, ThioTEPA, Triaziquone, Triethylenemelamine, Procarbazine, Dacarbazine, etopside, Temozolomide, Altretamine, Mitobronitol, Actinomycin, Bleomycin, Mitomycin and Plicamycin 
     
     
         122 . The method of  claim 121 , wherein the ATR inhibitor is administered sequentially with the DNA damaging agent. 
     
     
         123 . The method of  claim 106 , wherein the cancer cell is of a cancer selected from the group consisting of melanoma, lung cancer, osteosarcoma, ovarian cancer, colorectal cancer, and breast cancer. 
     
     
         124 . A method of preventing cell repair from DNA damage comprising administering to a patient in need thereof a therapeutically effective amount of an ATR inhibitor compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         an agent which inhibits or modulates a base excision repair protein. 
       
     
     
         125 . A method of sensitizing cells to DNA damaging agents comprising administering to a patient in need thereof a therapeutically effective amount of an ATR inhibitor compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         an agent which inhibits or modulates a base excision repair protein.