Compounds useful as inhibitors of atr kinase

Abstract

The present invention relates to pyrrolopyrazines 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 . A method for treating cancer in a patient in need thereof comprising administering a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is phenyl optionally substituted with 0-4 occurrences of J; 
       
       
         
           
           
               
               
           
         
         A 1  is a 5-membered heteroaryl wherein X is carbon, nitrogen, oxygen, or sulfur; when X is nitrogen or carbon; 
         A 2  is phenyl or a 6-membered heteroaryl having 1-3 nitrogen atoms; A 2  is independently and optionally substituted with up to 2 occurrences of halo or CN; 
         A 3  is an 8-10 membered bicyclic heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 
         Z 1  is H, a C 1-6 aliphatic; wherein 0-2 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, C(O); or a 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic aromatic ring having 0-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a C 1-10 aliphatic; wherein 0-4 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, C(O); a C 3-6 cycloalkyl, or a 3-6 membered heterocyclic ring having 1-2 heteroatoms selected from O, NR′, or S; Z 1  is optionally substituted with 1-5 J 1  groups; 
         Z 2  is H, a 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic aromatic ring having 0-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a C 1-10 aliphatic; wherein 0-4 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, C(O), a C 3-6 cycloalkyl, or a 3-6 membered heterocyclic ring having 1-2 heteroatoms selected from O, NR′, or S; Z 2  is optionally substituted with 1-5 J 2  groups; 
         Z 3  is H, C 3-6 cycloalkyl, halo, CN, NO 2 , or a C 1-10 aliphatic; wherein 0-4 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, or C(O); Z 3  is optionally substituted with 1-5 J 3  groups; 
         Z 4  is a 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic aromatic ring having 0-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; Z 4  is optionally substituted with 1-5 J 4  groups; 
         V is a C 1-10 aliphatic group wherein one methylene unit is optionally replaced with S(O) 2 ; 
         R 2  is 3-7 membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; R 2  is optionally substituted with 1-3 occurrences of halo, CN, C 3-6 cycloalkyl, or C 1-10 aliphatic; wherein up to 3 methylene units of said C 1-10 aliphatic are optionally replaced with NR′, O, S, or CO; 
         each J 1 , J 2 , and J 4  is independently halo, CN, NO 2 , or X 1 ; 
         J A  is X A  or X A -Q A ; 
         X A  is a C 1-6 aliphatic; wherein 0-4 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, or C(O); wherein said C 1-6 aliphatic is optionally substituted with halo or C 1-3 alkyl; 
         Q A  is phenyl; 
         X 1  is a C 1-6 aliphatic; wherein 0-4 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, or C(O), wherein X 1  is optionally and independently substituted with 1-4 occurrences of J X1 ; 
         J X1  is halo or a 3-6 membered monocyclic ring having 0-2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 
         J 3  is halo, CN, phenyl, a 4-6 membered heterocyclic ring having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a C 1-6 aliphatic optionally substituted with 1-3 occurrences of halo; 
         each R′ and R″ is independently hydrogen or C 1-6 alkyl; 
         t is 0 or 1; 
         provided that 
         when A 3  is 
       
       
         
           
           
               
               
           
         
       
       then R 1  is not optionally substituted phenyl;
 when A 2  is pyridinyl, then R 1  is not optionally substituted phenyl; 
 when A 2  is pyrrolyl, then R 1  is not optionally substituted cyclohexyl; 
 when A 2  is phenyl, then R 1  is not an optionally substituted group selected from pyridinyl, morpholinyl, or piperazinyl; 
 when A 2  is phenyl and R 1  is phenyl; R 1  is substituted with 4-SO 2 (C 1-6 alkyl) as shown in formula ii-a; 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1  wherein
 A 1  is 
 
       
         
           
           
               
               
           
         
         A 2  is a 6-membered heteroaryl having 1-3 nitrogen atoms; and 
         Z 1  is a 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic aromatic ring having 0-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a C 1-10 aliphatic; wherein 0-4 methylene units of said C 1-10 aliphatic are optionally replaced with —NR′—, —O—, —S—, C(O); a C 3-6 cycloalkyl, or a 3-6 membered heterocyclic ring having 1-2 heteroatoms selected from O, NR′, or S; Z 1  is optionally substituted with 1-5 J 1  groups; and 
         J 3  is halo, CN, phenyl, a 4-6 membered heterocyclic ring having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a C 1-6 aliphatic optionally substituted with 1-3 occurrences of halo. 
       
     
     
         3 . The method of  claim 1 , wherein A
 is   
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein A
 is   
       
         
           
           
               
               
           
         
       
     
     
         5 - 7 . (canceled) 
     
     
         8 . The method of  claim 3 , wherein A 1  is 
       
         
           
           
               
               
           
         
       
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 9 , wherein X 1  is O. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . The method of claim  12 , wherein Z 1  is phenyl. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 15 , wherein J 1  is —CH 2 NHR′ or CHC 1-6 alkyl)NHR′. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein A
 is   
       
         
           
           
               
               
           
         
       
     
     
         19 - 22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein A
 is   
       
         
           
           
               
               
           
         
       
     
     
         24 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         30 - 32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein R 1  is a monocyclic ring. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of claim  36 , wherein R 1  is phenyl. 
     
     
         38 - 48 . (canceled) 
     
     
         49 . The method of  claim 1  wherein the compound is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         50 - 51 . (canceled) 
     
     
         52 . The method of  claim 1 , further comprising administering to said patient an additional therapeutic agent selected from a DNA-damaging agent; wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said compound as a single dosage form or separately from said compound as part of a multiple dosage form. 
     
     
         53 . The method of  claim 52 , wherein said DNA-damaging agent is selected chemotherapy or radiation treatment. 
     
     
         54 - 59 . (canceled) 
     
     
         60 . The method of  claim 53 , wherein said cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer. 
     
     
         61 - 73 . (canceled) 
     
     
         74 . A method for treating cancer in a patient in need thereof comprising administering compound I-67 or I-68: