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 compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof wherein: 
         Q is a 5-6 membered monocyclic aromatic or nonaromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         J is H, halo, ═O, CN, V 1 , (V) t -R 2 , or 
       
       
         
           
           
               
               
           
         
         each V and V 1  is independently a C 1-10 aliphatic group wherein up to 3 methylene units are optionally replaced with O, NR″, C(O), S, S(O), or S(O) 2 ; wherein said C 1-10 aliphatic group is optionally substituted with 1-3 occurrences of halo or CN; 
         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, ═O, 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; 
         J 1  is halo, CN, or C 1-2 aliphatic wherein up to one methylene unit is optionally replaced O, NR + , or S; 
         A is X, Q 1 , or X-Q 1 ; 
         X is C 1 -C 6 alkyl wherein up to one methylene unit of said C 1 -C 6 alkyl is optionally replaced with —O—, —S—, or —NR X —; X is optionally substituted with 1-2 occurrences of J X ; 
         Q 1  is a 3-6 membered monocyclic aromatic or nonaromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic aromatic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q 1  is optionally substituted with 0-2 occurrences of J Q1 ; 
         J X  is phenyl or C 1-4 alkyl wherein 0-2 methylene units of said C 1-6 alkyl are replaced with NR X , O, S, or C(O); 
         J Q1  is halo, CN, oxo, X 1 —R, or —(X 1 ) p -Q 4 ; 
         X 1  is C 1-6 alkyl wherein 0-2 methylene units of said C 1-6 alkyl are replaced with NR X1 , O, S, or C(O); X 1  is optionally substituted with 1-2 occurrences of C 1-3 alkyl or halo; 
         Q 4  is a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; Q 4  is optionally substituted with 1-2 occurrences of J Q4 ; 
         J Q4  is halo, CN, or C 1-6 alkyl wherein up to 2 methylene units of said C 1-6 alkyl are optionally replaced with O, NR*, S, C(O), S(O), or S(O) 2 ; and wherein said C 1-6 alkyl is optionally substituted with 1-3 occurrences of halo; 
         R 1  is H, C 1-4 alkyl 0-2 methylene units of said C 1-4 alkyl are replaced with NR, O, S, or C(O); wherein the C 1-4 alkyl is optionally substituted with phenyl, OH, or C 3-6 cycloalkyl; 
         or A and R 1  join together to form Q 3 ; 
         Q 3  is a 3-7 membered monocyclic ring having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; Q 3  is optionally fused to a phenyl ring or Q 3 , together with Q 5  form a 8-10 membered spirocyclic or bridged ring system; 
         Q 5  is a 3-6 membered monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, and sulfur; 
         each Q 3  and Q 5  is optionally substituted with 1-3 occurrences of J Q3  or J Q5  respectively; 
         each J Q3  and J Q5  is independently halo, NH 2 , OH or C 1-6 alkyl wherein 1-2 methylene units are optionally replaced with O, NH, S, or C(O); 
         J a  is H or C 1-6 alkyl; 
         J b  is C 1-6 alkyl; 
         or J a  and J b  join together to form a 3-7 membered monocyclic saturated ring having 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein said monocyclic ring is optionally substituted with 1-2 occurrences of halo or C 1-3 alkyl; 
         J c  is CN or L-Z; 
         L is C(O), S(O) 2 , or C(O)NR + ; 
         Z is (U) r -Q 2  or C 1-6 alkyl wherein 0-2 methylene units of said C 1-6 alkyl are replaced with O or NR + ; 
         U is C 1-2 alkyl; 
         Q 2  is C 3-6 cycloalkyl or 4-6 membered saturated or partially saturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; 
         p, q, r and t are each independently 0 or 1; 
         each R, R′, R″, R + , R X , R X1 , and R* is independently H or C 1-4 alkyl wherein said C 1-4 alkyl is optionally substituted with 1-4 halo. 
       
     
     
         2 - 39 . (canceled) 
     
     
         40 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         41 . A method for treating cancer in a patient comprising administering a compound of  claim 1  or a pharmaceutically acceptable derivative thereof. 
     
     
         42 - 78 . (canceled) 
     
     
         79 . A method of treating non-small cell lung cancer comprising administering to a patient a compound of  claim 1  in combination with one or more of the following additional therapeutic agents: Cisplatin or Carboplatin, Etoposide, and ionizing radiation. 
     
     
         80 - 114 . (canceled) 
     
     
         115 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein A, R 1 , Q, J, J 1 , and q are as defined in  claim 1 ; 
         comprising 
       
       
         
           
           
               
               
           
         
         deprotecting the compound of formula A-v, wherein PG′ is a suitable nitrogen protecting group and A, Q, R 1 , J, J 1 , and q are as defined in  claim 1 ; under suitable deprotection conditions to provide a compound of formula I. 
       
     
     
         116 . The process of claim  0 , further comprising the step of reacting the compound of formula A-iv: 
       
         
           
           
               
               
           
         
         wherein PG′ is a suitable nitrogen protecting group and Q, J, J 1 , and q are as defined in  claim 1 ; 
         with NH(R 1 )(A) under suitable carbonylation conditions to provide a compound of formula A-v. 
       
     
     
         117 . The process of claim  0 , further comprising the step of reacting a compound of formula A-iii: 
       
         
           
           
               
               
           
         
         wherein Q, J, J 1 , and q are as defined in  claim 1 ; with a suitable protecting group precursor under suitable nitrogen-protecting conditions to provide a compound of formula A-iv. 
       
     
     
         118 . The process of claim  0 , further comprising the step of iodinating a compound of formula 
       
         
           
           
               
               
           
         
         wherein Q, J, J 1 , and q are as defined in  claim 1 ; under suitable iodination conditions to provide a compound of formula A-iii. 
       
     
     
         119 . The process of claim  0 , further comprising the step of reacting a compound of formula A-i: 
       
         
           
           
               
               
           
         
         with a compound of formula X: 
       
       
         
           
           
               
               
           
         
         wherein G is either absent or an appropriate cross coupling group and J, J 1 , and q are as defined in  claim 1 ; under suitable SNAr reaction conditions or suitable metal mediated reaction conditions such as Suzuki coupling, Stille coupling, or Buchwald-Hartwig coupling reaction conditions to provide a compound of Formula A-ii.