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 
         R 1  is hydrogen, C 1-6 alkyl, or a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently 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; R 1  is optionally substituted with 0-4 occurrences of J; 
         A is 
       
       
         
           
           
               
               
           
         
         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; 
         J is halo, CN, or V, or (V) t —R 2 ; 
         V is 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, 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 or optionally substituted pyrazinyl; 
 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 compound 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 compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 3 , wherein A 1  is selected from the following: 
       
         
           
           
               
               
           
         
       
       wherein X 1  is O, NR, or S; R is H or C 1-6 alkyl. 
     
     
         6 . The compound of  claim 3 , wherein A 1  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , wherein X 1  is S. 
     
     
         8 . The compound of  claim 3 , wherein A 1  is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein X 1  is S or O. 
     
     
         10 . The compound of  claim 9 , wherein X 1  is O. 
     
     
         11 . The compound of  claim 1 , wherein Z 1  is C 1-6 alkyl 
     
     
         12 . The compound of  claim 1 , wherein Z 1  is a 5-6 membered aromatic ring. 
     
     
         13 . The compound of  claim 6 , wherein Z 1  is COOH. 
     
     
         14 . The compound of  claim 12 , wherein Z 1  is phenyl. 
     
     
         15 . The compound of  claim 12 , wherein Z 1  is optionally substituted with 1-2 J 1  groups. 
     
     
         16 . The compound of  claim 15 , wherein J 1  is —CH 2 NHR′ or CHC 1-6 alkyl)NHR′. 
     
     
         17 . The compound of  claim 16 , wherein R′ is H. 
     
     
         18 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 18 , wherein A 2  is phenyl and Z 2  is CN, CH 2 OH, CH 2 OCH 3 , CONH 2 , CON(CH 3 ) 2 , OCH 3 , or tretrazolyl. 
     
     
         20 . The compound of  claim 18 , wherein A 2  is a 6-membered heteroaryl having 1-2 nitrogen atoms. 
     
     
         21 . The compound of  claim 20 , wherein A 2  is pyridinyl or pyrimidinyl. 
     
     
         22 . The compound of  claim 21 , wherein A 2  is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 23 , wherein A 3  is an 8-10 membered bicyclic heteroaromatic ring having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. 
     
     
         25 . The compound of  claim 24 , wherein said heteroaromatic ring is benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, azaindolyl, indolyl, indazolyl, benzothienyl, benzofuranyl, dihydrothienodioxinyl, quinolinyl, or isoquinolinyl. 
     
     
         26 . The compound of  claim 25 , wherein A is 
       
         
           
           
               
               
           
         
       
       Y is O, NR, or S; wherein R is H or C 1-4 alkyl. 
     
     
         27 . The compound of  claim 24 , wherein A is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 24 , wherein A is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         30 - 50 . (canceled) 
     
     
         51 . A method for treating cancer in a patient comprising administering a compound of  claim 1  or a pharmaceutically acceptable derivative thereof. 
     
     
         52 - 73 . (canceled)