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 of formula IA-i: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is a C 1 -C 10 aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with O, NR 0 , S, C(O) or S(O) 2 ; 
         R 5  is H; a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 5  is optionally substituted with 1-5 J 5  groups; 
         each J 5  is independently halogen, NO 2 , CN, O(haloC 1-4 aliphatic), haloC 1-4 aliphatic, or a C 1-6 aliphatic group wherein up to 2 methylene units are optionally replaced with C(O), O, or NR′; 
         each R′ is independently H or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1-4 halo; 
         G is S; 
         Q 1 -Q 2  is naphthyl; 
         L is a C 1-4 alkyl chain wherein up to two methylene units of the alkyl chain are optionally replaced with O, S, or —C(O)—; 
         R 0  is H or C 1 -C 6 alkyl wherein one methylene unit of the alkyl chain can be optionally replaced with O, NH, N(C 1-4 alkyl), or S; 
         R 1  and R 2  are independently H or C 1 -C 6 alkyl; or 
         wherein R 1  and R 2 , taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, sulfur, or oxygen; 
         J 2  is halo; CN; a 5-6 membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, and sulfur; or a C 1-10 aliphatic group wherein up to 2 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 halo or CN; and said monocyclic ring is optionally substituted with 1-3 occurrences of halo; CN; a C 3-6 cycloalkyl; a 3-7 membered heterocyclyl containing 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur; or a C 1-4 alkyl wherein up to one methylene unit of the alkyl chain is optionally replaced with O, NR″, or S; and wherein said C 1-4 alkyl is optionally substituted with 1-3 halo; 
         m is 0 or 1; 
         p is 0 or 1; and 
         q is 0, 1, or 2. 
       
     
     
         246 . The compound of  claim 245 , wherein L is —C(O)—. 
     
     
         247 . The compound of  claim 245 , wherein R 1  and R 2 , taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, sulfur, or oxygen. 
     
     
         248 . The compound of  claim 247 , wherein said heterocyclic ring is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, or 1,4-oxazepanyl. 
     
     
         249 . The compound of  claim 248 , wherein said heterocyclic ring is optionally substituted with halo, CN, C 1-6 aliphatic, haloC 1-6 aliphatic, —C(O)O(C 1-6 aliphatic), C(O)H, C(O)(C 1-6 aliphatic), P(O)(OC 1-4 alkyl) 2 , NH(C 1-6 aliphatic), or N(C 1-6 aliphatic) 2 . 
     
     
         250 . The compound of  claim 245 , wherein R 1  is C 1 -C 6 alkyl. 
     
     
         251 . The compound of  claim 245 , wherein R 2  is C 1 -C 6 alkyl. 
     
     
         252 . The compound of  claim 245 , wherein m is 0. 
     
     
         253 . The compound of  claim 245 , wherein m is 1. 
     
     
         254 . The compound of  claim 245 , wherein p is 0. 
     
     
         255 . The compound of  claim 245 , wherein p is 1. 
     
     
         256 . The compound of  claim 245 , wherein R 5  is thienyl, thiazolyl, furanyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinonyl, pyridyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, 1,4-diazepanyl, azabicyclo[2.2.1]heptanyl, or phenyl. 
     
     
         257 . The compound of  claim 256 , wherein R 5  is phenyl, piperidinyl or thienyl. 
     
     
         258 . The compound of  claim 257 , wherein R 5  is phenyl. 
     
     
         259 . The compound of  claim 245 , wherein R 5  is optionally substituted with 1-2 J 5  groups. 
     
     
         260 . The compound of  claim 245 , wherein R 5  is H. 
     
     
         261 . A pharmaceutical composition comprising a compound of  claim 245 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         262 . A method for treating cancer in a patient comprising administering a compound of  claim 245 , or a pharmaceutically acceptable salt thereof. 
     
     
         263 . The method of  claim 262 , 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.