Compounds useful as inhibitors of atr kinase

Abstract

The present invention relates to pyrazine and pyridine 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 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 IV: wherein the variables are as defined herein.

1 . A compound of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 3  is H or methyl; 
         A is CH or N; 
         L 2  is C 1-10  aliphatic chain where up to 3 methylene units of said chain are optionally replaced with —O—, —S—, —N(R′)—, or —CO—; 
         R′ is H or C 1-4 alkyl; 
         m is 0 or 1; 
         R 2  is -Q or -Q-Q 1 ; 
         Q is a 3-8 membered monocyclic ring having 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and each Q is independently and optionally substituted with 1-4 J Q  groups; 
         Q is optionally fused to Q 1  to form a fused bicyclic ring Q-Q 1 ; or Q and Q 1  are optionally joined together at a carbon atom to form a spirocyclic bicyclic ring Q-Q 1 ; or Q and Q 1 , taken together, form a bridged bicyclic ring Q-Q 1 , wherein said bridge is 1-3 atoms long; 
         Q 1  is a 3-8 membered monocyclic ring having 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and each Q 1  is independently and optionally substituted with 1-4 J Q1  groups; 
         L is —OCH 2 —, C 2 aliphatic, —CO—, —C(O)NH—, —C(O)N(C 1-6 alkyl)-; 
         n is 0 or 1; 
         R 1  is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form a 8-10 membered bicyclic aryl or heteroaryl ring having 0-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R 1  is optionally substituted with 1-5 J 1  groups; 
         each J Q , J Q1 , and J 1  is independently halo, —CN, —NO 2 , —V—R, or —(V 2 ) m -Q 3 ; 
         V is a C 1-10 aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, nitrogen, sulfur, C(O), S(O), or S(O) 2 ; and V is optionally substituted with 1-6 occurrences of J V ; 
         V 2  is a C 1-10 aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, nitrogen, sulfur, C(O), S(O), or S(O) 2 ; and V is optionally substituted with 1-6 occurrences of J V2 ; 
         Q 3  is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each Q 3  is optionally substituted with 1-5 J Q3 ; 
         each J V  and J V2  is independently halogen, CN, NH 2 , NO 2 , C 1-4 aliphatic, NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , OH, O(C 1-4 aliphatic), CO 2 H, CO 2 (C 1-4 aliphatic), C(O)NH 2 , C(O)NH(C 1-4 aliphatic), C(O)N(C 1-4 aliphatic) 2 , NHCO(C 1-4 aliphatic), N(C 1-4 aliphatic)CO(C 1-4 aliphatic), SO 2 (C 1-4 aliphatic), NHSO 2 (C 1-4 aliphatic), or N(C 1-4 aliphatic)SO 2 (C 1-4 aliphatic), wherein said C 1-4 aliphatic is optionally substituted with halo; 
         each J Q3  is independently halo, oxo, CN, NO 2 , X—R, or —(X) p -Q 4 , 
         p is 0 or 1; 
         X is C 1-10 aliphatic; wherein 1-3 methylene units of said C 1-6 aliphatic are optionally replaced with —NR, —O—, —S—, C(O), S(O) 2 , or S(O); wherein X is optionally and independently substituted with 1-4 occurrences of NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO(C 1-4 aliphatic), CO 2 H, CO 2 (C 1-4 aliphatic), C(O)NH 2 , C(O)NH(C 1-4 aliphatic), C(O)N(C 1-4 aliphatic) 2 , SO(C 1-4 aliphatic), SO 2 (C 1-4 aliphatic), SO 2 NH(C 1-4 aliphatic), SONH(C 1-4 aliphatic) 2 , NHC(O)(C 1-4 aliphatic), N(C 1-4 aliphatic)C(O)(C 1-4 aliphatic), NHSO 2 (C 1-4 aliphatic), or N(C 1-4 aliphatic)SO 2 (C 1-4 aliphatic), wherein said C 1-4 aliphatic is optionally substituted with 1-3 occurrences of halo; 
         Q 4  is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each Q 4  is optionally substituted with 1-5 J Q4 ; 
         J Q4  is halo, CN, or C 1-4 alkyl wherein up to 2 methylene units are optionally replaced with O, N, S, C(O), S(O), or S(O) 2 ; 
         R is H or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1-4 halo. 
       
     
     
         2 . The compound of  claim 1 , wherein R 3  is methyl. 
     
     
         3 . The compound of  claim 1 , wherein R 3  is H. 
     
     
         4 . The compound of  claim 2 , wherein n is 0. 
     
     
         5 . The compound of  claim 4 , wherein R 1  is isoxazolyl or oxadiazolyl. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is isoxazolyl. 
     
     
         7 . The compound of  claim 6 , wherein R 1  is optionally substituted with one occurrence of J 1 . 
     
     
         8 . The compound of  claim 7 , wherein J 1  is —(V 2 ) m -Q 3 . 
     
     
         9 . The compound of  claim 8 , wherein J 1  is phenyl. 
     
     
         10 . The compound of  claim 9 , wherein J 1  is phenyl optionally substituted with one occurrence of CH 2 NHCH 3 . 
     
     
         11 . The compound of  claim 2 , wherein n is 1. 
     
     
         12 . The compound of  claim 11 , wherein L is C(O)NH and R 1  is phenyl. 
     
     
         13 . The compound of  claim 1 , wherein m is 1. 
     
     
         14 . The compound of  claim 1 , wherein m is 0. 
     
     
         15 . The compound of  claim 14 , wherein Q is aromatic. 
     
     
         16 . The compound of  claim 15 , wherein R 2  is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or thienyl. 
     
     
         17 . The compound of  claim 1 , wherein Q is nonaromatic. 
     
     
         18 . The compound of  claim 17 , wherein R 2  is 1,2,3,6-tetrahydropyridinyl or pyridon-2-on-5-yl. 
     
     
         19 . The compound of  claim 1 , wherein J Q  is —V—R or —(V 2 ) m -Q 3 . 
     
     
         20 . The compound of  claim 19 , wherein V is —S(O) 2 — or —C(O)—; and V 2  is —S(O) 2 — or —C(O)—. 
     
     
         21 . The compound of  claim 20 , wherein R is C 1-4 alkyl and Q 3  is a 3-7 membered saturated or unsaturated monocyclic ring having 0-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 
     
     
         22 . The compound of  claim 1 , wherein n is 1, m is 0; L is —C(O)NH—; R 1  is phenyl; R 2  is phenyl; and J Q  is —V—R, wherein V is —SO 2 — or —CO—, and R is C 1-4 alkyl. 
     
     
         23 . The compound of  claim 1 , wherein A is N; R 3  is methyl or H; n is 0 or 1; m is 0; L is CONH; R 1  is isoxazolyl or phenyl; J 1  is phenyl optionally substituted with one occurrence of CH 2 NHCH 3 ; and R 2  is phenyl optionally substituted with SO 2 (C 1-4 alkyl). 
     
     
         24 . (canceled) 
     
     
         25 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         26 . A method for treating cancer in a patient comprising administering a compound of  claim 1  or a pharmaceutically acceptable derivative thereof. 
     
     
         27 . The method of  claim 26 , 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. 
     
     
         28 . The method of  claim 27 , wherein said DNA-damaging agent is chemotherapy or radiation treatment. 
     
     
         29 - 34 . (canceled) 
     
     
         35 . The method of  claim 26 , wherein said cancer is selected from the group consisting of lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer. 
     
     
         36 - 48 . (canceled) 
     
     
         49 . The compound of  claim 2 , wherein m is 0.