Compounds useful as inhibitors of atr kinase and combination therapies thereof

Abstract

The present invention relates to compounds useful as inhibitors of ATR protein kinase and combination therapies thereof. 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 of treating cancer in a patient comprising administering a compound of Formula I; 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form an 8-10 membered bicyclic aryl or heteroaryl ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 1  is optionally substituted with 1-5 J 1  groups; 
         R 2  is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form an 8-10 membered bicyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 2  is optionally substituted with 1-5 J 2  groups; 
         L is —C(O)NH— or —C(O)N(C 1-6 alkyl)-; 
         n is 0 or 1; 
         Each J 1  and J 2  is independently halo, —CN, —NO 2 , —V 1 —R, or —(V 2 ) m -Q; 
         V 1  is a C 1-10 aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with O, NR″, S, C(O), S(O), or S(O) 2 ; V 1  is optionally substituted with 1-6 occurrences of J V1 ; 
         V 2  is a C 1-10 aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with O, NR″, S, C(O), S(O), or S(O) 2 ; V 2  is optionally substituted with 1-6 occurrences of J V2 ; 
         m is 0 or 1; 
         Q is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is optionally substituted with 0-5 J Q ; 
         each J V1  or 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; 
         R is H or C 1-6 aliphatic wherein said C 1-6 aliphatic is optionally 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 2 H, CO 2 (C 1-4 aliphatic), CO(C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1-4 aliphatic; 
         each J Q  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), SO 2 N(C 1-4 aliphatic) 2 , NHC(O)(C 1-4 aliphatic), N(C 1-4 aliphatic)C(O)(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 nitrogen, oxygen, or sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or 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, NR*, 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; 
         R′, R″, and R* are each independently H, C 1-4 alkyl, or is absent; wherein said C 1-4 alkyl is optionally substituted with 1-4 halo; 
         wherein the cancer has one or more defects in the ATM signaling pathway and/or base excision repair. 
       
     
     
         2 - 7 . (canceled) 
     
     
         8 . A method of treating cancer in a patient comprising administering to the patient a compound of Formula I; 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in  claim 1 ; 
         and an additional therapeutic agent, wherein said additional therapeutic agent inhibits or modulates a base excision repair protein. 
       
     
     
         9 - 11 . (canceled) 
     
     
         12 . The method of  claim 8 , wherein said agent is selected from Olaparib (also known as AZD2281 or KU-0059436), Iniparib (also known as BSI-201 or SAR240550), Veliparib (also known as ABT-888), Rucaparib (also known as PF-01367338), CEP-9722, INO-1001, MK-4827, E7016, BMN673, or AZD2461. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1  or  claim 8 , further comprising administering to the 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. 
     
     
         15 - 30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein said cancer is a solid tumor selected from the following cancers: oral, lung, gastrointestinal: genitourinary tract, liver, bone, nervous system, gynecological, skin, thyroid gland, or adrenal gland. 
     
     
         32 - 35 . (canceled) 
     
     
         36 . The method of  claim 1 , wherein the additional therapeutic agent is gemcitabine and cisplatin and the cancer is the squamous subtype of non-small cell lung cancer. 
     
     
         37 - 53 . (canceled) 
     
     
         54 . A method of treating cancer in a patient comprising administering to the patient a compound of Formula I; 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in  claim 1 ; in combination with one or more of the following additional therapeutic agents: gemcitabine, cisplatin or carboplatin, ionizing radiation, and etoposide. 
       
     
     
         55 - 101 . (canceled) 
     
     
         102 . The method of any one of  claims 1 ,  8 , or  54 , wherein the compound has Formula IA-iii: 
       
         
           
           
               
               
           
         
         wherein 
         Ring A is 
       
       
         
           
           
               
               
           
         
         J 5 o is H, F, Cl, C 1-4 aliphatic, O(C 1-3 aliphatic), or OH; 
         J 5 p is 
       
       
         
           
           
               
               
           
         
         J 5 p1 is H, C 1-4 aliphatic, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl; wherein J 5 p1 is optionally substituted with 1-2 occurrences of OH or halo; 
         J 5 p2 is H, methyl, ethyl, CH 2 F, CF 3 , or CH 2 OH; 
         J 2 o is H, CN, or SO 2 CH 3 ; 
         J 2 m is H, F, Cl, or methyl; 
         J 2 p is —SO 2 (C 1-6 alkyl), —SO 2 (C 3-6 cycloalkyl), —SO 2 (4-6 membered heterocyclyl), —SO 2 (C 1-4 alkyl)N(C 1-4 alkyl) 2 , or —SO 2 (C 1-4 alkyl)-(4-6 membered heterocyclyl), wherein said heterocyclyl contains 1 heteroatom selected from oxygen, nitrogen, or sulfur; and wherein said J 2 p is optionally substituted with 1-3 occurrences halo, OH, or O(C 1-4 alkyl). 
       
     
     
         105 . The method of  claim 102 , wherein the compound is