Substituted quinoxaline dna-pk inhibitors

Abstract

The present invention relates to compounds useful as inhibitors of DNA-PK. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ring A is 
       
       
         
           
           
               
               
           
         
         Ring B is 
       
       
         
           
           
               
               
           
         
          wherein Ring B is optionally substituted with up to 4 fluorine atoms, up to two OH, or up to two C 1-4 alkyl, which is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two —OC 1-2 alkyl groups; 
         Ring C is a cyclohexane or a cyclobutane ring; 
         X is —NH—, —O—, or —OC 1-4  alkyl-; 
         each of R 1  and R 2  is, independently, hydrogen, —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —C 0-4  alkyl-NHR 4 , or —OR 4 , wherein R 1  and R 2  cannot simultaneously be hydrogen, and wherein R 1  and R 2  and the intervening carbon atom can form a dioxane or dioxolane ring; 
         R 3  is hydrogen, —C 1-4 alkyl, fluoro, chloro, —OC 1-2 alkyl, —C(O)H, —C(O)OH, —C(O)OC 1-2 alkyl, —CN, —C(O)NHC 1-2 alkyl, or —C(O)NH 2 , wherein each of said R 3  alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups; 
         R 4  is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, phenyl, a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, and quinoline, or a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, and tetrahydropyridopyrimidine, wherein each of said R 4  groups is optionally substituted with up to four Br, Cl, F, or C 1-4 alkyl, up to three CN, NO 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 0-4  alkyl-C 3-5  cycloalkyl, C 0-4  alkyl-O—C 1-4  alkyl, C 0-4  alkyl-O—C 0-4  alkyl-C 3-5  cycloalkyl, C(O)OC 1-4  alkyl, C(O)OC 0-4  alkyl-C 3-5  cycloalkyl, C 0-4  alkyl-C(O)NH 2 , C(O)NHC 1-4  alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5  cycloalkyl), CH 2 OR 5 , C 0-4  alkyl-C(O)R 5 , C 0-4  alkyl-C(O)N(R 5 ) 2 , C 0-4  alkyl—C(O)OR 5 , C 0-4  alkyl-NHC(O)R 5 , C 0-4  alkyl-N(R 5 ) 2 , a heterocyclic ring system selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine and piperazine, a heteroaryl ring system selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole and tetrazole, or up to two OR 5 , wherein each of said optional R 4  substituents is optionally substituted with up to four fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, up to two SC 1-4 alkyl groups, a C(O)C 1-4  alkyl, a C(O)OC 1-4  alkyl, or a C(O)OC 0-4  alkyl-C 3-5  cycloalkyl; and 
         each R 5  is, independently, hydrogen, C 1-4 alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, and pyrimidine, or a 4-6-membered heterocyclyl selected from oxetane, tetrahydrofuran, and tetrahydropyran, and each R 5  group is optionally substituted with chloro, up to three fluorine atoms, up to two C 1-2 alkyl, CH 2 OH, CN, up to two OH, up to two OC 1-2 alkyl, a spirooxetane, pyrrolidine, or triazole, or two R 5  groups together with the intervening nitrogen atom form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is cyclobutane. 
     
     
         3 . The compound of  claim 2 , wherein the compound is of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 - 9 . (canceled) 
     
     
         10 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein X is —O— or —OC 1-4  alkyl-. 
     
     
         11 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
     
     
         12 - 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is cyclohexane. 
     
     
         18 . The compound of  claim 17 , wherein the compound is of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound of  claim 18 , or a pharmaceutically acceptable salt thereof, wherein X is —NH—. 
     
     
         20 . The compound of  claim 17 , wherein the compound is of Formula (III-A): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . (canceled) 
     
     
         22 . The compound of  claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 2  is —C 0-4  alkyl-NHR 4  or —OR 4 . 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The compound of  claim 17 , wherein the compound is of Formula (III-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . (canceled) 
     
     
         27 . The compound of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —C 0-4  alkyl-NHR 4  or —OR 4 . 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
     
     
         31 . (canceled) 
     
     
         32 . The compound of  claim 18 , or a pharmaceutically acceptable salt thereof, wherein X is —O—. 
     
     
         33 . The compound of  claim 17 , wherein the compound is of Formula (III-C): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 - 37 . (canceled) 
     
     
         38 . The compound of  claim 17 , wherein the compound is of Formula (III-D): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . (canceled) 
     
     
         40 . The compound of  claim 38 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —C 0-4  alkyl-NHR 4  or —OR 4 . 
     
     
         41 - 43 . (canceled) 
     
     
         44 . The compound of  claim 32 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
     
     
         45 - 60 . (canceled) 
     
     
         61 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         62 - 63 . (canceled) 
     
     
         64 . A method of treating cancer or inhibiting cancer cell growth in a patient comprising administering to said patient an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, either alone or in combination with one or more additional therapeutic agent.