Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer

Abstract

The specification generally relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof, where Q, R 1 , R 2 , R 3 , R 4 and R 5 have any of the meanings defined herein. The specification also relates to the use of such compounds and salts thereof to treat or prevent ATM kinase mediated disease, including cancer. The specification further relates to crystalline forms of compounds of imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; intermediates useful in the manufacture of such compounds and salts; and to methods of treating ATM kinase mediated disease, including cancer, using such compounds and salts.

1 - 15 . (canceled) 
     
     
         16 . A method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         where:
 Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted by one hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted by one methyl group; 
 R 1  is methyl; 
 R 2  is hydrogen or methyl; or R 1  and R 2  together form an azetidinyl, pyrrolidinyl or piperidinyl ring; 
 R 3  is hydrogen or fluoro; 
 R 4  is hydrogen or methyl; and 
 R 5  is hydrogen or fluoro. 
 
       
     
     
         17 . The method according to  claim 16 , wherein said cancer is selected form the group consisting of gastric cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. 
     
     
         18 . The method according to  claim 16 , where Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl. 
     
     
         19 . The method according to  claim 16 , where Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or oxan-4-yl. 
     
     
         20 . The method according to  claim 16 , where R 1  is methyl and R 2  is hydrogen or methyl. 
     
     
         21 . The method according to  claim 16 , where R 3  and R 5  are both hydrogen. 
     
     
         22 . The method according to  claim 16 , where R 4  is methyl. 
     
     
         23 . The method according to  claim 16  where:
 Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl; 
 R 1  is methyl; 
 R 2  is hydrogen or methyl; or R 1  and R 2  together form an azetidinyl, pyrrolidinyl or piperidinyl ring; 
 R 3  is hydrogen or fluoro; 
 R 4  is hydrogen or methyl; and 
 R 5  is hydrogen or fluoro. 
 
     
     
         24 . The method according to  claim 16 , wherein the compound of Formula (I) is 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one. 
     
     
         25 . The method according to  claim 16 , wherein the compound of Formula (I) is a pharmaceutically acceptable salt of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one. 
     
     
         26 . The method according to  claim 16 , where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with radiotherapy. 
     
     
         27 . The method according to  claim 16 , where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with at least one additional anti-tumour substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738. 
     
     
         28 . A compound of Formula (IV), or a salt thereof, 
       
         
           
           
               
               
           
         
         where: 
         Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted by one hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted by one methyl group; 
         R 4  is hydrogen or methyl; 
         R 5  is hydrogen or fluoro; and 
         X 1  is a leaving group. 
       
     
     
         29 . The compound of Formula (IV), or a salt thereof as claimed in  claim 28 , wherein X 1  is an iodine, bromine, or chlorine atom or a triflate group. 
     
     
         30 . The compound of Formula (IV), or a salt thereof as claimed in  claim 28 , where the compound is 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.