Chemical compounds 542

Abstract

The present invention relates to compounds of Formula (I): to pharmaceutically acceptable salts thereof, to methods of using them to treat bacterial infections, and to methods for their preparation.

What is claimed is: 
     
         1 . A compound of Formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ring A is fused 5- to 7-membered non-aromatic heterocyclic ring, wherein said fused 5- to 7-membered non-aromatic heterocyclic ring is optionally substituted on carbon with one or more R 4 , and wherein any —NH— moiety of said 5- to 7-membered heterocyclic ring is optionally substituted with R 4* ; 
         W is selected from —O—, —NH—, —S—, and —S(O) 2 —; 
         X is selected from N and C—R 2 ; 
         Y is selected from N and C—R 3 ; 
         R 1  is selected from H, halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 1a , —SR 1a , —N(R 1a ) 2 , —N(R 1a )C(O)R 1b , —N(R 1a )N(R 1a ) 2 , —NO 2 , —N(R 1a )OR 1a , —ON(R 1a ) 2 , —C(O)H, —C(O)R 1b , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —C(O)N(R 1a )(OR 1a ), —OC(O)N(R 1a ) 2 , —N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —OC(O)R 1b , —S(O)R 1b , —S(O) 2 R 1b , —S(O) 2 N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1b , —C(R 1a )N(R 1a ), and —C(R 1a )═N(OR 1a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 10 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 10* ; 
         R 1a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 10* ; 
         R 1b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 10* ; 
         R 2  is selected from H, halo, and —CN; 
         R 3  is selected from H, halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —OR 3a , —SR 3a , and —N(R 3a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted on carbon with one or more R 30 ; 
         R 3a  in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl in each occurrence is optionally and independently substituted on carbon with one or more R 30 ; 
         R 4  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, —OR 4a , —SR 4a , —N(R 4a ) 2 , —N(R 4a )C(O)R 4b , —N(R 4a )N(R 4a ) 2 , —NO 2 , —N(R 4a )—OR 4a , —O—N(R 4a ) 2 , —C(O)H, —C(O)R 4b , —C(O) 2 R 4a , —C(O)N(R 4a ) 2 , —C(O)N(R 4a )(OR 4a )—OC(O)N(R 4a ) 2 , —N(R 4a )C(O) 2 R 4a , —N(R 4a )C(O)N(R 4a ) 2 , —OC(O)R 4b , —S(O)R 4b , —S(O) 2 R 4b , —S(O) 2 N(R 4a ) 2 , —N(R 4a )S(O) 2 R 4b , —C(R 4a )═N(R 4a ), and —C(R 4a )═N(OR 4a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 40 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 40* ; 
         R 4*  in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, —C(O)H, —C(O)R 4b , —C(O) 2 R 4a , —C(O)N(R 4a ) 2 , —S(O)R 4b , —S(O) 2 R 4b , —S(O) 2 N(R 4a ) 2 , —C(R 4a )═N(R 4a ), and —C(R 4a )═N(OR 4a ), wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 40* ; 
         R 4a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 40* ; 
         R 4b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R 40* ; 
         R 10  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 10a , —SR 10a , —N(R 10a ) 2 , —N(R 10a )C(O)R 10b , —N(R 10a )N(R 10a ) 2 , —NO 2 , —N(R 10a )—OR 10a , —O—N(R 10a ) 2 , —C(O)H, —C(O)R 10b , —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , —C(O)N(R 10a )(OR 10a ), —OC(O)N(R 10a ) 2 , —N(R 10a )C(O) 2 R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —S(O) 2 N(R 10a ) 2 , —N(R 10a )S(O) 2 R 10b , —C(R 10a )═N(R 10a ), and —C(R 10a )═N(OR 10a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein any —NH-moiety of said heterocyclyl is optionally substituted with R a* ; 
         R 10*  in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, —C(O)H, —C(O)R 10b , —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , —S(O)R 10b , —S(O) 2 R 10b , —S(O) 2 N(R 10a ) 2 , —C(R 10a )═N(R 10a ), and —C(R 10a )═N(OR 10a ), wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R a* ; 
         R 10a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R a* ; 
         R 10b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein any —NH— moiety of said heterocyclyl is optionally substituted with R a* ; 
         R 30  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —OR 30a , —SR 30a , and —N(R 30a ) 2 ; 
         R 30a  in each occurrence is independently selected from H and C 1-6 alkyl; 
         R 40  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 40a , —SR 40a , —N(R 40a ) 2 , —N(R 40a )C(O)R 40b , —N(R 40a )N(R 40a ) 2 , —NO 2 , —N(R 40a )—OR 40a , —O—N(R 40a ) 2 , —C(O)H, —C(O)R 40b , —C(O) 2 R 40a , —C(O)N(R 40a ) 2 , —C(O)N(R 40a )(OR 40a ), —OC(O)N(R 40a ) 2 , —N(R 40a )C(O) 2 R 40a , —N(R 40a )C(O)N(R 40a ) 2 , —OC(O)R 40b , —S(O)R 40b , —S(O) 2 R 40b , —S(O) 2 N(R 40a ) 2 , —N(R 40a )S(O) 2 R 40b , —C(R 40a )═N(R 40a ), and —C(R 40a )═N(OR 40a ); 
         R 40*  in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, —C(O)H, —C(O)R 40b , —C(O) 2 R 40a , —C(O)N(R 40a ) 2 , —S(O)R 40b , —S(O) 2 R 40b , —S(O) 2 N(R 40a ) 2 , —C(R 40a )═N(R 40a ), and —C(R 40a )═N(OR 40a ); 
         R 40a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; 
         R 40b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; 
         R a  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR m , —SR m , —N(R m ) 2 , —N(R m )C(O)R n , —N(R m )N(R m ) 2 , —NO 2 , —N(R m )—OR m , —O—N(R m ) 2 , —C(O)H, —C(O)R n , —C(O) 2 R m , —C(O)N(R m ) 2 , —C(O)N(R m )(OR m ), —OC(O)N(R m ) 2 , —N(R m )C(O) 2 R m , —N(R m )C(O)N(R m ) 2 , —OC(O)R n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R m ) 2 , —N(R m )S(O) 2 R n , —C(R m )═N(R m ), and —C(R m )═N(OR m ); 
         R a*  in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, —C(O)H, —C(O)R n , —C(O) 2 R m , —C(O)N(R m ) 2 , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R m ) 2 , —C(R m )═N(R m ), and —C(R m )═N(OR m ); 
         R m  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; and 
         R n  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl. 
       
     
     
         2 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Ring A is fused morpholine, wherein said fused morpholine is optionally substituted with one or more R 4 ; and   R 4  is C 1-6 alkyl.   
     
     
         3 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein:
 W is —O—;   X is C—H;   Y is C—R 3 ; and   R 3  is halo.   
     
     
         4 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein:
 R 1  is selected from C 1-6 alkyl, 3- to 5-membered carbocyclyl, 5- or 6-membered heterocyclyl, —OR 1a , —SR 1a , —N(R 1a ) 2 , —N(R 1a )C(O)R 1b , —C(O)N(R 1a ) 2 , —C(O)R 1b , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —C(O)N(R 1a )(OR 1a ), and —S(O) 2 R 1b , wherein said C 1-6 alkyl, 3 to 5-membered carbocyclyl, and 5- or 6-membered heterocyclyl are optionally substituted on carbon with one or more R 10 , and wherein any —NH— moiety of said 5- or 6-membered heterocyclyl is optionally substituted with R 10* ;   R 1a  in each occurrence is independently selected from H, C 1-6 alkyl, 3- to 5-membered carbocyclyl, and 5- or 6-membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 5-membered carbocyclyl, and 5- or 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 , wherein any —NH— moiety of said 5- or 6-membered heterocyclyl is optionally substituted with R 10* ;   R 1b  in each occurrence is independently selected from C 1-6 alkyl and 4- to 6-membered heterocyclyl, wherein said C 1-6 alkyl and 4- to 6-membered heterocyclyl are optionally and independently substituted on carbon with one or more R 10 , and wherein any —NH— moiety of said 4- to 6-membered heterocyclyl is optionally substituted with R 10* ;   R 10  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, 3- to 6-membered carbocyclyl, 5- or 6-membered heterocyclyl, —OR 10a , —SR 10a , —N(R 10a ) 2 , —N(R 10a )C(O)R 10b , —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , wherein said C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 5- or 6-membered heterocyclyl in each occurrence are optionally substituted with one or more R a , and wherein any —NH— moiety of said 5- or 6-membered heterocyclyl is optionally substituted with R a* ;   R 10*  in each occurrence is independently selected from C 1-6 alkyl and —C(O)R 10b ;   R 10a  in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl in each occurrence is optionally and independently substituted with one or more R a ;   R 10b  is C 1-6 alkyl;   R a  in each occurrence is independently selected from halo, —CN, and —OR m ;   R a*  is C 1-6 alkyl; and   R m  in each occurrence is independently selected from H and C 1-6 alkyl.   
     
     
         5 . A compound of Formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 1  is as described hereinabove, and: 
         W is O; 
         X is C—H; 
         Y is C—R 3 ; 
         R 1  is selected from aminocarbonyl, 2-aminopyrimidin-4-yl, 2-cyanopyrimidin-4-yl, 3,3-difluoroazetidin-1-yl, [(2,2-difluoroethyl)amino]carbonyl, difluoromethyl, (isopropylamino)carbonyl, methyl, (methylamino)carbonyl, 2-(methylsulfanyl)pyrimidin-4-yl, 1-methyl-1H-1,2,4-triazol-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidin-4-yl, pyrimidin-2-yl, 1,3-thiazol-2-yl, 1H-1,2,4-triazol-1-yl, 2H-1,2,3-triazol-2-yl, and trifluoromethyl. 
         R 3  is halo. 
       
     
     
         6 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , for use as a medicament. 
     
     
         7 . The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man. 
     
     
         8 . A method for treating a bacterial infection in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), as claimed in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , for use in treating a bacterial infection in a warm-blooded animal, such as man. 
     
     
         10 . A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , and at least one pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         11 . A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , said process comprising reacting a compound of Formula (A1): 
       
         
           
           
               
               
           
         
         with barbituric acid: 
       
       
         
           
           
               
               
           
         
         and thereafter if necessary: 
         i) converting a compound of Formula (I) into another compound of Formula (I); 
         ii) removing any protecting groups; and/or 
         iii) forming a pharmaceutically acceptable salt. 
       
     
     
         12 . A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , said process comprising reacting a compound of Formula (A3): 
       
         
           
           
               
               
           
         
         with a suitable ring-forming agent, 
         and thereafter if necessary: 
         i) converting a compound of Formula (I) into another compound of Formula (I); 
         ii) removing any protecting groups; and/or 
         iii) forming a pharmaceutically acceptable salt, 
         wherein: 
         L is a leaving group; and 
         Q is selected from —O— and —NH—.