Chemical compounds

Abstract

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use in the treatment of bacterial infections are also described.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from hydrogen, nitro, hydroxy, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkanoyl, C 1-4 alkylS(O) a  wherein a is 0 to 2 and C 3-6 cycloalkyl; wherein R 1  may be optionally substituted on carbon by one or more halo or cyclopropyl; 
 R 2  is selected from hydrogen, nitro, hydroxy, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkanoyl, C 1-4 alkylS(O) a  wherein a is 0 to 2 and C 3-6 cycloalkyl; wherein R 2  may be optionally substituted on carbon by one or more halo or C 3-6 cycloalkyl; 
 R 3  is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkanoyl, C 1-4 alkylS(O) a  wherein a is 0 to 2 and C 3-6 cycloalkyl; wherein R 3  may be optionally substituted on carbon by one or more halo or C 3-6 cycloalkyl; 
 W is —O—, —N(R 6 )— or —C(R 7 )(R 8 )—; 
 X is a direct bond, —CH 2 —, —C(O)— or S(O) q — (wherein q is 1 or 2); 
 Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 9 ; 
 R 4  and R 5  are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, C 1-4 alkoxyiminomethyl, N-hydroxyformamido, C 1-4 hydrazino, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, N—(C 1-4 alkyl)amino, N,N—(C 1-4 alkyl) 2 -amino, C 1-4 alkanoylamino, N—(C 1-4 alkyl)carbamoyl, N,N—(C 1-4 alkyl) 2 carbamoyl, N—(C 1-4 alkoxy)carbamoyl, N′—(C 1-4 alkyl)ureido, N′,N′—(C 1-4 alkyl) 2 ureido, N—(C 1-4 alkyl)-N—(C 1-4 alkoxy)carbamoyl, C 1-4 alkylS(O) a  wherein a is 0 to 2, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylamino, N—(C 1-4 alkyl)sulphamoyl, N,N—(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulphonylamino, C 1-4 alkylsulphonylaminocarbonyl, N′—(C 1-4 alkyl)hydrazinocarbonyl, N′,N′—(C 1-4 alkyl) 2 hydrazinocarbonyl, carbocyclyl-R 10 — or heterocyclyl-R 11 —; wherein R 4  and R 5  independently of each other may be optionally substituted on carbon by one or more R 12 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 13 ; 
 R 6 , R 7  and R 8  are independently selected from hydrogen or C 1-4 alkyl; 
 n is 1-4; wherein the values of R 4  may be the same or different; 
 m is 0-4; wherein the values of R 5  may be the same or different; 
 R 12  is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, N—(C 1-4 alkyl)amino, N,N—(C 1-4 alkyl) 2 amino, C 1-4 alkanoylamino, N—(C 1-4 alkylcarbamoyl, N,N—(C 1-4 alkyl) 2 carbamoyl, C 1-4 alkylS(O) a  wherein a is 0 to 2, C 1-4 alkoxycarbonyl, N—(C 1-4 alkyl)sulphamoyl, N,N—(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulphonylamino, C 1-4 alkoxycarbonylamino, carbocyclyl-R 14 — or heterocyclyl-R 15 —; wherein R 12  independently of each other may be optionally substituted on carbon by one or more R 16 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 17 ; 
 R 9 , R 13  and R 17  are independently selected from C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkylsulphonyl, C 1-4 alkoxycarbonyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N—(C 1-4 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; 
 R 10 , R 11 , R 14  and R 15  are independently selected from a direct bond, —O—, —N(R 18 )—, —C(O)—, —N(R 19 )C(O)—, —C(O)N(R 20 )—, —S(O) p —, —SO 2 N(R 21 )— or —N(R 22 )SO 2 —; wherein R 18 , R 19 , R 20 , R 21  and R 22  are independently selected from hydrogen or C 1-4 alkyl and p is 0-2; 
 R 16  is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof which is a compound of formula (IA). 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof which is a compound of formula (IB). 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof which is a compound of formula (IC). 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt thereof which is a compound of formula (IE): 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is NH, N(C 1-4 alkyl) or S; 
 wherein R 5a  and R 5b  are substituents as defined for R 5  or taken together with the carbons to which they are attached form a 6-membered carbocyclyl ring substituted by one or two groups which may be the same or different and which are selected from R 5 . 
 
     
     
         6 . The compound of any one of  claim 5 , or a pharmaceutically acceptable salt thereof which is a compound of formula (IF). 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1  is methyl. 
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof wherein R 2  is chloro. 
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt thereof wherein R 3  is chloro. 
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof wherein R 4  is a substituent on carbon and is selected from methoxy, hydroxy, methoxycarbonyl, fluoro, allyloxy, propoxy, N,N-dimethylcarbamoyl, morpholinocarbonyl, N-ethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, dimethylaminomethyl, N-methyl-N-methoxycarbamoyl, methoxymethyl, methylaminomethyl and carboxy. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof wherein R 5  is a substituent on carbon and is selected from halo, carboxy, carbamoyl, C 1-4 alkyl, C 1-4 alkoxy, N—(C 1-4 alkyl)carbamoyl, N—(C 1-4 alkoxy)carbamoyl or C 1-4 alkoxycarbonyl; wherein R 5  may be optionally substituted on carbon by one or more R 12 ; wherein R 12  is selected from C 1-4 alkoxy or carbocyclyl-R 14 —; and R 14  is a direct bond. 
     
     
         12 . The compound  claim 1 , or a pharmaceutically acceptable salt thereof wherein R 6  is hydrogen. 
     
     
         13 . A compound which is
 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1S)-2-methoxy-1-methylethyl]amino}carbonyl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(methylamino)carbonyl]-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid;   4-acetyl-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1R)-2-methoxy-1-methylethyl]amino}carbonyl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2S)-2-methoxypropyl]amino}carbonyl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2R)-2-methoxypropyl]amino}carbonyl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1R,2S)-2-fluorocyclopropyl]amino}carbonyl)-1,3-thiazole-5-carboxylic acid;   Cis(±)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylic acid;   Cis(±)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylic acid;   Cis(±)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinic acid;   2-((3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylic acid;   Cis(±)-2-(3-chloro-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylic acid;   2-((3S,4R)-4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;   Cis(±)-2-[4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-yn-1-yloxy)piperidin-1-yl]-1,3-thiazole-5-carboxylic acid;   Cis(±)2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-4-carboxylic acid; or   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[2-methoxy-1-(methoxymethyl)ethyl]amino}carbonyl)-1,3-thiazole-5-carboxylic acid;   or a pharmaceutically acceptable salt thereof.   
     
     
         14 . A compound which is:
 ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[2-methoxy-1-(methoxymethyl)ethyl]amino}carbonyl)-1,3-thiazole-5-carboxylate;   ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-carboxy-1,3-thiazole-5-carboxylate;   ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1S)-2-methoxy-1-methylethyl]amino}carbonyl)-1,3-thiazole-5-carboxylate; or   methyl 4-acetyl-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate;   or a pharmaceutically acceptable salt thereof.   
     
     
         15 . A pharmaceutical composition that comprises a compound of  claim 1  or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier. 
     
     
         16 . A method for inhibition of bacterial DNA gyrase and/or topoisomeraseIV in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.