Gyrase inhibitors

Abstract

Compounds comprising an indazolyl group and a thiazolyl group, preferably 7-substituted 3-(thiazol-2-yl)-1H-indazole compounds in which the indazolyl group and a thiazolyl group are each independently optionally substituted, are useful for the treatment or prophylaxis of bacterial infections in mammals. The compounds are believed to function by inhibiting gyrase B.

1 . A compound comprising an indazolyl group and a thiazolyl group, the compound being represented by the structure  
     
       
         
         
             
             
         
       
       wherein R7 is selected from the group consisting of C 1 -C 6  hydrocarbon, lower alkoxy, lower thioalkoxy, CN, NO 2 , halogen, CF 3 , and OCF 3 ; and  
       wherein the C 1 -C 6  hydrocarbon, indazolyl group, and thiazolyl group are optionally substituted on carbon;  
       or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.  
     
   
   
       2 . The compound of  claim 1 , wherein R7 is selected from the group consisting of methyl, ethyl, propyl, allyl, F, Cl, and Br.  
   
   
       3 . The compound of  claim 2 , wherein the propyl is cyclopropyl.  
   
   
       4 . The compound of  claim 2 , wherein R7 is selected from the group consisting of methyl, ethyl, F, and Cl.  
   
   
       5 . The compound of  claim 4 , wherein R7 is methyl.  
   
   
       6 . The compound of  claim 1 , wherein the indazolyl group bears at least one substituent selected from the group consisting of optionally substituted C 1 -C 6  hydrocarbon, optionally substituted heterocycle, lower alkoxy, CN, NO 2 , F, Cl, Br, CF 3 , and OCF 3 .  
   
   
       7 . The compound of  claim 6 , wherein the indazolyl bears at least one substituent selected from the group consisting of optionally substituted C 1 -C 6  hydrocarbon, F, and Cl.  
   
   
       8 . The compound of  claim 7 , wherein the indazolyl group bears at least one substituent selected from the group consisting of methyl, ethyl, propyl, allyl, methylcyclopropyl, F, and Cl.  
   
   
       9 . The compound of  claim 8 , wherein the indazolyl group bears at least one substituent selected from the group consisting of methyl, ethyl, F, and Cl.  
   
   
       10 . The compound of  claim 1 , wherein the thiazolyl group bears at least one substituent selected from the group consisting of optionally substituted C 1 -C 10  hydrocarbon, optionally substituted C 1 -C 10  heterocycle, optionally substituted carboxamido, optionally substituted aminocarboxy, optionally substituted C 1 -C 6  alkoxy, optionally substituted C 1 -C 6  alkoxycarbonyl, OH, and COOH.  
   
   
       11 . The compound of  claim 10 , wherein the thiazolyl group bears at least one substituent selected from the group consisting of methyl, ethyl, OH, COOH, COOCH 3 , and COOCH 2 CH 3 .  
   
   
       12 . The compound of  claim 10 , wherein the thiazolyl group bears at least one substituent selected from the group consisting of optionally substituted C 1 -C 10  hydrocarbon, optionally substituted C 1 -C 6  alkoxycarbonyl, COOH, OH, COOR 3 , and CONR 8 R 9 , 
 wherein R 3  is selected from the group consisting of optionally substituted heterocycle and C 1 -C 6  alkyl substituted by heterocycle;    wherein R 8  and R 9  are independently selected from the group consisting of H, optionally substituted heterocycle, and optionally substituted C 1 -C 6  hydrocarbon;    wherein R 8  and R 9  may together form a four-, five-, or six-membered optionally substituted heterocyclic ring including the N atom to which R 8  and R 9  are attached; and    wherein for said ring one to three carbon atoms may optionally each independently be replaced by an atom selected from the group consisting of N, O, and S.    
   
   
       13 . The compound of  claim 10 , wherein the thiazolyl group bears two substituents, each of which is independently selected from the group consisting of optionally substituted C 1 -C 10  hydrocarbon, COOH, optionally substituted C 1 -C 6  alkoxycarbonyl, OH, COOR 3 , and CONR 8 R 9 , 
 wherein R 3  is selected from the group consisting of optionally substituted heterocycle and C 1 -C 6  alkyl substituted by heterocycle;    wherein R 8  and R 9  are independently selected from the group consisting of H, optionally substituted heterocycle, and optionally substituted C 1 -C 6  hydrocarbon,    wherein R 8  and R 9  may together form a four-, five-, or six-membered optionally substituted heterocyclic ring including the N atom to which R and R′ are attached; and    wherein for said ring one to three carbon atoms may optionally each independently be replaced by an atom selected from the group consisting of N, O, and S.    
   
   
       14 . The compound of  claim 12 , wherein the substituent is selected from the group consisting of methyl, ethyl, OH, phenyl, COOH, COOCH 3 , COOCH 2 CH 3 , and N(CH 3 )(CH 2 CH 3 ).  
   
   
       15 . The compound of  claim 12 , wherein the thiazolyl group is attached to a carbonyl carbon of at least one substituent represented by a structure selected from the group consisting of  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       16 . The compound of  claim 10 , wherein the substituent is selected from the group consisting of phenyl and pyridyl, 
 wherein the phenyl is optionally substituted with at least one second substituent selected from the group consisting of OH, OCH 3 , F, Cl, Br, optionally substituted piperazin-1-yl, and optionally substituted morpholin-4-yl; and    wherein the pyridyl is optionally substituted with at least one third substituent selected from the group consisting of C 1 -C 6  alkyl, F, Cl, Br, I, CF 3  3,5-dimethyl-piperazin-1-yl, and morpholin-4-yl.    
   
   
       17 . The compound of  claim 16 , wherein the optionally substituted phenyl is selected from the group consisting of 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-fluoro-3-hydroxy-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl, 4-bromo-3-methoxy-phenyl, 4-(4-methyl-piperazin-1-yl)-phenyl, and 4-(morpholin-4-yl)-phenyl.  
   
   
       18 . The compound of  claim 16 , wherein the pyridyl is selected from the group consisting of pyridin-3-yl, 6-methyl-pyridin-3-yl, 6-chloro-pyridin-3-yl, and 6-trifluoromethyl-pyridin-3-yl.  
   
   
       19 . The compound of  claim 1 , wherein the compound is (3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone.  
   
   
       20 . The compound of  claim 1 , wherein the compound is (3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone.  
   
   
       21 . The compound of  claim 1 , wherein the compound is (3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone.  
   
   
       22 . The compound of  claim 1 , wherein the compound is (3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone.  
   
   
       23 . The compound of  claim 1 , wherein the compound is a (3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone in which the pyridyl is methyl substituted.  
   
   
       24 . The compound of  claim 1 , wherein the compound is (3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.  
   
   
       25 . The compound of  claim 1 , wherein the compound is (3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.  
   
   
       26 . The compound of  claim 1 , wherein the compound is (3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)-5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.  
   
   
       27 . The compound of  claim 1 , wherein the compound is (3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)-5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.  
   
   
       28 . The compound of  claim 1 , wherein the compound is [2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-methyl-piperazin-1-yl)-methanone.  
   
   
       29 . The compound of  claim 1 , wherein the compound is 1-[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-2-(1-methyl-piperidin-4-yl)-ethanone.  
   
   
       30 . The compound of  claim 1 , wherein the compound is [2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-(4-methyl-piperazin-1-yl)-azetidin-1-yl]-methanone.  
   
   
       31 . The compound of  claim 1 , wherein the compound is [2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-morpholin-4-yl-azetidin-1-yl)-methanone.  
   
   
       32 . The compound of  claim 1 , wherein the compound is [2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-(ethyl-methyl-amino)-azetidin-1-yl]-methanone.  
   
   
       33 . The compound of  claim 1  that is synthetically produced.  
   
   
       34 . The isolated, purified compound of  claim 1 .  
   
   
       35 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       36 . A method of treating or preventing a bacterial infection in a mammal, comprising administering to the mammal an effective amount of the composition of  claim 35 .  
   
   
       37 . A method of treating or preventing a bacterial infection in a mammal, comprising administering to the mammal an effective amount of the compound of  claim 1 .  
   
   
       38 . The method of  claim 37 , comprising identifying a mammal suffering from the bacterial infection.  
   
   
       39 . A method for making the compound of  claim 1 , comprising: 
 treating an optionally substituted indazole represented by the formula                        wherein R7 is selected from the group consisting of C 1 -C 6  hydrocarbon, lower alkoxy, lower thioalkoxy, CN, NO 2 , halogen, CF 3 , and OCF 3 ;    wherein the C 1 -C 6  hydrocarbon is optionally substituted; and    wherein LG represents a leaving group;      with a cyanide salt to form an optionally substituted indazole nitrile represented by the formula                          
   
   
       40 . The method of  claim 39 , wherein the leaving group is selected from the group consisting of chloro, bromo, iodo, trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate, and trifluoroacetate.  
   
   
       41 . The method of  claim 40 , wherein the leaving group is iodo.