Chemical compounds

Abstract

The invention relates to a compound which is a thiazole derivative of Formula (I), or a pharmaceutically acceptable salt thereof,wherein R1, R2, R3, R4, R5, R6, R7, , Z, L, X, m, n and p are as defined herein. The compounds are useful in the treatment and prevention of bacterial infection. The invention also relates to combinations of the compound of Formula (I) with further active agents.

1 - 33 . (canceled) 
     
     
         34 . A compound which is 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The compound of  claim 34 , which is 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid. 
     
     
         36 . The compound of  claim 34 , which is a sodium salt of 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid. 
     
     
         37 . A pharmaceutical composition comprising the compound of  claim 34 , together with at least one pharmaceutically acceptable carrier or diluent. 
     
     
         38 . The pharmaceutical composition of  claim 37 , further comprising an antibiotic agent. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the antibiotic agent is a β-lactam antibiotic. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the β-lactam antibiotic is selected from carbapenems, penicillins, cephalosporins and penems. 
     
     
         41 . The pharmaceutical composition of  claim 39 , wherein the β-lactam antibiotic is meropenem. 
     
     
         42 . The pharmaceutical composition of  claim 37 , further comprising a serine-β-lactamase inhibitor. 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein:
 i) the serine-β-lactamase inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
       
       wherein
 G is selected from —CN and —C(O)NR j R k ; 
 R k  is selected from —W and -Q-W; wherein W is selected from 5- to 6-membered heterocyclyl, R j  and —N(R j ) 2 ; and Q is selected from —NR j C(O)—, —C(O)—NR j —, C 1-3  alkylene, —O—C 1-3  alkylene and —N(R j )—C 1-3  alkylene; 
 each R j  is selected from H and unsubstituted C 1-3  alkyl; or 
 ii) the serine-β-lactamase inhibitor is selected from WCK4234, avibactam, relebactam, zidebactam and nacubactam, or pharmaceutically acceptable salts thereof. 
 
     
     
         44 . A method of removing or reducing antibiotic resistance in Gram-negative bacteria, comprising contacting the Gram-negative bacteria with a compound which is 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method of  claim 44 , wherein the method is a method of removing or reducing antibiotic resistance in Gram-negative bacteria in a subject in need thereof. 
     
     
         46 . The method of  claim 44 , wherein the Gram-negative bacteria are selected from Enterobacteriaceae, Pseudomonadaceae and Moraxellaceae. 
     
     
         47 . The method of  claim 46 , wherein the bacteria selected from Enterobacteriaceae, Pseudomonadaceae and Moraxellaceae are selected from Klebsiellapneumonia,  Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia  and  Acinetobacter baumannii.    
     
     
         48 . The method of  claim 44 , wherein the bacteria are Carbapenem Resistant Enterobacteriaceae. 
     
     
         49 . A method of treating or preventing bacterial infection in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound which is 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The method of  claim 49 , comprising administering to the subject an effective amount of 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid. 
     
     
         51 . The method of  claim 49 , comprising administering to the subject an effective amount of a sodium salt of 5-[[3,5-difluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid. 
     
     
         52 . The method of  claim 49 , wherein said method comprises further administering to said subject an effective amount of an antibiotic agent. 
     
     
         53 . The method of  claim 49 , wherein the bacterial infection is caused by bacteria selected from Enterobacteriaceae, Pseudomonadaceae and Moraxellaceae. 
     
     
         54 . The method of  claim 53 , wherein the bacteria selected from Enterobacteriaceae, Pseudomonadaceae and Moraxellaceae are selected from Klebsiellapneumonia,  Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia  and  Acinetobacter baumannii.    
     
     
         55 . The method of  claim 49 , wherein the bacterial infection is caused by Carbapenem Resistant Enterobacteriaceae.