Antibacterial compounds

Abstract

wherein the integers are as defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of tuberculosis.

1 . A compound of formula (IA) for use in the treatment of tuberculosis 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents C 1-6  alkyl or hydrogen; 
         L 1  represents a linker group —C(R a )(R b )—; 
         X 1  represents an optional carbocyclic aromatic linker group (which linker group may itself be optionally substituted by one or more substituents selected from fluoro, —OH, —OC 1-6  alkyl and C 1-6  alkyl, wherein the latter two alkyl moieties are themseleves optionally substituted by one or more fluoro atoms); 
         R a  and R b  independently represent hydrogen or C 1-6  alkyl (optionally substituted by one or more fluoro atoms); 
         X a  represents C(R c ) or N; 
         X b  represents C(R d ), N, O (in which case L 2  is not present) or C═O (in which case L 2  is also not present); 
         R c  and R d  independently represent H, F or —OR e  (wherein R e  represents H or C 1-6  alkyl optionally substituted by one or more fluoro atoms), or, R d  and L 2  may be linked together to form a 4- to 6-membered cyclic group (i.e. a spiro-cycle), optionally containing one to three heteroatoms; 
         q 1  represents —X c —(CH 2 ) n1 —X d —; 
         n1 repesents 0, 1 or 2; 
         q 2  represents —X e —(CH 2 ) n2 —X f —; 
         n2 represents 0, 1 or 2, but wherein n1 and n2 do not both represent 0; 
         X c  (which is attached to X a ) is either not present, or, when X a  represents CH, then X c  may represent —O—, —NH— or —S—; 
         X d  is either not present, or, when n1 represents 2 or when X c  is not present, X a  represents C(R c ) and n1 represents 1, then X d  may also represent —O—, —NH— or —S—; 
         X e  and X f  independently are either not present, or may independently represent —O—, —NH— or —S—, provided that the aforementioned heteroatoms are not directly attached to or a to another heteroatom; 
         q 3  represents —X g —(CH 2 ) n3 —X h —; 
         q 4  represents —X i —(CH 2 ) n4 —X j —; 
         n3 repesents 0, 1 or 2; 
         n4 represents 0, 1 or 2, but wherein n3 and n4 do not both represent 0; 
         X g , X h , X i  and X independently are either not present, or may represent —O—, —NH— or —S—, provided that the aforementioned heteroatoms are not directly attached to or a to another heteroatom; 
         when X b  represents O or C═O, then L 2  is not present; 
         when X b  represents C(R a ) or N, then L 2  may represent hydrogen, halo, —OR f , —C(O)—R g , C 1-6  alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from halo, C 1-6  alkyl (itself optionally substituted by one or more substituents selected from fluoro, —CF 3  and/or —SF 5 ), —OC 1-6 alkyl (itself optionally substituted by one or more fluoro atoms), —O-phenyl (itself optionally substituted by halo, C 1-6 alkyl, C 1-6 fluoroalkyl and/or —OC 1-6 alkyl) or —SF 5 ); 
         R f  represents hydrogen, C 1-6  alkyl (optionally substituted by one or more fluoro) or an aromatic group (itself optionally substituted by one or more substituents selected from halo, C 1-6 alkyl and —OC 1-6 alkyl, where the latter two alkyl moieties may themseleves be optionally substituted by one or more fluoro atoms); 
         R g  represents hydrogen or C 1-6 alkyl (optionally substituted by one or more substituents selected from fluoro, or —OC 1-3  alkyl, which latter moiety is also optionally substituted by one or more fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from halo, C 1-6  alkyl or —OC 1-6 alkyl); 
         ring A may be attached to the requisite amide moiety (i.e. the —C(O)—N(R 1 )— moiety) via either one of two possible bonds represented by the dotted lines, which bonds are linked to ring A at two different atoms (of that ring); 
         ring A is a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom); 
         ring B is a 5- or 6-membered ring, which may be aromatic or non-aromatic, optionally containing one to four heteroatoms (preferably selected from nitrogen, oxygen and sulfur); 
         either ring A and/or ring B may be optionally substituted by one or more substituents selected from: halo, C 1-6  alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) and/or —OC 1-6 alkyl (itself optionally substituted by one or more fluoro atoms), 
         or a pharmaceutically-acceptable salt thereof. 
       
     
     
         2 . A compound for use as claimed in  claim 1 , wherein:
 R 1  represents hydrogen;   R a  and R b  independently represent hydrogen; and/or   L 1  represents —CH 2 —.   
     
     
         3 . A compound for use as claimed in  claim 1  or  claim 2 , wherein X 1  represents a carbocyclic aromatic linker group that is:
 phenylene-(especially a 1,4-phenylene), e.g.: 
 
       
         
           
           
               
               
           
         
         naphthylene, e.g.: 
       
       
         
           
           
               
               
           
         
         quinolylene (such as 2-quinolylene), e.g.: 
       
       
         
           
           
               
               
           
         
         in which such linker groups are optionally substituted (e.g. by one or more substituents selected from fluoro, CH 3 , CF 3 , —OCH 3  and —OCF 3 ). 
       
     
     
         4 . A compound for use as claimed in any of the preceding claims, wherein the spiro-cyclic moiety, i.e. the combined X a  and X b -containing ring may be represented as follows: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound for use as claimed in any of the preceding claims wherein: ring A is represented as follows: 
       
         
           
           
               
               
           
         
       
       and/or
 ring B is represented as follows: 
 
       
         
           
           
               
               
           
         
         wherein “SUB” and “Sub” represent one or more possible substituents on the relevant atom (e.g. carbon or nitrogen atom). 
       
     
     
         6 . A compound for use as claimed in any one of the preceding claims, wherein the combined ring systems, i.e. Ring A and Ring B may be represented as follows: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where “SUB” represents one or more possible substituents on the bicycle (i.e. on ring A and/or on ring B) and “Sub” represents a possible optional substituent on the N atom of the bicycle (unsubstituted in this context would mean “NH”). 
       
     
     
         7 . A compound for use as claimed in any one of the preceding claims, wherein:
 X a  represents N or C(R c ) (e.g. CH);   X b  represents N, O, C(R c ) (e.g. CH) or C═O;   at least one of X a  and X b  represents N and the other represents C(R c ), N or (in the case of X b ) O;   both X a  and X b  do not represent C(R c );   X c  is not present or represents —O—;   X d  is not present;   X e  is not present;   X f  is not present;   X g , X h , X i  and X j  independently are not present;   n1 represents 0, 1 or 2;   n2 represents 1 or 2;   n3 represents 1 or 2;   n4 represents 1 or 2;   q 1  represents —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 — or “-” (i.e. in the latter case, n1=0, X c  is not present and X d  is not present);   q 2  represents —CH 2 — or —CH 2 —CH 2 —;   q 3  represents —CH 2 — or —CH 2 —CH 2 —; and/or   q 4  represents —CH 2 — or —CH 2 —CH 2 —.   
     
     
         8 . A compound for use as claimed in any one of the preceding claims, wherein L 2  represents hydrogen, halo (e.g. fluoro), —OR e , —C(O)R g , or an aromatic group (optionally substituted by one or two (e.g. one) substituent(s) selected from —OC 1-6 alkyl (itself optionally substituted by one or more fluoro atoms) or —SF 5 , or, alternatively by halo, e.g. fluoro). 
     
     
         9 . A compound for as claimed in  claim 9 , wherein R f  represents C 1-6 alkyl or an aryl group optionally substituted by C 1-3 alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a —CF 3  group) and/or R g  represents C 1-3 alkyl (optionally substituted by fluoro) or phenyl. 
     
     
         10 . A compound of formula (IA) as defined in  claim 1  but wherein:
 L 1  represents —CH 2 —; 
 X 1  is not present or X 1  represents a carbocyclic aromatic linker group; 
 when X 1  represents a carbocyclic linker group it represents phenylene (e.g. a 1,4-phenylene) for instance: 
 
       
         
           
           
               
               
           
         
         at least one of X a  and X b  represents N and the other represents C(R c ), N or (in the case of X b ) O; 
         the X a  and X b -containing spiro-cycle 3- to 6-membered ring attached to a 4- to 6-membered ring; 
         in one aspect L 2  represents an aromatic group (as defined herein) optionally substituted as defined herein, and/or, in another aspect L 2  represents —OR f  in which R f  represents an aryl group (as defined herein) optionally substituted as defined herein; 
         when L 2  represents an (optionally substituted) aromatic group, it may be phenyl or a 5- or 6-membered heterocyclic group (e.g. containing at least one nitrogen atom, so forming a pyridyl, thiazolyl or triazolyl ring; in a major embodiment the heterocyclic group is a pyridyl), where the optional substituents are as defined herein; 
         optional substituents on aromatic L 2  groups are selected from halo, C 1-6  alkyl, —CF 3 , —OC 1-6  alkyl and —OCF 3 ; 
         when R f  represents an aryl group, then it is preferably phenyl optionally substituted by C 1-3  alkyl, itself optionally substituted by fluoro); 
         ring A and ring B together represent a 8 or 9-membered bicyclic ring (ring A is a 5-membered ring and ring B may be a 5 or 6-membered ring, in which both rings are preferably aromatic) containing at least one nitrogen atom (and in a major embodiment, at least one nitogen atom that is common to both rings); 
         optional substituents on ring A and ring B are halo, C 1-3  alkyl and —OC 1-3  alkyl, 
         or a pharmaceutically-acceptable salt thereof. 
       
     
     
         11 . A compound as claimed in  claim 10  wherein: 
       q 1  represents —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 — or “-” (i.e. in the latter case, n1=0, X c  is not present and X d  is not present); 
       q 2  represents —CH 2 — or —CH 2 —CH 2 —; 
       q 3  represents —CH 2 — or —CH 2 —CH 2 —; 
       q 4  represents —CH 2 — or —CH 2 —CH 2 —. 
     
     
         12 . A compound of formula (IB) as depicted below: 
       
         
           
           
               
               
           
         
         wherein 
         the integers are as hereinbefore defined, and where, preferably: 
         n1, n2, n3 and n4 independently represent 1; 
         at least one of X a  and X b  represents N and the other represents CH or N; 
       
     
     
         13 . A compound as defined in any one of  claims 10  to  12 , for use as a pharmaceutical. 
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of  claims 10 - 12 . 
     
     
         15 . Compound according to any one of  claims 10 - 12  for use in the treatment of tuberculosis. 
     
     
         16 . Use of a compound according to any one of  claims 1  to  12  for the manufacture of a medicament for the treatment of tuberculosis. 
     
     
         17 . A method of treatment of tuberculosis, which method comprises administration of a therapeutically effective amount of a compound according to any one of  claim 1  to  12 . 
     
     
         18 . A combination of (a) a compound according to any one of  claims 1  to  12 , and (b) one or more other anti-tuberculosis agent. 
     
     
         19 . A product containing (a) a compound according to any one of  claims 1  to  12 , and (b) one or more other anti-tuberculosis agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection. 
     
     
         20 . A process for the preparation of a compound of formula (IA) as claimed in  claim 1 , or  claims 10 - 12 , which process comprises:
 (i) reaction of a compound of formula (II),   
       
         
           
           
               
               
           
         
         in which the integers are defined in  claim 1 , with a compound of formula (III),
   LG 1 -L 2   (III)
 
 
         wherein L 2  is as defined in  claim 1  (but when L 2  is not hydrogen, halo or linked to O or S), and LG 1  is a suitable leaving group; 
         (ii) reaction of a compound of formula (IV), 
       
       
         
           
           
               
               
           
         
         wherein the integers are as defined in  claim 1 , or a suitable derivative thereof, such as a carboxylic acid ester derivative, with a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         wherein the integers are as hereinbefore defined, under amide coupling reaction conditions; 
         (iii) coupling of a compound of formula (VI), 
       
       
         
           
           
               
               
           
         
         wherein the integers are as defined in  claim 1 , and LG 2  represents a suitable leaving group, with a compound of formula (VI), 
       
       
         
           
           
               
               
           
         
         wherein the integers are as defined in  claim 1 ; 
         (iv) coupling of a compound of formula (VIII), 
       
       
         
           
           
               
               
           
         
         wherein the integers are as defined in  claim 1 , and LG 3  represents a suitable leaving group as described above with respect to LG 2  (and may particularly represent chloro, bromo or iodo), with a compound of formula (IX),
   LG 4 -L 2   (IX)
 
 
         wherein L 2  is as defined in  claim 1  (but when L 2  is not hydrogen, halo or linked to O or S), and LG 4  is a suitable group.