Compounds

Abstract

The present invention provides a compound of formula (I), and its use in methods of treatment, including the treatment of bacterial infections. Methods for the preparation of the compound of formula (I) are also provided. The compound of formula (I) has the structure shown below, where —R6 and —R7 are each together with the carbonyl group and nitrogen alpha to the carbon to which it is attached an amino acid residue, except that R6 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a phenylalanine, leucine or valine residue and/or —R7 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a leucine, iso-leucine, phenylalanine, threonine, valine or nor-valine residue, and -T, -A1, -A2, -A3 and —R10 are as discussed in the application:

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         -T is R T —X—; 
         -A 1 - is absent; 
         -A 2 - is an amino acid residue selected from threonine and serine; 
         -A 3 - is an amino acid residue represented by: 
       
       
         
           
           
               
               
           
         
         
           where the asterisk is the point of attachment to -A 2 -, and —R 3  is C 1-6  alkyl having one amino or one hydroxyl substituent; 
         
         —X— is —C(O)—, —NHC(O)—, —OC(O)—, —CH 2 — or —SO 2 —; 
         —R T  is an amino-containing group: 
       
       
         
           
           
               
               
           
         
         where:
 —R A  is -L A -R AA ; 
 -Q- is a covalent bond or —CH(R B )—; 
 —R B  is hydrogen; 
 and, where -Q- is a covalent bond, —R A  is -L A -R A , and where -Q- is —CH(R B )— one or both of —R A  and —R B  is not hydrogen; 
 —R 16  is independently hydrogen or C 1-4  alkyl; 
 —R 17  is independently hydrogen or C 1-4  alkyl; 
 or —NR 16 R 17  is a guanidine group; 
 —R AA  is independently selected from C 1-12  alkyl, C 3-10  cycloalkyl, C 4-10  heterocyclyl, and C 5-12  aryl; 
 -L A - is independently a covalent bond or a linking group selected from —R L —*, —O-L AA -*, —OC(O)-L AA -*, —N(R 11 )-L AA -*, and —C(O)-L AA -*, where the asterisk indicates the point of attachment of the group -L A - to —R AA ; 
 and each -L AA - is independently a covalent bond or —R L ; 
 and each —R L — is independently selected from C 1-12  alkylene, C 2-12  heteroalkylene, C 3-10  cycloalkylene and C 5-10  heterocyclylene, and where -L AA - is connected to a group C 1-12  alkyl, —R L — is not C 1-12  alkylene: 
 and each C 1-12  alkyl, C 3-10  cycloalkyl, C 4-10  heterocyclyl, C 5-12  aryl, C 1-12  alkylene, C 2-12  heteroalkylene, C 3-10  cycloalkylene and C 5-10  heterocyclylene group is optionally substituted, where —R S  is an optional substituent to carbon and —R 12  is an optional substituent to nitrogen; 
 each —R S  is independently selected from —OH, —OR 12 , —OC(O)R 12 , halo, —R 12 , —NHR 12 , —NR 12 R 13 , —NHC(O)R 12 , —N(R 12 )C(O)R 12 , —SH, —SR 12 , —C(O)R 12 , —C(O)OH, —C(O)OR 12 , —C(O)NH 2 , —C(O)NHR 12  and C(O)NR 12 R 13 ; except that —R 12  is not a substituent to a C 1-12  alkyl group; or where a carbon atom is di-substituted with —R S , these groups may together with the carbon to which they are attached form a C 3-6  carbocycle or a C 5-6  heterocycle, where the carbocycle and the heterocycle are optionally substituted with one or more groups —R 12 ; 
 each —R 12  is independently C 1-6  alkyl, C 1-6  haloalkyl, phenyl or benzyl; 
 each —R 13  is independently C 1-6  alkyl, C 1-6  haloalkyl, phenyl or benzyl; 
 or —R 12  and —R 13 , where attached to N, may together form a 5- or 6-membered heterocyclic ring, which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, phenyl or benzyl; 
 each —R 11  is independently hydrogen or C 1-4  alkyl; and 
 
         —R 6  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is an amino acid residue; 
         —R 7  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is an amino acid residue; 
         and —R 6  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a phenylalanine, leucine or valine residue and/or —R 7  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a leucine, iso-leucine, phenylalanine, threonine, valine or nor-valine residue; 
         R 10  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached, is a threonine or leucine residue; 
         and salts, solvates, protected forms and/or prodrug forms thereof. 
       
     
     
         2 . The compound of  claim 1 , or a salt thereof, wherein —R 6  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a phenylalanine, leucine or valine residue. 
     
     
         3 . The compound of  claim 2 , or a salt thereof, wherein —R 7  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is a leucine, iso-leucine, phenylalanine, threonine, valine or nor-valine residue. 
     
     
         4 . The compound of any one of  claim 1 , or a salt thereof, wherein —R 6  is C 1-12  alkyl, C 0-12  alkyl(C 3-10  cycloalkyl), C 0-12  alkyl(C 3-10  heterocyclyl) or C 0-12  alkyl(C 5-10  aryl), where the C 1-12  alkyl, C 3-10  cycloalkyl group C 3-10  heterocyclyl group, and the C 5-10  carboaryl group are optionally substituted. 
     
     
         5 . The compound of  claim 4 , or a salt thereof, wherein —R 6  is:
 (i) optionally substituted C 1-12  alkyl: 
 (ii) C 0-12  alkyl(C 5-10  aryl), where the C 5-10  carboaryl group is optionally substituted; or 
 (iii) C 0-12  alkyl(C 3-10  cycloalkyl), where the C 3-10  cycloalkyl group is optionally substituted. 
 
     
     
         6 - 15 . (canceled) 
     
     
         16 . The compound of  claim 5 , or a salt thereof, wherein C 0-12  alkyl(C 5-10  aryl) is C 1  alkyl(C 5-10  aryl). 
     
     
         17 . The compound of  claim 4 , or a salt thereof, wherein —R 6  is C 0-12  alkyl(C 3-10  cycloalkyl), where the C 3-10  cycloalkyl group is optionally substituted. 
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 17 , wherein the C 3-10  cycloalkyl group is unsubstituted. 
     
     
         20 . (canceled) 
     
     
         21 . The compound of any one of  claim 17 , or a salt thereof, wherein C 0-12  alkyl(C 3-10  cycloalkyl) is C 1  alkyl(C 3-10  cycloalkyl), such as C 1  alkyl(C 6  cycloalkyl). 
     
     
         22 . The compound according to  claim 4 , or a salt thereof, wherein —R 6  is optionally substituted C 1-12  alkyl. 
     
     
         23 - 25 . (canceled) 
     
     
         26 . The compound according to  claim 1 , or salt thereof, wherein:
 (i) -A 2 - is L-threonine or L-serine; and/or   (ii) —R 3  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached, is α,γ-diaminobutyric acid (Dab) or α,β-diaminopropionic acid (Dap), such as L-Dab or L-Dap; and/or   (iii) —R 10  together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is a threonine residue, such as L-threonine; and/or   (iv) —X— is —C(O)—.   
     
     
         27 - 50 . (canceled) 
     
     
         51 . A pharmaceutical composition comprising a compound according to  claim 1 . 
     
     
         52 - 54 . (canceled) 
     
     
         55 . A method of treating a Gram-negative bacterial infection in a patient, comprising administering a compound, or salt thereof, of  claim 1  to the patient. 
     
     
         56 . The method of  claim 55 , wherein the Gram-negative bacterial infection is selected from  Escherichia  spp.,  Klebsiella  spp.,  Enterobacter  spp.,  Salmonella  spp.,  Shigella  spp.,  Citrobacter  spp.,  Morganella morganii, Yersinia pseudotuberculosis  and other Enterobacteriaceae,  Pseudomonas  spp.,  Acinetobacter  spp.,  Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio , acetic acid bacteria,  Legionella  and alpha-proteobacteria. 
     
     
         57 - 73 . (canceled) 
     
     
         74 . The compound according to  claim 1 , or a salt thereof, wherein -Q- is a covalent bond. 
     
     
         75 . The compound according to  claim 1 , or a salt thereof, wherein -Q- is —CH(R B )—.