Polymyxin compounds and uses thereof

A compound of formula (I):

• wherein:
• -T is RT—X—;
• -A1- is absent
• -A2- is an amino acid residue selected from threonine and serine;
• - A3- is an amino acid residue represented by:
• where the asterisk is the point of attachment to -A2-, and —R3 is C1-6 alkyl, having one amino or one hydroxyl substituent;
• —X—is —C(O)—, —NHC(O)—, —OC(O)—, —CH2—or —SO2—;
• —RT is an amino-containing group:
• where:
• —RA is hydrogen or -LA-RAA;
• -Q- is —CH(RB)—;
• RB is -LBRBB, -LB- is a covalent bond, and —RBB is C3-12 alkyl;
• —R16 is independently hydrogen or C1-4 alkyl;
• —R17 is independently hydrogen or C1-4 alkyl;
• or —NR16R17 is a guanidine group;
• or —R17 and —RA together form a 5- to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle;
• or —R17 and —RB together form a 5- to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle;
• where —R17 and —RA together form a monocyclic nitrogen-containing heterocycle, each ring carbon atom in the monocyclic nitrogen-containing heterocycle formed by —R17 and —RA is optionally mono-or di-substituted with —RC, and the monocyclic heterocycle is substituted with at least one group selected from —RC, —RN, —RNA and -LB-RBB,
• where —R17 and —RB together form a monocyclic nitrogen-containing heterocycle, each ring carbon atom in the monocyclic nitrogen-containing heterocycle formed by —R17 and —RB is optionally mono-or di-substituted with —RC, and the monocyclic heterocycle is substituted with at least one group selected from —RC, and —RN, or the monocyclic heterocycle is optionally substituted when —RA is -LA—RAA,
• and the monocyclic nitrogen-containing heterocycle optionally contains one further nitrogen, oxygen or sulfur ring atom, and where a further nitrogen ring atom is present it is optionally substituted with -RN, with the exception of a further nitrogen ring atom that is connected to the carbon that is a to the group —X—, which nitrogen ring atom is optionally substituted with —RNA;
• where —R17 and —RA or —R17 and —RB together form a bicyclic nitrogen-containing heterocycle, each ring carbon atom in the bicyclic nitrogen-containing heterocycle formed by —R17 and —RA or —R17 and —RB is optionally mono-or di-substituted with —RD;
• and the bicyclic nitrogen-containing heterocycle optionally contains one, two or three further heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur, and where further nitrogen ring atoms are present, each further nitrogen ring atom is optionally substituted with —RN, with the exception of a nitrogen ring atom that is connected to the carbon that is a to the group —X—, which nitrogen ring atom is optionally substituted with —RNA;
• and where R17 and —RA or —R17 and —RB together form a 5-to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle, and a carbon ring atom in —R17 and —RA or —R17 and —RB 5- to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle is optionally substituted with oxo (═O);
• each —RC is independently -LCRCC;
• each —RD is independently selected from —RC, halogen, —NO2, —OH, and —NH2;
• each —RN is independently -LN-RNN;
• each —RNA is independently —RLRNN or —RNN;
• —RAA, —RCC and —RNN, where present, is independently selected from C1-12 alkyl, C3-10 cycloalkyl, C4-10 heterocyclyl, and C5-12 aryl;
• each -LA- is independently a covalent bond or a linking group selected from RL-*, O-LAA-*, —OC(O)-LAA-*, and —C(O)-LAA-*, where the asterisk indicates the point of attachment of the group -LA- to —RAA;
• each -LB- and -LC-is independently a covalent bond or a linking group selected from —RL- *, —O-LAA-*, —OC(O)-LAA-*, —N(R11)—LAA-*, —N(R11) C(O)-LAA-*, —C(O)-LAA-*, —C(O)O-LAA-*, and —C(O)N(R11)-LAA-*, and optionally further selected from —N(R11)S(O)-LAA-*, —N(R11)S(O)2-LAA-*, —S(O)N(R11)-LAA-*, and —S(O)2N(R11)-LAA-* where the asterisk indicates the point of attachment of the group -LB- to —RBB or the group -LC- to -RCC;
• each -LN- is independently a covalent bond or a group selected from —S(O)-LAA-*, —S(O)2-LAA-*, —C(O)-LAA-* and —C(O)N(R11)-LAA*, where the asterisk indicates the point of attachment of the group -LN- to —RNN;
• and each -LAA- is independently a covalent bond or —RL-;
• and each —RL-is independently selected from C1-12 alkylene, C2-12 heteroalkylene, C3-10 cycloalkylene and C5-10 heterocyclylene, and where -LAA- is connected to a group C1-12 alkyl, —RL- is not C1-12 alkylene;
• and each C1-12 alkyl, C3-10 cycloalkyl, C4-10 heterocyclyl, C5-12 aryl, C1-12 alkylene, C2-12 heteroalkylene, C3-10 cycloalkylene and C5-10 heterocyclylene group is optionally substituted with —RS and —R12, where —RS is an optional substituent to carbon and —R12 is an optional substituent to nitrogen;
• each —RS is independently selected from —OH, —OR12, —OC(O)R12, halogen, —R12, —NHR12, —NR12R13, —NHC(O)R12, —N(R12)C(O)R12, —SH, —SR12, —C(O)R12, —C(O)OH, —C(O)OR12, —C(O)NH2, —C(O)NHR12 and C(O)NR12R13;
• except that —R12 is not a substituent to a C1-12 alkyl group;
• or where a carbon atom is di-substituted with —RS, these groups may together with the carbon to which they are attached form a C3-6 carbocycle or a C5-6 heterocycle, where the carbocycle and the heterocycle are optionally substituted with one or more groups —R12;
• each —R12 is independently C1-6 alkyl, C1-6 haloalkyl, phenyl or benzyl;
• each —R13 is independently C1-6 alkyl, C1- 6 haloalkyl, phenyl or benzyl;
• or —R12 and -R13, where attached to N, may together form a 5-or 6-membered heterocyclic ring, which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, phenyl or benzyl;
• each —R11 is independently hydrogen or C1-4 alkyl;
• —R6 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is an amino acid residue;
• —R7 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is an amino acid residue;
• and —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, isoleucine, phenylalanine, threonine, valine or norvaline residue;
• R10 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached, is a threonine or leucine residue;
• or a salt, protected form, and/or prodrug form thereof.