SS-lactamase inhibitors

A combination therapeutic product comprising a β-lactamase inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, and one or more β-lactam antibiotics, wherein the β-lactamase inhibitor of Formula I has the structural formula given below:

• wherein:
• Q is absent or selected from O, CH2, NH or S;
• ring atoms X1, X2, X3, X4 and X5 are either all carbon atoms or one or two of X1, X2, X3, X4 and X5 are nitrogen atoms;
• n is 0 or 1;
• R1 is a substituent group selected from hydrogen, halo, cyano, nitro, hydroxy or a group of the formula:
• —Y—X—Z
• wherein
• Y is absent or a linker group of the formula —[CRA1RA2]m— in which m is an integer selected from 1 or 2, and RA1 and RA2 are each independently selected from hydrogen or (1-2C)alkyl;
• X is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(ORA3)—, —N(RA3)—, —N(RA3)—C(O)—, —N(RA3)—C(O)O—, —C(O)—N(RA3)—, —N(RA3)C(O)N(RA3)—, —S—, —SO—, —SO2—, —S(O)2N(RA3)—, or —N(RA3)SO2— wherein RA3 is selected from hydrogen or (1-2C)alkyl;
• and
• Z is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
• and wherein Z is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NRA6RA7, —(CRA4RA5)p—NRA6RA7 (wherein p is selected from 1, 2 or 3), (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NRA6RA7, NRA4C(O)RA5 NRA4S(O)2RA5 and S(O)2NRA4RA5;
• wherein RA4 and RA5 are each independently selected from hydrogen or (1-4C)alkyl;
• and wherein RA6 and RA7 are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkylamino, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;
• or RA6 and RA7 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring;
• and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, amino, (1-2C)alkoxy, or (1-2C)alkyl;
• R2 is a substituent group selected from hydrogen, halo, cyano, nitro, hydroxy or R2 is selected from:
• (i) —C(O)OR2A, wherein R2A is selected from hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl or heterocyclyl-(1-2C)alkyl, each of which is optionally substituted by one or more substituent groups selected from oxo, halo, cyano, nitro, hydroxy, carboxy, amino, (1-4C)alkoxy, (1-4C)alkyl, or (1-4C)alkanoyl;
• (ii) —C(O)NR2BR2C;
• wherein R2B and R2C are each independently selected from hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl or heterocyclyl-(1-2C)alkyl, each of which is optionally substituted by one or more substituent selected from oxo, halo, cyano, nitro, hydroxy, carboxy, amino, (1-4C)alkoxy, (1-4C)alkyl, or (1-4C)alkanoyl;
• (iii) —C(O)NR2DNR2BR2C;
• wherein R2D is selected from hydrogen or (1-6C)alkyl and R2B and R2C are as defined above;
• (iv) tetrazolyl;
• (v) triazolyl;
• (vi) —B(OR2F)(OR2G), wherein R2F and R2G are each independently selected from hydrogen, (1-6C)alkyl or R2F and R2G are linked such that, together with the B and O atoms, they form a 5 or 6-membered heterocyclic ring, which is optionally substituted by (1-2C)alkyl;
• or
• (vii) trifluoromethylketone;
• R3 is absent or a substituent group selected from halo, cyano, nitro, hydroxy or a group of the formula:
• —Y2—X2—Z2
• wherein
• Y2 is absent or a linker group of the formula [CRC1RC2]n— in which n is an integer selected from 1 or 2, and RC1 and RC2 are each independently selected from hydrogen or (1-2C)alkyl;
• X2 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(ORC3)—, —N(RC3)—, —N(RC3)—C(O)—, —N(RC3)—C(O)O, —C(O)—N(RC3)—, —N(RC3)C(O)N(RC3)—, —S—, —SO—, —SO2—, —S(O)2N(RC3)—, or —N(RC3)SO2— wherein RC3 is selected from hydrogen or (1-2C)alkyl;
• and
• Z2 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
• and wherein Z2 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NRC4RC5, (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NRC4RC5, NRC4C(O)RC5, NRC4S(O)2RC5 and S(O)2NRC4RC5;
• wherein RC4 and RC5 are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;
• or RC4 and RC5 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring;
• and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z2 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NRC6RC7, (1-2C)alkoxy, or (1-2C)alkyl;
• wherein RC6 and RC7 are selected from hydrogen or (1-2C)alkyl;
• with the proviso that when n is O, Q is not absent.
• or a pharmaceutically acceptable salt thereof.