Inhibitors of metallo-beta-lactamases

A compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below:

• wherein
• R1 is selected from hydrogen or;
• (1-4C)alkyl, wherein each (1-4C)alkyl is optionally substituted by one or more substituent groups selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR1AR1B or (1-4C)alkoxy, wherein R1A and R1B are each independently selected from hydrogen or (1-2C)alkyl;
• R2 is selected from:
• i) —C(O)OH;
• ii) —C(O)OR2A, wherein R2A is selected from (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 RA;
• iii) —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 groups RA;
• iv) —C(O)NR2DNR2BR2E;
• wherein R2D is selected from hydrogen or (1-6C)alkyl and R2B and R2C are as defined above;
• v) tetrazolyl;
• vi) triazolyl;
• vii) —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;
• viii) trifluoromethylketone;
• or
• ix) cyano;
• x) —[C(O)]vS(NR2X)(O)NR2BR2C (where v is 0 or 1), wherein R2X is selected from hydrogen, (1-6C)alkyl, C(O)RX, C(O)ORX, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl or heterocyclyl-(1-2C)alkyl, wherein RX is selected from (1-6C)alkyl, aryl or heteroaryl, each of which is optionally substituted with one or more RA, and wherein R2B and R2C are as defined above;
• xi) —[C(O)]wN(R2B)S(NR2X)(O)RX (where w is 0 or 1), wherein R2B, R2X and RX are each as defined above;
• or
• xii) —S(O)yNR2BR2C (wherein y is 1 or 2), and wherein R2B and R2C are as defined above,
• and wherein RA is selected from oxo, halo, cyano, nitro or a group of the formula:
• —Y2—X2—Z2
• wherein
• Y2 is absent or a linker group of the formula —[CRA1RA2]m— in which m is an integer selected from 1, 2, 3 or 4, and RA1 and RA2 are each independently selected from hydrogen or (1-2C)alkyl;
• X2 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 methyl;
• 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, NRA4RA5, (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)NRA4RA5, NRA4C(O)RA5, NRA4S(O)2RA5 and S(O)2NRA4RA5;
• wherein RA4 and RA5 are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;
• or RA4 and RA5 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, NRA6RA7, (1-2C)alkoxy, or (1-2C)alkyl;
• wherein RA6 and RA7 are selected from hydrogen or (1-2C)alkyl;
• R3 is selected from halo, cyano, hydroxyl, aryl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl, wherein said aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl is optionally substituted by one or more RB;
• RB is halo, cyano, nitro, hydroxy or a group:
• —Y3—X3—Z3
• wherein
• Y3 is absent or a linker group of the formula —[CRB1RB2]n— in which n is an integer selected from 1, 2, 3 or 4, and RB1 and RB2 are each independently selected from hydrogen or (1-2C)alkyl;
• X3 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(ORB3)—, —N(RB3)—, —N(RB4)—C(O)—, —N(RB4)—C(O)O—, —C(O)—N(RB3)—, —N(RB4)C(O)N(RB3)—, —S—, —SO—, —SO2—, or —N(RB4)SO2— wherein RB3 and RB4 are each independently selected from hydrogen or methyl;
• and
• Z3 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
• and wherein Z3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NRB5RB6, (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NRB5RB6, NRB5C(O)RB6, NRB5S(O)2RB6 and S(O)2NRB5RB6;
• wherein RB5 and RB6 are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;
• or RB5 and RB6 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring;
• and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z3 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NRB7RB8, (1-2C)alkoxy, or (1-2C)alkyl;
• wherein RB7 and RB8 are selected from hydrogen or (1-2C)alkyl;
• or RB3 and Z3 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring, which is optionally substituted by oxo, halo, cyano, nitro, hydroxy, carboxy, NRB5RB6, (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, C(O)NRB5RB6, NRB5C(O)RB6, NRB5S(O)2RB6 and S(O)2NRB5RB6;
• X1 is selected from N or C—R4;
• R4 is selected from halo, cyano, nitro, hydroxy or a group
• —Y4—X4—Z4
• wherein:
• Y4 is absent or a linker group of the formula —[CR4AR4B]n— in which q is an integer selected from 1 or 2 and R4A and R4B are each independently selected from hydrogen or methyl;
• X4 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR4C)—, —N(R4C)—, —N(R4D)—C(O)—, —N(R4D)—C(O)O—, —C(O)—N(R4C)—, —S—, —SO—, —SO2—, —S(O)2N(R4C)—, or —N(R4D)SO2— wherein R4C and R4D are each independently selected from hydrogen or (1-4C)alkyl;
• and
• Z4 is hydrogen or (1-4C)alkyl which is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR4ER4F or (1-2C)alkoxy;
• wherein R4E and R4F are each independently selected from hydrogen or (1-2C)alkyl;
• R5 is selected from hydrogen, halo, cyano, nitro, hydroxy or a group of the formula:
• —Y5—X5-Q5-Z5
• wherein Y5 is absent or a linker group of the formula —[CR5AR5B]p— in which p is an integer selected from 1 or 2, and R5A and R5B are each independently selected from hydrogen or (1-2C)alkyl;
• X5 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR5C)—, —N(R5C)—, N(R5D)—C(O)—, —N(R5D)—C(O)O—, —C(O)—N(R5C)—, —N(R5D)C(O)N(R5C)—, —S—, —SO—, —SO2—, —S(O)2N(R5C)—, or —N(R5D)SO2— wherein R5C and R5D are each independently selected from hydrogen or (1-6C)alkyl;
• Q5 is absent or a (1-4C)alkylene optionally interrupted with one or more 0 or S atoms;
• and
• Z5 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
• and wherein Z5 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR5ER5F (1-4C)alkoxy, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkyl sulphonyl, aryl, aryloxy, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, Si[(1-4C)alkyl]3, C(O)R5E, C(O)OR5E, OC(O)R5E, C(O)NR5ER5F, NR5EC(O)R5F, NR5ES(O)2R5F and S(O)2NR5ER5F;
• wherein R5E and R5F are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;
• or R5E and R5F can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring;
• and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z5 is optionally further substituted by one or more substituent groups selected from halo, (1-2C)haloalkyl, cyano, nitro, hydroxy, carboxy, NR5GR5H, (1-2C)alkoxy, or (1-2C)alkyl;
• wherein R5G and R5H are selected from hydrogen or (1-2C)alkyl;
• or R5C and Z5 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring, which is optionally substituted by oxo, halo, cyano, nitro, hydroxy, carboxy, NR5ER5F, (1-4C)alkoxy, (1-4C)alkyl, (1-4C)haloalkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, C(O)R5E, C(O)OR5E, OC(O)R5E, C(O)NR5ER5F, NR5EC(O)R5F, NR5ES(O)2R5F and S(O)2NR5ER5F.