Substituted tricyclic heterocyclic compounds as metallo-beta-lactamase inhibitors

A compound of formula I,

• a stereoisomer thereof, or a pharmaceutically acceptable salt thereof
• wherein
• R1 is selected from the group consisting of
• (i) —OH;
• (ii) —NRaRb, wherein Ra and Rb are independently selected at each occurrence from hydrogen, unsubstituted or substituted alkyl, and unsubstituted or substituted cycloalkyl;
• methoxy;
• or Ra and Rb together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
• (iii) —ORc, wherein Rc is selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl, C1-2 alkyl, aryl, aryl-C1-2 alkyl, heteroaryl, heteroaryl-C1-2 alkyl, heterocyclyl or heterocyclyl-C1-2 alkyl, each of which is optionally substituted by one or more substituent groups;
• (iv) —Rd, wherein Rd is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
• R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, —C(O)ORe, —OC(O)ORe, —O(CRaRb)r-C(O)ORe, —(CRaRb)r—C(O)ORe, —C(O)Rh, NRfRg, —C(O)NRfRg, —NRfC(O)Rh, —NRfS(O)2Rg, —S(O)0-2Re, and —S(O)2NRfRg,
• Ra and Rb, which may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
• or Ra and Rb together with the carbon atom to which they are attached, may form a unsubstituted or substituted 3 to 7 membered saturated carbocyclic ring;
• Re, which may be same or different at each occurrence, is independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted alkyl;
• Rf and Rg, which may be same or different at each occurrence, are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, —(CRaRb)r-C(O)ORe, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl;
• or Rf and Rg together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to 10 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;
• at each occurrence, Rh is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
• ‘n’ is an integer ranging from 0 to 5, both inclusive;
• ‘r’ is an integer ranging from 1 to 3, both inclusive;
• X1, X2, X3, X3 or X5 are selected from C or N, with the proviso that only one or two of X1, X2, X3, X3 or X5 can be N;
• R3 is selected from hydrogen, halo, cyano, nitro, hydroxy or a group -A1-B1-C1
• wherein, A1 is absent or a linker group of the formula —[CR1AR1B]p—in which p is an integer selected from 1 or 2, 3 or 4, and R1A and R1B are each independently selected from hydrogen or C1-2 alkyl;
• B1 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR1C)—, —N(R1C)—, N(R1D)C(O), —N(R1D)—C(O)O—, —C(O)—N(R1C)—, —N(R1D)C(O)N(R1C)—, —S—, —SO—, —SO2—, —S(O)2N(R1C)—, or —N(R1D)SO2— wherein R1C and R1D are each independently selected from hydrogen or methyl;
• and
• C1 is hydrogen, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, aryl, C3-4 cycloalkyl, C3-6 cycloalkenyl, heterocyclyl, or heteroaryl;
• and wherein C1 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR1ER1F, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, aryl, aryloxy, aryl-C1-2 alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C1-2 alkyl, heteroaryl, heteroaryloxy, heteroaryl-C1-2 alkyl, C(O)NR1ER1F, NR1EC(O)R1F, NR1ES(O)2R1F and S(O)2NR1ER1F;
• wherein R1E and R1F are each independently selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl or C3-6 cycloalkyl C1-2 alkyl;
• or R1E and R1F 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 C1 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NR1GR1H, C1-2 alkoxy, or C1-2 alkyl;
• wherein R1G and R1H are selected from hydrogen or C1-2 alkyl;
• or R1C and C1 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, NR1ER1F, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, or C(O)NR1ER1F, NR1EC(O)R1F, NR1ES(O)2R1F and S(O)2NR1ER1F;
• R4 is selected from hydrogen, cyano, halo, nitro, hydroxy or a group
• -A2-B2-C2
• wherein, A2 is absent or a linker group of the formula —[CR2AR2B]q— in which q is an integer selected from 1 or 2, 3 or 4, and R2A and R2B are each independently selected from hydrogen or C1-2 alkyl;
• B2 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR2C)—, —N(R2C)—, N(R2D)—C(O)—, —N(R2D)—C(O)O—, —C(O)—N(R2C)—, —N(R2D)C(O)N(R2C)—, —S—, —SO—, —SO2—, —S(O)2N(R2C)—, or —N(R2D)SO2— wherein R2C and R2D are each independently selected from hydrogen or methyl;
• and
• C2 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C3-4 cycloalkyl, C3-6 cycloalkenyl, heterocyclyl;
• or heteroaryl
• and wherein C2 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR2ER2F, C1-4 alkoxy, C3-8 cycloalkyl, C1-4 alkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkylsulphonyl, C1-4 alkanoyl, aryl, aryloxy, aryl-C1-2 alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C1-2 alkyl, heteroaryl, heteroaryloxy, heteroaryl-C1-2 alkyl, C(O)NR2ER2F, NR2EC(O)R2F, NR2ES(O)2R2F and S(O)2NR2ER2F;
• wherein R2E and R2F are each independently selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl or C3-4 cycloalkyl C1-2 alkyl;
• or R2E and R2F 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 C2 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NR2GR2H, C1-2 alkoxy, or C1-2 alkyl;
• wherein R2G and R2H are selected from hydrogen or C1-2 alkyl;
• or R2C and C2 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, NR2ER2F, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, or C(O)NR2ER2F, NR2EC(O)R2F, NR2ES(O)2R2F and S(O)2NR2ER2F;
• R5 is selected from hydrogen, halo, cyano, hydroxy, nitro, or a group
• -A3-B3-C3
• wherein, A3 is absent or a linker group of the formula —[CR3AR3B]r—in which r is an integer selected from 1 or 2, 3 or 4, and R3A and R3B are each independently selected from hydrogen or C1-2 alkyl;
• B3 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR3C)—, —N(R3C)—, N(R3D)—C(O)—, —N(R3D)—C(O)O—, —C(O)—N(R3C)—, —N(R3D)C(O)N(R3C)—, —S—, —SO—, —SO2—, —S(O)2N(R3C)—, or —N(R3D)SO2— wherein R3C and R3D are each independently selected from hydrogen or methyl;
• and
• C3 is hydrogen, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C3-4 cycloalkyl, C3-4 cycloalkenyl, heteroaryl or heterocyclyl;
• and wherein C3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR3ER3F, C1-4 alkoxy, C3-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, aryl, aryloxy, aryl-C1-2 alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C1-2 alkyl, heteroaryl, heteroaryloxy, heteroaryl-C1-2 alkyl, C(O)NR3ER3F, NR3EC(O)R3F, NR3ES(O)2R3F and S(O)2NR3ER3F;
• wherein R3E and R3F are each independently selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl or C3-6 cycloalkyl C1-2 alkyl;
• or R3E and R3F 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 C3 is optionally further substituted by halo, nitro, cyano, hydroxy, caboxy, NR3GR3H, C1-2 alkoxy, or C1-2 alkyl;
• wherein R3G and R3H are selected from hydrogen or C1-2 alkyl;
• or R3C and C3 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, hydroxy, nitro, carboxy, NR3ER3F, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, or C(O)NR3ER3F, NR3EC(O)R3F, NR3ES(O)2R3F and S(O)2NR3ER3F;
• R6 is selected from hydrogen, halo, cyano, nitro, hydroxy or a group
• -A4-B4-C4
• wherein, A4 is absent or a linker group of the formula —[CR4AR4B]s— in which is an integer selected from 1 or 2, 3 or 4, and R4A and R4B are each independently selected from hydrogen or C1-2 alkyl;
• B4 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)—, —N(R4D)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 methyl;
• and
• C4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C3-6 cycloalkyl, C3-6 cycloalkenyl, heterocyclyl, or heteroaryl,
• and wherein C4 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR4ER4F, C1-4 alkoxy, C3-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, aryl, aryloxy, aryl-C1-2 alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C1-2 alkyl, heteroaryl, heteroaryloxy, heteroaryl-C1-2 alkyl, C(O)NR4ER4F, NR4EC(O)R4F, NR4ES(O)2R4F and S(O)2NR4ER4F;
• wherein R4E and R4F are each independently selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl or C3-6 cycloalkyl C1-2 alkyl;
• or R4E and R4F 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 C4 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NR4GR4H, C1-2 alkoxy, or C1-2 alkyl;
• wherein R4G and R4H are selected from hydrogen or C1-2 alkyl;
• or R4C and C4 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, NR4ER4F, C1-4alkoxy, C1-4 alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, or C(O)NR4ER4F, NR4EC(O)R4F, NR4ES(O)2R4F and S(O)2NR4ER4F;
• R7 is selected from hydrogen, halo, nitro, cyano, hydroxy or a group
• -A5-B5-C5
• wherein, A5 is absent or a linker group of the formula —[CR5AR5B]t— in which ‘t’ is an integer selected from 1 or 2, 3 or 4, and R5A and R5B are each independently selected from hydrogen or C1-2 alkyl;
• B5 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 methyl;
• and
• C5 is hydrogen, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C3-6 cycloalkyl, C3-6 cycloalkenyl, heteroaryl or heterocyclyl;
• and wherein C5 is optionally further substituted by one or more substituent groups independently selected from oxo, cyano, halo, nitro, carboxy, hydroxy, NR5ER5F, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, aryl, aryloxy, aryl-C1-2 alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C1-2alkyl, heteroaryl, heteroaryloxy, heteroaryl-C1-2alkyl, C(O)NR5ER5F, NR5EC(O)R5F, NR5ES(O)2R5F and S(O)2NR5ER5F;
• wherein R5E and R5F are each independently selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl or C3-4 cycloalkyl C1-2 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 C5 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NR5GR5H, C1-2 alkoxy, or C1-2 alkyl;
• wherein R5G and R5H are selected from hydrogen or C1-2 alkyl;
• or R5C and C5 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, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, or C(O)NR5ER5F, NR5EC(O)R5F, NR5ES(O)2R5F and S(O)2NR5ER5F;
• R8 and R9, are selected from group, which may be same or different at each occurrence, are independently selected from hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
• or R8 and R9 together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
• R10 and R11, which may be same or different at each occurrence, are independently selected from hydrogen, cyano, halogen, hydroxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
• or R10 and R11 together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring.