Enzyme Inhibitors

A compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof:

• wherein
• R1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group;
• R2 is the side chain of a natural or non-natural alpha amino acid;
• Y is a bond, —C(═O)—, —S(═O)2—, —C(═O)O—, —C(═O)NR3—, —C(═S)—NR3, —C(═NH)NR3 or
• —S(═O)2NR3— wherein R3 is hydrogen or optionally substituted C1-C6 alkyl;
• L1 is a divalent radical of formula (Alk1)m(Q)n(Alk2)p— wherein
• m, n and p are independently 0 or 1,
• Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X2-Q1- or -Q1X2— wherein X2 is —O—, S— or NRA— wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,
• Alk1 and Alk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene , or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NRA—) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl;
• X1 represents a bond;
• —C(═O);
• or —S(═O)2—;
• —NR4C(═O)—, —C(═O)NR4—, —NR4C(═O)NR5—, —NR4S(═O)2—, or —S(═O)2NR4— wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl;
• z is 0 or 1;
• A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH—Y-L1-X1-[CH2],- and HONHCO-[LINKER]- are attached different ring atoms;
• and
• -[Linker]- represents a divalent linker radical of formula —(CH2)x-Z-L2- linking a ring atom in A with the hydroxamic acid group CONHOH, wherein
• x is 0 or 1;
• Z is a bond, —NR3C(═O)—, —C(═O)NR3—, —NR4C(═O)—NR3—, —C(═S)—NR3, —C(═NH)—NR3—NR3S(═O)2—, or —S(═O)2NR3— wherein R3 is hydrogen or C1-C6 alkyl;
• —C(═O);
• or —S(═O)2—;
• and
• L2 represents an optionally substituted, straight or branched, C4-C7 alkylene, C4-C6 alkenylene or C4-C6 alkynylene radical which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NRA—) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl.

A compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof:

• wherein
• R1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group;
• R2 is the side chain of a natural or non-natural alpha amino acid;
• Y is a bond, —C(═O)—, —S(═O)2—, —C(═O)O—, —C(═O)NR3—, —C(═S)—NR3, —C(═NH)NR3 or
• —S(═O)2NR3— wherein R3 is hydrogen or optionally substituted C1-C6 alkyl;
• L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p— wherein
• m, n and p are independently 0 or 1,
• Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X2-Q1- or -Q1-X2- wherein X2 is —O—, S— or NRA— wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,
• Alk1 and Alk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NRA—) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl;
• X1 represents a bond;
• —C(═O);
• or —S(═O)2—;
• —NR4C(═O)—, —C(═O)NR4—, —NR4C(═O)NR5—, —NR4S(═O)2—, or —S(═O)2NR4— wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl;
• z is 0 or 1;
• A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH—Y-L1-X1—[CH2]z— and HONHCO-[LINKER]- are attached different ring atoms;
• and
• -[Linker]- represents a divalent radical of formula —(CH2)n-L3-Ar1-L4- wherein
• x is 0 or 1;
• L3 is Z or L2 or Z-L2 wherein Z is as defined in claim 1 and L2 is a bond or an optionally substituted divalent C1-C3 alkylene radical;
• Ar1 is a divalent phenyl radical or a divalent mono-, or bi-cyclic heteroaryl radical having 5 to 13 ring members, and
• L4 is a bond or optionally substituted —CH2— or —CH═CH—,

A compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof:

• wherein
• R1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group;
• R2 is the side chain of a natural or non-natural alpha amino acid;
• Y is a bond, —C(═O)—, —S(═O)2—, —C(═O)O—, —C(═O)NR3—, —C(═S)—NR3, —C(═NH)NR3 or
• —S(═O)2NR3— wherein R3 is hydrogen or optionally substituted C1-C6 alkyl;
• L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p— wherein
• m, n and p are independently 0 or 1,
• Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X2-Q1- or1-QX2- wherein X2 is —O—, S— or NRA— wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,
• Alk1 and Alk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NRA—) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl;
• X1 represents a bond;
• —C(═O);
• or —S(═O)2—;
• —NR4C(═O)—, —C(═O)NR4—, —NR4C(═O)NR5—, —NR4S(═O)2—, or —S(═O)2NR4— wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl;
• z is 0 or 1;
• A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH—Y-L1-X1—[CH2]z— and HONHCO-[LINKER]- are attached different ring atoms;
• and
• -[Linker]- represents a divalent radical of formula —(CH2)x-L3-B—Ar1-L4- wherein
• x is 0 or 1;
• L3 is Z or L2 or Z-L2 wherein Z is as defined in claim 1 and L2 is a bond or an optionally substituted divalent C1-C3 alkylene radical;;
• Ar1 is a divalent phenyl radical or a divalent mono-, or bi-cyclic heteroaryl radical having 5 to 13 ring members, and
• L4 is a bond or optionally substituted —CH2— or —CH═CH—, and
• B is a mono- or bi-cyclic heterocyclic ring system.