GB2533136A - Compounds - Google Patents

Abstract

Thiazole sulphonamide compounds of general formula (I), or salts or prodrugs thereof: (Formula I) wherein R1 is hydrogen, halogen, CN or optionally substituted C1-6alkyl; R11 is hydrogen or C1-4alkyl optionally substituted with halogen or hydroxyl; Y1 is a bond or C1-3alkylene; A1 is optionally substituted C6-10aryl, 5-10 membered heteroaryl, or optionally substituted 3-10-membered carbocyclyl or heterocyclyl; Y2 is (Het)p(Alk1)q- or (Het2)t-(Alk2)-(Het3)-(Alk3)s; p, q, r and s are 0 or 1; Alk1, Alk2 or Alk3 are optionally substituted C1-6alkylene, C2-6alkenylene or C2-6alkynylene such that if two alkyl substituents are present on the same carbon atom in the alkylene, alkenylene or alkynylene moiety they form together with the C atom to which they are attached a C3-6cycloalkyl ring; Het1, Het2 and Het3 are O, S, SO2, NR8b, C(O), C(O)NR8b, NR8bC(O) or C(N-OR8b)-; R8b is H or optionally substituted C1-4­alkyl; A2 is is optionally substituted C6-10aryl, 5-10-membered heteroaryl, or optionally substituted 3-10-membered carbocyclyl or heterocyclyl; may be useful for inhibiting metallo-β-lactamase (MBL) enzymes, including NDM-1, and therefore useful in combination with β-lactam antibiotics in the prevention and treatment of bacterial infection. The corresponding ester prodrug compounds of formula (II) are also detailed.

Description

COMPOUNDS

The present invention relates to novel compounds and their use as inhibitors of metallo-Plactamase (MBL) enzymes More particularly, the invention relates to thiazole sulfonamide derivatives Bacteria in both clinical and non-clinical settings are becoming increasingly resistant to conventional antibiotics, and this resistance is becoming a serious clinical and epidemiological problem for human health. In Gram-negative bacteria, resistance to antibiotics often arises from the production by the organism of P-lactamases, especially metallo-13-lactamases (MBL).

MBL are resistance determinants of increasing clinical relevance. In fact, because of their broad range, potent carbapenemase activity and resistance to inhibitors, these enzymes can confer resistance to almost all P-lactam antibiotics.

MBLs were first detected in the mid-1960s as carried by mobile DNA elements in species with only low pathogenic potential. However, genes encoding MBL spread among major Gram-negative bacteria during the 1990s and this has led to a health crisis arising from the international dissemination of carbapenem-resistant Enterobacteriaceae producing the VIM-type and NDM-type metallo-p-lactamases.

Functional features of these Enterobacteriaceae include potent carbapenemase activity and resistance to clinical p-lactamase inhibitors (clavulanate and sulfones) The activity against P-lactams differs between the different metallo-P-lactamases, and substrate specificity might vary from a narrow range (eg, the CphA metallo-P-lactamase of Aeromonas hydrophda), to an extended range (eg, the VIM-type metallo-P-lactamases, which can degrade almost all classes of P-lactams apart from the monobactams).

There are three major structural subclasses of MBL which share substantial internal diversity. Members of the different subclasses differ not only in their high degree of sequence diversity, but also in the structure of their active sites. In enzymes of subclasses B1 and B3, the active site contains two zinc ions in members of subclass B2, the active site contains only one zinc ion.

Acquired metallo-P-lactamases have been detected in strains of Enterobacteriaceae, Pseudomonas aerugthosa, Acinetobacter battmannii, and other Gram-negative bacteria.

Among acquired MEL, almost all the enzymes belong to subclass Bl, which indicates an overall higher propensity for members of this subclass to be captured and spread with mobile genetic elements than for members of subclasses B2 and B3.

As an example, the subclass Bl comprises the IMP-type, the VIM-type, and the NDM-type enzymes.

The IMP-type enzymes, including IMP-1, were first detected in Japan in the late 1980s, and have since been reported worldwide in Enterobacteriaceae and in Gram-negative bacteria. The IMP-type enzymes have broad substrate specificity with a high affinity for cephalosporins and carbapenems, but they have little activity against Temocillin.

The VIM-type enzymes, including VIM-2, were first discovered in Europe in the late 1990s and have since been reported worldwide. VIM-type enzymes were initially detected in P. aerugthosa and in other Gram-negative bacteria, but have since emerged in Enterobacteriaceae, and have become a major problem in some settings. More than 20 different VIM allotypes are known, each with a defined geographical distribution except for VIM-1 and VIM-2, which share a broader distribution than the IMP-type enzymes. The VIM-type metallo-13-lactamases show even broader substrate specificities than the IMP-types, being able to hydrolyse 6-a-methoxy-penicillins. Furthermore, the VIM-type enzymes are unique in the metallo-P-lactamases in that they have a high affinity for carbapenems.

New Delhi metallo-P-lactamase 1 (NDM-1) is a novel metallo-P-lactamase identified initially in a patient hospitalized in New Delhi with an infection caused by Klebsiellet pneumoniae. Subsequently, organisms in the Enterobacteriacecte family containing this new P-lactamase have been found widely distributed throughout India, Pakistan, and Bangladesh and are now occurring in the United Kingdom and in many other countries. The New Delhi metallo-P-lactamase 1 (NDM-1) is a polypeptide of 158 amino acids in length (Accession number AB571289) capable of hydrolyzing a wide range of P-lactam antibiotics including penicillins, cephalosporins and carbapenem antibiotics that are a mainstay for the treatment of antibiotic-resistant bacterial infections. Therefore there is an urgent need for identifying new compounds for detecting and/or inhibiting N1BL bacteria.

The present inventors have determined that a particular group of thiazole sulfonamides, having an extended ring sti-ucture attached to the sulfonamide group, are capable of inhibiting MBLs, including NDM-1, and are therefore useful for use in combination with P-lactam antibiotics.

The present invention therefore provides a compound which is a th azole sulfonamide of general formula (I), or a salt or prodrug thereof Ri 1 yl_Al_y2_A2 N-S 02

OH

(Formula 1) wherein: W is hydrogen, halogen, CN or R12; wherein R12 is C1 to Co alkyl optionally substituted with one or more substituent Ka, or 3-to 6-membered cycloalkyl or 3-to 6-membered heterocyclyl, either of which is optionally substituted with one or more substituent W; each 1r is independently halogen, CN, OH or C1 to C4 alkoxy optionally substituted by one or more substituent selected from halogen and OH; each Re is independently halogen, CN, OH, oxo or C1 to C4 alkyl or C1 to C4 alkoxy optionally substituted by one or more substituent selected from halogen and OH; w is hydrogen or C1 to C4 alkyl optionally substituted by one or more substituent selected from halogen and OH, each R8 and R9 are independently H or Ci to C4 alkyl optionally substituted by one or more substituent selected from halogen and OH, or where R8 and R9 are joined to the same nitrogen atom, may together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclyl or heteroaryl ring, which ring is optionally substituted by one or more substituents selected from halogen, OH, and -NH); Y1 is a bond or a C1 to C3 alkylene group, A' is a C6 to C10 aryl, a 5-to 10-membered heteroaryl or 3-to 10-membered carbocyclyl or heterocyclyl moiety, wherein A' is unsubstituted or substituted with one or more substituent selected from Rb, halogen, OH, CN, C(0)NRan 8b, NR8C(0)R8b, -NR8R8b, and from Ci to C4 alkoxy and Ci to C4 alkyl groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen, OH and Rb; Rb is selected from -NR8R9, -NR8C(R9)=NR9, -C(=NR8)-NR8R9, and -NR8C(=NR9)NR8R9, and from 5-or 6-membered heterocyclyl and heteroaryl groups which are unsubstituted or substituted with one or more substituents selected from halogen, OH, and -NH) and from C, to C4 alkyl, C, to C4 alkoxy, (C, to C4 alkyl)amino and di(C, to C4 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more substituents selected from halogen, OH and -NR8R9, R8b is selected from H and Ci to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OR8 and Rb, or where R8b and R8 are joined to the same nitrogen atom, may together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclyl or heteroaryl ring, which ring is optionally substituted by one or more substituents selected from halogen, OH, and -NH); Y2 is a group of formula -(fletl)p-(Alkl)q-or -(Het2),-(A11(2)-(Het3)-(A1k3),-, wherein p, q, r and s are independently 0 or 1; Alkl, A1k2 and A1k3 independently represent C1 to Co alkylene, C2 to C6 alkenylene, or C2 to Co alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from Rb, halogen, OR" and -NR8R81' and, when two substituents are present on the same carbon atom in the alkylene, alkenylene or alkynylene moiety, from two alkyl groups which join together with the C atom to which they are attached to form a C3 to C6 cycloalkyl ring; and Hetl, Het2 and Het3 independently represent -0-, -S-, -502-, _NR81' c(0) -C(0)NR8b-, -NR81'C(0)-or -C(N-0R5-; A2 represents a cyclic group selected from C6 to C10 aryl, 5-to 10-membered heteroaryl and 3-to 10-membered carbocyclyl or heterocyclyl; wherein one atom in the cyclic group may be replaced by a moiety R34 wherein R34 is selected from C=0, C=NR8; C=NORK and N+-0-; wherein A2 is substituted by n groups R2; n is 0, 1, 2, 3 or 4; each R2 independently represents: (i) a group R24 which is selected from -R3, -0k3, -SR3, NO2, -C(0)0R8, -C(0)NR8R81' , -NR8C(0)R8b, -NR8C(0)R8b, -NR8Rd, -NR8C(R9)=NR9, -C(=NR8)-NR8R9 and -NR8C(=NR9)NR8R9 and from C, to C4 alkyl, C, to C4 alkoxy and -S(Ci to C4 alkyl) groups which are (a) substituted with one or more substituents selected from Rb and from Ct to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups; or (ii) a group R21' which is selected from halogen, CN, OH and -Nine and from C1 to C4 alkyl and C1 to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen and OH, wherein 12° and fe are each independently H or Ci to C4 alkyl, Rd is a C1 to C4 alkyl group which is substituted by one or more substituent selected from halogen, OR8 and RI), each group R' is independently selected from phenyl and 5-to 10-membered heterocyclyl or heteroaryl groups, wherein R3 is unsubstituted or substituted with one or more substituents selected from halogen, OH, NO2, CN, -C(0)0R8, -C(0)NR8R9, -NR8C(0)R9 and -NH2 and from Ci to C4 alkyl, Ci to C4 alkoxy, (C1 to C4 alkyl)amino and di(C, to C4 alkyl)amino groups wherein the alkyl moiety of the alkyl, alkoxy or allcylamino group is optionally further substituted with one or more substituents selected from halogen, ORB, -COORB and -NR8129; wherein when Y2 is a group of formula -(Hetl)p-(Alkl)w, then n is 1, 2, 3 or 4 and at least one group R2 represents R2a In particular, the present invention provides compounds of formula (I) and salts thereof wherein one or preferably both of the following features are fulfilled.

(a) Y2 is a group of formula -(Het2),--(A1k2)-(Het3)-(A11c3),-; (b) n is 1, 2, 3 or 4 and at least one group R2 represents R2' Preferred compounds are those wherein Y2 is a group of formula -(F1et2),-(Alk2)-(Flet3)-(Alk3)5-As used herein, a Ci to C6 alkyl group is a linear or branched alkyl group containing from 1 to 6 carbon atoms. Typically a Ci to Co alkyl group is a Ci to C4 alkyl group, which is a linear or branched alkyl group containing from 1 to 4 carbon atoms. Examples of Ci to Co alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl and hexyl. A CI to C4 alkyl group is typically a CI to C2 alkyl group. A Ci to C2 alkyl group is methyl or ethyl, typically methyl. For the avoidance of doubt, where two alkyl groups are present, the alkyl groups may be the same or different.

As used herein, a C, to C4 alkoxy group is typically a said C, to C4 alkyl group attached to an oxygen atom. Typically, a C1 to C4 alkoxy group is a C1 to C3 alkoxy group.

Examples of Ci to C4 alkoxy groups include methoxy, ethoxy, propoxy and butoxy.

Typically, a C1 to C3 alkoxy group is a C1 to C2 alkoxy group, i.e. methoxy or ethoxy. For the avoidance of doubt, where two alkoxy groups are present, the alkoxy groups may be the same or different.

As used herein, a C, to C6 alkylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms from a CI to C6 alkane. The two hydrogen atoms may be removed from the same carbon atom or from different carbon atoms. Typically a C, to C6 alkylene group is a CI to C4 alkylene group. Examples of C., to C4 alkylene groups include methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene and tert-butylene. A C1 to C4 alkylene group is typically a C1 to C2 alkylene group. A CI to C2 alkyl group is methylene or ethylene, typically methylene. For the avoidance of doubt, where two alkylene groups are present, the alkylene groups may be the same or different.

As used herein, a C? to C6 alkenylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms from a C. to Co alkene. The two hydrogen atoms may be removed from the same carbon atom or from different carbon atoms. Typically a C2 to C6 alkenylene goup is a C, to C4 alkenylene group. Examples of C., to C4 alkenylene groups include ethenylene, n-propenylene, iso-propenylene, n-butenylene, sec-butenylene and tert-butenylene. A C, to C4 alkenylene group is typically a C2 alkenylene, i.e. ethenylene. For the avoidance of doubt, where two alkenylene groups are present, the alkenylene groups may be the same or different.

As used herein, a C2 to C6 alkynylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms from a C2 to C6 alkyne. The two hydrogen atoms may be removed from the same carbon atom or from different carbon atoms. Typically a C2 to C6 alkynylene group is a C2 to C4 alkynylene group. Examples of C, to C4 alkynylene groups include ethynylene, n-propynylene, iso-propynylene, nbutynylene, sec-butynylene and tert-butynylene. A C2 to C4 alkynylene group is typically a C, alkynylene, i.e. ethynylene. For the avoidance of doubt, where two alkynylene groups are present, the alkynylene groups may be the same or different.

An alkyl, alkoxy, alkylene, alkenylene or alkynylene group as used herein may be unsubstituted or substituted. Substituted alkyl, alkenyl, alkynyl, alkoxy, alkylene, alkenylene or alkynylene groups typically carry from one to three, e.g. one, or two, e.g. one substituent, the substituents being as defined herein. The substituent may be present on any atom in the group or moiety. The substituents on a substituted alkyl, alkoxy, alkylene, alkenylene or alkynylene group are typically themselves unsubstituted.

As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine.

As used herein, a 3-to 6-membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, typically cyclopentyl or cyclohexyl.

As used herein a 3-to 10-membered carbocyclyl group is a saturated or partially saturated, monocyclic or bicyclic group containing from 3 to 10 carbon atoms. A carbocyclyl group may contain one or more double bonds, or it may be a saturated group. Typically, a 3-to 10-membered carbocyclyl group as used herein is a 3-to 6-membered cycloalkyl group.

As used herein a C6 to C10 and group or moiety is a monocyclic or fused polycyclic aromatic group. C6 to Cio aryl groups contain from 6 to 10 carbon atoms in the ring portion. Examples include phenyl (i.e. monocyclic), naphthyl, indenyl and indanyl (i.e. fused bicyclic) groups. Phenyl is preferred.

As used herein a 3-to 10-membered heterocyclyl group is a cyclic group containing from 3 to 10, e.g. from 5 to 10, such as 5 or 6, atoms selected from C, 0, N and S in the ring. A 3-to 6-membered heterocyclyl group is a cyclic group containing from 3 to 6, e.g. 5 or 6, atoms selected from C, 0, N and S in the ring. A 5-to 10-membered heterocyclyl group is typically a 5-to 6-membered heterocyclyl group. A 5-to 6-membered heterocyclyl group is typically a monocyclic ring. Alternatively, a 5-to 10-membered heterocyclyl group may be an 8-to 10-membered bicyclic heterocyclyl group. A heterocyclyl group contains at least one heteroatom, and typically 1, 2, 3 or 4 heteroatoms. The heteroatom or heteroatoms are typically selected from 0, N, and S. A heterocyclyl group may be saturated or partially saturated. A partially saturated heterocyclyl group contains at least one, typically 1, 2 or 3 double bonds.

As used herein a 5-to 10-membered heteroaryl group or moiety is a monocyclic or fused polycyclic aromatic group or moiety containing from 5 to 10, e.g. 5 or 6, atoms selected from C, 0, N and S. A 5-to 10-membered heteroaryl group or moiety is typically a 5-to 6-membered heteroaryl group or moiety. A 5-to 6-membered heteroaryl group or moiety is typically a monocyclic ring. Alternatively, a 5-to 10-membered heteroaryl group or moiety may be an 8-to 10-membered bicyclic heteroaryl group or moiety. A heteroaryl group or moiety contains at least one heteroatom, and typically 1, 2, 3 or 4 heteroatoms.

The heteroatom or heteroatoms are typically selected from 0, N, and S. Examples of 5-to 6-membered heterocyclyl rings include piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl. Examples of 8-to 10-membered bicyclic heterocyclyl rings include tetrahydronaphthyridinyl, dihydropyrazolotriazolyl, tetrahydroisoquinolinyl, quinalin-2-one, triazolopyridin-3-one, quinazolinone, naphthyridin-l-one, and dihydroisoquinalin-2-one Examples of 5-to 6-membered heteroaryl groups and moieties include pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl and oxadiazolyl groups and moieties. Examples of 8-to 10-membered bicyclic heteroaryl groups and moieties include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, indazolyl, imidazopyridinyl, triazolopyridinyl, pyridopyridazinyl, benzimidazolyl, naphthyridinyl, pyridopyrimidinyl, purinyl and isoquinalin-2-oxide groups and moieties An aryl or heteroaryl moiety as used herein is bidentate aryl or heteroaryl moiety which is linked to two further groups or moieties and which may optionally be substituted on any further available ring atoms. A heteroaryl or heterocyclyl group or moiety may be joined to the remainder of the molecule via any carbon or nitrogen ring atom, in some embodiments, the ring nitrogen atom may carry a charge. A heterocyclyl or heteroaryl group or moiety may have one or more, typically one, atom in the ring replaced with a group selected from C=0, C=NR8; C=NOR8 and N11-0-, typically 1211 is C=0 or A carbocyclyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group or moiety as used herein may be unsubstituted or substituted. A substituted group or moiety is typically substituted by 1, 2, 3 or 4, e.g. 1 or 2, such as 1 substituent. Substituents on a heteroaryl or heterocyclyl moiety may be carried on a carbon atom or a heteroatom. Substituents may be carried on a nitrogen atom, optionally leading to a quaternary nitrogen carrying a positive charge. Substituents on a carbocyclyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group or moiety are typically themselves unsubstituted. For the avoidance of doubt, when two or more substituents are present, the substituents may be the same or different.

As used herein, a salt is typically a pharmaceutically acceptable salt. As used herein a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

In Formula (I), the stereochemistry is not limited. In particular, compounds of formula (I) containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. Further, for the avoidance of doubt, the compounds of the invention may be used in any tautomeric form.

Typically, the agent or substance described herein contains at least 50%, preferably at least 60, 75%, 90% or 95% of a compound according to Formula (I) which is enantiomerically or diasteriomerically pure. Thus, the compound is preferably substantially optically pure.

In some suitable compounds of general formula (I), Ri is hydrogen, halogen, CN or R12, wherein R12 is CI to C6 alkyl optionally substituted with one or more substituent 118; wherein W is as defined above. More suitably, R' is hydrogen, C1 to C4 alkyl optionally substituted with one or more halo substituent. Most preferably, RI is hydrogen or unsubstituted CI to C4 alkyl, most preferably hydrogen.

-

K is typically hydrogen or unsubstituted Ct to C4 alkyl, most preferably hydrogen.

In further embodiments, in the compounds of general formula (I), independently or in combination: R' is hydrogen; and R' 'is hydrogen.

Each R8 and R9 are typically independently H or unsubstituted CI to C4 alkyl, for example H. Preferably, Y1 is a bond.

Al is typically phenyl or a 5-to 6-membered heteroaryl or heterocyclyl moiety. Typically, the heteroaryl or heterocyclyl moiety contains 1, 2 or 3 heteroatoms selected from N, 0 and S. Preferably, Al is phenyl or a 5-to 6-membered heteroaryl moiety. Examples of suitable groups A' include phenyl, pyridyl, pyrrolyl and pyrazolyl, in particular phenyl, pyridyl and pyrazolyl. Preferably, Al is phenyl.

The groups Al and Y2 (and other positions) may carry a polar substituent Rb. These groups Rb are groups known for their properties in increasing the polarity of a compound. Preferred groups RI' include -NR8R9, -NR8C(R9)=NR9, -C(=NR8)-NR8R9 and -NR8C(=NR9)NR8R9, and 5-or 6-membered heterocyclyl and heteroaryl groups which are unsubstituted or substituted with one or more substituents selected from -NH) and -N(C, to alky1)2 and from CI to C2 alkyl, CI to C2 alkoxy and (CI to C2 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH2; wherein each R8 and R9 is the same or different and selected from H and unsubstituted CI to C2 alkyl. Preferred groups Rb include -NR8R9 and 5-or 6-membered heterocyclyl and heteroaryl groups selected from imidazolyl, pyrrolyl, pyridinyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl, the heterocyclyl and heteroaryl groups being unsubstituted or substituted with one or more substituents selected from -NH2 and -N(CI to C, alky1)2 and from CI to C9 alkyl, CI to C2 alkoxy and (CI to C2 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH2; wherein each R8 and R9 is the same or different and selected from H and unsubstituted CI to C., alkyl. Particularly preferred groups are -NR8R9, wherein each R8 and R9 is the same or different and selected from H and unsubstituted CI to C.,) alkyl.

A' is unsubstituted or substituted with one or more, e.g. 1, 2 or 3, e.g. 1 or 2, such as 1, substituent. The substituents are typically selected from Rb, halogen, OH, CN and -NR8R8b, and from CI to C4 alkoxy and CI to C4 alkyl groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen, OH and NR8R9, where R8b is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, and BY and R9 each independently represent H, methyl or ethyl. Preferred substituents are halogen, OH, CN, methoxy, ethoxy, methyl, ethyl and tritluoromethyl. Most preferably, Al is unsubstituted.

When Y2 is a group of formula -(Hetl)p-(Alkl)q-, typically at least one of p and q is 1. Preferably, when Y2 is a group of formula -(Hetl)p-(AlkOcr, it is a group of formula -Hetl-, Alkl-, or -(Hett)-(Alk1)-. Heti is typically -0-or -Me-, wherein BY is hydrogen or unsubstituted C1 to C4 alkyl, preferably Heti is -0-or -NH-. Alkl is typically C1 to C4 alkylene, which is unsubstituted or substituted with one or more substituents selected from Rb, halogen, OR" and -NHR81', wherein R81" is selected from H and C1 to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, and R8 and R9 each independently represent H, methyl or ethyl. Preferred substituents on Alkl are halogen and OH. Preferably Alkl is unsubstituted CI to C; alkylene.

When Y2 is -(Het2),-(A11(2)-(Het3)-(Alk3),-, typically at least one of r and s is 0. When Y2 is -(Het2),-(Alk2)-(Het3)-(Alk3),-, it is preferably -(A1k2)-(Het3)-, -(Het2)-(A1k2)-(Het3)-or -(A11c2)-(1-let3)-(Alk3)-.

A1k2 and A1k3 are typically each independently C1 to C6alkylene, C2 to C6 alkenylene, or C9 to C6 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from Rb, halogen, OR81' and -NHR81', wherein R81' is selected from H and CI to Ct alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, and R8 and R9 each independently represent H, methyl or ethyl. Preferably A1k2 and A1k3 are each independently C1 to C4 alkylene, C2 to C4 alkenylene, or C.2 to C4 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from OR8 and -NR8R9, wherein R8 and R9 are each independently hydrogen or C1 to C2 alkyl. The substituents are most preferably selected from OH and -NH2.

_

Het2 and Het3 typically independently represent -0-, -S-, -SO2-, _NRsb_, C(0)NRsb_ or _ Nitsbc(-)_, tiwherein R81 is selected from H and C1 to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, where R8 and R9 are each independently hydrogen or C1 to C2 alkyl Preferably, Het2 and Het3 independently represent -0-, -S-, -SO2-, -NR8-, -C(0)NR8-or -NR8C(0)-, wherein R8 and R9 are each independently hydrogen or C1 to C2 alkyl.

In one preferred embodiment, Y2 is -(Het2),-(Alk2)-(Het3)-(A1k3),-, wherein r, s, Het2, Het3, Alk2 and A1k3 are as defined above. In a particularly preferred embodiment, Y2 is -(A1k2)-(Het3)-, wherein A1k2 and Het3 are as defined above, preferably wherein A1k2 is unsubstituted Ci to C4 alkylene, preferably C., or C; alkylene and Het3 is -0-or -NH-. Most preferred groups Y2 are -CH2CH20-and -CH2CH2CH20-.

A2 typically represents a cyclic group selected from phenyl, cyclohexyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl, wherein one atom in the cyclic group may be replaced by a moiety 1284 wherein Fe4 is selected from C=0, C=NRg; C=NORg and NI±-0-, typically R34 i S C=0 or N+-0-. Examples of suitable groups A2 include phenyl, cyclohexyl, pyridinyl, piperidinyl, piperazinyl, imidazolyl, pyrrolidinyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyridopyridazinyl, pyridopyrimidinyl, purinyl, tetrahydroisoquinolinyl, indazolyl, imidazopyridinyl, benzimidazolyl, dihydropyrazolotriazolyl, naphthyridinyl, tetrahydronaphthyridinyl, triazolopyridin-3-one, naphthyridin-l-one, quinazolinone, isoquinalin-2-oxide, quinalin-2-one and dihydroi soquinalin-2-one.

A2 is substituted by n groups R2, wherein n is 0, 1,2, 3 or 4, typically 0, 1 or 2, e.g. 0 or 1 In one embodiment, n is 1, 2, 3 or 4, typically 1 or 2, e.g. 1. In this embodiment at least one group R2 is a group R28. In this embodiment, ring A2 carries at least one (typically one) substituent R2a, and may optionally carry 1, 2 or. .3 substituents R214 Preferably, in this embodiment, ring A2 is substituted by one group R2e and 0, 1 or 2, e.g. 0 or 1, groups R2b. More preferably in this embodiment, n is 1 and ring A2 is substituted by one group R28.

Preferred groups R2b are selected from halogen, OH and -Nal groups, and from Ci to C4 alkyl and Ci to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more, e.g. 1 or 2, substituents selected from halogen and OH; wherein Re and Rf are hydrogen or methyl.

Typically, R28 is selected from -R3, -01e, -C(0)NR8R8b, -NR8C(0)R8b, -NR8C(0)R8b and -NRgRd and from C, to C4 alkyl and Ci to C4 alkoxy groups which are (a) substituted with one or more (e.g. 1, 2 or 3, e.g. 1 or 2) substituents selected from Rb and from Ci to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more (e.g. 1 or 2) substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups; wherein R81' is selected from H and 01 to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, and R8 and R9 are independently selected from hydrogen and unsubstituted C, to C2 alkyl Rd is typically a Ci to C4 alkyl group which is substituted by one or more substituent selected from halogen, OR8 and NR8R9, where R8 and R9 are independently selected from hydrogen and unsubstituted CI to C2 alkyl. Preferably, Rd is a CI to C4 alkyl group which is substituted by one or more NR8R9 groups, where R8 and R9 are independently selected from hydrogen and unsubstituted CI to C2 alkyl.

Alkyl, alkoxy and -S-alkyl groups on R2" may be substituted with a polar group Rb in order to provide increased polarity of the compound. Preferred groups Rb are those as defined above. Particularly preferred groups ftb as substituents on alkyl, alkoxy and -S-alkyl groups at R2" include le include -NR8R9 and unsubstituted or substituted 5-or 6-membered heterocyclyl and heteroaryl groups. Particularly preferred 5-or 6-membered heterocyclyl and heteroaryl groups are selected from imidazolyl, pyrrolyl, pyridinyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, morpholinyl, pyTrolidinyl, piperidinyl and piperazinyl. The heterocyclyl and heteroaryl groups are preferably unsubstituted or substituted with one or more substituents selected from -NH2 and -N(01 to C2 alky1)2 and from C1 to C2 alkyl, CI to C2 alkoxy and (01 to C7 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH, ; wherein each R8 and R9 is the same or different and selected from H and unsubstituted 01 to C2 alkyl.

R' is typically selected from phenyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl. In one embodiment, R3 is phenyl or a 5-to 6-membered heteroaryl or heterocyclyl group. Heteroaryl or heterocyclyl rings at le typically contain 1, 2 or 3 heteroatoms selected from N, 0 and S. Examples of suitable rings at RI' include phenyl, imidazole, triazole, oxadiazole, pyridine, morpholine, pyrrolidine, piperazine and isoquinoline.

R3 is unsubstituted or substituted by one or more substituents, e.g. 1, 2, 3 or 4, e.g. 1, 2 or 3, such as 1 or 2 substituents. Preferred substituents include halogen, OH, NO2, CN, and -NH, and C1 to C2 alkyl, CI to C) alkoxy, (C1 to C2 alkyl)amino and di(Ci to C) alkyl)amino groups wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more (e.g. 1, 2 or 3, e.g. 1 or 2) substituents selected from halogen, OR8, -COOR8 and -NR8R9, wherein R8 and R9 are independently selected from hydrogen and unsubstituted C, to C72 alkyl. More preferred substituents include NO2, -NR8R9 and C, to C2 alkyl which is unsubstituted or substituted with one or two substituents selected from halogen, OH, -COOH and -NH2.

In one embodiment, the compounds described herein are thiazole sulfonamides of formula (I) or salts or prodrugs thereof, wherein: R1 is hydrogen or unsubstituted C14 alkyl, -n x is hydrogen or unsubstituted C1-4 alkyl; Y1 is a bond; A' is phenyl or a 5-to 6-membered heteroaryl or heterocyclyl moiety, wherein A' is unsubstituted or substituted with one or more substituents selected from Rb, halogen, OH, CN and -NR8R8b, and from C1 to C4 alkoxy and C1 to C4 alkyl groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen, OH and NR8R9; R81' is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9; R8 and R9 each independently represent H, methyl or ethyl; Rb is selected from -NR8R9, -NR8C(R9)=NR9, -C(=NR8)-NR8R9 and -NR8C(=NR9)NR8R9, and 5-or 6-membered heterocyclyl and heteroaryl groups which are unsubstituted or substituted with one or more substituents selected from -NH2 and -N(Ci to C, alky1)2 and from C1 to C2 alkyl, C1 to C2 alkoxy and (CI to C2 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH)); y2 is (i) a group of formula -(Hetl)p-(Alkl)c, wherein at least one of p and q is 1 and the other is 0 or 1, wherein Het] is -0-, -NH-or -N(C, to C4 alkyl); and Alkl is C, to C4 alkylene, which is unsubstituted or substituted with one or more substituents selected from Rb, halogen, OR8b and -NBR8b-or (ii) a group of formula -(Het2),--(Alk2)-(Het3)-(Alk3),-, wherein at least one of r and s is 0 and the other is 0 or 1; wherein A1k2 and Alk3 are each independently CI to C6 alkylene, C, to C6 alkenylene, or C2 to C6 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from Rb, halogen, OR8b and -NHR81'; and Het2 and Het3 independently represent -0-, -S-, -SO2-, -NR8b- -C(0)NR8b-or A2 represents a cyclic group selected from phenyl, cyclohexyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl, wherein one atom in the cyclic group may be replaced by a moiety 1214 wherein Ri4 is selected from C=0 and wherein A2 is substituted by n groups R2, wherein n is 0, 1 or 2; each R2 independently represents (i) a group R2a which is selected from -RI', -C(0)NR8R81', _NRsc(o)Rsb, -NR8C(0)R81' and -NR8Rd and from C1 to C4 alkyl and C1 to C4 alkoxy groups which are (a) substituted with one or more substituents selected from Rb and from CI to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups; or (ii) a group R21' which is selected from halogen, CN, OH and -NReltf groups and from C1 to C4 alkyl and Ci to C4 alkoxy groups which are unsubstituted or substituted by one or more substituents selected from halogen and OH; wherein Re and Rf are hydrogen or methyl; Rd is a CI to C4 alkyl group which is substituted by one or more substrtuent selected from halogen, OR" and NR"R", Ttll is selected from phenyl, and from 5-to JO-membered heteroaly1 and heterocyclyl groups; wherein It' is unsubstituted or substituted by one or more substituents selected from halogen, OH, NO2, CN, and -NH2 and from C, to C2 alkyl, C, to C2 alkoxy, (CI to C2 alkyl)amino and di(C, to C2 alkyl)amino groups wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more substituents selected from halogen, OR", -COOR" and -NR8129.

The compounds, salts or prodrugs of this embodiment have at least one, preferably both, of the following features: (a) Y2 is (ii) a group of formula -(Het2),-(Alk2)-(Het3)-(Alk3),-, wherein r, s, Het2, Het3, A1k2 and A1k3 are as defined above; and (b) n is 1 or 2 and at least one group R2 is a group R2". Preferably, the compounds have at least feature (a).

In another embodiment, the compounds described herein are thiazole sulfonamides of formula (IA) or salts or prodrugs thereof N./1 n _ A l_y2_A2 HN-S02

OH

Formula (IA) wherein: Yl is a bond; Al is an unsubstituted moiety selected from phenyl and 5-to 6-membered heteroaryl; Y2 is (i) a group of formula -(Hen)p-(Alk 1)q-, wherein at least one of p and q is 1 and the other is 0 or 1, wherein Heti is -0-or -N1-1-; and Alkl is unsubstituted C, to C3 alkylene; or (ii) a group of formula -(Het2),-(Alk2)-(Het3)-(A1k3),-, wherein at least one of r and s is 0 and the other is 0 or 1; wherein Alk2 and Alk3 are each independently C, to C4 alkylene, C2 to C4 alkenylene or C, to C4 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from OR8 and -NR8R9; and Het2 and Het3 independently represent -0-, -S-, -SO2-, -N118-, -C(0)NR8-or -NR8C(0)-; R8 and R9 are each independently hydrogen or C1 to C2 alkyl, A2 represents a cyclic group selected from phenyl, cyclohexyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl, wherein one atom in the cyclic group may be replaced by a moiety R34 wherein R34 is selected from C=0 and wherein A2 is substituted by n groups R2, wherein n is 0, 1 or 2; each R2 independently represents (i) a group R2' which is selected from -123, -C(0)NR8R81', _NRsc(o)Rsb, -NR8C(0)R81' and -NR8Rd and from C1 to C4 alkyl and C1 to C4 alkoxy groups which are (a) substituted with one or more substituents selected from Rb and from C1 to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups, wherein R81' is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9; or (ii) a group R2b which is selected from halogen, OH and -Nal groups and from C1 to C4 alkyl and C1 to C4 alkoxy groups which are unsubstituted or substituted by one or more substituents selected from halogen and OH; wherein Re and Ware hydrogen or methyl; Rd is a C1 to C4 alkyl group which is substituted by one or more NR8R9 groups, R" is -NR8R9 or a 5-or 6-membered heterocyclyl or heteroaryl group which is unsubstituted or substituted with one or more substituents selected from -NEI7 and -N(Ct to C2 alky1)2 and from Ci to C2 alkyl, CI to C2 alkoxy and (C1 to C2 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH2, and R1 is selected from phenyl, and from 5-to 10-membered heteroatyl and heterocyclyl groups; wherein R3 is unsubstituted or substituted by one or more substituents selected from NO2, -NR8R9 and CI to C7 alkyl which is unsubstituted or substituted with one or two substituents selected from halogen, 01-1, -COOH and -NI-I2.

The compounds or salts or prodrugs of this embodiment have at least one, preferably both, of the following features: (a) Y2 is (ii) a group of formula -(Het2),(Alk2)-(Het3)-(Alk3),-, wherein r, s, 1-Iet2, 1-let3, A1k2 and Alk3 are as defined above; and (b) n is 1 or 2 and at least one group R2 is a group R2a.

Most preferably, in this embodiment Y2 is (ii) a group of formula -(Het2),-(A1k2)-(Het3)-(Alk3),-.

In a particularly preferred embodiment, the compounds described herein are thiazole sulfonamides of formula (IA) or salts or prodrugs thereof y2_ A2 HN-S02

OH

Formula (IA) wherein: Y1 is a bond; A1 is an unsubstituted moiety selected from phenyl and 5-to 6-membered heteroaryl; Y2 is -(A1k2)-(Het3)-, wherein A1k2 is unsubstituted CI to C4 alkylene, preferably C2 or Cl alkylene, and Het3 is -0-or -NH-; R8 and R9 are each independently hydrogen or CI to C2 alkyl, A2 represents a cyclic group selected from phenyl, cyclohexyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl, wherein one atom in the cyclic group may be replaced by a moiety It21/ wherein R34 is selected from C=0 and wherein A2 is substituted by n groups R2, wherein n is 0, t or 2; each R2 independently represents (i) a group R2a which is selected from -le, -OW, -C(0) NRsRsb, _N s R c(0)Rsb, -NR8C(0)R81' and -NR8Rd and from CI to C4 alkyl and CI to C4 alkoxy groups which are (a) substituted with one or more substituents selected from Rb and from C, to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups, wherein R8b is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9; or (ii) a group R2b which is selected from halogen, OH and -NReltf groups and from CI to C4 alkyl and CI to C4 alkoxy groups which are unsubstituted or substituted by one or more substituents selected from halogen and OH; wherein 12' and R1 arehydrogen or methyl; Rd is a CI to C4 alkyl group which is substituted by one or more NR8R9 groups; Rb is -NR8R9 or a 5-or 6-membered heterocyclyl or heteroaryl group which is unsubstituted or substituted with one or more substituents selected from -NH2 and -N(Ci to C2 alky1)2 and from C1 to C2 alkyl, CI to C2 alkoxy and (CI to C2 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH2, and 123 is selected from phenyl, and from 5-to 10-membered heteroaryl and heterocyclyl groups; wherein Te is unsubstituted or substituted by one or more substituents selected from NO2, -NR8R9 and C1 to C, alkyl which is unsubstituted or substituted with one or two substituents selected from halogen, 01-1, -COOH and -N112.

Particularly preferred compounds are Compounds 1 to 84 listed in the Examples herein and salts, in particular pharmaceutically acceptable salts, thereof The term "prodrug" as used herein refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, eta!, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the invention or a pharmaceutically acceptable salt of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-C8)alkyl, (C2-Ci2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methy1-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methy1-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyflaminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C,-C2)alkylamino(C2-C1)alkyl (such as 13-dimethylaminoethyl), carbamoy1-(CI-C2)alkyl, N,N-di(C -C2)alkylcarbamoy1-(CIC2)alkyl and piperidino-, pyn-olidino-or morpholino(C2-C3)alkyl.

Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxymethyl, 1-((Ci-C6)alkanoyloxy)ethyl, 1 -m ethyl-1 -((C i-C6)al kanoyl o xy)ethyl (C i-C6)alkoxy carbonyl o xym ethyl, N-(C -C6)al koxycarbonyl am i n omethyl, succinoyl, (C -C6)alkanoyl, a-am i no(C -C4)allcanoyl, arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each aaminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)2, -P(0)(0(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate) If a compound of the invention incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyakyl derivative, an (oxodioxolenyl)methyl derivative, an N-Nlannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine For examples, see Simplicio, et at, Molecules 2008, 13, 519 and references therein Particularly preferred prodrugs of the compounds described herein are those of formula Ri /YAYA N-S02 0 R5 Formula (II) wherein Fe, le I, \I', A', Y2 and A2 are as defined herein, and R5 is a (C,-C8)alkyl, (C2-Ci2)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methy1-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyflamino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C-C3)alkyl, carbamoy1-(Ci-C2)alkyl, N,N-di(Ci-C2)alkylcarbamoy1-(C1-C2)alkyl piperidino-, pyrrolidino-or morpholino(C2-C3)alkyl group Preferred prodrugs are those wherein R5 is a (Ci-C6)alkyl or (C2-C6)a1kanoy1oxymethy1 group.

Compounds of general formula (I) may be prepared according to the methods set out in the following schemes.

Scheme 1

CN (9)

Sodium 1 nitrite

CN HO, 0

(10) 0Q2 Sodium I dithionate (7) NH S=C=N -Q1 (11) IAmidation ON RIY.X2 0 (8) (8) H2N R1)N N 0 (14) X -S Q \ Lawesson's reagent Or 11, R1--4N 0 ON 0 0 I 0Q2 R1 0 01\ NaH (15) N -S -R2 # H 01 0 = H 0Q2 0 -4-(12) 002 002 I o (s) (13) II 2 (4) oQ2 X -S-RII Compounds of general formula (4) 0Q2 QI\ (P 2 R (3) 111--R # H Q = Protecting group H 11 2

N-S-R

OH (16b) Ri H 2

N-S-R (4)

wherein which Rl is as defined for general formula (I), Ql is either a protecting group or a group Ril as defined for general formula (I); Q2 is CI to C4 alkyl or benzyk and R2 is -Y'-as defined for general formula (I) or a group which can be transformed in one or multiple steps into a group -Y1-A1-Y2-A2 as defined for general formula (I); may be prepared according to Scheme 1 from a compound of general formula (2): x' (2) wherein R' is as defined for general formula (I), Q2 is Ci to C4 alkyl or benzyl, and X' is a leaving group, such as a halogen, for example bromine, and a sulphonamide of general formula (3).

N-S-R2

H II (3)

wherein Q' is either a protecting group or a group RH as defined for general formula (I); and R2 is -YI-A1-Y2-A2 as defined for general formula (I) or a group which can be transformed in one or multiple steps into a group -YI-AI-Y2-A2 as defined for general formula W. Typically the reaction may be carried out in the presence of a palladium or copper catalyst, for example tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) or cuprous iodide (CuI) at elevated temperature, typically 70 to 110°C, more usually 75 to 95°C, under an inert atmosphere, for example nitrogen or argon.

When Pd2dba3 is used as the catalyst, the reaction is suitably carried out in the presence of a ligand for palladium, for example 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) and a base, for example caesium carbonate.

In some cases, compounds of general formula (3) may be prepared from compounds of general formula (8): (8) s -Y1-A1-Y2-A2 2 wherein R2 i A as defined for general formula (I) or a group which can be i_Ai_y2_A2; transformed in one or multiple steps into a group -Y by an aminolysis reaction with an amine of formula QINF12 wherein Q' is either hydrogen, a protecting group, such as p-methoxybenzyl, or a group R11 as defined for general formula (I).

Aminolysis reactions are well known and, for example, the preparation of primary sulfonamides by the reaction of sulfonyl chlorides with ammonia is described by Li el al, Syttlelt, (2006), 725. In this case the reaction was carried out in tetrahydrofuran. An alternative procedure using dichloromethane as solvent is described by Hu et al, JA.C.S., (2008), 130, 13820 and Yuriev et al (European Journal of Medicinal Chemistry 39, 385) carried out the reaction in water.

A compound of general formula (2) can be prepared from a compound of general formula (1): (1) wherein R1 is not hydrogen; and Q2 is CI to C4 alkyl or benzyl; by halogenation, for example bromination Conditions for bromination include treatment with 1,2-dibromotetrachloroethane in the presence of a base A compound of general structure (4) may alternatively be formed, according to Scheme 1, from the reaction between an intermediate of general formula (7): Qi

NH (7)

wherein R1 is as defined for general formula (I); Q2 is Ci to C4 alkyl or benzyl and Q1 is either a protecting group or a group R11 as defined for general formula (I), and a sulfonyl halide of general formula (8) 0 I I X1-S-R2

I I (8)

wherein R2 is -Y1-A1-Y2-A2 as defined for general formula (I) or a group which can be transformed in one or multiple steps into a group -Y1-A1-Y2-A2.

The compound of general formula (7) may first be treated with a strong base such as an alkali metal hydride, typically sodium hydride, under anhydrous conditions, for example in a dry organic solvent, for example a cyclic ether such as tetrahydrofuran and following this, the compound of general formula (8) may be added to the reaction mixture A thiazole intermediate of general structure (7) may be formed by the reaction of an isocyanide (5):

NC

0Q2 (5) wherein Q2 is Ci to C4 alkyl or benzyl, and an isothiocyanate (6): S=C=N-Q1 (6) wherein Q1 is either a protecting group or a group R11 as defined for general formula (I).

The reaction may be carried out at a temperature of about 15-30°C, typically room temperature under anhydrous conditions, for example in a dry organic solvent such as tetrahydrofuran. The base may be an alkali metal alkoxide, for example sodium or potassium tert-butoxide. Typically, the compound of general formula (5) is mixed with the base in the solvent, following which the compound of general formula (6) is added and the mixture stirred until the reaction is complete.

Compounds of general formulae (5) and (6) are well known and are either readily available or may be prepared by methods known to those skilled in the art.

Thus, in a further aspect of the invention there is provided an alternative process for the preparation of a compound of general formula (4), according to Scheme 1, by the reaction of compound of general formula (13): (13) wherein, Q2 is C1 to C4 alkyl or benzyl, and R1 is as defined for general formula (I); with a sulfonyl halide of general formula (8): (8) wherein R2 is -Y1-A1-Y2-A2 as defined for general formula (I) or a group which can be transformed in one or multiple steps into a group -Y1-A1-Y2-A2; and X1 is a halide, most commonly chloride.

The reaction may be conducted in a polar organic solvent, typically a chlorinated solvent such as dichloromethane, and in the presence of a mild base, for example pyridine.

Typically the reaction is conducted at a temperature of about 15 to 30°C, usually at room temperature.

Alternatively, in cases where it is necessary to use less mild conditions, a stronger base, for example sodium hydride may be used. Tetrahydrofuran is a suitable solvent in such cases. 5 Compounds of general formula (4) in which Q1 is other than hydrogen may be prepared by reductive amination of the compound of general formula (13) prior to reaction with the compound of general formula (8). For example, the primary amine of general formula (13) can be alkylated using a reductive alkylation process. For example, the amine can be treated with an aldehyde (such as formaldehyde or p-methoxybenzaldehyde) and a borohydride (such as sodium triacetoxyborohydride, or sodium cyanoborohydride) in a solvent (such as a halogenated hydrocarbon, for example di chloromethane, or an alcohol, for example ethanol) and, where necessary, in the presence of an acid (such as acetic acid). The products of such a reaction could be sulfonylated using a moiety of the general formula (8) to give compounds of general formula (4).

Alternatively, compounds of general formula (4) in which Q1 is H may be treated with a base (such as sodium hydride or potassium t-butoxide) in an appropriate solvent (such as THF) in the presence of an alkylating agent of the general formula Q'-X, where X is a suitable leaving group (such as methyl iodide or benzyl bromide) and RI' is defined for general formula (I), to give compounds of the general formula (4).

(see Smith, March, March's Advanced Organic Chemistry, 56 Edition, Wiley: New York, 2001).

The synthesis of compounds of general formula (13) is based on well-known literature procedures and is illustrated in Scheme I. Thus, compounds of general formula (13) may be prepared from compounds of general formula (12) o CN (12) wherein RI is as defined for general formula (I), and Q2 is C1 to C4 alkyl or benzyl, preferably ethyl; by reaction with Lawesson's reagent (2,4-bis(4-methoxypheny1)-1,3,2,4-dithiadiphosphetane-2,4-disulfide). The reaction may be carried out in a non-polar organic solvent, for example toluene, under an inert atmosphere such as nitrogen and at elevated temperature, for example 50 to 90°C, usually about 60-80°C.

Compounds of general formula (12) in which RI is other than hydrogen may be prepared by reaction of a compound of general formula (11)

ON (11)

wherein Q2 is C1 to C4 alkyl or benzyl; with a compound of general formula (14) or (15): 0 0 Ri X2 0 R1 (14) (15) wherein RI is as defined for general formula (I); and X' is a leaving group, for example a halide, particularly chloride.

The reaction may be carried out in the presence of an organic base such as pyridine or triethylamine and at a temperature of about 15 to 30°C, typically at room temperature.

When RI is H, it is not possible to use this method because the compounds of formula (14) -formyl chloride, and (15) -formyl anhydride, are insufficiently stable Therefore, when R1 is H, the compounds of formula (12) may be prepared by reaction of a compound of general formula (11) with a mixture of formic acid and a carboxylic acid halide or anhydride, for example acetyl chloride or acetic anhydride.

Compounds of general formula (14) and (15) are well known and are readily available or may be prepared by methods familiar to those of skill in the art.

Compounds of general formula (11) may be prepared from compounds of general formula (10):

CN HO, (10)

wherein Q2 is C1 to C4 alkyl or benzyl; by reaction with a base followed by sodium dithionate in aqueous solution. Suitable bases include alkali metal bases, for example sodium, potassium or lithium hydroxide, with sodium hydroxide being particularly suitable. The reaction may be carried out at a temperature of about 15 to 30°C, typically at room temperature.

Compounds of general formula (10) may be prepared from compounds of general formula (9):

CN

002 (9) wherein Q2 is C1 to C4 alkyl or benzyl, by reaction with sodium nitrite Typically the reaction is conducted in acidic solution and at reduced temperature, for example -5 to 5°C Compounds of general formula (4) may be converted into compounds of general formula (16a) and (16b) 0 0 11 2 H II 2

N-S-R N-S-R

II

OH (16b)

wherein Q1 is R11 as defined for general formula (I), Q2 is C1 to C4 alkyl or benzyl, and R2 is -Y1-A1-Y2-A2 as defined for general formula (I); by hydrolysis.

Base hydrolysis may be conducted in a suitable solvent, for example a polar solvent such as a mixture of tetrahydrofuran and water at a temperature of 10-50°C, especially 15-25°C, for example room temperature. An example of base hydrolysis would be the conversion of a compound of general formula (4), wherein Q' is hydrogen and Q2 is C, to C4 alkyl, for example ethyl, into a compound of general formula (16b).

Acid hydrolysis is typically carried out using aqueous TFA, for example 95% TFA. The reaction may be conducted at a temperature of 10-50°C, especially 15-25°C, for example room temperature. An example of acid hydrolysis would be the conversion of a compound of general formula (4), wherein Q1 is hydrogen or an acid labile protecting group, such as 4-methoxybenzyl, and Q2 is tert-butyl, into a compound of general formula (16b). Another example would be the conversion of a compound of general formula (4), wherein Q1 is as defined for general formula (I) and Q2 is tert-butyl, into a compound of general formula (16a).

Thus, in a further aspect of the invention there is provided a process for the preparation of a compound of general formula (I), the process comprising the reaction of a compound of general formula (4) with a base or an acid.

Compounds of general formula (4) where R2 is not -Y'-A'-Y2-A2 would require further modification of R2 such that it becomes -Y1-A1-1/2-.A 2 as defined for general formula (I).

Methods for the preparation of compounds of the invention where further modifications to R2 are required are given in Schemes 2 and 3.

Scheme 2 0, 2 U Ar (25) U Pg (19)

NCS

or DCDMH nPg (20) Arl X3/ protection (18) OH Alcohol Arl X3/ (17) PhCH2SH U Pg (22) Ar2OH (23) or Ar2X3 (24) Q \ 11 N-S-Ar 0Q2 (21) IDeprotection (Lit 0 \ II N-S-Ar 0, n Pg *MI 0.1\

NH

(4) 002 O,Arl Cl 0 Ar2OH (23) Base Vs-Ra nRb (28) I (27) HN,Rb QI\ N-S-Ar (26) IRb = H Amidation Ra

I

N n

II S 0 0 (29)

In Scheme 2, sulfonyl chloride compounds of formula (20) are generally known, otherwise they may be prepared from compounds of general formula (17). Many standard groups are available, to those skilled in the art, for protection of the alcohol functionality in (17), for example acetate (COCH3). Compounds of general formula (18) may thus be formed by the treatment of a compound of general formula (17) with acetic anhydride or acetyl chloride in the presence of a base such as triethylamine and optionally an activating agent such as cA\ N,N-dimethylaminopyridine (DMAP). A protected compound of general formula (18) may be converted into a benylic thioether of formula (19) by reaction with benzyl mercaptan.

Typically the reaction may be carried out in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), a ligand for palladium, for example 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), and a base, for example caesium carbonate, at elevated temperature, typically 70 to 110°C, more usually 100°C, under an inert atmosphere, for example nitrogen or argon.

A compound of general formula (20) may be prepared from a compound (19) using either N-chlorosuccinimide (NCS) or 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) in an acidic medium, and subsequently be reacted with an compound of general formula (4) as described in Scheme 1 to give a compound (21).

Deprotection of the alcohol functionality in compounds of type (21) can be achieved under various conditions, dependent upon the nature of Pgi. For example when Pgi is acetyl (COCH3), treatment with potassium carbonate in methanol can provide a compound of general formula (22). Subsequent reaction with either a phenol (23, Ar2OH) or an aryl halide (24, Ar2X3) may provide a compound of formula (25).

Reaction conditions for the formation of compounds of general formula (25) by the reaction between alcohol (22) and phenol (23) would most commonly be triphenylphosphine, which may be optionally supported on a macromolecular solid such polystyrene, and a di-alkyl azodicarboxylate such as the diisopropyl derivative (DIAD) or the ethyl derivative (DEAD) in a suitable solvent such as tetrahydroffiran (ITLF). The process is typically carried out at room temperature and with optional sonication.

Conditions for the reaction between an alcohol of formula (22) and an aryl halide (24), or other suitable activated aryl system such as an awl triflate, are a palladium catalyst, such as palladium acetate, a suitable palladium ligand, and a base such as caesium carbonate in a solvent such as toluene, dioxane or tetrahydrofuran. The process is generally carried out at elevated temperatures, typically 80-110°C, under an inert atmosphere such as nitrogen or argon An effective palladium ligand is 5-[di(1-adamantyl)phosphino]-1',3',5'-tripheny1-17141,41bipyrazole (Ad-BGPhos).

The alcohol functionality of compounds of general formula (22) may also be activated by conversion into a group X4. in compounds of general formula (26), X4 is for example bromide, tosylate, mesylate etc. Conditions for the conversion of (22) into (26) are generally known to those skilled in the art. For example, to prepare a compound of formula (26) wherein X4 is bromide, tetrabromomethane and triphenylphosphine in dichloromethane are effective conditions. For conversion of alcohol (22) into the corresponding mesylate (26, X4 is OSO2CH3), methanesulfonyl chloride and triethylamine in a solvent such as dichloromethane can be used. For both transformations temperatures of -10 to 20°C are typical.

Replacement of group X4 in compounds of general formula (26) with a nucleophile such as an amine (27) may provide compounds of type (28) and an alternative method for the formation of ether compounds of general formula (25) would be the reaction between (26) and a phenol (23) in the presence of a base such as potassium carbonate.

Compounds (28) in which Ra or Rb, or IV and Rb, is H may be further reacted to form an amide (29). Conditions for the reaction include a carboxylic acid (R°C.02H) and an amide coupling agent in the presence of a base such as N,N-diisoproylethylamine (DIPEA) in a solvent such as N,N-dimethylformamide (DIVLF), or an acid chloride (RTOCI) in the presence of a base such as tri ethyl amine or pyridine in a solvent such as dichloromethane, Scheme 3 /Rh QIN\ 1:1) 1 OH

HN

N-S-Ar-c Rh "

S II NI RI 0 \ ,

(42) IR oo2 Q\o vN-S-Ar °O (40) QI\ lei OH N-S-ArL( °O Rg (41)

RP-OH

I mCPBA Ql 0 N-S-Ar S \ 00 Wee-4N (39) W 0 -0 1 ef)'e 01\

NH

II

0I-S-Ar-X1 5 (30) \ (Fi) Rd Qi 01\ 0I Rd N-S-Ari-X5 HN (32) Re N-S-Ar-N Re °O °O (33) = Rf (34) (35) Rf \Hydrogenation 01, 9 \ II 0 \Rf (36) Re = (CH2)"0H activation as e.g. bromide Nu' Nui Re = (CH2)"OH activation as e.g. bromide °I\ (I3 N-S-Ar \Nui °O (37) 1 Hydrogenation Q1 0 \ H, N-R-Ar-\ OC12 (38) \Nu" According to Scheme 3, compounds of general formula (31) may be prepared from compounds of formula (4) in which R1 is as defined for general formula (I), Q1 is either a protecting group or a group R11 as defined for general formula (1), and Q2 is C1 to C4 alkyl or benzyl, and a sulfonyl chloride (30) in which X5 is a halogen, particularly chloride, or trifl ate (OSO2CF3) The reaction may be conducted in a polar organic solvent, typically a chlorinated solvent such as dichloromethane, and in the presence of a mild base, for example pyridine. Typically the reaction is conducted at a temperature of about 15 to 30°C, usually at room 10 temperature.

Alternatively, in cases where it is necessary to use less mild conditions, a stronger base, for example sodium hydride may be used. Tetrahydrofuran is a suitable solvent in such cases.

The group X in compounds of formula (31) may be substituted by an amine (32) of formula RdleINH in the presence of a base, such as diisopropylethylamine (D1PEA) in a solvent such as acetonitrile The reaction is generally carried out under microwave irradiation at 90 to 110°C.

Compounds of type (35) may also be prepared from compounds of general formula (31) by reaction with a terminal acetylene (34). The reaction requires a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), copper(I)iodide and a base such as triethylamine in an organic solvent The reaction is generally carried out in tetrahydrofuran at elevated temperatures of 60 to 70°C under an inert atmosphere, for example nitrogen or argon.

Group Rf may be further modified in compounds of type (35). For example, where Rr contains an alcohol functionality, it may be converted into an aryl ether (37) as described for Scheme 2. Alternatively, alcohols of type (35) may be converted into the corresponding halide, mesylate or tosylate, and subsequently treated with a nucleophile Nu' such as an amine, alcohol, phenol, thiol, imidazole, pyridine etc. in the presence of a suitable base if required to give compounds of general formula (37) The acetylene triple bond in compounds of general formulae (35) and (37) may be reduced to give compounds (36) and (38), respectively. This may be generally undertaken using hydrogen gas and a palladium catalyst supported on carbon, typically palladium hydroxide.

Compounds of general formula (36) may be treated similarly to compounds (35) to form compounds (38) According to Scheme 3, a compound of general formula (41) may be prepared from an epoxide (40) by reaction with a phenol or alcohol Rg0H under suitable reaction conditions which may include the use of a base such as sodium hydride in a dry organic solvent such as tetrahydrofuran. Similarly, epoxide (39) may be reacted with an amine RbR1N1H to provide amino alcohols of formula (42).

An epoxide of general formula (40) may be prepared from compounds (39) by treatment with an oxidising agent such as meta-chloroperbenzoic acid (mCPBA) in a solvent such as dichloromethane. Compounds (39) may be prepared from compounds of general formula (31) by reaction with vinylboronic acid or a boronate ester thereof The reaction between (31) and vinylboronic pinacol ester requires a palladium catalyst, such as [1,1'-bi s(di phenyl phosphi n o)ferrocen eidi chl oropalladi um (I I) complex with di chl orom eth an e (Pd(dpp0C12.012C12), and a base, for example caesium carbonate. The reaction may be carried out in a mixture of an organic solvent, such as dioxane, and water at elevated temperatures of 80-110°C under an inert atmosphere such as nitrogen or argon.

Groups Ra, Rb, R°, Rd, Re, Rf, Rg, R, Ar2 and Ar' in Schemes 2, 3 and 4 may be further modified using standard chemistries known to those skilled in the art at any suitable point in the syntheses of the compounds of the invention, including the removal of protecting groups, and protecting groups Q1 and Q2 removed according to Scheme 1 and the conversion of compounds of general formula (4) into (16a) and (16b) using either acid or base conditions.

As already discussed, the compounds described herein are inhibitors of metallo-13-lactamase (MBL) enzymes and are therefore useful in removing or reducing resistance of Gram-negative bacteria to antibiotics.

Therefore, in a further aspect of the invention there is provided a compound as described herein for use in medicine, particularly in the removal or reduction of antibiotic resistance in Gram-negative bacteria.

In addition there is provided the use of the compounds described herein in the preparation of a medicament for removing or reducing resistance of Gram-negative bacteria to antibiotics.

There is also provided a method for reducing or removing resistance of Gram-negative bacteria to antibiotics, the method comprising administering to a patient in need of such treatment an effective amount of a compound as described herein.

The Gram-negative bacteria of which antibiotic resistance can be removed using the compounds of general formula (I) are bacteria which produce metallo-13-lactamases, which may be metallo-p-lactamases of subclasses Bl, B2 or B3, for example IMP-type (including IMP-D, VIM-type (including VIM-1 and VIM-2) and NDM-type (including NDM-1) enzymes.

Typical examples of such bacteria include Enterobacteriaceae (such as Klebsiella pneumonia and Escherichia colt), Pseudomonadaceae (such as Pseudomonas aeruginosa 25 and Burkholderia cepacia) and Acinelobacier bammuuni..

In another aspect of the invention there is provided a product comprising a compound as described herein in combination with an antibiotic agent.

In a further aspect of the invention, there is provided a product comprising a compound as described herein in combination with an antibiotic agent for the treatment of a bacterial infection, particularly a bacterial infection which is resistant to treatment with the antibiotic when used alone.

In using the product, the compound of general formula (I) may be administered simultaneously with the antibiotic or the two agents may be administered separately, either immediately after one another or at different times The antibiotic agent may be a f3-lactam antibiotic, for example an antibiotic selected from carbapenems, penicillins, cephalosporins and penems.

Examples of carbapenem antibiotics include Imipenem, Meropenem, Ertapenem, Doripenem, Biapenem and Tebipenem.

Examples of penicillins include Amoxicillin, Ampicillin, Ticarcillin, Piperacillin and Cloxacillin Examples of cephalosporins include Cefazolin, Ceftriaxone, Ceftazidine and Ceftobiprole.

Examples of penems include Faropenem.

In a further aspect of the invention there is provided the use of a compound as described herein in the preparation of a medicament for the treatment of a bacterial infection, preferably in combination with an antibiotic agent, particularly a bacterial infection which is resistant to treatment with the antibiotic when used alone.

The invention also provides a method for the treatment of a bacterial infection, the method comprising administering to a patient in need of such treatment an effective amount of a compound as described herein, preferably in combination with an antibiotic agent. The bacterial infection is typically a bacterial infection which is resistant to treatment with the antibiotic when used alone.

Suitable antibiotics are as set out above.

The compound as described herein will generally be formulated for administration by a desired route.

In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable excipient or carrier.

In some embodiments, the composition may also comprise an antibiotic agent, especially an antibiotic agent as discussed above The excipient and/or the carrier, or, if more than one be present, each of the excipients and carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

The formulations include those suitable for oral, rectal, nasal, topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.

The route of administration will depend upon the condition to be treated but preferred compositions are formulated for oral, parenteral or topical administration, especially oral or parenteral administration and more especially parenteral administration, especially intravenous administration.

The composition may be prepared by bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound as described herein in conjunction or association with a pharmaceutically acceptable carrier or vehicle.

Formulations for oral administration in the present invention may be presented as. discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc For compositions for oral administration (e.g. tablets and capsules), the term acceptable carrier" includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, di calcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

For topical application to the skin, compounds of general formula (I) may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia Parenteral formulations will generally be sterile.

In a further aspect of the invention there is provided a process for the preparation of a pharmaceutical or veterinary composition, the process comprising admixing a compound as described herein, a pharmaceutically acceptable excipient or carrier and optionally an antibiotic agent.

Typically, the dose of the compound will be about 0.01 to 100 mg/kg, so as to maintain the concentration of drug in the plasma at a concentration effective to inhibit MBL enzymes.

The precise amount of the compound as described herein which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

Since the compounds as described herein are inhibitors of MBL enzymes, they can also be used in a method for the detection of bacteria which express MBL enzymes, i.e. which are wholly or partially resistant to 13 lactam antibiotics.

Therefore in a further aspect of the invention there is provided a method of determining whether bacteria express MBL enzymes, the method comprising contacting a test sample suspected of containing an MBL enzyme with a compound of general formula (I); detecting MBL enzyme activity in the test sample.

MBL enzyme activity may be detected by adding to the test sample a detection solution comprising a detector compound containing a p lactam ring, for example a 0 lactam antibiotic, including any of the compounds discussed above. If the test sample comprises bacteria which express an MBL enzyme, this enzyme will hydrolyse the 13 lactam ring of the detector compound.

The hydrolysis can be detected in a number of ways including spectrophotometric methods. One simple way of detecting the hydrolysis reaction is to include in the detection solution a pH indicator which changes colour according to the acidity of its environment. Since the hydrolysis of the f3 lactam ring leads to the production of a carboxylic acid, the pH of the detection solution will change on contact with bacteria which produce IVII3L enzymes and this can be visualised using a pH indicator.

As just described, suitable detector compounds include antibiotics, for example any of the compounds mentioned above as being suitable for use in combination with the compounds of general formula (I).

The test sample may comprise bacteria suspected of expressing an MBL enzyme, for example a liquid sample comprising a suspension of such bacteria The bacteria may express any MBL enzyme, for example an enzyme of subclass B 1, B2 or B3. However, in many cases the enzyme expressed is of subclass Bl, for example an IMP-type, VIM-type or NDM-type enzyme.

Suitably, a compound of general formula (I) is added to the test sample, typically at a concentration of between 10 nM and 10 RIVI.

Typically a control sample is also provided which is identical to the test sample; no compound as described herein is added to the control sample The presence and amount of MBL enzyme in the sample can be determined by adding the detector compound to the test sample and to the control sample and detecting any difference in the degree of hydrolysis seen in the test and control samples For example, when a pH indicator is used as a means of detecting hydrolysis, the presence of MEL enzyme can be determined by a difference in the colour of the test and control samples.

In a further aspect of the invention, there is provided a kit for carrying out the method of determining whether bacteria express MEL enzymes, the kit comprising: i. a compound of general formula (1) as defined above; a detector compound containing a 13 lactam ring; and means for detecting hydrolysis of the 13 lactam ring of the detector compound.

Suitably these agents will be provided in suitable containers. The compound as described herein may be any of the compounds described above; and the detector compound and the means for detecting hydrolysis are suitably the agents described above for the method of determining whether bacteria express MBL enzymes.

The invention will now be described in greater detail with reference to the following examples.

Examples

Preparative HPLC conditions Preparative HPLC was carried out using either a XSELECT CSH Prep C18 OBD [(30x150mm), 5pm)] column eluting with water/acetonitrile (+0.1% formic acid) at 60mL/min or a XSELECT CSH Prep C18 OBD [(19x250mm), 51,1m)] column eluting with water/acetonitrile (+0.1% formic acid) at 18mL/min or a XSELECT CSH Prep C6 Phenyl OBD [(19x250mm), Sum] column eluting with water/acetonitrile (+0.1% formic acid) at 18mL/min or a Kinetex Biphenyl 100A -AXIA [(21.2x]00mm), 5pm)]. Detection was achieved using either an Agilent 6120 series Single Quadrupole Mass Spectrometer or a UV, diode array (190-450nm).

Analytical LC-MS conditions: Method 1 Column: Acquity BEH C18, (2.1 x 100mm), 1.7um; Flow 0 4mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0.0/5, 0.4/5, 6.0/ 95, 6.8/95, 7.0/5, 8.0/5 Method 2 Instrument: HP] 100 (binary pump/PDA detector) + Platform LC Mass Spectrometer Column: Phenomenex Luna C18(2), (4.6 x 30mm), 3pm; Flow 2.0mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0.0/5, 0.5/5, 4.5/95, 5.5/95, 6.0/5 Method 3 Instrument: Waters (1525 binary pump/PDA detector) + Waters ZMD Mass Spectrometer Column: Phenomenex Luna C18(2), (4.6 x 30mm), 3pm; Flow 2 OmL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0.0/5, 0.5/5, 4.5/95, 5.5/95, 6.0/5 Method 4 Instrument: HP1050 (quaternary pump/PDA detector) + Platform II Mass Spectrometer Column: Phenomenex Luna C18(2), (4.6 x 30mm), 3pm; Flow 2.0mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0.0/5, 0.3/5, 4.3/95, 5.3/95, 5.8/5, 6.0/5 Method 5 Instrument: IIP1100 (quaternary pump/PDA detector) + ZQ Mass Spectrometer Column: Phenomenex Luna C18(2), (4.6 x 30mm), 3pm, Flow 2.0mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0.0/5, 0.3/5, 4.3/95, 5.3/95, 5.8/5, 6.0/5 Method 6 Column: Aquity UPLC BEH C18, (2.1 x 50), 1.7p.m; Flow 0 6mL/min Mobile Phase A: 0.05% formic acid (aq), B: 0.05% formic acid in acetonitrile Gradient: T/%B 0/3, 0.3/3, 3.5/98, 4.8/98, 5/3, 5.01/3 Method 7 Column: XBridge C18 (4.6 x 50mm), 2.5[1m; Flow 1.0mL/min Mobile Phase A: 5nM ammonium acetate (aq), B: acetonitrile Gradient: T/%B 0/5, 0.5/5, 1/15, 3.3/98, 5.2/98, 5.5/5, 6.0/5 Method 8 Column: Aquity UPLC BEH C18, (2.1 x 50), 1.7p.m; Flow 0 6mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0/3, 0.2/3, 2.8/98, 3.8/98, 4/3 Method 9 Column: Aquity UPLC BEH C18, (2.1 x 50), 1.7pm; Flow 0 8mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0/3, 0.2/3, 2.2/98, 3.5/98, 3.6/3, 3.8/3 Method 10 Column: Aquity UPLC BEH C18, (2.1 x 50), 1.7pm; Flow 1.3mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0/5, 0.5/5, 1/15, 3.3/98 5.2/98, 5.5/5, 6.0/5 Method 11 Column: Aquity UPLC BEH C18, (2.1 x 50), 1.7p.m; Flow 0 6mL/min Mobile Phase A: 0.1% formic acid (aq), B: 0.1% formic acid in acetonitrile Gradient: T/%B 0/3, 0.2/3, 2.5/98, 3.8/98, 4.2/3, 4.5/3 1H NIVIR spectra 11-1 NMR spectra were obtained at 300 or 400 MHz in deuterated CDC13 or DMSO-d6 solutions (reported in ppm), using chloroform as the reference standard (7.25ppm). When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), hr (broadened), dd (doublet of doublets), dt (doublet of triplets), ohs (obscured). Coupling constants, when given, are reported in hertz (Hz).

Abbreviations The following abbreviations were used: DMIF: dimethyl formamide DMSO: dimethyl sulfoxide IMS: industrial methylated spirits Pd2dba3: tris(dibenzylidene-acetone)dipalladium(0) Pd(dppf)C12.DCM: [1,1'-Bis(diphenylphosphino)ferrocene]d chloro palladium(II); complex with dichloromethane Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0) Pd(OAc)2: palladium (II) acetate DMAP: 4-dimethylaminopyridine HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-N-pyridinium-3-oxide hexafluorophosphate TEA: triethylamine DIPEA: N,N-Diisopropylethylamine TFA: trifluoroacetic acid Xantphos: 4,5-Bi s(diphenylphosphino)-9,9-dimethylxanthene DIAD: diisopropyl azodicarboxylate Ad-BGPhos: -[di(1-adamantyl)phosphino]-1',3 ',5'-tripheny1-1 E-[1,4']bipyrazole Cs2CO3: cesium carbonate Pd(OH)2: palladium hydroxide PS-PH3: Triphenylphosphine, polymer-bound (Copolymer of styrene and divinylbenzene) BOP reagent: (benzotri azol-1-y1 o xy)tri s(di m ethyl amin o)ph osph oni um hexafluorophosphate Rt: retention time min: minutes.

All sulfonyl chlorides whose synthesis is not described herein were commercially available or were prepared by literature methods.

Example 1:

OH

Intermediate IF (116mg, 0.174mmol) was treated with 95% TFA(aq) (2 5mL) at room temperature and the mixture stirred for 2 hours. The solvent was removed in vacua and the residue azeotroped with toluene then methanol to dryness. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 1 (23.5mg) as an off-white solid 11-1 NMR (DMSO-d6) 6: 8.45 (1H, s), 7.75 (2H, d), 7.51 (211, d), 6.90 (2H, d), 6.84 6.80 (21-1, m), 4.21 (21-1, t), 3.50 (4H, t), 3.09 (214, t), 2.69 (4H, t).

LCIVIS (Method 1) Rt 3.56 min; m/z (M+H)+ 490.

Intermediate 1F Intermediate 1E (100mg, 0.198mmol), 2-(morpholin-4-yl)phenol (36mg, 0.198mmol) and triphenylphosphine (62mg, 0.238mmol) were dissolved in dry tetrahydrofuran (2mL). To this, DIAD (0.047mL, 0.238mmo1) was added at room temperature and the mixture was stirred for 48 hours. The mixture was concentrated in vacua to dryness. The residue was extracted with ethyl acetate, washed with brine, dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-80% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in mew) to give Intermediate 1F (116mg).

LCMS (Method 2) Rt 4.20 min; m/z(M+H)-666 Intermediate lE

HO

Intermediate 1D (4.21g, 7.69mmol) was dissolved in methanol (150mL). To this, a solution of potassium carbonate (4.25g, 30.76mmol) in water (75mL) was added at room temperature and the mixture was stirred for 2 hours. The mixture was concentrated in %unto to half volume and diluted with water. The solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane, washed with brine, dried with Na2SO4, filtered and concentrated in vacno to give Intermediate 1E (3.69g) as an orange solid.

LCMS (Method 2) Rt 3.51 min; m/z(M+H)-505 Intermediate 1D 5-(4-NIethoxy-benzylamino)-thiazole-4-carboxylic acid tert-butyl (Intermediate 2) (3.23g, 10.07mmol) was dissolved in dry tetrahydrofuran (100mL). To this, sodium hydride (60% disp. in oil; 604mg, 15.1mmol) was added at room temperature and the mixture was stirred for 30 minutes. To this, a solution of Intermediate 1C (2.91g, 11.08mmol) in dry tetrahydrofuran (50mL) was added and the mixture stirred at room temperature for 2 hours.

The mixture was concentrated in mem) to a quarter volume and partitioned between ethyl acetate and 10% citric acid solution. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in rani° to dryness. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in WIC710 to give Intermediate 1D (107mg) as an orange glass LCMS (Method 2) Rt 3.97 min; m/z(M+H) 547 Intermediate 1C 0 S=0 \CI Intermediate 1B (3.49g, 12.19mmol) was dissolved in acetonitrile (120mL), acetic acid (4.5mL) and water (3mL). To this, 1,3-dichloro-5,5-dimethylhydantoin (4.8g, 24.38mmol) was added in portions at 0°C and the mixture stirred at 0°C for 2 hours. The mixture was concentrated in wow to near dryness and dissolved in dichloromethane. The organic layer was washed with ice cold saturated NaHCO3 solution, brine, dried with Na2SO4, filtered and concentrated in mut° to dryness. The residue was purified by chromatography on silica eluting with 0-25% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in;wow to give Intermediate 1C (2.91g) as a clear oil.

1H NIVIR (CDC13) 6: 8.01 -7.97 (2H, m), 7.50 7.45 (2H, m), 4.34 (2H, t), 3.07 (2H, t), 2.04 (3EL s).

Intermediate 1B A mixture of Intermediate IA (2.95g, 12.13mmol), benzyl mercaptan (I.42mL, 12.13mmol), Pd2dba3 (277mg, 0.303mmol), xantphos (351mg, 0.607mmol), DIPEA (4.23mL, 24.26mmol) and dry dioxane (15mL) was heated at 100°C under nitrogen for 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with water, brine, dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 050% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 1B (3.49g) as a red oil.

1H NN4R (CDC13) 6: 7.28 -7.26 (71-1, m), 7.12 -7.08 (21-1, m), 4.24 (2H, t), 4.09 (21-1, s), 2.88 (21-1, t), 2.02 (3H, s).

Intermediate IA 4-Bromophenethyl alcohol (2.75g, 13.68mmol), TEA (2.86mL, 20.52mmol) and DMAP (167mg, 1.37mmol) were dissolved in dichloromethane (75mL) To this, a solution of acetic anhydride ( I.55mL, I 6.42mm ol) in dichloromethane (25mL) was added drop wise at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacua to dryness and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water, brine, dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-35% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate IA (3.05g) as a clear oil.

1H NN4R (CDC13) 6: 7.44 -7.40 (2H, m), 7.11 -7.07 (21-1, m), 4.25 (21-1, t), 2.89 (2H, t), 2.03 (3H, s) Intermediate 2 A suspension of potassium tert-butoxide (874mg, 7.79mmol) in dry tetrahydrofuran (10mL) was stirred vigorously at room temperature. To this, a solution of tert-butyl isocyanoacetate (1.0g, 7.08mmol) in dry tetrahydrofuran (5mL) was added drop wise and the mixture stirred at room temperature for 10 minutes. To this, a solution of 4-methoxybenzyl isothiocyanate (1.27g, 7.08mmol) in dry tetrahydrofuran (5mL) was added drop wise at room temperature. After 2 hours the solution was poured into saturated NaHCO1 solution and extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to dryness. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvent removed by evaporation in vacua to give Intermediate 2 (852mg) as a pale yellow solid.

111 NMR (CDCI3) 6: 7.81 (1H, m), 7.73 (1H, br s), 7.31-7.23 (2H, m), 6.92-6.85 (2H, m), 4.35 (2H, d), 3.80 (3H, s), 1.61 (9H, s) LCMS (Method 2) Rt 3.70 min; m/z(M+H)-321

Examples 2 to 22

The following compounds were prepared using a similar method to that for Example I. 0 n o=s

NH

HO

Example

Structure LCMS Method Rt (min) Mass [M-FH] 2.34 406 3 0 1 2.85 474 0 *

N

4 --'-'-'o 1 4.02 490 0 0 N,.,, H 1 2.95 489 le 0 0 N","-- 6 o 1 146 472 HN 1

I o 0 is

7 0, NH2 1 2.87 448 8 o 1 2.77 448 0 H --, 9 NH 1 142 474 0 1110 o ------''''''-, N 1 3.08 458 o I,--

I

0 N, -5-

N

11 N 1 2.41 445 o 0 -,,,c,---1-

N

12 o 1 2.93 482 N. 13 NH 1 3.00 460 111/ 1110 0 14 III 0 N 1 3.18 409 / - 1 2.79 471 0 o 1110 N' 16 1110 0 II, N-c"S 1 3.58 472 1 N N=171 17 1101, 1110 0 1 3.61 473 \ 18 ° 1 2.70 477 111° III° ..".....",..H, N ° H 19 N-"---- 1 2.71 470 0 o.

\ 1 3.69 459

NH

21 CI 1 4.58 439 0, 22 1111 ° III it> 1 2.87 485

Example 23:

Intermediate 23F (200mg, 0.3mmol) was dissolved in acetonitrile (3.0mL) To this, iodomethane (426mg, 3.0mmol) was added at room temperature and the mixture stirred at room temperature for 3 days. The mixture was concentrated in vacua to dryness and the residue triturated with diethyl ether. The residue was treated with 95% TFA(aq) (6 OmL) at room temperature and the mixture stirred for 2 hours. The solvent was removed in vacua and the residue azeotroped with toluene. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 23 (1 lmg) as an off-white solid.

1H NMR (DMSO-d5) 6 13.55 (1H, s), 9.59 (1H, s), 8.17 -8.15 (1H, m), 7.98 (1H, s), 7.87 - 7.85 (1H, m), 7.68-7.66 (1H, m), 7.61 -7,55 (3H, m), 7.44 -7.35 (2H, m), 7.11 -7.07 (21-1, m), 4.24 (2H, t), 3.89 (31-1, s), 3.07 (21-1,0; LCMS (Method 1) Rt 2.84 min; m/z (M+H)+ 485 Intermediate 23F Intermediate 23E (250mg, 0.5mmol), 4-(imidazol-1-yl)phenol (96mg, 0.6mmol) and triphenylphosphine (160mg, 0.6mmol) were dissolved in dry tetrahydrofuran (10mL) To this, DIAD (120mg, 0.6mmol) was added at room temperature and the mixture was stirred for 3 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 23F (200mg).

1H NN4R (CDC13) 6: 8.49 (1H, s), 7.77 (2H, s), 7.69 -7.62 (21-I, m), 7.58 -7.49 (1H, m), 7.50 -7.40 (1H, m), 7.33 -7.22 (1 1-1, m), 7.10-6.93 (61-1, m), 6.76-6.72 (2H, m), 4.86 (2H, s), 4.19 (211, 0, 3.74 (3H, s), 3.15 (211, 0, 1.50 (9H, s); Intermediate 23E Intermediate 23D (2.60g, 4.76mmol) was dissolved in methanol (80mL) To this, a solution of potassium carbonate (2.62g, 19.0mmol) in water (40mL) was added at room temperature and the mixture was stirred for 90 minutes. The mixture was concentrated in vacuo to half volume and diluted with water. The mixture was extracted with ethyl acetate, dried with NIgSat, filtered and concentrated in Pacno to give Intermediate 23E (2.12g).

111 NMR (CDC13) 6: 8.56 (111, s), 7.65 -7.54(2H, m), 7.48-7.36 (2H, m), 7.12 -7.08 (2H, m), 6.79 -6.74 (2H, m), 4.89 (2H, s), 3.86 (2H, q), 3.76 (31I, s), 2.91 (2H, t), 1.90 (1H, t), 1.48 (9H, s) Intermediate 23D o- 5-(4-NIethoxy-benzylamino)-thiazole-4-carboxylic acid tert-butyl ester (Intermediate 2) (1.94g, 6.1mmol) and 15-crown-5 (134mg, 0.61mmol) were dissolved in dry tetrahydrofuran (40mL) To this, sodium hydride (60% disp, in oil; 370mg, 9.15mmol) was added at room temperature and the mixture was stirred for 10 minutes. To this, Intermediate 23C (1.60g, 6.1mmol) was added and the mixture stirred at room temperature for t hour. The mixture was partitioned between ethyl acetate and 10% citric acid solution. The organic layer was dried with MgSO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-60% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in ractio to give Intermediate 23D (2.61g) as a pale yellow solid.

1H NIVIR (CD03) 8: 8.56 (11-I, s), 7.63 -7.59 (21-1, m), 7.46-7.41 (2H, m), 7.11 -7.07 (2H, m), 6.78 -6.74 (2H, m), 4.87 (2H, s), 4.26 (2H, t), 3.76 (3H, s), 2.97 (211, t), 2.03 (3H, s), 1.52 (9H, s) Intermediate 23C Intermediate 23B (2.6g, 9.0mmol) was dissolved in acetonitrile (90mL) and acetic acid (3.5mL) To this, 1,3-dichloro-5,5-dimethylhydantoin (3.52g, 18.0mmol) was added in portions at 0°C and the mixture stirred at room temperature for 5 hours. The mixture was concentrated in vactio to near dryness and dissolved in dichloromethane. The organic layer was washed with ice cold saturated NaHCO3 solution, brine, dried with MgSO4, filtered and concentrated in vactro to dryness. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 23C (1.66g) as a yellow oil.

1H NMR (CDC13) 6: 8.01 -7.97 (2H, m), 7.50 7.45 (2H, m), 4.34 (2H, t), 3.07 (2H, t), 2.04 (3H, s). (349757) Intermediate 23B A mixture of Intermediate 23A (2.20g, 9.0mmol), benzyl mercaptan (1.12g, 9.0mmol), Pd2dba3 (206mg, 0.23mmol), xantphos (260mg, 0.45mmol), DIPEA (2.32g, 18.0mmol) and dry dioxane (15mL) was heated at 100°C under nitrogen for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 23B (2.63g) as a yellow oil.

111 NMR (CDC13) 6: 7.31 -7.09 (8H, m), 7.08 -6.98 (1H, m), 4.22 (211, t), 4.11 (2H, s), 2.87 (2H, t), 2.02 (31-1, s).

Intermediate 23A 3-Bromophenethyl alcohol (2.0g, 10.0mmol), TEA (1.51g, 15.0mmol) and DIMAP (122mg, 1.0mmol) were dissolved in dichloromethane (50mL) To this, a solution of acetic anhydride (1.22g, 12.0mmol) in dichloromethane (20mL) was added drop wise at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacua to dryness and the residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 23A (2.24g) as a clear oil.

111 NMR (CDC13) 6: 7.41 -7.32 (211, m), 7.22 -7.11 (2H, m), 4.27(2H, t), 2.91(211, t), 2.04 (311, s).

Example 24

The following Example was prepared using a similar method to that for Example 23 *^*, ,R 0=S

NH

HO

Example 25:

S 0--\NH

OH

Intermediate 25A (122mg, 0.193mmo1) was treated with 95% TFA(aq) (2mL) at room temperature and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue azeotroped with toluene to dryness. The residue was triturated with ethyl acetate and the solid collected by filtration. The solid was purified by reverse phase HPLC. The fractions containing the desired product were filtered to collect precipitated solid and dried under vacuum to give Example 25 (24.7mg) as a cream solid.

1H NMR (DM SO-d() 6: 9.49 (1H, s), 8.50 (1H, d), 8.24 (1H, s), 8.05 (1H, d), 7.80(H, d), 7.73 -7.67 (3H, m), 7.53 (2H, d), 7.42 (1H, d), 4.43 (2H, t), 3.21 (2H, t).

Example

Structure LCMS Method Rt (min) Mass [M+H] 1 2.84 471 oc, LCMS (Method 1) Rt 2.82 min; m/z (M+H)+ 456.

Intermediate 25A A mixture of Intermediate IE (150mg, 0.297mmo1), 5-bromoisoquinoline (77mg, 0.372mmol), Pd(OAc)2 (8mg, 0.036mmol), Ad-BGPhos (48mg, 0.072mmol), Cs2CO3 (145mg, 0.446mmo1) and toluene (2mL) was heated at 90°C under argon for 18 hours. After cooling to room temperature, the mixture was diluted with dichloromethane and methanol (1: 1) and the solid removed by filtration. The filtrate was eluted from a SCX-2 cartridge with 2N NH3 in methanol and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 25A (134mg) as a clear gum.

LCMS (Method 5) Rt 3.19 min; m/z (M+H)± 632

Examples 26 to 43

The following compounds were prepared using a similar method to that for Example 25.

0 n o=s

NH

HO

Example Structure LCMS Rt Mass Method (min) [M+II] 26 2,79 456 27 N0 1 3.16 472 1 W * o * 28 0 o * 1 2.89 485

-

N--N=7.1 29 0 o 0,- 1 2.89 485

N /N-S

*o * 1 2.85 471

-N

N-S H

31 * o * 1 2A5 514 N=17,/N--\--NH2 32 * o 1 2.87 456 33 o 1 2.80 470 0 II, ''* N 34 * 0, 1 3.65 459 / NN / * OS --.. 1 109 482

---

36 * o * --, 1 2.73 456

N

37 0 o * N 1 2.79 456

N

38 0 1 2.83 456 II illir 39 * o 0 N 6 2.03 456 o * o III( 6 2.65 486 N --=--\ 41 * ",...rN 8 1.56 462 NH2

I

42 11 1.89 457 1,".....)N I 1 N 43 N 1 2.98 469 IP 1110

Example 44:

OH

Intermediate 44C (100mg, 0.154mmol) was treated with 95% TFA(aq) (10mL) at room temperature and the mixture stirred for 3 hours. The solvent was removed in WICTIO and the residue azeotroped with toluene to dryness. The solid was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 44 (23.5mg) as a white solid.

1H NIVIR (DMSO-d6) 6: 9.58(111, s), 8.55 (111, d), 8.32 -8.22 (211, m), 7.87 -7.64 (611, m), 7.47 (1H, d), 5.17 -5.11 (1E1, m), 4.34 -4.21 (2FI, m) LCMS (Method 1) Rt 2.39 min; m/z (M+H)± 472.

Intermediate 44C 5-hydroxyisoquinoline (50mg, 0.34mmol) was dissolved in dry DIVIT (0.5mL). To this, sodium hydride (60% disp. in oil; 13.6mg, 0.34mmol) was added at room temperature and the mixture was stirred for 30 minutes. To this, a solution of Intermediate 44B (140mg, 0.28mmol) in DIVIF (0 5mL) was added at room temperature and the mixture was stirred at 90°C for 18 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with Na7SO4, filtered and concentrated in VaC110 to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in %unto to give Intermediate 44C (70mg).

LCMS (Method 5) Rt 2.82 min; m/z(M+H) 648 Intermediate 44B Intermediate 44A (365mg, 0.75mmol) was dissolved in dichloromethane (10mL). To this, 3-chloroperbenzoic acid (448mg, 2.0mmol) was added at room temperature and the mixture was stirred for 42 hours. The mixture was washed with saturated NaHCO3 solution, dried with Na2SO4, filtered and concentrated in mato to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 44B (206mg) as a clear oil.

LCMS (Method 3) Rt 3.81 mm; m/z(M+H) 525 Intermediate 44A A mixture of 5-[(4-Bromo-benzenesulfony1)-(4-methoxy-benzy1) -aminokthiazole-4-carboxylic acid tert-butyl ester (Intermediate 17) (539mg, 1.0mmol), vinylboronic acid pinacol ester (0.203mL, 1.2mmol), Pd(dppf)C12.DCM (40mg, 0.05mmol), Cs2CO3 (409mg, 1.5mmol), dioxan (2mL) and water (0.2mL) was heated at 90°C under argon for 3 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in mow to dryness. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 44A (365mg) as a white solid.

LCMS (Method 3) Rt 4.11 min; nth (M+H)+ 509 (+Na) Intermediate 17 o-Intermediate 2 (2.0g, 6.24mmol) was dissolved in dry tetrahydrofuran (60mL). To this, sodium hydride (60% disp. in oil; 325mg, 8.1 Immo° was added at room temperature and the mixture was stirred for 30 minutes. To this, 4-bromobenzenesulfonyl chloride (2.4g, 9.36mm ol) was added and the mixture stirred at room temperature for 20 hours. Water was added, and the reaction mixture extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated hi vacua to dryness. The residue was purified by chromatography on silica eluting with 10-25% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvent removed by evaporation in vacua to give Intermediate 17 (2.02g).

LCMS (Method 2) Rt 3.95 mm; m/z(M+H) 492

Example 45

OH

Intermediate 45A (106mg, 0.145mmol) was treated with 95% TFA(aq) (1 5mL) at room temperature and the mixture stirred for 2 hours. The solvent was removed in vacua and the residue azeotroped with toluene to dryness. The residue was triturated with diethyl ether and the resulting solid dried under vacuum. The solid was purified by reverse phase HPLC.

The fractions containing the desired product were combined and lyophilised to give Example 45 (33mg) as a pale yellow solid.

1H NMR (DM SO-d6) 6: 8.77 -8.77 (1H, m), 8.40 (1H, s), 8.27 -8.15 (2H, m), 7.93 -7.89 (2H, m), 7.77-7.72 (1H, m), 7.59-7.47(2H, m), 7.12 (1H, s), 3.75-3.66 (2H, m), 3.46 - 3.39 (2H, m).

LCMS (Method 1) Rt 3.76 min; m/z (M+H)+ 556.

Intermediate 45A A mixture of 5-[(6-Chloro-pyridine-3-sulfony1)-(4-methoxy-benzyl) -aminokthiazole-4-carboxylic acid tert-butyl ester (Intermediate 20) (100mg, 0.202mmol), 442-aminoethylthio)-2-(trifluoromethyl)quinolone (275mg, 1.01mmol) and acetonitrile (1 5mL) was heated by microwave irradiation for 60 minutes at 100°C. To this, 4-(2-aminoethylthio)-2-(trifluoromethyl)quinolone (137mg, 0.504mmol) was added and the mixture was heated by microwave irradiation for 60 minutes at 100°C. To this, DLPEA (0.176mL, 1.0 lmmol) was added and the mixture was heated by microwave irradiation for 60 minutes at 110°C then for 60 minutes at 120°C. The volatiles were removed in vacno and the residue purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacIto to give Intermediate 45A (106mg) as a pale yellow glass.

LCMS (Method 4) Rt 4.20 min; m/z(M+H) 732.

Intermediate 20 Intermediate 2 (1.2g, 3.73mmol) and 15-crown-5 (0 ImL) were dissolved in dry tetrahydrofuran (50mL). To this, sodium hydride (60% di sp. in oil; 224mg, 5.6mmol) was added at room temperature and the mixture was stirred for 30 minutes. To this, 2-chloropyridine-5-sulfonyl chloride (950mg, 4.48mmol) was added and the mixture stirred at room temperature for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to dryness. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 20 (1.1g) as an orange solid.

LCMS (Method 2) Rt 4.00 min; m/z(M+H) 496

Example 46

The following compound was prepared using a similar method to that described for Example 45.

HO

Example Structure LCMS Rt Mass Method (min) [M+H]+

---

46 --... N".*-^,,,," 0 N.z.,,,, 1 2.91 422

N

H --""

Example 47

HO

Intermediate 47C (590mg, 0.823mmol) was treated with 95% TFA(aq) (10mL) at room temperature and the mixture stirred for 1 hour. The solvent was removed in yam° and the residue azeotroped with toluene to dryness. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 47 (22mg) as a white solid.

1H NIVIR (DMSO-d6) 6: 8.01 (1H, s), 7.64 -7.61 (2H, m), 6.94 -6.91 (2H, m), 5.12(111, dd), 4.57 (111, dd), 3.49(111, d), 3.35 (2H, dd), 2.90 (3H, s), 2.84 (411, s), 1.95 (111, dd).

LCMS (Method 1) Rt 2.13 min; m/z (M+H)+441.

Intermediate 47C Sodium hydride (60% disp. in oil; 36.4mg, 0.91mmol) was added to thy DMF (5mL) at room temperature and stirred for 10 minutes under argon. To this, Intermediate 47A (235mg, 0.91mmol) was added at room temperature and the mixture stirred for 10 minutes. To this, a solution of Intermediate 47B (363mg, 0.759mmo1) in dry DMF (1mL) was added over 2 minutes at room temperature; the mixture was stirred for 18 hours. The mixture was quenched with water (20mL) and acetic acid (0 lmL) and extracted with dichloromethane. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacito to give Intermediate 47C (590mg) as a yellow gum. LCMS (Method 3) Rt 3.75 min; m/z(M+H)-717.

Intermediate 47B 5-(4-Methoxy-benzylamino)-thiazole-4-carboxylic acid tert-butyl ester (1.0g, 3.12mmol) was dissolved in dry tetrahydrofuran (10mL). To this, sodium hydride (60% disp. in oil; 187mg, 4.68mmol) was added at room temperature and the mixture was stirred for 30 minutes. To this, a solution of 4-fluorobenzenesulfonyl chloride (729mg, 3.75mmol) in dry tetrahydrofuran (5mL) was added and the mixture stirred at room temperature for 17 hours. The reaction mixture was diluted saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-33% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vanto to give Intermediate 47A (800mg) as a yellow glass.

LCMS (Method 4) Rt 3.93 min; m/z(M+H) 479.

Intermediate 47A o

HO N,

N-Boc-cis-4-hydroxy-D-proline (1.57g, 6.79mmol) was suspended in dichloromethane (30mL), To this, DIPEA (1.33g, 10.3mmol), DMAP (846mg, 6.92mmol) and dimethylamine hydrochloride (841mg, 10.3mmol) were added sequentially and the mixture stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane. The organic layer was washed with 0.3M KI-121304 solution, saturated NaHCO3 solution and brine. The organic layer was dried with MgSO4, filtered and concentrated in mow to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/dichloromethane then 5-10% methanol/dichloromethane. The fractions containing the desired product were combined and the solvents removed by evaporation in vont° to give Intermediate 47A (1.19g) as a white solid.

LCMS (Method 4) Rt 2.13 min; m/z(M+H) 259

Example 48:

OH

Intermediate 48C (40mg, 0.068mmol) was treated with 95% TFA(aq) (10mL) at room temperature and the mixture stirred for 18 hours. The solvent was removed in maw and the residue azeotroped with toluene to dryness. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 48 (12mg) as a white solid.

1H NMR (DMSO-d6) 6: 9.47 -9.43 (111, m), 8.51 (111, s), 8.24 (111, s), 8.08 (1H, d), 7.78 (1H, d), 7.71 -7.65 (3H, m), 7.41 -7.32 (3H, m), 4.19 (2H, 0.2.88 (2H, t), 2.21 -2.12(2H, 20 m).

LCMS (Method 1) Rt 3.00 min; m/z (M-Elif 470.

Intermediate 48C Intermediate 48B (330mg, 0.563mmo1) was dissolved in IMS (3mL) To this, Pd(OH)2 (20 °O on carbon, 33mg) was added and the mixture stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and concentrated in vacua to dryness to give Intermediate 48C.

LCMS (Method 5) Rt 3.27 mm; m/z(M+H)-590 Intermediate 48B A mixture of Intermediate 48A (108mg, 0.21mmol), 5-bromoisoquinoline (52mg, 0.25mmol), Pd(OAc), (4mg, 0.02mmol), Ad-BGPhos (12mg, 0.04mmol), Cs2CO3 (103mg, 0.3 lmmol) and toluene (1mL) was heated at 80°C under argon for 6 hours. After cooling to room temperature, the mixture was filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 48B (75mg) as a white solid.

LCMS (Method 5) Rt 3.40 min; m/z (M+H)+ 642.

Intermediate 48A o-A mixture of 5-[(4-Bromo-benzenesulfony1)-(4-methoxy-benzy1) -aminokthiazole-4-carboxylic acid tert-butyl ester (Intermediate 17) (539mg, 1.0mmol), propargyl alcohol (0.233mL, 4.0mmol), Pd(PPh3)4 (115mg, 0.1mmol), copper (I) iodide (6mg, 0.03mmol), 5 TEA (0.277mL, 2 Ommol) and dry tetrahydrofuran (5mL) was heated at reflux under argon for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate/cyclohexane. The fractions containing the desired 10 product were combined and the solvents removed by evaporation in vacua to give Intermediate 48A (370mg) as a white solid.

LCMS (Method 5) Rt 3.49 min; m/z (M+H)11 515.

Example 49 to 53

The following compounds were prepared using a similar method to that described for

Example 48

HO

Example Structure LCMS Method Rt (min) Mass [M+11]11 49 40 0 N 1 2.98 --,..,,, 46S6 ---, 40 -....." 0 40 ---\ 1 2.95 481 N \ LiN 51 0 0 401 ---\ N \ 1 3.02 481 - i Li 52 00 o 01 N"---LiN 1 2.96 485 53 le 0 0 L.iN 1 3.02 485

Example 54:

OH

Intermediate 54B (113mg, 0.174mmol) was treated with 95% TFA(aq) (2mL) at room temperature and the mixture stirred for 2 hours. The solvent was removed in vacua and the residue azeotroped with toluene to dryness. The residue was triturated with diethyl ether and the resulting solid dried under vacuum. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 54 (39mg) as a white solid.

1H NMR (DM SO-d6+ TFA-d) 6: 8.62 (H, s), 8.14 (1 H, dd), 8.06 -8.00 (IH, m), 7.84 (2H, d), 7.51 (21-1, d), 7.41 OH, d), 7.02 (IH, dd), 4.29 (2H, br s), 3.98 -3.03 (10H, m); LCMS (Method 1) Rt 2.04 min; m/z (M+H)+ 474 Intermediate 54B

N N

A mixture of Intermediate 54A (113mg, 0.172mmol), 1-(2-pyridyl)piperazine (140mg, 0.858mmol) and acetonitrile (1 3mL) was heated by microwave irradiation for 40 minutes at 100°C. The volatiles were removed in vacuo and the residue purified by chromatography on silica eluting with 0-5% methanol/dichloromethane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacno to give Intermediate 54B (113mg) as a colourless oil.

LCMS (Method 4) Rt 2.51 min; m/z(M+H)-650 Intermediate 54A Intermediate 1E (300mg, 0 595mmol) and p-toluenesulfonyl chloride (362mg, 1 90mmol) were dissolved in dichloromethane (4mL) To this, TEA (0.099mL, 0.713mmol) was added at room temperature and the mixture stirred for 21 hours. To this, TEA (0 099mL, 0.713mmol) and DMAP (7.3mmg, 0.059mmol) were added at room temperature and the mixture stirred for 20 hours. To this, TEA (0.099mL, 0.713mmol) and DMAP (7.3mmg, 0.059mmol) were added at room temperature and the mixture stirred for 20 hours. The mixture was diluted with dichloromethane, washed with water and filtered through a phase separator cartridge. The solvent was removed in mew) and the residue purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 54A (224mg) as a colourless oil.

LCMS (Method 4) Rt 4.22 min; m/z(M+H) 659

Examples 55 to 57

The following compounds were prepared using a similar method to that described for Compound 54

HO

Example Structure LCMS Method Rt (min) Mass [M+I-I]+ III N 101 1 3.05 472 56 1401 1 2.86 474 o -%"N 57 1 2,03 447

Example 58:

OH

Intermediate 58C (111mg, 0.149mmol) was treated with 95% TFA(aq) (3mL) at room temperature and the mixture stirred for 4 hours. The mixture was concentrated by positive flow of N2 and dried under vacuum. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 58 (15.3mg) as a white solid.

1H NMR (DMSO-d6) 6: 8.02 (1H, d), 7.63 -7.56 (2H, m), 7.30-7.21 (2H, m), 3.53 -3.42 (2H, m), 3.19-3.06 (2H, m), 2.87-2.66(7H, m), 2.12 (1H, d), 1.84 (1H, d), 1.76-1.64 (1H, m), 1.58 (21-1, t), L24 -1.07 OH, m), LOS -0.92 (1H, m). LCIVIS (Method 1) Rt 2.32 min; m/z (M+H)+ 467.

Intermediate 58C o-A mixture of Intermediate 57B (75mg, 0.145mmol), 1-Boc-4-piperidylacetic acid (53mg, 0.218mmol), HATTJ (83mg, 0.218mmol), Siliabond morpholine (1.29mmol/g; 170mg, 0.218mmol) and dry acetonitrile (5mL) was stirred at room temperature for 3 days. The mixture was diluted with dichloromethane (5mL) and filtered through a Siliaprep SPE cartridge Carbonate (2g). The filtrate was concentrated by a positive flow of -1\T2 to dryness to give Intermediate 57C (111mg).

LCMS (Method 2) Rt 4.14 min; m/z (M+H)+ 743 Intermediate 58B Intermediate 58A (2.24g, 3.84mmoi) was dissolved in methylamine solution (2M in tetrahydrofuran; 45mL) and stirred at room temperature in a sealed vial for 3 days. The mixture was concentrated in vacua to dryness and the residue purified by chromatography on silica eluting with 0-10% 2M NH3 in methanol/ethyl acetate. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 58B (1.66g) as a yellow solid. LCMS (Method 2) Rt 2.49 min; miz (M+H)+ 518 Intermediate 58A -0 S-it 8=0 Intermediate lE (3.0g, 5.94mmol) and TEA (1.25mL, 8.91mmol) were dissolved in dichloromethane (125mL). To this, a solution of methanesulfonyl chloride (0 55mL, 7.13mmol) in dichloromethane (25mL) was added drop wise at 0°C then stirred at room temperature for 3 days. The mixture was washed with IN hydrochloric acid solution, dried with Na2SO4, filtered and concentrated in vactio to dryness. The residue was purified by chromatography on silica eluting with 0-40% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 58A (2.24g) as a solid.

LCIVIS (Method 2) Rt 3.80 min; m/z (M+H)+ 583

Examples 59 to 76

The following compounds were prepared using a similar method to that described for Compound 58

HO

Example Structure LCMS Method Rt (min) Mass [M+I-I]+ li ci

N

59 I 1 2.20 476 ----"-----

I

--..;,..,....",N 401 Nj.'-'---° 1 2.30 453 1 NH 61 1.11 0 ------- 1 238 467 j-,,,,,"-----,,,,,.,NH

N

I

62 0N 0 NH2 1 2.66 489

I

63 0 o 1 2.32 467

I NH2

64 lei o 1 2.47 481 " I NH2 0 N 0 NH2 1 1.98 479

I

NH N==-1 66 ".,---",.."-NH 2 1 2.57 475 N, I = 67 41111 0 N:.,> 1 2.90 447

I I

68 0 o 1 2.42 512 i 5 N-1N 69 0 o 1 2.44 497 N 0:4 I' 0 co 1 2.61 532 "--,,,,,,,,,,.....*,,,N,,,.., : I 1 71 40 0 1 2.63 497 i 10 72 40 0 1 2A5 497 N *-N 73 Ili 0 1 2A4 497 iN 74 40 0 1 3.03 513 i 410 rrik 1 N N"-----zi ill 0 1 2A6 447 N---'N-I----I 76 401 N 0 0----1 1 3.15 477 "-N 1 --","2.----

Example 77:

OH

Intermediate 77E (55mg, 0.127mmol) was dissolved in tetrahydrofuran (3m L) and water (1mL). To this, lithium hydroxide monohydrate (53.5mg, 1.27mmol) was added at room temperature and stirred for 48 hours. The mixture was concentrated in vacuo, diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid solution. The product was collected by filtration, washed with diethyl ether and dried under vacuum to give Example 77 (27mg) as a white solid.

1H NMR (DIVISO-d6) 6: 8.37 (1H, br s), 7.74 (2H, d), 7.49 (2H, d), 725 (2H, t), 6.91 (3H, d), 4.19(211, t), 3.08(211, t) LCIVIS (Method 6) Rt 2.66 min; m/z(M+H) 405 Intermediate 77E Intermediate 77D (350mg, 0.805mmol) was dissolved in acetonitrile (5.25mL) To this, potassium carbonate (278mg, 2.01mmol) and phenol (91mg, 0.966mmo1) were added at room temperature and the mixture stirred at 70°C for 16 hours under N). After cooling to room temperature the mixture was filtered and the inorganic salts washed with acetonitrile. The filtrate was concentrated in vactio to dryness and the residue purified by chromatography on silica eluting with 0-10% methanol/dichloromethane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacno to give Intermediate 77E (110mg) as a brown oil.

LCMS (Method 6) Rt 3.10 mm; m/z (M+H)± 433 Intermediate 77D // S=0

NH

// S=0 /0 NH -*0 Intermediate 77C (1 4g, 3.92mmol) and TEA (990mg, 9.81mmol) were dissolved in dichloromethane (14mL) To this, methanesulfonyl chloride (540mg, 4.71mmol) was added drop wise at 0°C and the mixture stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and washed with saturated citric acid solution.

The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 030% ethyl acetate/petroleum ether. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 77D (1.4g) as a brown oil.

LCMS (Method 9) Rt 1.89 min; m/z (M+1-1)+ 435 Intermediate 77C a-7 Intermediate 77B (800mg, 2.01mmol) was dissolved in methanol (20mL) To this, a solution of potassium carbonate (1.08g, 7.83mmol) in water (10mL) was added at room temperature and the mixture was stirred for 3 hours. The mixture was concentrated in vacua, dissolved in water and washed with 10% methanol in dichloromethane. The aqueous layer was acidified with IN hydrochloric acid solution and extracted with 10% methanol in dichloromethane. The organic layer was dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 60% ethyl acetate/petroleum ether. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 77C (500mg) as an brown solid.

LCMS (Method 10) Rt 1.74 min; m/z(M+H) 357.

Intermediate 77B Sodium hydride (929mg, 23.23mmol) was suspended in dry tetrahydrofuran (20m1). To this, a solution of ethyl 5-aminothiazole-4-carboxylate (2.0g, 11.61mmol) in dry

HO

0 S=0 NH /1 S=0

NH

tetrahydrofuran (20mL) was added drop wise at 0°C under argon and the mixture stirred at 0°C for 15 minutes. To this, a solution of Intermediate 76A (3.65g, 13.94mmol) in dry tetrahydrofuran (10mL) was added drop wise at 0°C and the mixture stirred at room temperature for 5 hours. The mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered and concentrated in WIC/10 to dryness. The residue was purified by chromatography on silica eluting with 40% ethyl acetate/petroleum ether. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 77B (1.1g) as a brown oil.

LCMS (Method 9) Rt 1.99 min; m/z(M+H)+ 397 Intermediate 77A 3=0

CI

A solution of phenethyl acetate (50g, 304.48mmol) in dichloromethane (600mL) was added drop wise to chlorosulfonic acid (355g, 3045mmol) at 0°C and the mixture stirred at room temperature for 3 hours. The mixture was poured into ice/water and extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered and concentrated in vacua to dryness. The residue was purified by chromatography on silica eluting with 60% dichloromethane/petroleum ether. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 77A (45.0g) as a yellow oil.

1H NIVIR (CDC13) 6: 8.00 (2H, d), 7.50 (2H, d), 4.35 (2H, t), 3.08 (2H, t), 2.05 (3H, s).

Example 78 to 81

The following compounds were prepared using a similar method to that described for

Example 77.

HO

Example Structure LCMS Method Rt (min) Mass [M+1-If 78 -,.."5,---- 6 1.90 406 79 1 6 179 406 -,,,..,----N "'- 6 223 457

IS

81 NI ---'''N 7 2A8 457 SI 0 or

Example 82:

N 0H

A mixture of Intermediate 82A (175mg, 0.3 Immo°, 2-phenylimidazole (222mg, 1.5mmol), potassium carbonate (43mg, 0.3 lmmol) and acetonitrile (6.0mL) was heated by microwave irradiation for 60 minutes at 130°C. The mixture was concentrated in vacuo to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was dried with MgSO4, filtered and the solvents removed by evaporation in vacua to dryness. The residue was treated with 95% TFA(aq) (5m1) at room temperature and the mixture stirred for 3 hours. The solvent was removed in vacua and the residue azeotroped with toluene to dryness. The residue was dissolved in ethyl acetate and triturated with diethyl ether; the solid was collected by filtration and dried under vacuum. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 82 (5.3mg) as a white solid.

I H NMR (DM SO-d6) 6: 8.02 (1 H, s), 7.61 (1H, s), 7.52-7.36 (6H, m), 7.29(21-I, d), 7.00 (2H, d), 4.29 (211, t), 2.98 (211, t).

LCMS (Method 1) Rt 2.55 min; m/z (M+H)± 455.

Intermediate 82A Intermediate 1E (1.0g, 2.0mmol) was dissolved in dichloromethane (15mL) To this, tetrabromomethane (720mg, 2.2mmol) was added and the mixture cooled to 0°C. To this, triphenylphosphine (620mg, 2.4mmol) was added in portions at 0°C and the mixture stirred at room temperature for 90 minutes. The mixture was concentrated in vacua and the residue purified by chromatography on silica eluting with 0-50% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacua to give Intermediate 82A (795mg).

IH NMR (CDC13) 6: 8.55 (1H, s), 7.73 -7.69 (211, m), 7.33 (211, d), 7.10 -7.06 (2H, m), 6.78 -6.74 (211, m), 4.88 (2H, s), 3.76(311, s), 3.58 (211, t), 3.23 (2H, t).

Example 83

The following compound was prepared using a similar method to that described for Compound 82.

HO

Example Structure LCIMS Method Rt (min) Mass [A/1+N+ 83 el 1 2.82 455

Example 84: \NH

OH

Intermediate 84A (100mg, 0.211mmol) was dissolved in tetrahydrofuran (2mL) and water (1mL). To this, lithium hydroxide monohydrate (88mg, 2.11mmol) was added at room temperature and stirred for 48 hours. The mixture was concentrated in vacno, diluted with water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid solution. The solid was collected by filtration, washed with diethyl ether and dried under vacuum. The residue was purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilised to give Example 84 (27mg) as a white solid.

1H NMR (DMSO-d5) 6: 8.11 -7.98 (2H, m), 7.77 -7.61 (2H, m), 7.58-7.36 (m, 5H), 4.85 -4.70 (21-1, m), 3.35 -3.10 (21-1, m) LCMS (Method 8) Rt 2.08 min; m/z(M+H) 446 Intermediate MA Intermediate 84C (79 I mg, 2.22mmol) was dissolved in dry tetrahydrofuran (2 mL). To this, BOP reagent (982mg, 2.22mmol) and Cs2C01 (1.4g, 4.44mmol) were added at room temperature and the mixture was stirred at 60°C for 4 hours under N). To this, a solution of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (150mg, 1.11mmol) was added drop wise at 60°C and the mixture stirred for 16 hours. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered and concentrated in mew) to dryness. The residue was purified by chromatography on silica eluting with 60% ethyl acetate/petroleum ether. The fractions containing the desired product were combined and the solvents removed by evaporation in VaC110 to give Intermediate 84A (105mg) as a pale yellow solid. LCMS (Method 8) Rt 2.39 mm; m/z(M+H) 474 Example 85: In vitro MBL inhibition assay The MBL enzyme VIM-1 is produced and purified as disclosed in Franceschini N, et al, Antimicroh Agents & Chemotherapy. (2000), 44(11), 3003-7.

The MBL enzyme IMP-1 is produced and purified as disclosed in Laraki et al, Antimicrobial Agents' S.-Chemotherapy, (1999), 43(4), 902-906.

The MBL enzyme NDM-1 is produced and purified as disclosed in Yong eta!, Antimicrobial Agents & Chemotherapy, (2009) 53(12), 5046-54 Reaction buffers were prepared in a UV-transparent 96-well microplate. The buffer contains 10 mM HEPES pH 7.5, 50 ttM ZnSO4. Enzymes were prepared in enzymatic buffer which contains 10 mNI HEPES pH 7.5, 50 p.NI ZnSO4, 20 p.g/mL BSA. An fixed amount of protein (75 ng) was added to each well. The compounds of Table B (from Ito 50 MM) were added to the reaction buffers so as to test their MBL inhibition activity.

As a positive control of IVIBL inhibition, EDTA (25mM) was also added in one well. As a negative control of MEL inhibition, one well without any added compound was used. Each test was performed in duplicate.

All compounds of the invention were found to have a Ki <50 uM, many having a Ki of <1 RAT and some of them having a Ki of < 0.3 uM, against all three enzymes. The compounds of the invention all had Ki values against IMP-1 that are much lower than that of pyridine-2-carboxylic acid, which was found to have a Ki value of 300 jtM. All compounds of the invention also show a high biological activity against NDM-1 and VIM- 1. These results clearly show that the compounds of the invention have a better activity against MBL enzymes than pyridine-2-carboxylic acid.

Example 86: Antibiotic activity of /3-lactam antibiotics on RIBL expressing bacteria in the presence of the compounds of the invention The operation is carried out using the so-called 'broth micro-dilution method' according to the protocols M07-A8 established by the Clinical Laboratory Standards institute (CLSI). Serial dilutions of the [3-lactam antibiotic (Meropenem) are prepared in 96-well plates in cation-adjusted Mueller-Hinton broth (CAMHB); the concentration range is defined from 0.03 mg/L to 512 mg/L.

The compounds of Table B are added at a constant concentration of 100 ttNI. The clinical strains used in these potentiation experiments are NTBCO20 (E. coli strain expressing NDM-1, TEM-1 and CTX-M-15; NTBCO23 (K. pneumoniae strain expressing VIM-1 and SHV-5) and NTBC062 (K. pneumoniae strain expressing VIM-1 and SHV-5). A bacterial inoculum of each strain is adjusted to a 0.5 McFarland turbidity standard in physiologic serum (0.9 % NaC1), then diluted 1:100 in CAMHB and added to each well to give a final bacterial cell number of 5x105 CFU/well. After incubation for 18-20 hours in a heating chamber at 37°C, the growth inhibition is evaluated by the absence of any bacterial development and minimal inhibitory concentrations (MIC) are taken as the lowest concentration of antibiotic at which the test organism did not show visible growth; results are confirmed by measuring the optical density (OD) at 600 nm in a spectrophotometer. The MIC of Meropenem is obtained at a concentration of 100 [NI of the test inhibitor. The MIC values of Meropenem (absence of inhibitor) against the NTBCO20, NTBCO23 and NTBC062 strains are 128, 64 and 16 jtg/mL respectively.

The Ki values in jiM and the MIC' s in jig/mL of Meropenem against the corresponding clinical strain (shown in brackets after the Ki values) are set out in Table B, according to the following scheme where Ki values of < 0.1 uM are designated A; Ki values of 0.1 to 0.6 uM are designated B and Ki values of > 0.6 RIM are designated C; similarly MIC values of < 1 jig/mL are designated (A); MIC values of 1 -2 jig/mL are designated (B); MIC values of >2 ug/mL are designated (C).

Table B

Name Example NDM-1 VIM-2 IMP-1 ANT951 25 B (C) A (B) B (B) ANT 1041 49 B (C) A (C) B (B) ANT1074 33 A (C) B (C) N/A* (A) ANT1073 32 B (C) A (C) N/A* (C) ANT1031 15 B (B) A (B) B (B) ANT1127 24 A (A) A (A) N/A* (A) ANT1198 50 A (A) A (A) N/A* (A) *N/A = not available It can be seen that several inhibitors at 100 jiM reduce the MIC values of Meropenem against the three representative clinical strains from 128, 64 and 16 ug/mL to < 1 ug/mL.

Example 87: kit for detecting bacteria expressing a MBL enzyme A kit according to the invention comprises: a bacterial lysis buffer, for example Tri s-HC1 20 mmol/L lysis buffer, a carbapenemase activity detection solution, for example a solution made of 3 mg of imipenem monohydrate, pH 7.8, phenol red solution, and 0.1 mmol/L ZnSO4. The phenol red solution has been prepared by mixing 2 mL of a phenol red solution 0.5')//0 (wt/vol) with 16.6 mL of distilled water. The pH value has then been adjusted to 7.8 by adding drops of 1 N NaOH, a compound of the invention, or a plurality of compounds of the invention, and instructions of use.

The instructions of use are as follows.

One calibrated amount of the tested bacterial strain is resuspended in the bacterial lysis buffer, vortexed for 1 minute and further incubated at room temperature for 30 minutes.

This bacterial suspension is centrifuged at 10,000 x g at room temperature for 5 minutes. 30 gL of the supernatant, corresponding to the cell-free enzymatic suspension, are mixed in 96-well trays with 100 gL of the carbapenemase activity detection solution. In some of the wells the compound of the invention is added at a fixed concentration, preferably between 10 nIM and 10 uM. The trays are incubated at 37°C for a maximum of 2 hours. The colour of the solution in each well is assessed visually or using a spectrophotometer at the appropriate wavelength.

The detection technique is based on the variation of the pH of the solution due to hydrolysis of the P-lactam ring of imipenem by MBL enzymes. The color of the detection solution turns from red to orange or yellow for tested strains that produce MBL enzymes. When a compound of the invention is added to the reaction solution, change of color or absence of change indicates the presence or absence of MBL enzymes.

Claims (3)

1. CLAIMS1. A compound which is a thiazole sulfonamide of general formula (1), or a salt or prodrug thereof: R11OH(Formula I) wherein: R' is hydrogen, halogen, CN or R'2; wherein _1(-12 is C1 to C6 alkyl optionally substituted with one or more substituent 118; or 3-to 6-membered cycloalkyl or 3-to 6-membered heterocyclyl, either of which is optionally substituted with one or more substituent R; each le is independently halogen, CN, OH or Ci to C4 alkoxy optionally substituted by one or more substituent selected from halogen and OH; each Fe is independently halogen, CN, OH, oxo or Ci to C4 alkyl or C, to C4 alkoxy optionally substituted by one or more substituent selected from halogen and OH; lc is hydrogen or Ci to C4 alkyl optionally substituted by one or more substituent selected from halogen and OH; each R8 and R9 are independently H or Ci to C4 alkyl optionally substituted by one or more substituent selected from halogen and OH, or where R8 and R9 are joined to the same nitrogen atom, may together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclyl or heteroaryl ring, which ring is optionally substituted by one or more sub stituents selected from halogen, OH, and -NH2; Y1 is a bond or a Ci to C3 alkylene group, Al is a Co to Cia aryl, a 5-to 10-membered heteroaryl or 3-to 10-membered carbocyclyl or heterocyclyl moiety, wherein Al is unsubstituted or substituted with one or more substituent selected from RI', halogen, OH, CN, C(0)NR8R8b, NR8C(0)R8b, -NR8R81' , and from CI to C4 alkoxy and Ci to C4 alkyl groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen, OH and Rb; Rb is selected from -NR8R9, -NR8C(R9)=NR9, -C(=NR8)-NR8R9, and -NR8C(=NR9)NR8R9, and from 5-or 6-membered heterocyclyl and heteroaryl groups which are unsubstituted or substituted with one or more substituents selected from halogen, OH, and -NH2 and from Ci to C4 alkyl, CI to C4 alkoxy, (CI to C4 alkyl)amino and di(Ci to C4 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more substituents selected from halogen, OH and -NR8R9, R8b is selected from H and Ci to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OR8 and Rb, or where R8b and R8 are joined to the same nitrogen atom, may together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclyl or heteroaryl ring, which ring is optionally substituted by one or more substituents selected from halogen, OH, and -NH4; Y2 is a group of formula -(Hetl)p-(Alkl)q-or -(Het2),-(A1k2)-(Het3)-(A1k3),-, wherein p, q, r and s are independently 0 or 1; Alkl, A1k2 and A1k3 independently represent CI to Co alkylene, C2 to C6 alkenylene, or C2 to Co alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from RP, halogen, OR8b and -NR8R81' and, when two substituents are present on the same carbon atom in the alkylene, alkenylene or alkynylene moiety, from two alkyl groups which join together with the C atom to which they are attached to form a C3 to C6 cycloalkyl ring, and Hell, Het2 and Het3 independently represent -0-, -S-, -SO2-, -NR8b-, -C(0)NR8b-, -NR81'C(0)-or -C(N-OR8)-; A2 represents a cyclic group selected from C6 to Cm aryl, 5-to 10-membered heteroaryl and 3-to 10-membered carbocyclyl or heterocyclyl; wherein one atom in the cyclic group may be replaced by a moiety R.-24 wherein R34 is selected from C=0, C=NR8, C=NOR8 and 1\1+-0-; wherein A2 is substituted by n groups R2; n is 0, I, 3 or 4; each R2 independently represents: (i) a group R2a which is selected from -Fe, -Ore, -SR', NO2, -C(0)0128, -C(0)NR8R8b, -NR8C(0)R8b, -NR8C(0)R8b, -NR8Rd, -NR8C(R9)=NR9, -C(=NR8)-NR8R9 and -NR8C(=NR9)NR8R9 and from Ci to C4 alkyl, Ci to C4 alkoxy and -S(Ci to C4 alkyl) groups which are (a) substituted with one or more substituents selected from Rb and from CI to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups, or (ii) a group R2b which is selected from halogen, CN, OH and -NReRf and from Ci to C4 alkyl and Ci to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen and OH, wherein le and Rf are each independently H or Ci to C4 alkyl, Rd is a C, to C4 alkyl group which is substituted by one or more substituent selected from halogen, OR% and Rb; each group 122 is independently selected from phenyl and 5-to 10-membered heterocyclyl or heteroaryl groups, wherein RI' is unsubstituted or substituted with one or more substituents selected from halogen, OH, NO2, CN, -C(0)0R8, -C(0)NR8R9, -NR8C(0)R9 and -NH2 and from Ci to C4 alkyl, Ci to C4 alkoxy, (C1 to C4 alkyl)amino and di(CI to C4 alkyl)amino groups wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more substituents selected from halogen, OR8, -COOR8 and -N128129; wherein when Y2 is a group of formula -(Hetl)p-(Alk1)(1-, then n is 1, 2, 3 or 4 and at least one group R2 represents R2a.
2. 2. A compound according to claim 1, wherein Y2 is a group of formula -(Het2),-(A11(2)-(Het3)-(Alk3),-.
3. 3. A compound according to any one of the preceding claims, wherein Rl and are hydrogen A compound according to any one of the preceding claims, wherein Y' is a bond.5. A compound according to any one of the preceding claims, wherein Al is an unsubstituted group selected from phenyl and 5-to 6-membered heteroaryl and heterocyclyl moieties.6. A compound according to any one of the preceding claims, wherein Rb is -NR8R9, -NR8C(R9)=NR9, -C(=NR8)-NR8R9 or -NR8C(=NR9)NR8R9, or a 5-or 6-membered heterocyclyl or heteroaryl group which is unsubstituted or substituted with one or more substituents selected from -NH2 and -N(Ci to C. alkyl), and from CI to C. alkyl, CI to C. alkoxy and (CI to C2 alkyeamino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH2; wherein each R8 and le is the same or different and selected from H and unsubstituted C, to C2 alkyl.7. A compound according to any one of the preceding claims, wherein Y2 is a group of formula -(A1k2)-(Het3)-, -(Het2)-(A1k2)-(Het3)-or -(A1k2)-(Het3)-(A1k3)-.8. A compound according to claim 7, wherein A1k2 and A1k3 are each independently CI to C4 alkylene, C2 to C4 alkenylene, or C2 to C4 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from OR8 and -NR8R9, and Het2 and Het3 independently represent -0-, -S-, -SO2-, -NR8-, -C(0)NR8-or -NR8C(0)-, wherein R8 and R9 are each independently hydrogen or CI to C2 alkyl 9. A compound according to claim 8, wherein Y2 is -(A1k2)-(Het3)-, wherein A1k2 is unsubstituted C1 to C4 alkylene and Het3 is -0-or -NH- 10. A compound according to any one of the preceding claims, wherein n is 0, 1 or 2 11 A compound according to any one of the preceding claims, wherein n is 1 and ring 12. A compound according to any one of the preceding claims, wherein R2a is selected from -Fe, -OR', -C(0)NR8R8b, -NR8C(0)e, -NR8C(0)R8b and -NR8Rd and from C, to C4 alkyl and C, to C4 alkoxy groups which are (a) substituted with one or more substituents selected from Rb and from C1 to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups; wherein R81' is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, and R8 and R9 are independently selected from hydrogen and unsubstituted CI to C9 alkyl.13. A compound according to any one of the preceding claims, wherein Rd is a C1 to C4 alkyl group which is substituted by one or more NR8R9 groups, where R8 and R9 are independently selected from hydrogen and unsubstituted CI to C2 alkyl.14. A compound according to any one of the preceding claims, wherein 122 is selected from phenyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl, wherein 122 is unsubstituted or substituted by one or more substituents selected from halogen, OH, NO2, CN, and -NH, and C1 to C2 alkyl, C1 to C2 alkoxy, (C1 to C2 alkyl)amino and di(Ci to C2 alkyl)amino groups wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more substituents selected from halogen, Ole, -COOR8 and -NR8R9, wherein R8 and R9 are independently selected from hydrogen and unsubstituted Ci to C2 alkyl.15. A compound according to claim 1, wherein: R1 is hydrogen or unsubstituted C14 alkyl; R" K is hydrogen or unsubstituted C14 alkyl, 111 is a bond; A' is phenyl or a 5-to 6-membered heteroaryl or heterocyclyl moiety; wherein A' is unsubstituted or substituted with one or more substituents selected from Rb, halogen, OH, CN and -NR8R8b, and from C, to C4 alkoxy and CI to C4 alkyl groups which are themselves unsubstituted or substituted by one or more substituents selected from halogen, OH and NR8R9; R8b is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9, R8 and R9 each independently represent H, methyl or ethyl; R" is selected from -NR8R9, -NR8C(R9)=NR9, -C(=NR8)-NR8R9 and -NR8C(=NR9)NR8R9, and 5-or 6-membered heterocyclyl and heteroaryl groups which are unsubstituted or substituted with one or more substituents selected from -NI-I2 and -N(Ci to C, alky1)2 and from C, to C2 alkyl, C, to C2 alkoxy and (C, to C2 alkyl)amino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -N112; Y2 is (i) a group of formula -(Hetl)p-(Alkl)q-, wherein at least one of p and q is 1 and the other is 0 or 1, wherein HetIl is -0-, -NH-or -N(Ci to C4 alkyl), and Alkl is C1 to C4 alkylene, which is unsubstituted or substituted with one or more substituents selected from re, halogen, OR" and -NHR8b; or (ii) a group of formula -(Het2),-(A1k2)-(Het3)-(A11c3),-, wherein at least one of r and s is 0 and the other is 0 or 1; wherein A1k2 and A11c3 are each independently C1 to C6 alkylene, C2 to C6 alkenylene, or C2 to C6 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from le, halogen, OR8b and -NHIeb; and Het2 and Het3 independently represent -0-, -S-, -SO2-, -NR8b- -C(0)NRsb_ or A2 represents a cyclic group selected from phenyl, cyclohexyl, 5-to 10-membered heteroaryl and 5-to 10-membered heterocyclyl, wherein one atom in the cyclic group may be replaced by a moiety R34 wherein R34 is selected from C=0 and wherein A2 is substituted by n groups R2, wherein n is 0, 1 or 2; each R2 independently represents (i) a group R2' which is selected from -R3, -OW, -C(0)NR8R81', _NRsc(o)Rsb, -NR8C(0)R81' and -NR8Rd and from C1 to C4 alkyl and CI to C4 alkoxy groups which are (a) substituted with one or more substituents selected from Rb and from CI to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups, or (ii) a group R2b which is selected from halogen, CN, OH and -NRbRf groups and from CI to C4 alkyl and C1 to C4 alkoxy groups which are unsubstituted or substituted by one or more substituents selected from halogen and OH; wherein R° and Rf are hydrogen or methyl; Rd is a C, to C4 alkyl group which is substituted by one or more substituent selected from halogen, Ole and NR8R9; R3 is selected from phenyl, and from 5-to 10-membered heteroaryl and heterocyclyl groups; wherein R3 is unsubstituted or substituted by one or more substituents selected from halogen, OH, NO2, CN, and -NH, and from C1 to C2 alkyl, C1 to C2 alkoxy, (C1 to C.) alkyl)amino and di(Ci to C2 alkyl)amino groups wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with one or more substituents selected from halogen, OR8, -COOR8 and -NR8R9.16. A compound according to claim 1, wherein the compound is a thiazole sulfonamide of formula (IA) or a salt or prodrug thereof: ni_y2_A2 HN-S02OHFormula (TA) wherein: Y1 is a bond; A' is an unsubstituted moiety selected from phenyl and 5-to 6-membered heteromyl; Y2 is (i) a group of formula -(Hetl)p-(Alkl)q-, wherein at least one of p and q is 1 and the other is 0 or 1, wherein Heti is -0-or -NH-; and Alkl is unsubstituted CI to CI alkylene; or (ii) a group of formula -(Het2),-(A1k2)-(Het3)-(A11c3),-, wherein at least one of r and s is 0 and the other is 0 or 1, wherein A1k2 and A1k3 are each independently CI to C4 alkylene, C2 to C4 alkenylene or C;) to C4 alkynylene moieties which are unsubstituted or substituted with one or more substituents selected from OW and -NR8R9; and Het2 and Het3 independently represent -0-, -S-, -SO2-, -NR8-, -C(0)NR8-or -NR8C(0)-, R8 and R9 are each independently hydrogen or CI to C2 alkyl; A2 represents a cyclic group selected from phenyl, cyclohexyl, 5-to 10-membered heteromyl and 5-to 10-membered heterocyclyl, wherein one atom in the cyclic group may be replaced by a moiety le wherein le is selected from C=0 and wherein A2 is substituted by n groups R2, wherein n is 0, 1 or 2; each R2 independently represents (i) a group R2a which is selected from -R3, -0R3, -C(0)Na', -NR5C(0)R8b, -NR5C(0)R8b and -NRgRd and from C, to C4 alkyl and CI to C4 a1koxy groups which are (a) substituted with one or more substituents selected from BY and from CI to C4 alkoxy groups which are themselves unsubstituted or substituted by one or more substituents selected from -0R8 and -NR8R9, and (b) optionally further substituted with one or more halogen or OH groups, wherein R8b is selected from H and CI to C4 alkyl groups which are optionally substituted by one or more substituent selected from halogen, OH and NR8R9; or (ii) a group R2b which is selected from halogen, OH and -Nal groups and from C, to C4 alkyl and CI to C4 alkoxy groups which are unsubstituted or substituted by one or more substituents selected from halogen and OH; wherein R.° and Rf are hydrogen or methyl; Rd is a C1 to C4 alkyl group which is substituted by one or more NR8R9 groups, Rb is -NR8R9 or a 5-or 6-membered heterocyclyl or heteroaryl group which is unsubstituted or substituted with one or more substituents selected from -NH, and -N(Ci to C2 alky1)2 and from C1 to C2 alkyl, C1 to C2 alkoxy and (C1 to C, alkyDamino groups, wherein the alkyl moiety of the alkyl, alkoxy or alkylamino group is optionally further substituted with -NH,; and R3 is selected from phenyl, and from 5-to 10-membered heteroaryl and heterocyclyl groups; wherein 112 is unsubstituted or substituted by one or more substituents selected from NO2, -NR8R9 and C, to C, alkyl which is unsubstituted or substituted with one or two substituents selected from halogen, OH, -COOH and -NF12.17. A compound according to claim 16, wherein Y2 is (ii) a group of formula -(Het2),-(A1k2)-(Het3)-(Alk3),-.18. A compound according to claim 17, wherein Y2 is -(A1k2)-(Het3)-, wherein A1k2 is unsubstituted CI to C4 alkylene, preferably C2 or C1 alkylene, and Het3 is -0-or -NH-; 19. A compound according to claim 1, which is: 1 5-1[(4-{242-(morpholin-4-yl)phenoxy]ethyl 1-phenyl)sulfonyl]ami no 1--1,3-thiazole- 4-carboxylic acid 2 54( {4[2-(pyridin-4-yloxy)ethyl]phenyl sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.3 5-11(4-{212-(pyrrolidin-l-yOphenoxy]ethyl) phenyl)sulfonyl]amino) -1,3-thiazole- 4-carboxyl i c acid.4 5-{[(4-(2[3-(morpholin-4-yOphenoxy]ethyl}phenyl)sulfonyl]ami no -1,3-thiazole- 4-carboxylic acid.5-{ [(4-{243-(p perazin-l-yephenoxy]ethyl phenyl)sulfonyl]ami no 15--1,3-thiazole- 4-carboxyl i c acid.6 5-{ [(4-{2-[(2-oxo-1,2-dihydroquinolin-8-ypoxy]ethyllpheny1)su1fony1laminol-1, 3-thiazole-4-carboxylic acid 7 5-{ [(4-{ 213-(2-ami noethyl)phenoxy]ethyl lphenyl)sulfonyl]amino) -1,3-thiazole-4-carboxyl i c acid.8 5-( {[4-(2-(4-[(methylamino)methyllphenoxy ethyl)phenyl]sulfonyll amino)-1,3-thiazole-4-carboxylic acid.9 5-11(4-{2-[(1-oxo-1,2,3,4-tetrahydroi soquinol in-5-yl)oxy]ethyllphenyl)sulfonyl]aminol -1,3-thiazole-4-carboxylic acid.5-[({ 4-[2-(pyrido[3,4-d]pyri dazin-l-yloxy)ethyl]phenyl sulfonyDamino]-1,3-thiazole-4-carb oxylic acid.11 54( {442-(i m dazo[1,2-a]pyTi din-8-yloxy)ethyl]phenyl sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.12 5-{ [(4-{242-(pyridin-2-yl)phenoxy]ethyllphenyl)sulfonyl]amino}-1, 3-thiazole-4-carboxylic acid.13 5-[( 4-[2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)ethyl]phenyllsulfonyl)amino - 1,3-thiazole-4-carboxylic acid 14 5-{ [(4-{ 2-[(1-methy1-1H-pyrazol-5-ypoxy]ethyllphenyl)sulfonyl]amino -1,3 -thiazole-4-carboxyli c acid.5-{ [(4-1244-(1H-imidazol-1-yl)phenoxy]ethyl}phenyl)sulfonyllaminol-1, 3-thiazole-4-carboxyli c acid.16 5-1[(4-2-[4-(1H-1,2,4-triazol-1-yl)phenoxy]ethyl) phenyl)sulfonyl]amino) -1,3 -thiazole-4-carboxyli c acid.17 5-{ [(4-{ 242-(1,3,4-oxadiazo1-2-y1)phenoxy]ethyllphenyl)sulfonyl]amino -1,3 -thiazole-4-carb oxylic acid.18 5-1[(4-{244-(g1ycylamino)phenoxylethy1 phenyl)sulfonyl]amino -1,3-thiazole-4-carboxyli c acid.19 5-1[(4-{ 24(2-methy1 quinolin-8-y0oxy]ethyl} phenyOsulfonyl]ami no} -1,3-thiazole- 4-carboxyl i c acid.5-1[(4-(24(3-methyl -1H-indazol-4-ypoxylethylfphenyl)sulfonyl]aminol -1,3-thiazole-4-carb oxylic acid.21 54(1442-(2-chl orophenoxy)ethyl 'phenyl} sulfonyl)amino]-1,3-th azole-4-carboxyl i c acid.22 5-[(4-{2-[4-(1H-imidazol-1-ylmethyl)phenoxy]ethyl iphenyl)sulfonyllamino) -1,3-thiazole-4-carboxylic acid.23 5-{ [(3-{244-(3-methy1-1 Fl-imi dazol-3-ium-1-yl)phen oxy]ethyl lphenypsul fonyl]amino) i no) -1,3 -thi azole-4-carb oxyl ate.24 5-1[(3-{244-(1 H-imidazol-1-yl)phenoxy]ethyl}phenyl)sulfonyl]amino}-1, 3-thiazole-4-carboxylic acid.5[({442-(isoquinolin-5-yloxy)ethyl]pheny11 sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.26 54(1442-(quinolin-7-yloxy)ethyl]phenyl sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.27 5-1[(4-{2[(2-oxidoisoquinolin-5-yl)oxy]ethyl lphenyl)sulfonyl]aminol -1,3-thiazole-4-carboxyli c acid.28 5-[(4-{244-(1-methy1-1H-imidazol-4-yl)phenoxylethyl5phenyl)sulfonyl]amino) - 1,3-thiazole-4-carboxylic acid.29 5-[(4-{244-(1-methy1-1H-imidazol-5-yl)phenoxylethyl5phenyl)sulfonyl] amino1- 1,3-thiazole-4-carboxylic acid 5-1[(4-{ 244-0 H-imidazol-5-yl)phenoxy]ethyllphenyl)sulfonyl]aminol-1, 3-thiazole-4-carboxyli c acid.31 5-(1[4-(2-14-[1-(2-aminoethy1)-1H-imidazol-4-yl]phenoxylethyl)phenyl sul fonyl lami no)-1,3-thiazole-4-carboxylic acid.32 5[({442-(isoquinolin-4-yloxy)ethyl]pheny11 sulfonypamino]-1,3-thiazole-4-carboxylic acid.33 5-1[(4-{ 24(2-methyl quinolin-6-y0oxy]ethyllphenyl)sulfonyl]amino1-1,3-thiazole- 4-carb oxyli c acid.34 5-{ [(4-{2-[(2-methyl-2H-indazol-4-ypoxylethyl phenyl)sulfonyl]aminol -1,3-thiazole-4-carb oxylic acid.5-11(4-{214-(pyridin-3-yl)phenoxy]ethyl iphenyl)sulfonyl]aminol -1,3-thiazole-4-carboxyl i c acid.36 54({442-(isoquinolin-6-y1oxy)ethyl]pheny1 Isulfonyl)amino]-1,3-thiazole-4-carboxylic acid.37 54( {442-(i soquin olin-7-yloxy)ethyl]phenyl sul fonyl)am ino]-1,3-thi azole-4-carboxyl i c acid.38 5-[({342-(isoquinolin-5-yloxy)ethyl]phenyl -Isulfonypamino]-1,3-thiazole-4-carboxylic acid.39 5[({442-(quinolin-5-yloxy)ethyl]phenyl} sulfonyl)amino]-1,3-thiazole-4-carboxyl i c acid.5-{ [(4-{2-[(3-methoxyi soquinolin-8-yl)oxylethyl Iphenyl)sulfonyl]aminol -1,3-thiazole-4-carb oxylic acid.41 5-11(4-{ 2-[(2-amino-9H-puri n-6-yl)oxy]ethyl Thhenyl)sulfonyljamino) -1,3-thiazole-4-carb oxylic acid.42 5-[({ 4-[2-(1,7-naphthyridin-4-yloxy)ethyl]phenyllsulfonyl)am no -1,3-thiazole-4-carboxylic acid.43 5-) [(4-{2-[isoquinolin-5-yl(methyeaminc]ethyl}phenyl)sulfonyl]aminol -1,3-thiazole-4-carboxyli c acid.44 5-[({441-hydroxy-2-(isoquinolin-5-yloxy)ethyl]phenyl) sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.5-[( 6-[(2-{ [2-(trifluoromethyDquinolin-4-yl]sulfanyl ethyDamino]pyridin-3-yl IsulfonyDamino]-1,3-thiazole-4-carboxylic acid.46 5-{ [(6-{ [2-(pyridin-2-yloxy)ethyl]aminolpyridin-3-ypsulfonyllaminol-1, 3-thiazole-4-carboxylic acid.47 5-{ [(4-{ [(3R,5R)-5-(dimethylcarbamoyl)pyrroli din-3-yl]oxy iphenyl)sulfonyl]aminol -1,3-thiazole-4-carboxylic acid.48 54{443-(isoquinolin-5-yloxy)propyl]phenyllsulfonyl)amino]-1, 3-thiazole-4-carboxylic acid.49 54( { 443-(isoquinolin-5-yloxy)prop-1-yn-l-yl]phenyl)sulfonyl)amino]-1, 3-thiazole-4-carboxylic acid.5-{ [(4-{3-[4-(1H-imidazol-1-yl)phenoxy]prop-1-yn-l-yllphenyl)sulfonyl]amino}- 1,3-thiazole-4-carboxylic acid.51 5-11(3-{ 314-(1 H-imidazol-1-y1)phenoxy]prop-1-yn-l-y1)phenyl)sulfonyl]amino) - 1,3-th i azol e-4-carboxyl i c acid.52 5-{ [(4-(3-[4-(114-imidazol-1-y1)phenoxy]propyl}phenyl)sulfonyl]amino} -1,3-thiazole-4-carb oxylic acid.53 5-{ [(3-{314-(111-imidazol-1-y1)phenoxy]propyl}phenyl)sulfonyl]amino} -1,3-thiazole-4-carboxyli c acid.54 5-{ [(4-{2[4-(pyridin-2-yDpiperaz n-1-yl]ethyl iphenypsulfonyllamino) -1,3 -thiazole-4-carb oxylic acid.5-[({4-[2-(3-phenyl pi peri di n-1-ypethyl 'ph enyl} sulfonyl)amino]-1,3 -thi azole-4-carboxyl i c acid.56 5-{ [(4-{2-[(2R)-2-phenylmorpholin-4-yl]ethyl}phenyl)sulfonyl]amino} -1,3-thiazole-4-carboxylic acid.57 5-1[(4-{2-[ethyl(pyridin-4-ylmethyl)amino]ethyl} phenyl)sulfonyl]amino) thiazole-4-carb oxylic acid.58 5-{ [(4-12-[methyl(p peridin-4-ylacetyl)amino]ethyllphenyesulfonyll amino -1,3-thiazole-4-carboxylic acid.59 5-( {[4-(2-[amino(pyri din-3-yl)acetyl](methyl)ami no} ethyl)ph enyl] sul fonyl}amino)-1,3-thiazole-4-carboxylic acid 5-{ [(4-{24methyl(piperidin-4-ylcarbonyl)amino]ethyl} phenyl)sulfonyl]amino) -1,3-thiazole-4-carboxylic acid.61 5-{ [(4-{24methyl(piperidin-3-ylacetyl)aminolethyl}phenyl)sulfonyl]amino} -1,3-thiazole-4-carboxylic acid.62 5-{ [(4-{ 2-[(3-amino-3-phenylpropanoy1)(methyl)amino]ethyl} phenyl)sulfonyl]amino) -1,3-thiazole-4-carboxylic acid.63 5-({[4-(2-{[(trans-4-aminocyclohexyl)carbonyl](methyl)aminol ethyl)phenylisulfonyl) amino 1,3-thiazole-4-carboxylic acid.64 5-[(4-{2-R [trans-4- (aminomethypcyclohexyl]carbony11(methyl)amino] ethyllphenypsulfonyllamino1-1,3-thiazole-4-carboxylic acid.5-1[(4-{21L-histidyl(methyl)aminojethyl Thhenyl)sulfonyljamino)-1,3-thiazole-4-carboxylic acid 66 5-0 [4-(2-{ [(2R)-2-amino-2-ph enyl acety11(m ethyl)amin ethyl)phenyl] sul fonylf am ino)-1,3-thiazol e-4-carboxyl i c acid 67 5-( [(4-{2-[methyl(pyridin-2-ylcarbonyl)aminoiethyl lphenyl)sulfonyl]aminol -1,3-thiazole-4-carb oxylic acid.68 5-(1[4-(2-{ [4-(1H-imidazol-1-yl)benzoyl](m ethyl)am in ol ethyl)phenyl]sulfonyl} amino)-1,3-thiazole-4-carboxylic acid 69 5-{[(4-{2-[(isoquinolin-5-ylcarbonyl)(methyl)amincdethyllphenyl) sulfonyllaminol-1,3-thiazole-4-carboxylic acid 5-[({ 4-[2-(methyl [2-(morpholin-4-yl)pyridin-4-yl]carbonyl} am ino)ethyl Thhenyl} sul fonyl)am in o]-1,3-thi azole-4-carboxyl i c acid.71 5-{ [(4-f2-[methyl(quinolin-6-y1 carbonyeamino]ethyl) phenyesulfonyl]amino) -1,3-thiazole-4-carboxylic acid.72 5-1[(4-{21(isoquinolin-7-ylcarbonyl)(methypamino]ethyl}ph enyesul fonyliamin ol-1,3-thiazol e-4-carb oxyli c acid.73 5-{ [(4-{2-[(isoquinolin-6-ylcarbonyl)(methyl)amincdethyl}phenyl) sulfonyllamino}-1,3-thiazole-4-carboxylic acid.74 5-(1[4-(2-{methyl[4-(1H-1,2,4-triazol-1-yObenzoyl] amino -lethyl)phenyl]sulfonyllamino)-1,3-thiazole-4-carboxylic acid 5-[(4-{24methyl(pyridin-4-ylcarbonyl)aminolethyl}phenyl)sulfonyllam no1-1,3-thiazole-4-carboxylic acid.76 5-G [4-(2-{ [(2-methoxypyri din-3-yl)carb onyl](methyl)amino1ethyl)phenyl] sulfonyllamino)-1,3-thiazole-4-carboxylic acid.77 5-(f [4-(2-phenoxyethyl)phenyl]sulfonyl} am ino)-1,3 -thi azole-4-carb oxyl ic acid.78 5[({442-(pyridin-2-yloxy)ethyl]phenyl} sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.79 54( { 442-(pyridin-3-yloxy)ethyllphenyl sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.54( [4[2-(quinoxalin-5-yloxy)ethyllphenyl sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.81 5[({442-(quinazolin-8-yloxy)ethyl]phenyl} sulfonyl)amino]-1,3-thiazole-4-carboxylic acid.82 54(04242-phenyl-1 H-imi dazol-1-ypethyl 'phenyl sulfonyl)amino]-1,3-thiazole- 4-carboxylic acid.83 5-R04244-phenyl-1 H-imi dazol-1-yl)ethyl 'phenyl Isulfonyl)amino]-1,3-thiazole- 4-carboxylic acid, or 84 5-[( 4-[2-([1,2,4]triazolo[4,3-a]pyridin-3-yloxy)ethyl]phenyllsulfonyl)amino] -1,3-thiazole-4-carboxylic acid, or a pharmaceutically acceptable salt of one of the above compounds.20. A compound according to any one of the preceding claims, wherein the compound is a prodrug of formula (II): R11 /11_A1_y2_A2 ^ v Formula (II) wherein RI, R11, y1, Al, y2 and A2 a A are as defined in any one of the preceding claims, and R5 is a (Ci-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C-C1)alkyl, carbamoy1-(C i-C2)alkyl, N,N-di(Ci-C2)alkylcarbamoy1-(CI-C2)alkyl piperidino-, pyrrolidino-or morpholino(C2-C3)alkyl group.21. A compound according to claim 20, wherein R5 is a (Ci-C6)alkyl or (C2-C6)alkanoyloxymethyl group.22. A compound according to any one of claims 1 to 21 for use in medicine.23. A compound according to any one of claims 1 to 21 for use in the removal or reduction of antibiotic resistance in Gram-negative bacteria.24. The use of a compound according to any one of claims 1 to 21 in the preparation of an agent for removing or reducing resistance of Gram-negative bacteria to antibiotics.25. A method for reducing or removing resistance of Gram-negative bacteria to antibiotics, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 21.26. A product comprising a compound according to any one of claims 1 to 21 in combination with an antibiotic agent 27. A product according to claim 26 for use in the treatment of a bacterial infection, particularly a bacterial infection which is resistant to treatment with the antibiotic when used alone.28. The use of a compound according to any one of claims 1 to 21 in the preparation of an agent for the treatment of a bacterial infection in combination with an antibiotic agent, particularly a bacterial infection which is resistant to treatment with the antibiotic when used alone.29. A method for the treatment of a bacterial infection, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 21 and an antibiotic agent.30. A product, product for use, a use or a method according to any one of claims 26 to wherein the antibiotic agent is a f3-lactam antibiotic.32 A product, product for use, a use or a method according to claim 30 wherein thef3-lactam antibiotic is selected from carbapenems, penicillins, cephalosporins and penems.A product, product for use, a use or a method according to any one of claims 26 to 32 wherein the Gram-negative bacteria are bacteria which produce metallo-f3-lactamases.34. A product, product for use, a use or a method according to any one of claims 26 to 33 wherein the Gram-negative bacteria are selected from Enterobacteriaceae (such as Klebsiella pneumonia and Escherichia coh), Pseudomonadaceae (such as Pseudomonas aeruginosa and Burkholderia cepacia) and Acinetobacter bctumannii.35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient or carrier.36. A pharmaceutical composition according to claim 36, further comprising an antibiotic agent.37 A pharmaceutical composition according to claim 36 wherein the antibiotic agent is af3-lactam antibiotic 38. A pharmaceutical composition according to claim 37 wherein the P-lactam antibiotic is selected from carbapenems, penicillins, cephalosporins, oxacephems, 25 monobactums, and penems.40. A method of determining whether bacteria express MBL enzymes, the method comprising: contacting a test sample suspected of containing an MBL enzyme with a compound as defined in any one of claims 1 to 21; detecting MBL enzyme activity in the test sample.41. A method according to claim 40, wherein MBL enzyme activity is detected by adding to the test sample a detection solution comprising a detector compound containing a lactam ring and detecting hydrolysis of the Olactam ring in the detector compound.42 A method according to claim 41 wherein the detection solution further includes a pH indicator and which changes colour on hydrolysis of the 0 lactam ring in the detector compound.43. A method according to any one of claims 40 to 42 wherein the test sample comprises bacteria suspected of expressing an MBL enzyme.44. A kit for carrying out a method according to any one of claims 40 to 43, the kit comprising: a compound according to any one of claims 1 to 21; ii. a detection solution comprising a detector compound containing a f3 lactam ring; and means for detecting hydrolysis of the 0 lactam ring of the detector compound.