Nora inhibitors

Abstract

The disclosure relates to compounds of formula (I). The compounds may be used to inhibit the protein NorA. The compounds may be used to resensitise bacteria to fluoroquinolone antibiotics. In an embodiment, the compounds may be used in combination with a fluoroquinolone antibiotic to treat a bacterial infection.

Description

The present disclosure relates to compounds for use in inhibiting the protein NorA. The compounds may be used to resensitise bacteria to fluoroquinolone antibiotics. The compounds may be used in combination with a fluoroquinolone antibiotic to treat a bacterial infection. Antimicrobial resistance (AMR.) is a leading cause of death worldwide, with a recent analysis in The Lancet concluding that AMR accounted for 1.29 million deaths in 2019 (Murray et al., The Lancet, 2019, 399 (10325), 629-655). Methicillin-resistant S. aureus (MRSA) is estimated to be responsible for almost 50% of these deaths, with secondary nosocomial infections threatening to prevent routine surgeries and curtail medical advancement. The unmet need described above is a worldwide challenge, with 10 million deaths per annum predicted globally by 2050. The impact is greatest in low or middle income countries (LMICs). The problem is further exacerbated by a slow development pipeline and identification of antibiotics with novel mechanisms of actions. Of the 30-40 compounds currently in clinical development targeting priority pathogens designated by the World Health Organisation (WHO), all belong to existing classes, and thus rapid development of resistant populations to these new therapeutics could be expected if approved. NorA is a multidrug efflux transporter protein in Staphylococcus aureus (S. aureus). In particular, multidrug transporter NorA contributes to the resistance of Staphylococcus aureus to fluoroquinolone antibiotics by promoting their active extrusion from the cell (Costa et al., Front. Genet., 2019, 9 (710)). The NorA protein effluxes fluoroquinolone antibiotics, such as ciprofloxacin, from bacterial cells, resulting in a subinhibitory concentration of the antibiotic in the bacteria cells and allowing for bacterial cell survival and increased mutagenesis than can result in antibiotic resistance. There are examples in the literature of NorA inhibitors. Some of these examples are peptides, which are generally hard to optimise for use in humans due to challenging pharmacokinetic properties. The present invention has arisen from the inventors' work in attempting to identify potent small molecule NorA inhibitors. In a first aspect of the invention, there is provided a compound of formula (I): R1 L1 r3-4 l2~l3 \ R2 (I) wherein R1 is CN, COOR4, H, halogen, OR4, CONR4R5, NR4R5, NR4COR5, NO2, SR4, SOR5, S(O)SR4, S(O)NR4R5, NR4SO2R5, SO2.NR4R5, SO2R5 or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl; R2 is a mono or bicyclic optionally substituted Cs-Cio aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cs-Ce cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R3 is a mono or bicyclic optionally substituted Cs-Cio aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R4 is H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl; R5 is H, OR6, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl; R6 is H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl; L1 is absent, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, C=O, S=O, SO2, -CH2C(O)-, -CH2CONH- or -CONH-; L2 is absent, CH, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, C=O, S=O, SO2, -CH2C(O)-, - CHC(O)-, -CH2CONH-, -CHCONH- or -CONH-; L3 is a mono or bicyclic optionally substituted Ce-Cto arylene, mono or bicyclic optionally substituted 5 to 10 membered heteroarylene, optionally substituted Cs-Ce cycloalkylene or an optionally substituted mono or bicyclic 3 to 8 membered heterocyclylene; or a pharmaceutically acceptable complex, salt, solvate, tautomeric or polymorphic form thereof. The compounds of the first aspect may be provided as a pharmaceutical composition. Hence, in a second aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle. The pharmaceutical composition may further comprise an antibiotic. The inventors have also found that compounds of formula (I) may be used as a medicament. Hence, in a third aspect, there is provided the compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect, for use as a medicament. The inventors have also found that compounds of formula (I) are useful in inhibiting the NorA protein in bacteria. Hence, in a fourth aspect, there is provided a compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect, for use in inhibiting the NorA protein. In a fifth aspect, there is provided a method of inhibiting the NorA protein, the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect. The NorA protein may be in bacteria. Preferably in Staphylococcus aureus (S.aureus). The inventors have also found that compounds of formula (I) are useful in resensitising bacteria to antibiotics. Accordingly, in a sixth aspect, there is provided a compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect, for use in resensitising bacteria to an antibiotic or potentiating the therapeutic efficacy of an antibiotic to bacteria. In a seventh aspect, there is provided a method of resensitising a bacteria to an antibiotic or potentiating the therapeutic efficacy of an antibiotic to a bacteria, the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect. Preferably, the subject is suffering from a bacterial infection. The inventors have found that the compounds of formula (I) may be used in combination with an antibiotic to treat a bacterial infection, in therapy or as a medicament. By inhibiting the NorA protein, it is possible to treat, ameliorate or prevent a Staphylococcus aureus (S.aureus) infection using an antibiotic or antimicrobial in a subject. Accordingly, in an eighth aspect there is provided an antibiotic and a compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect, for use in treating, ameliorating or preventing a bacterial infection. In a ninth aspect, there is provided a method of treating, ameliorating or preventing a bacterial infection, the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of an antibiotic and a compound the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of the second aspect. The compound of formula (I) may be administered before, after, and / or together with the antibiotic. The antibiotic may be included in the composition of the second aspect, or may be separate thereto. The bacterial infection is preferably caused by Staphylococcus aureus (S.aureus). The S. aureus may be a methicillin-resistant strain of S. aureus or a methicillin-sensitive strain of S. aureus. Preferably the antibiotic is a fluoroquinolone antibiotic. The fluoroquinolone antibiotic may be ciprofloxacin, moxifloxacin, levofloxacin or ofloxacin. More preferably the antibiotic is ciprofloxacin. The weight ratio of the antibiotic to the compound of formula (I) may be between 1:5,000 and 5,000:1, between 1:2,500 and 2,500:1, between 1:1,000 and 1,000:1, between 1:750 and 750:1, between 1:700 and 700:1, between 1:650 and 650:1, between 1:500 and 500:1, between 1:250 and 250:1, between 1:100 and 100:1, between 1:10 and 10:1, between 1:5 and 5:1, between 1:3 and 3:1, between 1:2 and 2:1 or between 1:1.5 and 1.5:1. The weight ratio of the antibiotic to the compound of formula (I) may be about 1:1. The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. Throughout the description and the claims of this specification the word "comprise" and other forms of the word, such as "comprising" and "comprises," means including but not limited to, and is not intended to exclude for example, other additives, components, integers, or steps. As used in the description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions. "Optional" or "optionally" means that the subsequently described event, operation or circumstances can or cannot occur, and that the description includes instances where the event, operation or circumstance occurs and instances where it does not. The term "alkyl" as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to ten carbon atoms, i.e. Ci-Cio alkyl. Ci-Cio alkyl includes for example methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, / sobutyl, sec-butyl, tert-butyl, / sopentyl, neopentyl, / sohexyl, heptyl, octyl, nonyl and decyl. An alkyl group can be unsubstituted or substituted with one or more of halogen, OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)2, OC(O)R7, COOR7, CONR7R8, =NOR7, NR7C(O)R8, SO2R7, SO2NR7R8, azido, optionally substituted C6-Cio arylf optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cs-Ce cycloalkyl and optionally substituted 3 to 8 membered heterocycle. Accordingly, it will be appreciated that an optionally substituted Ci-Cio alkyl may be an optionally substituted Ci-Cio haloalkyl, i.e. a Ci-Cio alkyl substituted with at least one halogen, and optionally further substituted with one or more of OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)2, OC(O)R7, COOR7, CONR7Rs, = NOR7, NR7C(O)R8, SO2R7, SO2NR7R8, azido, optionally substituted Ce-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered heterocycle. The optionally substituted C1-C10 alkyl may be a polyfluoroalkyl, preferably a C1-C3 polyfluoroalkyl. R7 and R8 are independently H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-Cio alkynyl. The term "alkylene", as used herein, unless otherwise specified, refers to a bivalent saturated straight or branched hydrocarbon. An optionally substituted alkylene group may be as defined above in relation the alkyl group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. "Alkenyl" refers to olefinically unsaturated hydrocarbon groups which can be unbranched or branched. Accordingly, an alkenyl group may comprise a cis double bond and / or a trans double bond. In certain embodiments, the alkenyl group has 2 to 6 carbons, i.e. it is a C2-Ce alkenyl. C2-C0 alkenyl includes for example vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl. An alkenyl group can be unsubstituted or substituted with one or more of halogen, OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)2, OC(O)R7, COOR7, CONR7R8, =NOR7, NR7C(O)R8, SO2R7, SO2NR7Ra, azido optionally substituted Ce-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered heterocycle. The term "alkenylene", as used herein, unless otherwise specified, refers to a bivalent, olefinically unsaturated, straight or branched hydrocarbon. An optionally substituted alkenylene group may be as defined above in relation the alkenyl group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. "Alkynyl" refers to acetylenically unsaturated hydrocarbon groups which can be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbons, i.e. it is a Cj-Cs alkynyl. C2-Ce alkynyl includes for example propargyl, propynyl, butynyl, pentynyl and hexynyl. An alkynyl group can be unsubstituted or - 7 - substituted with one or more of halogen, OR7, NR7R8, C(O)R7, CN, oxo, 0P(0)(0H)2, OC(O)R7, COOR7, CONR7R8, = NOR7, NR7C(O)R8, SO2R7, SO2NR7R8, azido, optionally substituted Ce-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cb-Cs cycloalkyl and optionally substituted 3 to 8 membered heterocycle. The term "alkynylene", as used herein, unless otherwise specified, refers to a bivalent, acetylenically unsaturated, straight or branched hydrocarbon. An optionally substituted alkynylene group may be as defined above in relation the alkynyl group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. The term "halo" or "halogen" includes fluoro (-F), chloro (-CI), bromo (-Br) and iodo (I). "Aryl" refers to an aromatic 6 to 10 membered hydrocarbon group. Examples of a Cs-C12 aryl group include, but are not limited to, phenyl, o-naphthyl, p-naphthyl, tetra hydronaphthyl and indanyl. The term includes bicyclic groups where one of the rings is aromatic and the other is not. It may be appreciated that in aryl groups all of the ring atoms are carbon. An aryl group can be unsubstituted or substituted with one or more of optionally substituted Ci-Cs alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)2, OC(O)R7, COOR7, CONR7R8, =NOR7, NR7C(O)R8, SO2R7, SO2NR7R8, azido, optionally substituted Cs-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered heterocycle. "Arylene" refers to a bivalent aromatic 5 to 10 membered hydrocarbon group. An optionally substituted arylene group may be as defined above in relation the aryl group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. Accordingly, a cycloalkyl group may comprise one or more double bonds. Representative examples of a Cb-Cs cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A cycloalkyl group can be unsubstituted or substituted with one or more of optionally substituted Ci-Cs alkyl, optionally substituted Cz-Cs alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)z, OC(O)R7, COOR7, CONR7R8, = NOR7, NR7C(O)R8, SO2R7, SO2NR7R8, azido, optionally substituted Cb-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cb-Cb cycloalkyl and optionally substituted 3 to 8 membered heterocycle. "Cycloalkylene" refers to a bivalent non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. An optionally substituted cycloalkylene group may be as defined above in relation the cycloalkyl group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. "Heteroaryl" refers to a monocyclic or bicyclic aromatic 5 to 10 membered ring system in which at least one ring atom is a heteroatom. The term includes bicyclic groups where one of the rings is aromatic and the other is not. For groups where one of the rings is aromatic and the other is not, the group will be considered to be a heteroaryl group if either or both rings contain at least one ring atom which is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl may contain 1, 2, 3 or 4 heteroatoms. Examples of 5 to 10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-l,2,4-triazole, IH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5 to 10 membered heteroaryl groups include those where a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5 or 6membered monocyclic heteroaryl ring. A heteroaryl group can be unsubstituted or substituted with one or more of optionally substituted Ci-Cs alkyl, optionally substituted Cz-Ce alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)2, OC(O)R7, COOR7, CONR7R8, =NOR7, NR7C(O)R8, SO2R7, SO2NR7R8, azido, optionally substituted Cb-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cb-Cb cycloalkyl and optionally substituted 3 to 8 membered heterocycle. "Heteroarylene" refers to a bivalent monocyclic or bicyclic aromatic 5 to 10 membered ring system in which at least one ring atom is a heteroatom. An optionally substituted heteroarylene group may be as defined above in relation the heteroaryl group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. "Heterocycle" or "heterocyclyl" refers to 3 to 8 membered monocyclic, bicyclic or bridged molecules in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. The heterocycle may contain 1, 2, 3 or 4 heteroatoms. A heterocycle may be saturated or partially saturated. Exemplary 3 to 8 membered heterocyclyl groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetra hydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-l-yl, tetra hydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane, oxazine. A heterocyclyl group can be unsubstituted or substituted with one or more of optionally substituted Ci-Cs alkyl, optionally substituted C2-C6 alkenyl, optionally substituted Cz-Ce alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OP(O)(OH)2, OC(O)R7, COOR7, CONR7R8, =NOR7, NR7C(O)R8, SO2R7, SOzNR7R8, azido, optionally substituted Cs-Cw aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cs-Cs cycloalkyl and optionally substituted 3 to 8 membered heterocycle. "Heterocycylene" refers to a bivalent 3 to 8 membered monocyclic, bicyclic or bridged molecules in which at least one ring atom is a heteroatom. An optionally substituted heterocycylene group may be as defined above in relation the heterocycle group, but with a hydrogen atom removed therefrom to cause the group to be bivalent. A complex of the compound of formula (I) may be understood to be a multicomponent complex, wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The complex may be other than a salt or solvate. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The term "pharmaceutically acceptable salt” may be understood to refer to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, adepic, aspartic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2- ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) base addition salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminium ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminium, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyiamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like. Pharmaceutically acceptable salts may include, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride, hydrobromide and hydroiodide, carbonate or bicarbonate, sulfate or bisulfate, borate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, sulfamate, nitrate, orotate, oxalate, palmitate, pamoate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, camsylate, citrate, cyclamate, benzoate, isethionate, esylate, formate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methylsulphate, naphthylate, 2-napsylate, nicotinate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluceptate, gluconate, glucoronate, hexafluorophosphate, hibenzate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, xinofoate and the like. The term "solvate" may be understood to refer to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. DzO, da-acetone and da-DMSO. L1 may be absent, optionally substituted Ct-Ce alkylene, optionally substituted Cz-Ce alkenylene or optionally substituted Cz-Ce alkynylene. More preferably, L1 is absent, optionally substituted C1-C3 alkylene, optionally substituted C2-C3 alkenylene or optionally substituted C2-C3 alkynylene. The alkylene, alkenylene or alkynylene may be unsubstituted or substituted with a halo, preferably fluoro. Preferably, the alkylene, alkenylene or alkynylene is unsubstituted. Accordingly, L1 may be a C1-C3 alkylene, more preferably -CH2- or -CH2CH2-, and most preferably -CH2-. R1 may be CN, COOR4, OR4, CONR4R5, NR4R5, NR4COR5, NOz, SOR5, S(O)SR4, S(O)NR4R5, NR4SOzR5, S0zNR4R5, SO2R5 or optionally substituted 5 or 6 membered heteroaryl. The 5 or 6 membered heteroaryl may be tetrazole. R4 may be H, optionally substituted Ci-Cs alkyl, optionally substituted C2-C6 alkenyl or optionally substituted Cz-Ca alkynyl. More preferably, R4 is H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. R5 may be H, OR6, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl or optionally substituted Cz-Cs alkynyl. More preferably, R4 is H, OR6, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. R6 may be H, optionally substituted Ci-Ca alkyl, optionally substituted Cz-Ce alkenyl or optionally substituted Cz-Ce alkynyl. More preferably, R6 is H, optionally substituted C1-C3 alkyl, optionally substituted Cz-C3 alkenyl or optionally substituted Cz-Cs alkynyl. Most preferably, R6 is H. In each case, the alkyl, alkenyl or alkynyl may be unsubstituted or substituted with a halo, preferably fluoro. Preferably, the alky, alkenyl or alkynyl is unsubstituted. R4 may be H or C1-C3 alkyl. In some embodiments, R4 is H or CH3. Most preferably, R4 is H. R5 may be H, OH or C1-C3 alkyl. In some embodiments, R5 is H, OH or CH3. Most preferably, R5 is H. More preferably, R1 is CN, COOR4 or CONR4R5. R4 and R5 may independently be H, optionally substituted Ci-Cs alkyl, optionally substituted Cz-Ce alkenyl or optionally substituted Cz-Ce alkynyl. More preferably, R4 and R5 are independently H, optionally substituted C1-C3 alkyl, optionally substituted Cz-Cs alkenyl or optionally substituted Cz-C3 alkynyl. The alkyl, alkenyl or alkynyl may be unsubstituted or substituted with a halo, preferably fluoro. Preferably, the alky, alkenyl or alkynyl is unsubstituted. R4 and R5 may be independently H or C1-C3 alkyl. In some embodiments, R4 and R5 may be H or CH?,. Most preferably, R4 and R5 are H. In some embodiments R1 is CN. In preferred embodiments R1 is COOR4. R4 may be as defined above. Accordingly, R1 may be COOH or COOCH3, and most preferably is COOH. In a preferred embodiment, L1 is -CH2- or -CH2CH2- and R1 is COOR4. More preferably, L1 is -CH2- and R1 is COOR4. Most preferably, L1 is -CH2- and R1 is COOH. L2 may be absent, CH, optionally substituted Ci-Ce alkylene, optionally substituted C2-Ce alkenylene or optionally substituted C2-C6 alkynylene. More preferably, L2 is absent, CH, optionally substituted C1-C3 alkylene, optionally substituted C2-C3 alkenylene or optionally substituted C2-C3 alkynylene. The alkylene, alkenylene or alkynylene may be unsubstituted or substituted with a halo, preferably fluoro. Preferably, the alkylene, alkenylene or alkynylene is unsubstituted. Preferably, L2 is CH or CH2, and more preferably is CH. Accordingly, the compound of formula (I) may be a compound of formula (la): R1 L1 (la) L3 may be a mono or bicyclic optionally substituted Ce-Cio arylene or a mono or bicyclic optionally substituted 5 to 10 membered heteroarylene. More preferably, L3 is an optionally substituted phenylene or an optionally substituted 5 or 6 membered heteroarylene. Most preferably, L3 is an optionally substituted mono or bicyclic 5 membered heteroarylene. In some preferred embodiments, L3 is an optionally substituted pyrazole group. The optionally substituted arylene or heteroarylene may be unsubstituted or substituted with between 1 and 5 substituents. More preferably, the optionally substituted arylene or heteroarylene is unsubstituted or substituted with between 1 and 3 substituents. Most preferably, the arylene or heteroarylene is substituted with 1 or 2 substituents. The or each substituent may be selected from the list consisting of optionally substituted Ci-Ce alkyl, optionally substituted Cz-Cs alkenyl, optionally substituted Cz-Cs alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, COOR7, CONR7R8, NR7C(O)R8, optionally substituted Ce-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted Cs-Ce cycloalkyl and optionally substituted 3 to 8 membered heterocycle. More preferably, the or each substituent is selected from the list consisting of optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, phenyl optionally substituted with a halo, 5 or 6 membered heteroaryl optionally substituted with a halo, C3-C0 cycloalkyl optionally substituted with a halo and 3 to 6 membered heterocycle optionally substituted with a halo. The alkyl, alkenyl or alkynyl may be unsubstituted or substituted with a halo, preferably fluoro. Even more preferably, the or each substituent is C1-C3 alkyl, halogen or phenyl. The halogen may be fluoro, chloro or bromo, and is preferably chloro. In some embodiments, L3 may be X1 is CR9 or N; X2 is CR10 or N; X3 is CR'11 or N; R9 to R11 are independently H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted Cz-Ce alkynyl, halogen, OR7, NR7RS, C(O)R7, CN, COOR7, CONR7R8, NR7C(O)RS, optionally substituted Ce-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3 to 8 membered heterocycle; and a wavy line and asterisk indicate the attachment of the group L3 to R2, and a wavy line and no asterisk indicates the attachment of the group L3 to the group L2, or in embodiments where L2 is absent to the carbon atom which is bonded to R3. Preferably, X1 is CR9. R9 may be H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl or halogen. More preferably, R9 is H, Ci-Cs alkyl or halogen. Even more preferably, R9 is H or Cl. Most preferably, R9 is H. In an alternative embodiment, X1 is N. Preferably, X2 is CR10. r Vr10 In embodiments where X2 is CR10 or L3 is              , R10 may be H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, phenyl optionally substituted with a halo, 5 or 6 membered heteroaryl optionally substituted with a halo, C3-C6 cycloalkyl optionally substituted with a halo or a 3 to 6 membered heterocycle optionally substituted with a halo. More preferably, R10 is H, C1-C3 alkyl, halogen or phenyl. Even more preferably, R10 is H, CH3, CH2CH3 or phenyl. Most preferably, R10 is CH3. Preferably, X3 is N. R2 may be an optionally substituted phenyl, an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 5 or 6 membered heterocycle. R2 may be an optionally substituted phenyl, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted Cs-Ce cycloalkyl or an optionally substituted 5 or 6 membered heterocycle. R2 may be an optionally substituted phenyl, an optionally substituted pyrindinyl, an optionally substituted thiazolyl, an optionally substituted quinolyl or an optionally substituted cyclohexyl. Most preferably, R2 is an optionally substituted phenyl. The R2 aryl, heteroaryl, cycloalkyl or heterocycle may be unsubstituted or substituted with between 1 and 5 substituents. More preferably, the aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with between 1 and 3 substituents or between 1 and 2 substituents. Even more preferably, the aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with 1 substituent. Most preferably, the aryl, heteroaryl, cycloalkyl or heterocycle is substituted with 1 substituent. In embodiments where the R2 group is a six membered ring the substituent may be in the para, meta or ortho position. Preferably, the substituent is in the para or meta position and most preferably in the para position. In embodiments where R2 is a substituted aryl, a substituted heteroaryl, a substituted cycloalkyl or a substituted heterocycle, the or each substituent may independently be selected from the list consisting of optionally substituted Ci-Ce alkyl, optionally substituted Cz-Ca alkenyl, optionally substituted Ca-Ca alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, COOR7, CONR7R8, NR7C(O)R8 and azido. More preferably, the or each substituent on the aryl, heteroaryl, cycloalkyl or heterocycle may independently be selected from the list consisting of optionally substituted Ci-Cs alkyl, halogen, OR7 and CN. Even more preferably, the or each substituent on the aryl, heteroaryl, cycloalkyl or heterocycle may independently be selected from the list consisting of optionally substituted methyl, fluoro, chloro, OR7 and CN. R7 and R8 may independently be H, optionally substituted Ci-Ca alkyl, optionally substituted C2-Ca alkenyl or optionally substituted Cz-Ce alkynyl. More preferably, R7 and R8 are independently H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Most preferably, R7 and R8 are optionally substituted methyl. In embodiments where the R2 aryl, heteroaryl, cycloalkyl or heterocycle is substituted with an optionally substituted alkyl, an optionally substituted alkenyl or an optionally substituted alkynyl and / or is substituted with one or more of OR7, NR7R8, C(O)R7, COOR7, CONR7R8 or NR7C(O)R8, and one or more R7 or R8 group is an optionally substituted alkyl, an optionally substituted alkenyl or an optionally substituted alkynyl, the alkyl, alkenyl or alkynyl may be unsubstituted or substituted with a halo, preferably fluoro. The or each substituent on the aryl, heteroaryl, cycloalkyl or heterocycle may be CH3, CF3, fluoro, chloro, OCHs or CN. Most preferably, the substituent on the aryl, heteroaryl, cycloalkyl or heterocycle is chloro. wherein each R12 is H, optionally substituted C1-C3 alkyl, halogen, OR7 or CN. More preferably, each R12 is H, optionally substituted methyl, fluoro, chloro, OR7 or CN. R7 may be as defined above. Even more preferably, R12 is H, CH3, CF3, fluoro, chloro, OCH3 or CN. Most preferably, each R12 is H or Cl. In a preferred embodiment, R2 is          r12, wherein R12 is H, optionally substituted C1-C3 alkyl, halogen, OR7 or CN. More preferably, R12 is H, optionally substituted methyl, fluoro, chloro, OR7 or CN. R7 may be as defined above. Even more preferably, R12 is H, CH3, CF3, fluoro, chloro, OCH3 or CN. Most preferably, R12 is Cl. R3 may be a mono or bicyclic optionally substituted Cs-Cio aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl. More preferably, R3 is a bicyclic optionally substituted C10 aryl or a bicyclic optionally substituted 8 to 10 membered heteroaryl. In some embodiments, R3 is a bicyclic optionally substituted 9 membered heteroaryl. R3 may be an optionally substituted benzo[d]oxazolyl, an optionally substituted benzo[d]thiazolyl or an optionally substituted [l,2,4]triazolo[l,5-a]pyrimidinyl. The aryl or heteroaryl may be unsubstituted or substituted with one or more of optionally substituted Ci-Ce alkyl, optionally substituted Cz-Cs alkenyl, optionally substituted Cz-Cs alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OC(O)R7, COOR7, CONR7R8, NR7C(O)R8 or azido. More preferably, the aryl or heteroaryl is unsubstituted or substituted with one or more of optionally substituted C1-C3 alkyl, halogen, OR7 or NR7R8. R7 and R8 may independently be H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl or optionally substituted Cz-Ce alkynyl. More preferably, R7 and R8 are independently H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Most preferably, R7 and R8 are optionally substituted methyl. The alkyl, alkenyl or alkynyl may be unsubstituted or substituted with a halo, preferably fluoro. The aryl or heteroaryl may be unsubstituted or substituted with one or more of CH3, CF3, ethyl, fluoro or chloro. Most preferably, the aryl or heteroaryl may be unsubstituted or substituted with one or more of CF3, ethyl or chloro. X4 is CR'13 or N; X5 is CR14 or N; X6 is CR15 or N; X7 is CRiS or N; Xs is 0, S or NR17; X9 is CR18 or N; Xi0 is CR19 or N; and R13 to R19 are each independently H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OC(O)R7, COOR7, CONR7Ra, NR7C(O)R8 or azido. In some embodiments, X4 is CR13, Xs is CR14, X6 is CR15 and X7 is CR16. In alternative embodiment, X4 is N, X5 is CR14, X6 is CR15 and X7 is CR'16. Xs may be S. In an alternative embodiment, X8 is 0. X9 may be N. X10 may be N. R'13 to R19 are preferably each independently H, optionally substituted C1-C3 alkyl, halogen, OR7 or NR7R8. R7 and R8 may be as defined above. The alkyl, alkenyl or alkynyl may be unsubstituted or substituted with a halo, preferably fluoro. R13 to R19 may each independently be H, CH3, CF3, ethyl, fluoro or chloro. Most preferably, R13 - 18 - to R19 are each independently H, CF3, ethyl or chloro. In some embodiments, R13 to R19 are each H. In some embodiments, the compound of formula (I) is: It will be understood that the above compounds may exist as enantiomers and as diastereoisomeric pairs. These isomers aiso represent further embodiments of the invention. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereospecific and stereoselective reactions may be used to generate particular stereoisomers. Alternatively, mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994). The term 'NorA' refers to the NorA protein which is a multidrug efflux pump in Staphylococcus aureus. NorA is responsible for the efflux of fluoroquinolones from Staphylococcus aureus cells. It will be appreciated that the compounds described herein or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof may be used in in combination with, known therapies for treating, ameliorating or preventing a disease. The compound of Formula (I) may be combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment. It will be appreciated that the vehicle of medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given. Medicaments comprising the compounds described herein may be used in a number of ways. Suitable modes of administration include oral, parenteral, topical, inhaled / intranasal, rectal / intravaginal, and ocular / aural administration. Formulations suitable for the aforementioned modes of administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal / mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fastdisintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001). For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkylsubstituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1, by H. Lieberman and L, Lachman (Marcel Dekker, New York, 1980). Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres. The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3 / 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from Ipg to 20mg of the compound of the invention per actuation and the actuation volume may vary from Ipl to lOOpL A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from Ipg to lOOmg of the compound of formula (I). The overall daily dose will typically be in the range Ipg to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day. The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. The compounds of the invention may also be administered directly to a site of interest by injection of a solution or suspension containing the active drug substance. The site of interest may be a site of infection. Typical injection solutions are comprised of propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148. It will be appreciated that the amount of the compound that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the compound, and whether it is being used as a mono-therapy, or in a combined therapy. The frequency of administration will also be influenced by the half-life of the compound within the subject being treated. Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the pharmaceutical composition, the mode of administration, and the advancement of the disease. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration. Generally, for administration to a human, the total daily dose of the compounds of the invention is typically in the range 100 pg to 20 g, such as 1 mg to 10 g, for example 100 mg to 5 g. For example, oral administration may require a total daily dose of from 500 mg to 2,000 mg. Similarly, for administration to a human, the total daily dose of the antibiotic is also typically in the range 100 pg to 20 g, such as 1 mg to 10 g, for example 100 mg to 5 g. For example, oral administration may require a total daily dose of from 500 mg to 2,000 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. The compound may be administered before, during or after onset of the disease to be treated. Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to form specific formulations comprising the compounds according to the invention and precise therapeutic regimes (such as daily doses of the compounds and the frequency of administration). In a further aspect, there is provided a process for making the composition according to the second aspect, the process comprising contacting a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle. A "subject" may be a vertebrate, mammal, or domestic animal. Hence, compounds, compositions and medicaments according to the invention may be used to treat any mammal, for example livestock (e.g. a horse), pets, or may be used in other veterinary applications. Most preferably, however, the subject is a human being. A "therapeutically effective amount" of compound is any amount which, when administered to a subject, is the amount of drug that is needed to treat the target disease, or produce the desired effect, i.e. modulate the NorA protein. For example, the therapeutically effective amount of the compound of formula (I) used may be from about 0.01 mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg. It is preferred that the amount of compound is an amount from about 0.1 mg to about 250 mg, and most preferably from about 0.1 mg to about 20 mgThe therapeutically effective amount of the antibiotic may be the same or different A "pharmaceutically acceptable vehicle" as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions. In one embodiment, the pharmaceutically acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable vehicle may include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet-disintegrating agents. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid that is in admixture with the finely divided active agents (i.e. the compound according to the first, second and third aspects) according to the invention. In tablets, the active compound may be mixed with a vehicie having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid vehicles include, for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like. However, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compound according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and particularly subcutaneous injection. The compound may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. The compound and compositions of the invention may be administered in the form of a sterile soiution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The compounds used according to the invention can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. All features described herein (including any accompanying claims, drawings and abstract), and / or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. For a better understanding of the invention, and to show embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:- Figure 1 shows the results of an GFP-reporter based SOS response assay for compound 1 screened in combination with ciprofloxacin (CFX); Figure 2A shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 1 and CFX against SH1000 wild type (WT) S. aureus; Figure 2B shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 1 and CFX against a SH1000 norA knockout mutant of S. aureus; and Figure 2C shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 1 and CFX against a SH1000 norA overexpression mutant of S. aureus; Figure 3A shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 5 and CFX against SH1000 wild type (WT) S. aureus; and Figure 3B shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 5 and CFX against a SH1000 norA knockout mutant of S. aureus; Figure 4 shows the results of NorA efflux inhibition assays (fluorescence-based) for compounds 1 and 5; Figure 5A shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 1 and CFX against JE2 wild type (WT) S. aureus; Figure 5B shows a MIC checkerboard assay showing the growth-inhibitory interaction between compound 1 and CFX against JE2 wild type (WT) S. aureus; Figure 6 shows the effects of CFX and compound 5 (identified as AMR-09-005), alone and in combination, on prophage activation in vitro; Figure 7 shows the results of resistance acquisition experiments performed using minimum inhibitory concentration (MIC) assays to determine the resistance of S. aureus strains to compounds 1 and 5; and Figure 8 shows the number of S. aureus colony forming units from samples from mice treated with S.aureus and either vehicle (untreated), compound 5 alone, CFX alone or compound 5 and CFX in combination. Exampie 1 - Library screening A library of compounds was screened using a GFP-reporter based SOS response assay with ciprofloxacin (CFX) to assess their inhibitory potential for the DNA damage repair pathway known as the SOS response. A SOS reporter system was generated by transformation of JE2 cells such that they contained the PrecA-gfp reporter plasmid. Activation of the SOS response in these cells results in expression of GFP which can be monitored by fluorescence. ODsoo is a measure of light scattering which can be used to quantify the number of cells present in a sample, since more cells will result in increased light scattering. The SOS response was activated via treatment with 32 pg / ml CFX, to induce DNA damage, and the effect on cell number (ODsoo) and SOS activation (GFP fluorescence) was recorded in the presence of different concentrations of the compound being screened. Figure 1 shows the normalised GFP fluorescence / cell number results for the assay with compound 1. Figure 1 shows that SOS activation decreased with increasing concentrations of compound 1. Consequently, it was found that (£)-3-(1,3-benzothiazol-2-yl)-4-[3-(p-chlorophenyl)-4-pyrazolyl]-3-butenoic acid (compound 1) significantly inhibited the induction of the SOS response by the antibiotic ciprofloxacin, having an ECso of 31 - 3,400 nM. Example 2 - Structural optimisation The inventors wanted to see if they could identify compounds with improved activity. Accordingly, compounds 2-46 were synthesised. The remaining compounds were synthesised in accordance with general methods A-D and the specific methods described below. The inhibitory potential of compounds 1-46 was assessed using GFP-reporter -based SOS response assays. The results of these assays are shown in table 1. The ECso range given in the table is a 95% confidence interval range, calculated based upon the observed EC50 values for the compounds. Table 1: Structures of compounds obtained and results of fluorescence-based SOS response assays Cmpd Structure IUPAC Name ECso range (nM) 1 O HO— L JL? x............ / ^nh X N   '—(z i o Cl (E)-3-(l,3- benzothiazol-2- yl)-4-[3-(p- chlorophenyl)-4-pyrazolyl]-3-butenoic acid 50 - 500a 31 - 3,400b 2 p HO—\ / --\ I.X \ # 6- (benzo[<f]thiazol-2-yl)cyclohex-3-ene-l-ca rboxylic acid >30,000 3 0 HO— z>X^N ) I l| _____ / X / S   '—4. 1 r Nx 3- (benzo[<f]thiazol-2-yl)-4-(pyrazolo[l;5-a]pyridine-3-yl)but-3-enoic acid >30,000 4 0 HO-V z<X^N ) 1 IT ____Z _ X    / \ / ^NH \s?N 3- (benzo[d]thiazol-2-yl)-4-(lH-pyrazol-4-yl)but-3-enoic acid >30,000 Cmpd Structure IUPAC Name ECso range (nM) 5 0 HOy o Cl (E)-3-(l,3-benzothiazol-2- yl)-4-[3-(p-chlorophenyl)-!-methyl-4-pyrazolyl]-3-butenoic acid 0.1 --- 10a 6.1 - 8.5b 6 S                   i / yN / / / Cl N- (benzo[d]thiazol-2-yl)-3-(4-chlorophenyl)-lH-pyrazole-4-carboxamide >30,000 7 o HO-X 3- (benzo[d]thiazol- 2-yl)-4- phenylbut-3-enoic acid >30,000 8 HO \=o ZyN ) L           / ^NH S          z / । \^N Cl (E)-4-(l,3-benzothiazol-2-yl)-5-[3-(p-chlorophenyi)-4-pyrazolyl]-4-pentenoic acid 500 - 5,000a 380 - l,335b Cmpd Structure IUPAC Name ECso range (nM) 9 Li / S       '----v i \^N O Cl 2-(2-(3-(4-chlorophenyl)-lH-pyrazol-4-yl)vinyl)benzo[d] thiazole >30,000a 3,280 - 9,490b 10 \ / ° o—( S        x----( /     ! V-N Cl methyl (E)-3-(1,3-benzothiazol-2-yl)-4-[3-(p-chiorophenyl)-4-pyrazolyl]-3-butenoate 1,360 - 3,250 11 ,N N __ < i / S         '-----(Z ! \^N c5 Cl (E)-2-(l,3-benzothiazol-2-yl)-3-[3-(p-chlorophenyl)-4-pyrazolyl]acrylon itrile >10,000 12 / ? i                            CO       I 1 °x^ r o So 2:.. / (E)-3-(l,3-benzothiazol-2-yl)-4-[3-(p-methoxyphenyl)-4-pyrazolyl]-3-butenoic acid 715 - 1,535 Cmpd Structure IUPAC Name ECso range (nM) 13 0 HO-V b     '-—V   , \^N o Cl (E)-3-(benzo[d]thiazoi-2-yl)-4-(3-(4-chlorophenyl)-!-ethyl-lH-pyrazol-4-yl)but-3-enoic acid 3.3 - 20.5 14 \ if (E)-3-(benzo[d]thiazol-2-yl)-4-(5-chloro-l-methyl-3-phenyl-lH-pyrazol-4-yl)but-3-enoic acid 100 - 1,0003 22 - 140b 15 OH s / —4 H |         /    0 N 3- (benzo[d]thiazol-2-yl)propanoic acid >30,000 17 V o op” (E)-3-(benzo[d]thiazol-2-yl)-4-(l-phenyl-lH-pyrazoi-5-yi)but-3-enoic acid 300 - 3,0003 580 - >10,000b Cmpd Structure IUPAC Name ECso range (nM) 18 o ry-N 3 \= N V / (E)-3-(benzo[d]thiazoi-2-yl)-4-(l,3-diphenyl-lH-pyrazoi-4-yi)but-3-enoic acid 23 - 44 19 0 HO~X ysN y) a (E)-3-(5-chiorobenzo[d]th iazol-2-yl)-4-(3-(4-chlorophenyl)-l-methyl-lH-pyrazol“4-yl)but-3-enoic acid 3.8 - 6.2 20 T1 o 0 XksCx \ (E)-4-(3-(4-chlorophenyl)-l~ methyl-lH-pyrazol-4-yl)-3-(5-(trifluoromethyl) benzQ[d]thiazol-2-yi)but-3-enoic acid 56 - 150 21 p cf3 ho-^ AaJ , N        VsN C. j a (E)-4-(3-(4-chlorophenyl)-l-methyl-lH-pyrazoi-4-yi)-3-(5-ethyi-7-(trifluoromethyl)-[l,2,4jtriazolo[lf 5-a]pyrimidin-2-yl)but-3-enoic acid >10,000 Cmpd Structure IUPAC Name ECso range (nM) 22 O HO~7 N ) (E)-3-(benzo[d]thiazol-2-yl)~4-(l~ methyl-3-(4-(trifluoromethyl) phenyl)-lH-pyrazol~4-yl)but-3-enoic acid 20 - 200a 310 - 3,550b S     —30,000 24 \ O X T Z W & (E)-3- (benzo[d]thiazoi-2-yl)-4-(l-methyi-3-(p-toiyl)-1 / 7-pyrazol-4-yl)but-3-enoic acid 1 - 20a 5.8 - 9.8b 25 H v o XsY (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(4-fiuorophenyl)-!-methyl-lH-pyrazoi-4-yi)but-3-enoic acid 3 - 30a 5.9 - 14b Cmpd Structure IUPAC Name ECso range (nM) 26 O HO~\ \^N o (E)-3-(benzo[c / ]thiazol-2-yl)-4-(l-methyl-3-phenyl-lH-pyrazol-4-yl)but-3-enoic acid 1 - 100a 32 - 85b 27 p HQ-# 0        / * 4 / i \^N \^-7 (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-cyanophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid 200 - 2,000a 165 - 955b 28 O HO—p / i yiN v5 (E)-3-(benzo[d]thiazol-2-y|)-4-(l-methyl-3-(o-tolyl)- 1H-pyrazol-4-yl)but-3-enoic acid 1,000 - >30,000a 855 - 1820b 29 © HO-p li        % / ^nx ysN ci-4^ V! (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-chiorophenyi)-!-methyl-lH-pyrazol-4-yl)but-3-enoic acid 9.1 - 58 Cmpd Structure IUPAC Name ECso range (nM) 30 O HO~\ ZV-N ) s                   , \^N (E)-3-(benzo[d]thiazol-2-yl)~4-(l-methyl-3-(pynd ine-3-yl)-lH-pyrazol-4-yl)but-3-enoic acid 1,000 - >30,0003 1,640 - 2,770b 31 0 HO~# yyN / S    '—V i \^n o (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3- (pyrid ine-4-yl)-lH-pyrazol-4-yl)but-3-enoic acid 1,000 - >30,0003 2,780 - 7,275b 32 O HO-y Z^N ) I A / v_^n / S    x—e i V^N (E)-3-(benzo[d]thiazol-2-yi)-4-(3-cyclohexyi-1-methyl-lH-pyrazoi-4-yi)but-3-enoic acid 1,000 - >30,0003 16 - >10,000b 33 o HO-< Z^N / 4 N x v—( / i V^N Fj (E)-3-(benzo[c / ]thiazol-2-yl)-4-(l-methyl-3-(m-tolyl)-lH-pyrazoi-4-yi)but-3-enoic acid 200 - 391 Cmpd Structure IUPAC Name ECso range (nM) 34 0 H0-# ysN Cs (E)-3-(benzo[d]thiazol-2-yl)-4-(l~ methyl-3-(thiophen-2-yl)-lH-pyrazol-4-yl)but-3-enoic acid 19 - 97 35 O HO- / V-N \ k II \V / -- / N' £n F3C“vJ (E)-3-(l,3-benzothiazol-2-yl)-4-{l-methyl-3-[m-(trifiuoromethyl) phenyl]-4-pyrazolyl}-3-butenoic acid 128 - 426 36 O HO— / X \_N  \ L £1 / '^"o M XX ( / Cl (E)-3-(l,3- benzoxazol-2-yl)-4-[3-(p-chiorophenyi)-!-methyl-4-pyrazolyi]-3-butenoic acid 37 - 137 37 \ Z"»y I co         O o (E)-3-(l,3~ benzothiazol-2-yi)-4-[3-(3,4_ dichlorophenyl)-l-methyl-4-pyrazolyi]-3-butenoic acid 26 - 49 Cmpd Structure IUPAC Name ECso range (nM) 38 O _  HO—y / =N a (E)-3-(l,3-benzothiazol-2-y|)-4-[3-(6-chloro-3-pyridyl)-1 -methyl-4-pyrazolyl]-3-butenoic acid 299 - 7,880 39 HO- / 3 OrlJ N Cl (E)-3-(l,3-benzothiazol-2-yl)-4-[3-(5-chloro-2-thienyl)-1-methyl-4-pyrazolyl]-3-butenoic acid 70 - 173 40 0 HO- / ) L jl       n x (j / / N (E)-3-(l,3-benzothiazol-2-yl)-4-[3-(p-cyanophenyi)-!-methyi-4-pyrazolyl]-3-butenoic acid 74 - 1,405 41 0 HO~ / X^-S ) u          4. / >'N / \^n (E)-3-(l,3-benzothiazol-2-yi)-4-[3-(m-fluorophenyi)-!-methyl-4-pyrazolyl]-3-butenoic acid 34 - 2,150 Cmpd Structure IUPAC Name ECso range (nM) 42 0 HO-y / I v—(z i \^n (E)-3-(l,3-benzothiazol-2-yl)-4-[3-(m-methoxyphenyl)-l-methyl-4-pyrazolyl]-3-butenoic acid 647 - >10,000 43 0 HO—\ } N '----(Z ! y-N r \ Cl (E)-3-(l,3-benzothiazol-2-y|)-4-[3-(4-chloro-3-fluorophenyl)-l-methyl-4-pyrazolyl]-3-butenoic acid 5.9 - 140 44 0 HO—\ isiA'N        N yN rv yy / (E)-3-(l,3- benzothiazol-2-yl)-4-[3-(o-fiuorophenyl)-!-methyl-4-pyrazolyl]-3-butenoic acid 175 - 1,400 45 0 I / ^.        1 ° \ (E)-3-(l,3-benzothiazol-2-yi)-4-[l-methyi-3~(6-quinoiyl)-4-pyrazoiyl]-3-butenoic acid 274 - 575 10 5 value calculated based on initial experiments b value calculated subsequently based on additional repeats The results shown in Table 1 demonstrate that substituting moieties across groups of compound 1 resulted in surprisingly different effects. In particular, the inventors found that substituting the pyrazole with a methyl substituent resulted in significantly improved potency, see compounds 1 and 5. Conversely, substituting the benzothiazole with a benzoxazole ring leads to reduced activity, see compounds 5 and 36. Example 3 - Secondary Assays and Target Identification To determine the mechanism of action, minimum inhibitory concentration (MIC) checkerboard assays were prepared showing the ability of combinations of compound 1 and CFX to inhibit growth of wildtype S. aureus, a norA knockout mutant strain and a norA overexpression mutant strain, the results are shown in Figures 2A-C. Similarly, minimum inhibitory concentration (MIC) checkerboard assays were prepared showing the ability of combinations of compound 5 and CFX to inhibit growth of wildtype S. aureus and a norA knockout mutant strain, and the results are shown in Figures 3A and 3B. Figure 2A shows that when there is no CFX present, increasing the concentration of compound 1 has no significant effect on the ODsoovalue measured after 18 h incubation and growth of the wildtype S. aureus strain cannot be completely inhibited. Figure 2A also shows that increasing the concentration of CFX causes a decrease in the ODsoo value measured after 18 h incubation. At sufficient concentrations of CFX, it is possible to completely inhibit visible growth of the wildtype S. aureus. The concentration of CFX at which bacterial growth is completely inhibited is the minimum inhibitory concentration (MIC). So when used alone, the MIC of CFX against SH1000 WT is 0.5 pg / ml. Figure 2a shows that increasing concentration of compound 1 reduces the MIC of ciprofloxacin. This shows that compound 1 potentiates the activity of CFX against the wildtype strain of S. aureus. The combination may be viewed as synergistic. Figure 3A shows that compound 5 similarly potentiates the activity of CFX against the wildtype strain of S. aureus. Again, the combination may be viewed as synergistic. Comparison between Figures 2A and 3A shows that compound 5 reduced the MIC of CFX at lower concentrations than compound 1. The 2-fold synergy concentration, i.e. the concentration of compound that caused a 2-fold decrease in the MIC of CFX, was found to be 15 nM for compound 5, compared to 234 nM for compound 1. Similarly, the 4-fold synergy concentration, i.e. the concentration of compound that caused a 4fold decrease in the MIC of CFX, was found to be 234 nM for compound 5, compared to 1875 nM for compound 1. As shown in Figures 2B and 3B, no synergistic or potentiating effect was observed for compound 1 or compound 5 against a norA knockout mutant of S. aureus. As shown in Figure 2C, it was found that to inhibit the growth of a noM-overexpressing mutant of S. aureus, increased concentrations of compound 1 were required compared to those required to inhibit the growth of wildtype S. aureus. These results indicate that the synergy observed between compounds 1 and 5 and ciprofloxacin results from inhibition of the NorA efflux pump by compounds 1 and 5. Without wishing to be bound by theory, the inventors note that NorA effluxes fluoroquinolone antibiotics, such as ciprofloxacin, from bacteria cells. This results in a subinhibitory concentration of the antibiotic within the bacterial cells and allowing for bacterial cell survival and increased mutagenesis. Inhibition of the NorA efflux pump, for instance by compound 1, would thus re-sensitise S. aureus to a fluoroquinolone antibiotic. This explains the observed synergy / potentiating effect. The ability of compounds 1 and 5 to inhibit efflux of NorA pumps in S. aureus was confirmed using a fluorometric method that measured the accumulation of the universal efflux pump substrate ethidium bromide (EtBr), and the results are shown in Figure 4. It was found that compounds 1 and 5 both inhibited NorA efflux activity, with compound 1 having an IC50 value of 3000 nM and compound 5 having an IC50 value of 36 nM. The inventors aiso tested the ability of compounds 1 and compounds 5 to inhibit a different strain of S. aureus, JE2, both on their own and in the presence of CFX. The results are shown in Figures 5A and B. Figure 5A shows that when there is no CFX present, increasing the concentration of compound 1 has no significant effect on the ODeoo value measured after 18 h incubation and growth of the wildtype S. aureus strain cannot be completely inhibited. Figure 5A also shows that increasing the concentration of CFX causes a decrease in the ODeoo value measured after 18 h incubation. At sufficient concentrations of CFX, it is possible to completely inhibit visible growth of the wildtype S. aureus. The concentration of CFX at which bacterial growth is completely inhibited is the minimum inhibitory concentration (MIC). So when used alone, the MIC of CFX against JE2 WT is 8 pg / ml. Figure 5A shows that increasing concentration of compound 1 reduces the MIC of ciprofloxacin. This shows that compound 1 potentiates the activity of CFX against the wildtype strain of S. aureus. The combination may be viewed as synergistic. Figure 5B shows that compound 5 similarly potentiates the activity of CFX against the wildtype strain of S. aureus. Again, the combination may be viewed as synergistic. Comparison between Figures 5A and 5B shows that compound 5 reduced the MIC of CFX at lower concentrations than compound 1. The 2-fold synergy concentration, i.e. the concentration of compound that caused a 2-fold decrease in the MIC of CFX, was found to be 15 nM for compound 5, compared to 117 nM for compound 1. Similarly, the 4-fold synergy concentration, i.e. the concentration of compound that caused a 4fold decrease in the MIC of CFX, was found to be 234 nM for compound 5, compared to 938 nM for compound 1. Example 4 - Activity in Clinical Isolates The ability of the combination of compound 1 and CFX to inhibit clinical isolates of S. aureus was also tested, and the results are provided in Table 2. Table 2: Minimum inhibitor concentration (MIC) of ciprofloxacin, alone and in combination with 2 uM compound 1, against clinical isolates of S. aureus S. aureus n Ciprofloxacin MIC (pg / ml) Fold decrease Alone Compound 1 Methicillin-resistant 9 16-128 4-32 2-8 Methicillinsensitive 4 0.5-1 0.125-0.25 4 The fold decrease is the fold difference in MIC of CFX when used alone compared to when used in combination with compound 1. Example 5 - Mammalian Cell Toxicity The toxicity impact of compounds 1 and 5 on mammalian cells was investigated in vitro using HEK293T cells. It was found that both compounds 1 and 5 had CC50 values of >30000 nM, thus indicating that they are not cytotoxic. Example 6 - In vitro Pharmacokinetic Studies Certain pharmacokinetic parameters were determined for compounds 1 and 5, and these parameters are summarised in Table 3. Table 3: Pharmacokinetic parameters determined for compounds 1 and 5 Compound 1 Compound 5 Clearance in MLM (mi / min / kg) < 9.5 10.5 Solubility (mM) 84 80 Plasma protein binding (Fu) 0.0039 0.0033 MDCK-MDR1 Permeability (Papp, nm / sec) 56 133 A clearance in MLM of <20 ml / min / kg, solubility of >10 mM in aqueous buffer and MDCK-MDR1 permeability of >10 nm / sec are desirable in a drug candidate. Consequently, the results in Table 3 show that compounds 1 and 5 exhibit desirable drug-like properties. Example 7 - Prophage Activation Prophages, the genetic material of bacteriophages, can be activated by different environmental factors. The effects of CFX and compound 5, alone and in combination, on prophage activation was investigated in vitro and the results are shown in Figure 6 and Table 4. The inventors found that the concentration of plaque forming units (PFUs) was greatly reduced for ciprofloxacin in the presence of compound 5 compared to ciprofloxacin alone. Table 4:, Results of experiments tojnye^ ciprofloxacin and compound 5 by determination of plaque forming units (PFUs) PFU (mt) P value (DMSO vs Compound 5) DMSO Compound 5 (30 pM) Ciprofloxacin (0 pg / mL) 28100 35000 ns Ciprofloxacin (10 yg / mL) 1070000 76000 0.0008 Example 8 - Resistance Acquisition Resistance acquisition was investigated using MIC assays. The results of these experiments are shown in Figure 7 and Table 5. Table 5; Results of resistance acquisition experiments for S. aureus cultures treated ydthJ3MSOJ_compoundJ^_mmpounljL^^ ciprofloxacin. umuC::Tn is a mutant without error-prone polymerase associated with SOS response % cultures resistant WT um«C::Tn DMSO 72.9 37.5 Compound 1 37.5 10.4 Compound 5 0 0 Compound 4 (Inactive control) 70.8 43.8 The results shown in Table 5 demonstrate that the NorA inhibitors, compounds 1 and 5, reduce the emergence of resistance. It is noted that neither of the S. aureus cultures acquired resistance to treatment with ciprofloxacin and compound 5. Treatment with compound 1 resulted in a lower percentage of cultures resistant in the mutant strain than the wildtype S. aureus. This shows that the reduction in the emergence of resistance is likely a result of reduced induction of the mutagenic SOS response. Example 9 - In vivo pharmacokinetic studies In vivo pharmacokinetic studies were carried out to investigate how mice infected with S. aureus were affected by treatment with ciprofloxacin and compound 5, alone and in combination. In particular, the mean concentration of free (non plasma-bound) compound 5 in the blood was determined at time intervals up to 24 hours after treatment, and the results are shown in Table 6. Table 6: Mean total concentration and concentration of free (non plasma-bound) compound 5 in the blood of mice treated with a single 10 mg / kg dose of compound 5 Time (min) Mean cone (nM) Ctot Cfree 5 24800 81.7 15 21000 69.2 30 10000 32.9 60 2500 8.3 120 766 2.5 240 602 2 360 924 3 480 988 3 1440 56 0.2 The results showed that the concentration of free compound 5 in whole blood was greater than the concentration required for 2-fold synergy in vitro (15 nM) at least 30 minutes after a single 10 mg / kg dosage.. Example IO - In vivo pharmacokinetic efficacy The in vivo efficacy of compound 5 was investigated by measuring the number of S. aureus colony forming units from infected mice samples, and the results are shown in Figure 8. Tukey's multiple comparison test was applied to determine whether the mean number of colony forming units in different treatment groups significantly differed to the mean number of colony forming units in the untreated samples (samples treated with the vehicle only), and the results are shown in Table 7. Table 7: Results of Tukey’s multiple comparison test, comparing the number of colony forming units in infected mice samples treated with only vehicle (untreated), only ciprofloxacin, only Compound 5 or a combination of ciprofloxacin and Compound 5 mean logio CFU (n = 5) Mean difference to Vehicle 95% Confidence interval of difference P value Lower bound Upper bound Vehicle 3.31 Ciprofloxacin 3.25 0.0646 -0.661 0.789 0.994 Compound 5 2.96 0.352 -0.374 1.08 0.524 Combination 1.26 2.05 1.33 2.78 <0.0001 It was found that the mean number of colony forming units generated by the samples from mice treated with the combination of CFX and compound 5 was significantly less than the mean number of CFUs generated by the samples from mice treated with only vehicle, CFX only or compound 5 only. Methodology SOS response Serial dilutions of compound were prepared in TSB supplemented with 32 pg / ml ciprofloxacin in black-walled, flat-bottomed, 96-well plates in a final volume of 200 pl. JE2 containing the PrecA-gfp reporter plasmid was inoculated to 108 CFU / ml. Plates were incubated in an Infinite M200-PRO microplate reader (Tecan) at 37 °C with shaking (700 rpm) for 17 h and fluorescence (excitation 475; emission 525) and ODeoo determined every 15 min. ECso ranges were determined by calculating 95% confidence intervals for the mean log(ECso) values, taking the corresponding ECso values and choosing a range which encompassed these points. General Synthetic Procedures General Method A: Pyrazole / V-alkylation The appropriate pyrazole-4-carbaldehyde (1 equiv) was dissolved in anhydrous DMF. Cesium carbonate (2 equiv) and the appropriate alkyl halide (1.5 equiv) were added and the reaction stirred at 60 °C for 16 h. The reaction was poured onto water, stirred at r.t. for 1 h and subsequently extracted with EtOAc. The combined organic phases were washed with 10% LiCI, brine, dried using Na2S04 and solvent removed in vacuo. The crude product was purified using flash column chromatography. General Method B: Knoevenaqel condensation The appropriate propionic acid (0.876-1 equiv) and pyrazole-4-carbaldehyde (1 equiv) were dissolved in anhydrous DMF and sealed in a microwave vial. TMSCI (4.7-6 equiv) was added dropwise before heating the reaction to 110-135 °C for 9-24 h. The crude compound was precipitated in water, the solid collected and triturated in MeOH and the solid collected by vacuum filtration. The solid was further washed with cold MeOH and water and dried in vacuo. General Method C: Benzothiazole cyclisation The appropriate amino-benzenethiol (1 equiv) was dissolved in toluene. Succinic anhydride (1 equiv) was added, and the reaction stirred at r.t. for 4 h, followed by refluxing for a further 2 h. The reaction solvent was removed in vacuo. The crude solid was dissolved in minimal EtOAc and washed three times with sat. aq. NaHCOs. The combined aqueous phases were then neutralized to pH = 7 with 37% HCI. The precipitated product was then isolated through vacuum filtration, washed three times with cold water and dried in vacuo. General Method D: Suzuki coupling [l,r-bis(diphenylphosphine)ferrocene]dichloropalladium(II)-DCM (0.1 equiv) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (1 equiv), boronic acid (1-2 equiv) and 2 M sodium carbonate (1.5 equiv) in DME and heated in a microwave at 130 °C for 45 minutes. The reaction mixture was diluted with EtOAc, washed with water, brine, dried using N32SO4 and solvent removed in vacuo. The crude product was resuspended in DCM, filtered through a pad of Celite, and purified using flash column chromatography. Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (6) are given in parts-per-million downfield from tetramethylsilane (for ^-NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCh, deuterochloroform and do-DMSO, deuterodimethylsulphoxide. All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were performed under an atmosphere of nitrogen unless otherwise noted. Compound 5: (£)-3-(benzo[d]thiazol-2-yn-4-(3-(4-cNorophenyO-l-methyh lH-pyrazol-4-yl)but-3-enoic add Cl Step 1 Semicarbazide hydrochloride (765 mg, 9.68 mmol) and water (172 mL) were added in small portions to a stirred solution of 4'-chloroacetophenone (1.50 g, 9.22 mmol) and sodium acetate (1.11g, 12.9 mmol) in EtOH (172 mL). The reaction was refluxed for 16 h and then stirred at r.t. for 6 h. EtOH was removed in vacuo and the precipitate collected by vacuum filtration. (E)-2-(l-(4-chlorophenyl)ethylidene)hydrazine-l-carboxamide (1.76 g, 8.31 mmol, 90%) was obtained as a colourless solid. !H NMR (400 MHz, CDCb) 6 8.33 (s, 1H), 7.65-7.60 (m, 2H), 7.37-7.33 (m, 2H), 2.22 (s, 3H). Step 2 (E)-2-(l-(4-chlorophenyl)ethylidene)hydrazine-l-carboxamide (1.05, 4.96 mmol) was dissolved in anhydrous DMF (50 mL), cooled to 0 °C and POCh (6 mL) added dropwise. The reaction was allowed to heat to r.t., then heated at 60 °C for 16 h, before cooling to r.t. and stirred for 18 h. The reaction was quenched by pouring into ice-cold water and neutralized with 10 % NaOH. The mixture was cooled to 0 °C and extracted twice with DCM. The combined organic phases were washed with 10% LiCI, brine, dried using Na2S04 and the solvent removed in vacuo. The crude product was purified using flash column chromatography eluting with a gradient of 0-45% EtOAc in n-Hex. 3-(4-chlorophenyl)-lH-pyrazole-4-carbaldehyde (645 mg, 3.12 mmol, 63%) was obtained as an off-white solid. 1H NMR. (400 MHz, DMSO-d6) 6 13.81 (s, 1H), 9.89 (s, 1H), 8.58 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H). Step 3 According to general method A, 3-(4-chlorophenyl)-l / 7-pyrazole-4-carbaldehyde (479 mg, 2.32 mmol) was reacted with cesium carbonate (1.57 g, 4.64 mmol) and iodomethane (228 pL, 3.48 mmol) in anhydrous DMF (20 mL). The crude product was purified using flash column chromatography eluting with a gradient of 15-40% EtOAc in Hex. 3-(4-chiorophenyi)-l-methyl-l / - / -pyrazoie-4-carbaldehyde (221 mg, 1.39 mmol, 60%) was obtained as a light yellow solid. ’H NMR (400 MHz, CDCI3) 6 9.90 (s, 1H), 7.99 (s, 1H), 7.72-7.68 (m, 2H), 7.44-7.40 (m, 2H), 3.98 (s, 3H). Step 4 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (216 mg, 1.04 mmol) and 3-(4-chlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (247 mg, 1.10 mmol) were dissolved in anhydrous DMF (1.35 mL) and sealed in a microwave vial. TMSCI (709 pL, 5.48 mmol) was added dropwise before heating the reaction to 135 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(4-chlorophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (70.0 mg, 0.171 mmol, 16%) was obtained as a yellow solid. TH NMR (400 MHz, DMSO-d6) 6 12.50 (s, 1H), 8.11 (s, 1H), 8.07-8.00 (m, 1H), 7.98-7.91 (m, 1H), 7.63-7.53 (m, 4H), 7.49 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.41 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.33 (s, 1H), 3.97 (s, 3H), 3.89 (s, 2H). Compound 10: methyl (E)~3-(benzo[d]thiazol-2-yl)-4-(3-(4~chloropheny0-lH-pyrazol-4-yi)but-3-enoate Cl (E)-3-(benzo[djthiazol-2-yl)-4-(3-(4-chlorophenyl)-lH-pyrazol-4-yl)but-3-enoic acid (53.0 mg, 0.134 mmol) was suspended in MeOH (1.5 mL) and cooled to 0 °C. Thionyl chloride (19.0 pL, 0.254 mmol) was added and the reaction was left to stir at room temperature for 1 h. Additional thionyl chloride (10.0 pL, 0.134 mmol) was added and the reaction was stirred at r.t. for 16 h. The reaction was subsequently quenched with water and extracted three times with EtOAc. The combined organic phases were washed with brine, dried using MgSO4 and solvent removed in vacuo. The crude product was purified using flash column chromatography eluting with a gradient of 0- 70% EtOAc in n-Hex. Methyl (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(4-chlorophenyl)-lH-pyrazol-4-yl)but-3-enoate (14.3 mg, 34.9 pmol, 24%) was obtained as a yellow solid. TH NMR (400 MHz, CDCh) 3 7.98 (d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 7.84-7.78 (m, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.47-7.42 (m, 3H), 7.39-7.33 (m, 2H), 4.06 (s, 2H), 3.73 (s, 3H). Compound 11: (E)-2-(benzo[d]thiazol-2-yl)-3-(3-(4-chlorophenyl)-lH-pyrazol-4-yl)acrylomtnle Cl Benzothiazole-2-yl acetonitrile (50.0 mg, 0.281 mmol) and 3-(4-chlorophenyl)-lH-pyrazole-4-carbaldehyde (59.3 mg, 0.281 mmol) were dissolved in anhydrous DMF (0.34 mL) and sealed in a microwave vial. TMSCI (219 pL, 1.69 mmol) was added and the reaction heated to 135 °C for 2 hours. The crude product was precipitated with water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried using MgSO4 and solvent removed in vacuo. The crude product was purified using flash column chromatography eluting with a gradient of 0-60% EtOAc in n-Hex. Combined fractions were further purified using reverse phase flash column chromatography eluting with a gradient of 5-100% MeCN in H2O. (E)-2-(benzo[d]thiazol-2-yl)-3-(3-(4-chlorophenyl)-lH-pyrazol-4-yl)acrylonitrile (11.5 mg, 31.7 pmol, 11%) was obtained as a yellow solid. TH NMR (400 MHz, DMSO-de) 6 14.04 (s, 1H), 8.65 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.06-7.98 (m, 2H), 7.67 (s, 3H), 7.597.52 (m, 1H), 7.47 (t, j = 7.6 Hz, 1H). Compound 12: (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(4-methoxyphenyl)-lH-pyrazoi-4-yi)but-3-enoic acid According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (103 mg, 0.485 mmol) and 3-(4-Methoxyphenyl)-lH-pyrazole-4-carbaldehyde (100 mg, 0.485 mmol) were dissolved in anhydrous DMF (0.5 mL) and sealed in a microwave vial. TMSCI (314 pL, 2.42 mmol) was added dropwise before heating the reaction to 135 °C for 6 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(4-methoxyphenyl)-lH-pyrazol-4-yl)but-3-enoic acid 16.8 mg, 42.9 pmol, 8%) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO-de) 6 12.51 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.96-7.89 (m, 2H), 7.537.46 (m, 3H), 7.43-7.35 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 3.94 (s, 2H), 3.83 (s, 3H). Compound 13: (E)-3-(benzo[d’]thiazol-2“y0-4“(3-(4-chloropheny0-l-ethyl-lH-pyrazol-4-yl)but-3-enok add Step 1 According to general method A, 3-(4-chlorophenyl)-lH-pyrazole-4-carbaldehyde (301 mg, 1.46 mmol) was reacted with cesium carbonate (989 mg, 2.91 mmol) and iodoethane (184 pL, 2.19 mmol) in anhydrous DMF (13 mL). The crude product was purified using flash column chromatography eluting with a gradient of 10-40% EtOAc in n-Hex. 3-(4-chlorophenyl)-l-ethyl-lH-pyrazole-4-carbaldehyde (175 mg, 0.746 mmol, 51%) was obtained as a yellow solid. rH NMR (400 MHz, COCH) 5 9.90 (s, 1H), 8.02 (s, 1H), 7.75-7.67 (m, 2H), 7.46-7.38 (m, 2H), 4.23 (q, J = 7.3 Hz, 2H), 1.55 (t, J = 7.3 Hz, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (148 mg, 0.714 mmol) and 3-(4-chlorophenyl)-l-ethyl-lH-pyrazole-4-carbaldehyde (175 mg, 0.731 mmol) were dissolved in anhydrous DMF (1.10 mL) and sealed in a microwave vial. TMSCI (473 pL, 3.66 mmol) was added dropwise before heating the reaction to 100 °C for 14 h and then 120 °C for 2 h. (E)-3-(benzo[rf]thiazol-2-yl)-4-(3-(4-chlorophenyl)-l-ethyl-lH-pyrazol-4-yl)but-3-enoic acid (16.9 mg, 39.9 pmol, 5%) was obtained as a yellow solid. TH NMR (400 MHz, DMSO-de) 6 12.53 (s, 1H), 8.16 (s, 1H), 8.04 (dd, J = 8.0, 1.3 Hz, 1H), 7.98-7.91 (m, 1H), 7.63-7.53 (m, 4H), 7.49 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.41 (td, J = 7.6, 1.3 Hz, 1H), 7.34 (s, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.90 (s, 2H), 1.45 (t, j = 7.2 Hz, 3H). Compound 14: (E)-3-(benzo[d]thiazol-2-yn-4-(5-cNoro-l-methyl-3-phenyh XH-pyrazoh4"yi)but-3-enoic acid According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (129 mg, 0.624 mmol) and 5-chloro-l-methyl-3-phenyl-lH-pyrazole-4-carbaldehyde (152 mg, 0.689 mmol) were dissolved in anhydrous DMF (0.8 mL) and sealed in a microwave vial. TMSCI (419 pL, 3.29 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(5-chloro-l-methyl-3-phenyl-l / - / -pyrazol-4-yl)but-3-enoic acid (114 mg, 0.278 mmol, 43%) was obtained as a light brown solid. NMR (400 MHz, DMSO-de) 6 12.34 (s, 1H), 8.09 (dd, j = 7.9, 1.4 Hz, 1H), 8.02-7.92 (m, 1H), 7.72-7.65 (m, 2H), 7.52 (ddd, j = 8.1, 7.2, 1.4 Hz, 1H), 7.48-7.40 (m, 3H), 7.40-7.34 (m, 1H), 7.30 (s, 1H), 3.93 (s, 3H), 3.61 (s, 2H). Compound 17; (E)-3-(benzo[d]thiazol-2-yl)-4-(l-phenyl-lH-pyrazol-5-yl)but-3-enoic acid According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (109.3 mg, 0.527 mmol) and l-phenyl-lH-pyrazole-5-carbaldehyde (100 mg, 0.552 mmol) were dissolved in anhydrous DMF (0.514 mL) and sealed in a microwave vial. TMSCI (357 pL, 2.76 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[c / jthiazol-2-yl)-4-(l-phenyl-lH-pyrazol-5-yl)but-3-enoic acid (50.9 mg, 0.141 mmol, 27%) was obtained as a light pink solid. TH NMR (400 MHz, DMSO-de) 6 12.74 (s, 1H), 8.06 (dd, J = 8.0, 1.3 Hz, 1H), 8.02-7.97 (m, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.63-7.54 (m, 4H), 7.54-7.48 (m, 2H), 7.44 (td, J = 7.6, 1.3 Hz, 1H), 7.27 (s, 1H), 6.78 (d, J = 2.0 Hz, 1H), 4.02 (s, 2H). Compound 18: (E)-3-(benzo[d]thiazoi-2-yO-4-(l,3-diphenyl-lW-pyrazol-4- 5 yi)but-3-enoic acid According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (175 mg, 0.844 mmol) and l,3-diphenyl-lH-pyrazole-4-carbaldehyde (222 mg, 0.896 mmol) were dissolved in anhydrous DMF (1 mL) and sealed in a microwave vial. TMSCI (551 10 pL, 4.25 mmol) was added dropwise before heating the reaction to 110 °C for 16 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l,3-diphenyl-lH-pyrazol-4-yl)but-3-enoic acid (192 mg, 0.438 mmol, 52%) was obtained as a brown solid. TH NMR (400 MHz, DMSO-de) 6 12.52 (s, 1H), 8.83 (s, 1H), 8.09-8.03 (m, 1H), 7.97 (d, J = 8.1 Hz, 3H), 7.75-7.68 (m, 2H), 7.61-7.54 (m, 4H), 7.50 (td, J = 7.3, 1.5 Hz, 2H), 7.45-7.36 (m, 3H), 4.06 15    (s, 2H). Compound 19: (E)-3-(5-chlorobenzo[d]thiazol-2-yi)-4-(3-(4-chlorophenyl)-l-methyl-lW-pyrazol-4-yi)but-3-enoic acid O Cl Step 1 According to general method C, 2-amino-4-chlorobenzenethioi (320 mg, 2.00 mmol) was dissolved in toluene (20 mL) and succinic anhydride (200 mg, 2.00 mmol) added. 3-(5-chlorobenzo[d]thiazol“2-yl)propanoic acid (377 mg, 1.56 mmol, 78%) was obtained as a colourless solid. TH NMR (400 MHz, CDCb) 3 7.97 (d, j = 2.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 3.44 (t, j = 7.1 Hz, 2H), 3.02 (t, J = 7.1 Hz, 2H). Step 2 According to general method B, 3-(5-chlorobenzo[d]thiazol-2-yl)propanoic acid (61.0 mg, 0.251 mmol) and 3-(4-chiorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (54.0 mg, 0.265 mmol) were dissolved in anhydrous DMF (0.8 mL) and sealed in a microwave vial. TMSCI (169 pL, 1.33 mmol) was added dropwise before heating the reaction to 120 °C for 10 h. (E)-3-(5-chlorobenzo[d]thiazol~2-yl)-4-(3-(4-chlorophenyl)-l-methyl-l / 7-pyrazol-4-yl)but-3-enoic acid (66.8 mg, 0.151 mmol, 60%) was obtained as a colourless solid. TH NMR (400 MHz, DMSO-de) 3 12.58 (s, 1H), 8.14 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.59 (s, 4H), 7.48 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 (s, 1H), 3.98 (s, 3H), 3.89 (s, 2H). Compound 20: (E)-4-(3-(4-chloropheny0-l-methyl-lW-pyrazoh4-y0-3-(5-(tnfluoromethy0benzo[d]thsazol-2-y0but-3-enoiic add Step 1 According to general method C, 2-amino-4-trifluoromethylbenzenethiol (386 mg, 2.00 mmol) was dissolved in toluene (20 mL) and succinic anhydride (200 mg, 2.00 mmol) added. 3-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)propanoic acid (176 mg, 0.639 - 60 -mmol, 32%) was obtained as a colourless solid. NMR (400 MHz, CDCh) 6 8.28 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.65 (d, j = 9.0 Hz, 1H), 3.51 (t, J = 7.0 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H). Step 2 According to general method B, 3-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)propanoic acid (60.7 mg, 0.221 mmol) and 3-(4-chlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (60.2 mg, 0.282 mmol) were dissolved in anhydrous DMF (0.8 mL) and sealed in a microwave vial. TMSCI (169 pL, 1.33 mmol) was added dropwise before heating the reaction to 120 °C for 10 h. (E)-4-(3-(4-chlorophenyl)-l-methyl-lH-pyrazol-4-yl)-3-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)but-3-enoic acid (44.4 mg, 0.093 mmol, 42%) was obtained as a pale orange solid. ’H NMR (400 MHz, DMSO-de) 3 12.58 (s, 1H), 8.35-8.28 (m, 2H), 8.17 (s, 1H), 7.75 (dd, j = 8.9, 1.5 Hz, 1H), 7.60 (s, 4H), 7.42 (s, 1H), 3.99 (s, 3H), 3.92 (s, 2H). Compound 21: (E)-4-(3-(4-chlorophenyl)-l-methyhlH-pyrazol-4-yl)-3-(5-ethyi-7-(tnfluoromethyl)-[l,2,.4]triazolo[l,5-a]pyrimidin-2-yi)but~3~enoic acid O Cl According to general method B, 3-(5-ethyl-7-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)propanoic acid (39.0 mg, 0.136 mmol) and 3-(4-chlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (31.6 mg, 0.143 mmol) were dissolved in anhydrous DMF (0.8 mL) and sealed in a microwave vial. TMSCI (86.3 pL, 0.680 mmol) was added dropwise before heating the reaction to 120 °C for 10 h. (E)-4-(3-(4-chlorophenyl)-l-methyl-lH-pyrazol-4-yl)-3-(5-ethyl-7-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)but-3-enoic acid (46.1 mg, 93.9 pmol, 69%) was obtained as a pale orange solid. TH NMR (400 MHz, DMSO-de) 6 12.25 (s, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.67 (s, 1H), 7.62 (d, j = 8.5 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 3.97 (s, 3H), 3.10 (t, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H). Compound 22: (E)-3-(benzo[d]thiazoi-2-yi)-4-(l-methyl-3-(4-(trifiuoromethyi)phenyi)-lH-pyrazoi-4-yi)but-3-enoic add O f3c Step 1 According to general method A, 3-(4-(trifluoromethyl)phenyl)-lH-pyrazole-4-carbaidehyde (348 mg, 1.45 mmol) was reacted with cesium carbonate (945 mg, 2.90 mmol) and iodomethane (135 pL, 2,18 mmol) in anhydrous DMF (10 mL). The crude product was purified using flash column chromatography eluting with a gradient of 1540% EtOAc in n-Hex. l-methyl-3-(4-(trifluoromethyl)phenyl)-l / +-pyrazole-4-carbaldehyde (151 mg, 0.594 mmol, 41%) was obtained as a colourless crystalline solid. TH NMR (400 MHz, CDCI3) 3 9.93 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 4.01 (s, 3H), Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (54.6 mg, 0.263 mmol) and l-methyl-3-(4-(trifluoromethyl)phenyl)-lH-pyrazole-4-carbaldehyde (70.6 mg, 0.277 mmol) were dissolved in anhydrous DMF (1 mL) and sealed in a microwave vial. TMSCI (174 pL, 1.39 mmol) was added dropwise before heating the reaction to 135 °C for 18 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(4-(trifluoromethyl)phenyl)-l / 7-pyrazol-4-yl)but-3-enoic acid (82.9 mg, 0.187 mmol, 71%) was obtained as an off-white solid. *H NMR (400 MHz, DMSO-ds) 6 12.55 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.54-7.46 (m, 1H), 7.45-7.41 (m, 1H), 7.39 (s, 1H), 4.01 (s, 3H), 3.92 (s, 2H). Compound 23: (E)-3-(benzo[d’]thiazoh2“yO-4-(3-bromo-l-methyhlW-pyrazol-4-yl)but-3-enok acid Step 1 Anhydrous DMF (3 mL) was cooled to 0 °C and POCI3 (3 mL) was added dropwise. The mixture was aiiowed to warm to r.t. and stirred for 1 h. 3-bromo-l-methylpyrazole (1.00 g, 6.21 mmol) was added dropwise before the reaction was heated to 95 °C and stirred for 3 h. The reaction was then allowed to cool and quenched by pouring into cold water. The mixture was neutralized with 2M NaOH and the resultant precipitate was collected in vacuo, washed with cold water and dried in vacuo. 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (929 mg, 4.92 mmol, 79%) was obtained as a brown solid. NMR (400 MHz, DMSO-de) 6 9.69 (s, 1H), 8.46 (s, 1H), 3.89 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (97.2 mg, 0.469 mmol) and 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (100 mg, 0.529 mmol) were dissolved in anhydrous DMF (0.640 mL) and sealed in a microwave vial. TMSCI (337 pL, 2.60 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-bromo-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (89.0 mg, 0.235 mmol, 50%) was obtained as a yellow solid. !H NMR (400 MHz, MeOD) 6 7.99-7.91 (m, 3H), 7.51-7.46 (m, 1H), 7.41 (td, j = 7.6, 1.2 Hz, 1H), 7.32 (s, 1H), 3.97 (s, 2H), 3.94 (s, 3H). Compound 24: (E)-3-(benzo[d]thiazol-2-y0-4“(l-methyl-3-(p-tolyl)- 1H-pyrazol-4-yl)but-3-enok acid O Step 1 According to general method A, 3-(p-tolyl)-lH-pyrazole-4-carbaldehyde (300 mg, 1.61 mmol) was reacted with cesium carbonate (1.09 g, 3.22 mmol) and iodomethane (158 pL, 2.47 mmol) in anhydrous DMF (13 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. 1-methyl-3-(p-tolyl)-lH-pyrazole-4-carbaldehyde (150 mg, 0.750 mmol, 47%) was obtained as a colourless solid. *H NMR (400 MHz, CDCh) 6 9.90 (s, 1H), 7.96 (s, 1H), 7.61-7.54 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.95 (s, 3H), 2.38 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (136 mg, 0.657 mmol) and l-methyl-3-(p-tolyl)-lH-pyrazole-4-carbaldehyde (150 mg, 0.750 mmol) were dissolved in anhydrous DMF (0.8 mL) and sealed in a microwave vial. TMSCI (461 pL, 3.56 mmol) was added dropwise before heating the reaction to 120 °C for 12 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(p-tolyl)-lH-pyrazol-4-yl)but-3-enoic acid (15.3 mg, 37.3 pmol, 6%) was obtained as a yellow solid. rH NMR (400 MHz, DMSO-de) 6 12.52 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.52-7.43 (m, 3H), 7.43-7.38 (m, 1H), 7.36-7.29 (m, 3H), 3.96 (s, 3H), 3.90 (s, 2H), 2.37 (s, 3H) Compound 25: (E)-3-(benzo[d’]thiazoh2-y0-4“(3-(4-fluor'opheny0-l“methyl- lH-pyrazol-4-yl)but-3-enok add Step 1 According to general method A, 3-(4-fluorophenyl)-l / 7-pyrazole-4-carbaldehyde (300 mg, 1.58 mmol) was reacted with cesium carbonate (1.07 g, 3.16 mmol) and iodomethane (155 pL, 2.37 mmol) in anhydrous DMF (12 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. 3-(4-fluorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (111 mg, 0.543 mmol, 34%) was obtained as a colourless solid. !H NMR (400 MHz, CDCh) 6 9.89 (s, 1H), 7.98 (s, 1H), 7.77-7.68 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 3.97 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (99 mg, 0.478 mmol) and 3-(4-fluorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (111 mg, 0.543 mmol) were dissolved in anhydrous DMF (0.634 mL) and sealed in a microwave vial. TMSCI (334 pL, 2.58 mmol) was added dropwise before heating the reaction to 120 °C for 9 h. (E)-3-(benzo[c / ]thiazol-2-yl)-4-(3-(4-fluorophenyl)-l-methyl-l / 7-pyrazol-4-yl)but-3-enoic acid was obtained as a colourless solid. TH NMR (400 MHz, DMSO-de) 6 12.53 (s, 1H), 8.11 (s, 1H), 8.03 (dd, J = 7.9, 1.3 Hz, 1H), 7.97- 7.89 (m, 1H), 7.64- 7.56 (m, 2H), 7.48 (ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.41 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.38- 7.29 (m, 3H), 3.96 (s, 3H), 3.90 (s, 2H). Compound 26: (E)-3-(benzo[d’]thiazoh2-yO-4“(l-methyl-3-phenyl-lH-pyrazol-4-yl)but-3-enok acid O Step 1 According to general method A, 3-phenyl-lH-pyrazole-4-carbaldehyde (300 mg, 1.74 mmol) was reacted with cesium carbonate (1.18 g, 3.48 mmol) and iodomethane (171 pL, 2.61 mmol) in anhydrous DMF (14 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-45% EtOAc in n-Hex. l-methyl-3-phenyl-lH-pyrazole-4-carbaldehyde (154 mg, 0.826 mmol, 48%) was obtained as a yellow oil. *H NMR (400 MHz, CDCb) 3 9.89 (d, J = 1.3 Hz, 1H), 7.96 (s, 1H), 7.747.64 (m, 2H), 7.48-7.33 (m, 3H), 3.92 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (151 mg, 0.726 mmol) and l-methyl-3-phenyl-lH-pyrazole-4-carbaldehyde (154 mg, 0.826 mmol) were dissolved in anhydrous DMF (0.966 mL) and sealed in a microwave vial. TMSCI (508 pL 3.92 mmol) was added dropwise before heating the reaction to 120 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-phenyl-lH-pyrazol-4-yl)but-3-enoic acid (142 mg, 0.378 mmol, 52%) was obtained as a brown solid. TH NMR (400 MHz, DMSO-de) 6 12.52 (s, 1H), 8.11 (s, 1H), 8.03 (dd, J = 8.0, 1.3 Hz, 1H), 7.977.90 (m, 1H), 7.57 (dt, J = 6.4, 1.5 Hz, 2H), 7.54-7.38 (m, 5H), 7.36 (s, 1H), 3.97 (s, 3H), 3.91 (s, 2H). Compound 27: (E)-3-(benzo[d]thiazol-2-y0-4-(3-(3-cyanophenyi)-l-methyl-lH-pyrazob4-y0but-3-enoic add O Step 1 According to general method D, [1,1'-bis(diphenyiphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (120 mg, 0.635 mmol), 3-Cyanophenylboronic acid (187 mg, 1.27 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. 3-(4-formyl-l-methyl-lH-pyrazol-3-yl)benzonitrile (57.2 mg, 0.271 mmol, 43%) was obtained as a colourless solid. TH NMR (400 MHz, CDCb) 3 9.91 (s, 1H), 8.14 (t, J = 1.8 Hz, 1H), 8.08 (dt, J = 7.8, 1.5 Hz, 1H), 8.02 (s, 1H), 7.68 (dt, J = 7.8, 1.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 4.00 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (49.7 mg, 0.240 mmol) and 3-(4-formyl-l-methyl-lH-pyrazol-3-yl)benzonitrile (57.2 mg, 0.271 mmol) were dissolved in anhydrous DMF (0.317 mL) and sealed in a microwave vial. TMSCI (167 pL, 1.29 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-cyanophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (11.2 mg, 28.0 pmol, 12%) was obtained as a light brown solid. XH NMR (400 MHz, DMSO-ds) 3 12.53 (s, 1H), 8.13 (s, 1H), 8.06 (dd, J = 8.0, 1.3 Hz, 1H), 8.00-7.86 (m, 4H), 7.73 (t, j = 7.8 Hz, 1H), 7.49 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.34 (s, 1H), 3.99 (s, 3H), 3.89 (s, 2H). Compound 28: (E)-3-(benzo[d]thiazol-2-yO-4-(l-methyl-3-(o-tolyl)-lH-pyrazoi-4-yi)but-3-enoic acid O Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (120 mg, 0.635 mmol), o-tolylboronic acid (173 mg, 1.27 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. l-methyl-3-(o-tolyl)-lH-pyrazole-4-carbaldehyde (72.4 mg, 0.362 mmol, 57%) was obtained as a - 66 - yellow oil. *H NMR (400 MHz, CDCb) 6 9.60 (s, 1H), 8.01 (s, 1H), 7.39-7.18 (m, 4H), 3.99 (s, 3H), 2.30 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (67.0 mg, 0.323 mmol) and l-methyl-3-(o-tolyl)-l / 7-pyrazole-4-carbaldehyde (72.4 mg, 0.362 mmol) were dissolved in anhydrous DMF (0.424 mL) and sealed in a microwave vial. TMSCI (224 pL, 1.73 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(o-tolyl)-lH-pyrazol-4-yl)but-3-enoic acid (31.2 mg, 80.1 pmol, 25%) was obtained as a light brown solid. TH NMR (400 MHz, DMSO-ds) 3 12.50 (s, 1H), 8.20 (s, 1H), 7.98 (dd, J = 7.9, 1.3 Hz, 1H), 7.91-7.87 (m, 1H), 7.45 (ddd, j = 8.3, 7.2, 1.4 Hz, 1H), 7.40-7.35 (m, 3H), 7.337.26 (m, 1H), 7.24 (d, J = 7.4 Hz, 1H), 6.97 (s, 1H), 3.97 (s, 3H), 3.91 (s, 2H), 2.23 (s, 3H). Compound 29; (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-chlorophenyl)-l-methyl-lH-pyrazol-4-yl)but~3~eno5C add O Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (120 mg, 0.635 mmol), 3-chlorophenylboronic acid (199 mg, 1.27 mmol), and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. 3-(3-chlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (97.0 mg, 0.440 mmol, 69%) was obtained as a yellow oil. NMR (400 MHz, CDCb) 6 9.90 (s, 1H), 7.99 (s, 1H), 7.75 (dt, J = 1.7, 1.1 Hz, 1H), 7.67-7.57 (m, 1H), 7.43-7.35 (m, 2H), 3.98 (d, J = 8.9 Hz, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (80.2 mg, 0.387 mmol) and 3-(3-chlorophenyl)-l-methyl-l / 7-pyrazole-4-carbaldehyde (97.0 mg, 0.440 mmol) were dissolved in anhydrous DMF (0.514 mL) and sealed in a microwave vial. TMSCI (271 pL, 2.09 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-chlorophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (21.9 mg, 53.4 pmol, 14%) was obtained as a dark green solid. TH NMR (400 MHz, DMSO-de) 6 12.51 (s, 1H), 8.13 (d, J = 6.1 Hz, 1H), 8.05 (dd, J = 7.9, 1.3 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.62-7.58 (m, 1H), 7.55-7.46 (m, 4H), 7.44-7.38 (m, 1H), 7.35 (s, 1H), 3.97 (s, 3H), 3.89 (s, 2H). Compound 30: (E)-3-(benzo[d]thiazol-2-y0~4-(l-methyl-3-(67yndme-3-yl)-lH-pyrazol-4-yl)but-3-enoic add O 3-(1,3-benzothiazol-2-yl)propanoic acid (101 mg, 0.489 mmol) and l-methyl-3-(67yridine-3-yl)-lH-pyrazole-4-carbaldehyde (100 mg, 0.508 mmol) were dissolved in anhydrous DMF (0.625 mL) and sealed in a microwave vial. TMSCI (329 pL, 2.54 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. The reaction was quenched by pouring into water. The crude mixture was concentrated in vacuo and purified using reverse phase flash column chromatography eluting with a gradient of 5-100% ACN in H2O. Pure fractions were combined and the organic solvent removed in vacuo, resulting in precipitation of product out of the aqueous phase. The precipitated product was collected by vacuum filtration, washed with cold water and dried in vacuo. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(67yridine-3-yl)-lr / -pyrazol-4-yl)but-3-enoic acid (45.3 mg, 0.120 mmol, 25%) was obtained as a yellow solid. NMR (400 MHz, DMSO-de) 6 12.54 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (s, 1H), 8.04 (d, J = 7.5 Hz, 1H), 8.00-7.92 (m, 2H), 7.54 (dd, J = 8.0, 4.8 Hz, 1H), 7.49 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.35 (s, 1H), 3.99 (s, 3H), 3.90 (s, 2H). Compound 31: (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3“(67yridme-4-yl)-lH-pyrazol-4-yi)but-3-enoic add O According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (101 mg, 0.489 mmol) and l-methyl-3-(68yridine-4-yl)-lH-pyrazole-4-carbaldehyde (100 mg, 0.508 mmol) were dissolved in anhydrous DMF (0.625 mL) and sealed in a microwave vial. TMSCI (329 pL, 2.54 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(68yridine-4-yl)-lH-pyrazol-4-yl)but-3-enoic acid (34.5 mg, 91.7 pmol, 19%) was obtained as a yellow solid. TH NMR (400 MHz, DMSO-de) 6 12.56 (s, 1H), 8.91-8.85 (m, 2H), 8.17 (s, 1H), 8.11-8.07 (m, 1H), 8.06-8.02 (m, 2H), 8.01-7.96 (m, 1H), 7.54-7.49 (m, 2H), 7.45 (td, j = 7.6, 1.3 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 2H). Compound 32; (E)-3-(benzo[d]thiazol-2-yl)-4-(3-cydohexyhl-methyl-lH-pyrazol-4-yl)but-3-enoic acsd According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (101 mg, 0.488 mmol) and 3-cyclohexyl-l-methyl-lH-pyrazole-4-carbaldehyde (100 mg, 0.494 mmol) were dissolved in anhydrous DMF (0.625 mL) and sealed in a microwave vial. TMSCI (320 pL, 2.47 mmol) was added dropwise before heating the reaction to 110 °C for 9 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-cyclohexyi-l-methyi-l / 7-pyrazol-4-yl)but-3-enoic acid (32 mg, 83.4 pmol, 17%) was obtained as a yellow solid. *H NMR (400 MHz, DMSO-de) 6 12.48 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.96-7.88 (m, 2H), 7.48 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.40 (td, J = 7.6, 1.3 Hz, 1H), 7.36 (s, 1H), 3.84 (s, 5H), 2.85-2.70 (m, 1H), 1.87-1.75 (m, 4H), 1.74-1.67 (m, 1H), 1.58-1.32 (m, 4H), 1.24 (tt, J = 12.3, 3.4 Hz, 1H). Compound 33: (E)-3-(benzo[d]thiazol-2-yi)-4-(l-methyi-3-(m-toiyi)-lH-pyrazol-4-yl)but-3-enoic acid O Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (112 mg, 0.138 mmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (260 mg, 1.38 mmol), m-tolylboronic acid (374 mg, 2.75 mmol), and 2 M sodium carbonate (1.03 mL , 2.06 mmol) in DME (4 mL). The crude product purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. l-methyl-3-(m-tolyl)-lH-pyrazole-4-carbaldehyde (199 mg, 0.995 mmol, 72%) was obtained as a yellow solid. TH NMR (400 MHz, CDCb) 6 9.92 (s, 1H), 8.00 (s, 1H), 7.54-7.45 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.28-7.22 (m, 1H), 3.97 (s, 3H), 2.41 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (200 mg, 0.965 mmol) and l-methyl-3-(m-tolyl)-lH-pyrazole-4-carbaldehyde (199 mg, 0.995 mmol) were dissolved in anhydrous DMF (1.2 mL) and sealed in a microwave vial. TMSCI (612 pL, 4.73 mmol) was added dropwise before heating the reaction to 110 °C for 24 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(m-tolyl)-lH-pyrazol-4-yl)but-3-enoic acid (177 mg, 0.455 mmol, 47%) was obtained as a green solid. rH NMR (400 MHz, DMSO-ds) 6 12.46 (s, 1H), 8.10 (s, 1H), 8.06-8.02 (m, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.48 (ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.43-7.32 (m, 5H), 7.25 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 2H), 2.38 (s, 3H). Compound 34: (E)-3-(benzo[d]thiazoi-2-yi )-4-( l-methyl-3-(thiophen-2-yi)-lH-pyrazol-4-yl)but-3-enoic acid O Step 1 According to general method A, 3-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde (300 mg, 1.68 mmol) was reacted with cesium carbonate (1.14 g, 3.37 mmol) and iodomethane (165 pL, 2.53 mmol) in anhydrous DMF (13 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. l-methyl-3-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde (203 mg, 1.06 mmol, 63%) was obtained as a colourless solid. NMR (400 MHz, CDCb) 6 9.99 (s, 1H), 7.92 (s, 1H), 7.79 (dd, J = 3.7, 1.2 Hz, 1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.10 (dd, J = 5.1, 3.7 Hz, 1H), 3.92 (s, 3H). Step 2 According to general method B, 3-(1,3-benzothiazol-2-yl)propanoic acid (217 mg, 1.05 mmol) and l-methyl-3-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde (203 mg, 1.06 mmol) were dissolved in anhydrous DMF (1.34 mL) and sealed in a microwave vial. TMSCi (684 pL, 5.28 mmol) was added dropwise before heating the reaction to 110 °C for 24 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(thiophen-2-yl)-lH-pyrazol-4-yl)but-3-enoic acid (128 mg, 0.336 mmol, 32%) was obtained as a brown solid. TH NMR (400 MHz, DMSO-d6) 6 12.52 (s, 1H), 8.10 (s, 1H), 8.07 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 7.97-7.94 (m, 1H), 7.64 (dd, J = 5.1, 1.1 Hz, 1H), 7.53 (s, 1H), 7.50 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.42 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.28 (dd, J = 3.6, 1.1 Hz, 1H), 7.21 (dd, J = 5.1, 3.6 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 2H). Compound 35: (f)-3-(benzo[d]thiazol-2-y0-4-(l-methyl-3-(3- (triHuoromethynpheny0-XW-pyrazo§-4-y0but-3-enoic add Step 1 According to general method D, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), 3-trifluoromethylphenylboronic acid (186.0 mg, 1.22 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-40% EtOAc in n-Hex. 4-(4- formyl-l-methyl-lH-pyrazol-3-yl)benzonitrile (131.3 mg, 0.47 mmol, 55%) was obtained as a colourless solid. *H NMR (400 MHz, DMSO-ds) 6 9.88 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 3.99 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yl)propanoic acid (54.2 mg, 0.26 mmol) and 3-(3,4-dichlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (70.0 mg, 0.27 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (210 pL, 1.6 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (q-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(3-(trifluoromethyl)phenyl)-lH-pyrazol-4-yl)but-3-enoic acid (79.3 mg, 0.18 mmol, 69%) was obtained as a brown solid. *H NMR (400 MHz, DMSO-de) 6 8.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.91 - 7.84 (m, 2H), 7.84 - 7.72 (m, 2H), 7.59 -7.46 (m, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.38 (s, 1H), 4.00 (s, 3H), 3.90 (s, 2H). Compound 36: (£)-3-(benzcs[rf]oxazoi-2-yn-4-(3~(4-chlorophenyi)--l--methyh lH-pyrazol-4-yl)but-3-enoic add HO N According to general method B, 3-(1,3-benzo[d]oxazol-2-yl)propanoic acid (49.7 mg, 0.26 mmol) and 3-(4-chlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (59.6 mg, 0.27 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (315 pL, 2.48 mmol) was added dropwise before heating the reaction to 135 °C for 9 h. (H)-3-(benzo[d]oxazol-2-yl)-4-(3-(4-chlorophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (69.1 mg, 0.18 mmol, 65%) was obtained as a colourless solid. *H NMR (400 MHz, DMSO-da) 6 12.44 (s, 1H), 8.15 (s, 1H), 7.78 -7.67 (m, 2H), 7.61 (s, 1H), 7.59 (s, 4H), 7.43 - 7.30 (m, 2H), 3.98 (s, 3H), 3.83 (s, 2H). Compound 37: (E')-3-(benzo[d]thiazol-2-yQ-4-(3-(3,4-dichloropheny0-l- methyl-lH-pyrazol-4-yl)but-3-enoic acid Step 1 According to general method D, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (120 mg, 0.635 mmol), 3,4-dichlorophenylboronic acid (242.3 mg, 1.27 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-40% EtOAc in n-Hex. 3-(3,4-dichiorophenyl)-l-methyi-lH-pyrazole-4-carbaldehyde (79.3 mg, 0.311 mmol, 49%) was obtained as a colourless solid. XH NMR (400 MHz, DMSO-ds) 6 9.85 (s, 1H), 8.58 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.4, 2.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yl)propanoic acid (50.9 mg, 0.24 mmol) and 3-(3,4-dichlorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (66.0 mg, 0.25 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCi (190 pL, 1.6 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3,4-dichlorophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (64.0 mg, 0.14 mmol, 58%) was obtained as an off-white solid. *H NMR (400 MHz, DMSO-c / s) 6 12.51 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 3.96 (s, 3H), 3.90 (d, J = 1.7 Hz, 2H). Compounds 38: (F)-3-(benzo[d]thiazol-2-yQ-4-(3-(6-chloropyridin-3-y0-l- methyl-lH-pyrazol-4-yl)but“3-enoic acid Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-l / 7-pyrazole-4-carbaldehyde (120 mg, 0.635 mmol), (6-chloropyridin-3-yl)boronic acid (200 mg, 1.27 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-60% EtOAc in n-Hex. 3-(6-chloropyridin-3-yl)-l-methyl-l / - / -pyrazole-4-carbaldehyde (97.1 mg, 0.438 mmol, 69%) was obtained as a colourless solid. rH NMR (400 MHz, DMSO-de) 6 9.87 (s, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.63 (s, 1H), 8.32 (dd, J = 8.4, 2.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H). Step 2 According to general method B, 3-(benzo[djthiazol-2-yl)propanoic acid (23.7 mg, 0.12 mmol) and 3-(6-chloropyridin-3-yl)-l-methyl-lH-pyrazole-4-carbaldehyde (26.7 mg, 0.18 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (160 pL, 1.3 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(6-chloropyridin-3-yl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (20.0 mg, 0.05 mmol, 40%) was obtained as a brown solid. ’H NMR (400 MHz, DMSO-ds) 6 12.52 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 8.11 - 7.97 (m, 2H), 7.95 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.35 (s, 1H), 3.99 (d, J = 4.8 Hz, 3H), 3.89 (s, 2H). Compound 39: (E')-3-(benzo[d]thiazol-2-yQ-4-(3-(5-chlorothiophen-2-y0-l- methyl-lH-pyrazol-4-yl)but“3-enoic acid Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (120 mg, 0.635 mmol), (5-chlorothiophen-2-yl)boronic acid (206.2 mg, 1.27 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-40% EtOAc in n-Hex. 3-(5-chlorothiophen-2-yl)-l-methyl-lH-pyrazole-4-carbaldehyde (61.9 mg, 0.273 mmol, 43%) was obtained as a colourless solid. XH NMR (400 MHz, DMSO-de) 3 9.89 (s, 1H), 8.59 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 3.93 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazoi-2-yi)propanoic acid (42.8 mg, 0.20 mmol) and 3-(5-chlorothiophen-2-yl)-l-methyl-lH-pyrazole-4-carbaldehyde (49.2 mg, 0.21 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCi (160 pL, 1.3 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E,)-3-(benzo[d]thiazoi-2-yl)-4-(3-(5-chlQrothiophen-2-yl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (50.0 mg, 0.12 mmol, 60%) was obtained as a brown solid. !H NMR (400 MHz, DMSO-de) 6 8.58 (s, 1H), 8.11 - 8.04 (m, 1H), 7.98 (s, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 3.91 (s, 3H), 3.87 (s, 2H). Compound 40: (E')-3-(benzo[d]thiazoh2-yQ-4-(3-(4-cyanophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic add O N                          N Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), 4-cyanophenylboronic acid (179.9 mg, 1,22 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-40% EtOAc in n-Hex. 4-(4-formyl-l-methyl-lH-pyrazol-3-yl)benzonitrile (100.0 mg, 0.47 mmol, 50%) was obtained as a colourless solid. rH NMR (400 MHz, DMSO-d6) 3 9.88 (s, 1H), 8.61 (s, 1H), 8.15 -8.04 (m, 2H), 7.97 - 7.89 (m, 2H), 3.98 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yi)propanoic acid (72.5 mg, 0.34 mmol) and 4-(4-formyl-l-methyl-lH-pyrazol-3-yl)benzonitrile (77.0 mg, 0.36 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (280 pL, 2.2 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E')-3-(benzo[d]thiazol-2-yl)-4-(3-(4-cyanophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (77.0 mg, 0.19 mmol, 55%) was obtained as an off-white solid. rH NMR (400 MHz, DMSO-cfe) 6 8.14 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.95 (d, J = 6.5 Hz, 3H), 7.78 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.36 (s, 1H), 3.99 (s, 3H), 3.88 (s, 2H). Compound 41: (E')-3-(benzo[d]thiazoh2-yQ-4-(3-(3-HuorophenyQ-l-methyi- lH-pyrazol-4-yl)but-3-enoic add Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), 3-fluorophenylboronic acid (224 mg, 1.60 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-70% EtOAc in n-Hex. 3-(3-fluorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (100.0 mg, 0.479 mmol, 51%) was obtained as a colourless solid. rH NMR (400 MHz, DMSO-ds) 5 9.86 (s, 1H), 8.56 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.50 (q, J = 7.4 Hz, 1H), 7.26 (dt, J = 9.2, 5.0 Hz, 1H), 3.96 (s, 3H). Step 2 According to general method B, 3-(benzo[djthiazol-2-yl)propanoic acid (90.6 mg, 0.40 mmol) and 3-(3-fluorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (94.0 mg, 0.45 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (350 pL, 1.9 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-fluorophenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (88.5 mg, 0.23 mmol, 58%) was obtained as a brown solid. *H NMR (400 MHz, DMSO-cfe) 6 12.52 (s, 1H), 8.12 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.94 (t, J = 8.3 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.55 - 7.49 (m, 1H), 7.49 - 7.45 (m, 1H), 7.42 (s, 1H), 7.40 (t, J = 1.3 Hz, 1H), 7.38 (d, J - 4.8 Hz, 1H), 7.33 - 7.24 (m, 1H), 3.98 (s, 3H), 3.90 (s, 2H). Compound 42: (E')-3-(benzo[d]thiazoi-2-yi)-4-(3-(3-methoxyphenyi)-l-methyl-lH-pyrazol-4-yl)but“3-enoic acid (AMR-9-42) O Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), 3-methoxyphenylboronic acid (186 mg, 1.22 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-60% EtOAc in n-Hex. 3-(3-methQxyphenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (102.0 mg, 0.47 mmol, 50%) was obtained as a colourless solid. rH NMR (400 MHz, DMSO-ds) 6 9.85 (s, 1H), 8.51 (s, 1H), 7.39 (q, J = 1.2 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.99 (dt, J = 6.8, 2.5 Hz, 1H), 3.94 (s, 3H), 3.80 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yl)propanoic acid (66.4 mg, 0.3 mmol) and 3-(3-methoxyphenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (73.0 mg, 0.31 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCi (250 pL, 1.9 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(3-(3-methoxyphenyl)-l-methyl-lH-pyrazol-4-yl)but-3-enoic acid (73.5 mg, 0.18 mmol, 60%) was obtained as a brown solid. TH NMR (400 MHz, DMSO-cfe) 6 8.12 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.98 -7.90 (m, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.45 - 7.35 (m, 3H), 7.18 - 7.11 (m, 2H), 7.01 (d, J - 8.4 Hz, 1H), 3.98 (s, 3H), 3.89 (s, 2H), 3.80 (s, 3H). Compound 43: (E')-3-(benzo[d]thiazol-2-yQ-4-(3-(4-chloro-3-Huorophenyl)-l-methyl-lH-pyrazol-4-yl)but“3-enoic acid O Step 1 According to general method D, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), (4-chloro-3-fluorophenyl)boronic acid (279.1 mg, 1,6 mmol), and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-50% EtOAc in n-Hex. 3-(4-chloro-3-fluorophenyl)-l-methyl-lH-pyrazole-4-carbaldehyde (143.2 mg, 0.30 mmol, 64%) was obtained as a colourless solid. *H NMR (400 MHz, DMSO-ds) 6 9.85 (s, 1H), 8.59 (s, 1H), 7.97 (dd, J = 10.9, 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 3.96 (s, 3H). 13C NMR (101 MHz, DMSO-de) 6 184.2, 152.2 (d, J = 729.0 Hz), 148.6, 139.7, 132.8, 132.7, 130.7, 129.95, 125.3, 120.5, 116.3 (d, J = 22.8 Hz), 39.2. 19F NMR (377 MHz, DMSO-ds) 6 -116.03 - -116.16 (m). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yl)propanoic acid (92.2 mg, 0.44 mmol) and 3-(2-fluorophenyl)-l-methyi-lH-pyrazole-4-carbaldehyde (109.8 mg, 0.46 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (350 pL, 2.75 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E)-3-(benzo[d]thiazol-2-yl)-4-(l-methyl-3-(quinolin-6-yl)-lH-pyrazol-4-yi)but-3-enoic acid (87.0 mg, 0.20 mmol, 45%) was obtained as a brown solid. rH NMR (400 MHz, DMSO-ds) 6 12.54 (s, 1H), 8.12 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.57 (dd, J = 10.4, 1.9 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 7.35 (s, 1H), 3.97 (d, J = 4.3 Hz, 3H), 3.88 (s, 2H). 19F NMR (377 MHz, DMSO-de) 6 -115.48 - -115.61 (m). Compound 44: (E,)-3-(benzo[d]thiazoh2-yQ-4-(3-(2-HuorophenyQ-l-methyi- lH-pyrazol-4-yl)but-3-enoic add Step 1 According to general method D, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), 2-fluorophenylboronic acid (224 mg, 1.1 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-70% EtOAc in n-Hex. 3-(2-fluorophenyl)~ l-methyi-lH-pyrazole-4-carbaldehyde (80.0 mg, 0.39 mmol, 42%) was obtained as a colourless solid. NMR (400 MHz, DMSO-d6) 3 9.71 (d, J = 2.3 Hz, 1H), 8.52 (s, 1H), 7.59 - 7.47 (m, 2H), 7.37 - 7.26 (m, 2H), 3.96 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yi)propanoic acid (92.2 mg, 0.44 mmol) and 3-(2-fluorophenyl)-l-methyl-l / 7-pyrazole-4-carbaldehyde (95.6 mg, 0.46 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (350 pL, 2.75 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (E)~3-(benzQ[d]thiazol-2-yl)-4-(l-methyl-3-(quinolin-6-yl)-l / - / -pyrazol-4-yl)but-3-enoic acid (88.0 mg, 0.22 mmol, 50%) was obtained as a brown solid. *H NMR (400 MHz, DMSO-c / e) 6 8.20 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.52 - 7.45 (m, 3H), 7.41 - 7.34 (m, 3H), 7.14 (s, 1H), 3.98 (d, J = 3.4 Hz, 3H), 3.90 (s, 2H). Compound 45: (£')-3-(benzo[d]thiazol-2-yQ-4-(l-methy§-3-(qumobn-6-yO-lH-pyrazol-4-yl)but-3-enoic add O Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (178 mg, 0.940 mmol), quinolin-6-ylboronic acid (280.0 mg, 1.6 mmol), and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL) . The crude product was purified using flash column chromatography eluting with a gradient of 0-70% EtOAc in n-Hex. l-methyl-3-(quinolin-6-yl)-l / - / -pyrazole-4-carbaldehyde (156.1 mg, 0.66 mmol, 70%) was obtained as a colourless solid. NMR (400 MHz, CDCH) 6 10.02 (s, 1H), 8.95 (dd, J = 4.3, 1.7 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.24 (dd, J = 8.2, 1.7 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.13 (dd, J = 8.8, 1.9 Hz, 1H), 8.05 (s, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 4.04 (s, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yl)propanoic acid (23.4 mg, 0.13 mmol) and l-methyl-3-(quinolin-6-yl)-lH-pyrazole-4-carbaldehyde (33.0 mg, 0.14 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (150 pL, 2.26 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (H)-3-(benzo[c / ]thiazol-2-yl)-4-(l-methyl-3-(quinolin-6-yl)-l / 7-pyrazol-4-yl)but-3-enoic acid (37.2 mg, 0.09 mmol, 69%) was obtained as a grey solid. TH NMR (400 MHz, DMSO-ds) 6 8.07 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 19.2 Hz, 1H), 7.70 (dd, J = 4.9, 3.0 Hz, 1H), 7.64 (s, 1H), 7.48 (s, 1H), 7.40 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 3.94 (d, J = 3.6 Hz, 3H), 3.86 (s, 2H). Compound 46: (E')-3-(benzo[d]thiazoh2-yQ-4-(5-(4-chlorophenyl)-2-methyl- SH-lflfS-tnazo^-yObut-B-enoic acid O Step 1 According to general method D, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM (51.9 mg, 63.5 pmol) was added to 5-bromo-2-methyl-2H-l,2,3-triazole-4-carbaldehyde (158 mg, 0.82 mmol), 4-chlorophenylboronic acid (221.1 mg, 1,6 mmol) and 2 M sodium carbonate (480 pL, 0.952 mmol) in DME (1.85 mL). The crude product was purified using flash column chromatography eluting with a gradient of 0-15% EtOAc in n-Hex. 5-(4-chlorophenyl)-2-methyi-2H-l,2,3-triazole-4-carbaldehyde (110.8 mg, 0.50 mmol, 61%) was obtained as a colourless solid. *H NMR (400 MHz, CDCH) 6 10.18 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.48 - 7.40 (m, 2H), 4.32 (d, J = 1.6 Hz, 3H). Step 2 According to general method B, 3-(benzo[d]thiazol-2-yi)propanoic acid (68.1 mg, 0.32 mmol) and 5-bromo-2-methyl-2 / 7-l,2,3-triazole-4-carbaldehyde (76.5 mg, 0.33 mmol) were dissolved in anhydrous DMF (0.9 mL) and sealed in a microwave vial. TMSCI (260 pL, 2.00 mmol) was added dropwise before heating the reaction to 135 °C for 48 h. (5)-3-(benzo[d]thiazol-2-yl)-4-(5-(4-chlorophenyi)-2-methyl-2H-l,2,3-triazol-4-yl)but-3-enoic acid (128.0 mg, 0.31 mmol, 97%) was obtained as a grey solid. TH NMR (400 MHz, DMSO-d6) 6 12.40 (s, 1H), 8.12 - 8.07 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.56 - 7.50 (m, 1H), 7.49 - 7.44 (m, 1H), 7.41 (s, 1H), 4.29 (s, 3H), 4.25 (s, 2H). Checkerboards Synergy between compounds and antibiotics were determined using MIC checkerboard assays as described previously (Sabnis et ai., 2021 eLife). A range of antibiotic or compound concentrations was generated in TSB (200 pl) by making 2-fold serial dilutions in the wells of microtitre plates (96 well, clear bottom). To assess synergy, one plate was used to generate a concentration range of antibiotic across the plate and another range with a test compound was generated down another plate. Then, 100 pl of the diluted antibiotic from one plate was combined with the same volume of diluted compound from the second plate to produce a matrix of different concentrations of each compound. S. aureus cells were inoculated into the wells of the microtitre plates to a final concentration of 5 x 105 CFU ml-1 before incubation statically at 37°C for 18 h in air. Bacterial growth after 18 h incubation was measured by obtaining ODsssnm measurements using a Bio-Rad iMark microplate absorbance reader (Bio-Rad Laboratories, USA). Transposon mutagenesis (norA knockout strain in SH1000) The noM::Tn insertion was transduced from JE2 norA-.-.Tn (from the Nebraska Transposon Mutant Library https: / / pubmed.ncbi.nlm.nih.gov / 23404398 / ) into SH1000 by phage transduction with ipll. TSB (5 ml) supplemented with 5 mM CaCI2 was inoculated with 100 ul overnight culture of the JE2 norA: :Tn mutant and incubated for 3 h at 37 °C with shaking. 10-fold serial dilutions of cpll lysate were prepared in TMG buffer (10 mM Tris-HCI (pH 7.5), 10 mM MgSO4, 0.1 % gelatin), cpll lysate (100 pl) was mixed with 500 pl bacteria and incubated at room temperature for 30 min before 5 ml top agar (0.8 % agar, 0.8 % NaCI) was added and poured over agar plates and incubated overnight before phage were harvested in TMG buffer. Overnight cultures of SH1000 were concentrated 10-fold in TSB supplemented with 5 mM CaCI2 before 250 pl bacteria was mixed with 200 pl phage lysate and incubated for 20 min at 37 °C. Phage infection was stopped by three washes in cold 20 mM sodium citrate before plating onto TSA supplemented with 20 mM sodium citrate and 10 pg / ml erythromycin. Successful disruption of norA with the transposon was confirmed by PCR. Transposon mutagenesis (norA overexpression strain in SH1O00) Transposon mutagenesis was performed as described in Wang et al., 2011 (https: / / www.nature.com / articles / nchembio.643). Transposon libraries were plated on to TSA + 5 pg / ml erythromycin, 0.4 pg / ml ciprofloxacin and 0.25 pM compound 1 and incubated for 3 days at 37 Q. Genomic DNA was extracted from 2 ml overnight cultures and eluted in 200 pl water. 20 pl gDNA was digested with acil for 3 h at 37 “C. Restriction enzyme was inactivated at 65 for 20 min. 18 pl digest reaction was ligated with T4 ligase overnight at room temperature in a final volume of 100 pl. DNA was purified using the QIAGEN PCR purification kit, DNA molecules containing the transposon were amplified by PCR (30 cycles, annealing temp 63 “C, extension time 2 min) using Martn_F and Martn_R (Bae et al, 2004) and sequenced by Eurofins genomics using Martn__F. Ethidium bromide efflux 100 pl bacterial overnight culture was inoculated into 10 ml TSB and incubated for 2 h at 37X2 with shaking (180 rpm). Bacteria were incubated for 20 min with 10 pg / ml ethidium bromide at 25 pg / ml reserpine at 37X2 with shaking (180 rpm). Bacteria were washed twice in PBS and concentrated 10-fold before 20 pl was inoculated into 200 pl TSB + various concentrations of compound. Fluorescence (excitation 525 nm; emission 605 nm) was measured every min for 20 min. Clinical isolate synergy Two-fold serial dilutions of ciprofloxacin were prepared in 96-well plates in a final volume of 200 pl. Where appropriate, wells also contained 2 pM of compound 1 or 1 pM of compound 5. Bacterial strains were inoculated to 5 x 105 CFU / ml. Plates were incubated statically at 37X2 for 17 h and the MIC was determined as the lowest concentration that inhibited bacterial growth. The fold decrease in MIC was determined using the following equation: CFX MIC in the presence of compound 1 Mammalian ceil proliferation and cytotoxicity HEK293T cells were seeded in a 96-well plate (2000 cells / well) and grown in DMEM with 10% FBS overnight. The next day, the media was replaced with media containing compound (3 nM - 30 pM) and SYTOX™ Green Nucleic Acid Stain (dye, 250 nM final concentration). For controls, cells were treated with media containing 0.1% DMSO or 2 pg / mL puromycin. The cell plate was incubated at 37 °C with 5% CO2 in the incubator. Phase and green fluorescence were imaged every 4 h for 6 days with the Incucyte Live-Cell Analysis Systems. Intrinsic clearance (Cli) experiments The test compound (0.5pM) was incubated with female CD1 mouse liver microsomes (Xenotech ™ ; 0.5mg / mL 50mM potassium phosphate buffer, pH7.4) and the reaction started with addition of excess NADPH (8mg / mL 50mM potassium phosphate buffer, pH7.4). Immediately, at time zero, then at 3, 6, 9, 15 and 30 minutes an aliquot (50pL) of the incubation mixture was removed and mixed with acetonitrile (lOOpL) to stop the reaction. Internal standard was added to all samples, the samples centrifuged to sediment precipitated protein and the plates then sealed prior to UPLC-MSMS analysis eg. (Xevo TQ-S Micro, Waters ™). XLfit (IDBS, UK) was used to calculate the exponential decay and consequently the rate constant (k) from the ratio of peak area of test compound to Internal standard at each timepoint. The rate of intrinsic clearance (CLi) of each test compound was then calculated using the following calculation: CLi(mL / min / mg protein ) = k x V Where V (mL / mg protein) = incubation volume (0.5mL) / mg protein added (0.25 mg protein). Verapamil (0.5pM) was used as a positive control to confirm acceptable assay performance. "RealSOL" method for solubility Test compounds were dissolved in DMSO to give 10 mM solutions. Solubility test samples were prepared by adding a volume (5 pL) of the 10 mM solution to a volume (195 pL) of phosphate buffered saline, pH 7.4 (Sigma-Aldrich, Cat no. P4417, made as per manufacturer's instructions). This solution was then mixed for 24 hours (rotary mixing, 900 rpm, 25°C) excluding light. After mixing, the solubility test samples were filtered to remove any undissolved material using a proprietary filter (Millipore Multiscreen HTS filter, 96-well format). Samples were drawn through the filter using vacuum. The filtrate from the above was analysed for dissolved drug compound using a truncated UHPLC methodology. A Shimadzu Nexera X2 UHPLC system was used, with a reversed-phase column and a simple formic acid gradient elution. The UHPLC parameters are shown below: Parameter Value Mobile phase component A HPLC water plus 0.1% formic acid Mobile phase component B HPLC acetonitrile plus 0.1% formic acid Flow rate: 0.6 ml / min Gradient program: Initial: 98% A, 2% B At 1.2 mins: 2% A, 98% B At 2.0 mins: 2% A, 98% B Re-equilibration time: 0.6 min Autosampler temperature: 25°C Column: Hypersil Gold, C18 1.9 pm, 50 x 2.1 mm Column temperature: 50°C Detector wavelength: 254 nm Bandwidth; 4 nm A calibration solution was prepared in the following way: The same 10 mM solution used to prepare the solubility test sample was diluted in DMSO to give a 500 pM solution. This solution was then again diluted with 50:50 acetonitrile: water to give a 50 pM solution. Aliquots (0.2, 2.0 and 5.0 pL) of this 50 pM solution were then injected onto the UHPLC system and the areas of the resultant peaks integrated to produce a calibration line. Aliquots of the test sample filtrate (0.4 and 5.0 pL) were then injected onto the UHPLC system and the resultant peak areas for any peaks corresponding to the test compound determined and quantified using the calibration line (the injection volume that gave a peak area closest to the calibrated range was used for determining solubility). Plasma protein binding experiments In brief, a 96 well equilibrium dialysis apparatus was used to determine the free fraction in plasma for each compound (HT Dialysis LLC, Gales Ferry, CT). Membranes (12-14 kDA cut-off) were conditioned in deionised water for 60 minutes, followed by conditioning in 80:20 deionised water:ethanol for 20 minutes, and then rinsed in isotonic buffer before use. Female GDI mouse plasma was removed from the freezer and allowed to thaw on the day of experiment. Thawed plasma was then centrifuged (Allegra X12-R, Beckman Coulter, USA), spiked with test compound (final concentration 10 ug / mL), and 150 pL aliquots (n = 6 replicate determinations) loaded into the 96-well equilibrium dialysis plate. Dialysis vs isotonic buffer (150pL) was carried out for 5 hours in a temperature-controlled incubator at ca. 37°C (Barworld scientific Ltd, UK) using an orbital microplate shaker at 100 revolutions / minute (Barworld scientific Ltd, UK). At the end of the incubation period, 50 uL aliquots of plasma or buffer were transferred to micronic tubes (Micronic B.V., the Netherlands) and the composition in each tube balanced with control fluid (50 uL), such that the volume of buffer to plasma is the same. Sample extraction was performed by the addition of 200pL of acetonitrile containing an appropriate internal standard. Samples were allowed to mix for 1 minute and then centrifuged at 3000rpm in 96-well blocks for 15 minutes (Allegra X12-R, Beckman Coulter, USA) after which 150 uL of supernatant was removed to 50 uL of water. All samples were analysed by UPLC-MS / MS. The unbound fraction was determined as the ratio of the peak area in buffer to that in plasma. MDCK Passive Permeability MDCK-MDR1 cells (Netherlands Cancer Institute) were maintained in culture (DMEM, Gibco Cat: 61965-026 supplemented with 1% penicillin / streptomycin, 10% FCS) until required. For experimentation, cells were seeded onto individual transwell Thincerts' (Greiner, Cat 662610) at a density of 35,000 cells / well. Cells were grown at 37 °C, 5% COzfor 3 days. On day 4, media was replaced with fresh media and incubated for 1 hour. Media was removed and replaced with Dulbeccos PBS (Gibco, 14287-080) and cell inserts incubated for a further 1 hour. Dosing solutions containing 3 pM Test Compound, 10 pM Lucifer Yellow (1% DMSO) were prepared. 1.2 mL of PBS (1% DMSO) was added to wells of a 24-well cell culture plate (Corning, Cat 353504). 0.35 mL of dosing solution was added in duplicate to the apical side of the transwell and transwells transferred into the receiver plate solutions. Transwell plates were then incubated for 1 hour after which inserts were removed to an empty plate to prevent any further permeation of compound. 100 mL of solution from donor, receiver wells was removed to a 96 well plate alongside 100 mL of dosing solution. 150 pL of acetonitrile containing internal standard (eg 100 ng / mL Sulfadimethoxine) is then added to all samples prior to analysis by LC-MS / MS. Bupropion (positive controls) and Atenolol (negative control) were run alongside test compounds. To confirm monolayer integrity, a further 100 pL from each compartment is added of the 96 well F-bottomed microtitre plate containing the Lucifer Yellow standard curve for fluorescence determination of Lucifer Yellow concentrations. Papp (apparent permeability) values were calculated using the following equation: Papp (nm / sec) == (Volume receiver / 'A) * (Response receiver / Response donor) Incubation time (sec) Prophage activation Overnight cultures of S. aureus R.N451 (Selva et al. 2009) were diluted 10-fold in TSB containing 10 pg / ml ciprofloxacin + / - 30 pM compound 5 and incubated at 37 °C with shaking (180 rpm) for 6 h. Samples were centrifuged at 13,000 x g for 1 min and the supernatant filtered through a 0.2 pm filter. Plaque forming units (PFU) per ml were determined by spotting serial dilutions of the supernatant onto agar plates containing R.N4220. Spontaneous ciprofloxacin resistance frequency The wells of microtitre plates were filled with TSB (200 pl) containing 2X MIC ciprofloxacin(l pg mL4) and NorA inhibitor, DMSO or inactive control compound 4 (1 pM )and inoculated with 5 x 105 CFU / ml bacteria. Each inhibitor was tested using an independent plate, resulting in 96 parallel cultures for each inhibitor. After 18 h incubation at 37 °C, the number of wells with visible growth (indicative of resistance emergence) were enumerated and calculated as a percentage of total wells inoculated (96). In vivo PK method AMR-9-5 was dosed intraperitoneally as a solution at 1 mg free base / kg (dose volume 10 mL / kg; dose vehicle, 5% (v / v) dimethyl sulfoxide (DMSO), 40% polyethylene glycol 400 and 55% sterile deionized water) to female C57BL6 / J mice (n = 3). Blood samples (10 pL) were taken from each mouse prior to dose, 0.05, 0.25, 0.5, 1, 2, 4, 6, 8, and 24h post dose and mixed with distilled water (90 pL). After suitable sample preparation, the concentration of test compound in blood was determined by UPLC-MS / MS. In vivo infection method Animal work was conducted in accordance with the Animals (Scientific Procedures) Act 1986 and approved by the Imperial College Animal Welfare and Ethical Review Body (AWERB) (PPL70 / 7969, PF93C158E). Female C57BL / 6 mice (6-8 weeks, Envigo) were infected via the intraperitoneal route with 2.5 x 107 CFU S. aureus USA300 JE2. Two hours post infection, mice were treated with vehicle alone (no treatment), a 30 mg / kg dose of compound 5 (200 pL, 3 mg / mL), a 30 mg / kg dose of ciprofloxacin (200 pL, 3 mg / mL) or both ciprofloxacin and compound 5 combined, each at 30 mg / kg. The dose of ciprofloxacin used was chosen to mimic that used in humans [PMID: 31978152]. Treatments were administered in a mixture of 5% DMSO. 40% PEG400 and 55% Sterile deionised water via the intraperitoneal route. Eight hours post infection, animals were humanely killed by cervical dislocation, and death was confirmed by severing the femoral artery. The peritoneal cavity was washed with PBS, and CFU counts were determined on tryptic soy agar plates. The size of the groups used was based on power analysis of in vitro data. Mice were randomly assigned to treatment groups and the investigators conducting the experiment were blinded to the treatments administered.

Claims

1. A compound of formula (I):(I)wherein R1 is CN, COOR4, H, halogen, OR4, CONR4R5, NR4R5, NR4COR5, NO2, SR4, SOR5, S(O)SR4, S(O)NR4R5, NR4SO2R5, SO2NR4R5, SO2R5 or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl;R2 is a mono or bicyclic optionally substituted Cs-Cio aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle;R3 is a mono or bicyclic optionally substituted Ce-Cio aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle;R4is H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl;R5 is H, OR6, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl;R6 is H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl;L1 is absent, optionally substituted Ci-Cs alkylene, optionally substituted C2-Ce alkenylene, optionally substituted C2-C6 alkynylene, C=O, S=O, SO2, -CH2C(O)-, -CH2CONH- or -CONH-;L2 is absent, CH, optionally substituted Cs-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, C=O, S=O, SO2, ~CH2C(O)-, -CHC(O)-, -CH2CONH-, -CHCONH- or -CONH-;L3 is a mono or bicyclic optionally substituted Cs-Cio arylene, mono or bicyclic optionally substituted 5 to 10 membered heteroarylene, optionally substituted C3-C6 cycloalkylene or an optionally substituted mono or bicyclic 3 to 8 membered heterocyclylene;or a pharmaceutically acceptable complex, salt, solvate, tautomeric or polymorphic form thereof.- 89 -2. The compound according to claim 1, wherein L1 is absent, optionally substituted Ci-Ca alkylene, optionally substituted Cz-Cs alkenylene or optionally substituted Cz-Cs alkynylene.

3. The compound according to claim 2, wherein L1 is a C1-C3 alkylene, preferably -CHz- or -CH2CH2-, and most preferably -CH2-.

4. The compound according to any preceding claim, wherein R1 is CN, COOR4, OR4, CONR4R5, NR4R5, NR4COR5, NOz, SOR5, S(O)SR4, S(O)NR4RS, NR4SO?R5, SOzNR4R5, SO2R5 or optionally substituted 5 or 6 membered heteroaryl.

5. The compound according to claim 4, wherein R1 is CN, COOR4 or CONR4R5, and is preferably COOH or COOCH3, and most preferably is COOH.

6. The compound according to any preceding claim, wherein L2 is absent, CH, optionally substituted Ci-Cs alkylene, optionally substituted Cz-Ce alkenylene or optionally substituted Cz-Cs alkynylene.

7. The compound according to claim 6, wherein L2 is CH or CH2, and more preferably is CH.

8. The compound according to any preceding claim, wherein L3 is a mono or bicyclic optionally substituted Cs-Cio arylene or a mono or bicyclic optionally substituted 5 to 10 membered heteroarylene, preferably, L3 is an optionally substituted phenylene or an optionally substituted 5 or 6 membered heteroarylene, and most preferably, L3 is an optionally substituted mono or bicyclic 5 membered heteroarylene.

9. The compound according to claim 8, wherein the optionally substituted arylene or heteroarylene is unsubstituted or substituted with between 1 and 5 substituents, and the or each substituent is selected from the list consisting of optionally substituted Ci-Ce alkyl, optionally substituted Cz-Ce alkenyl, optionally substituted Cz-Co alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, COOR7, CONR7R8, NR7C(O)R8, optionally substituted Ca-Cio aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered heterocycle, and R7 and R8 are independently H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl.

10. The compound according to claim 9, wherein the or each substituent is selected from the list consisting of optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, phenyl optionally substituted with a halo, 5 or 6 membered heteroaryl optionally substituted with a halo, C3-C6 cycloalkyl optionally substituted with a halo and 3 to 6 membered heterocycle optionally substituted with a halo.

11. The compound according to any preceding claim, wherein R2 is an optionally substituted phenyl, an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 5 or 6 membered heterocycle, and preferably is an optionally substituted phenyl.

12. The compound according to claim 11, wherein the R2 aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with between 1 and 5 substituents, and the or each substituent may independently be selected from the list consisting of optionally substituted Ci-Ca alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, COOR7, CONR7R8, NR7C(O)R8 and azido, and R7 and R8 are independently H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl.wherein R12 is H, optionally substituted C1-C3 alkyl, halogen, OR7 or CN.

14. The compound according to any preceding claim, wherein R3 is a mono or bicyclic optionally substituted Cs-Cio aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.The compound according to claim 14, wherein R3 is15.X4 is CR13 or N;X5 is CRi4 or N;5 X6 is CR15 or N;X7 is CR16 or N;Xs is 0, S or NR17;X9 is CR18 or N;Xi0 is CR19 or N;10   R13 to R19 are each independently H, optionally substituted Ci-Cs alkyl, optionallysubstituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR7, NR7R8, C(O)R7, CN, oxo, OC(O)R7, COOR7, CONR7R8, NR7C(O)R8 or azido; andR7 and R8 are independently H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl or optionally substituted C2-C10 alkynyl.1516. The compound according to claim 1, wherein the compound of formula (I) is:

17. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle, wherein the compound of formula (I) is as defined in any one of claims 1 to 16.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition further comprises an antibiotic.

19. A compound of formula (I), as defined in any one of claims 1 to 16, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of claim 17 or claim 18, for use as a medicament.

20. A compound of formula (I), as defined in any one of claims 1 to 16, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the pharmaceutical composition of claim 17 or claim 18, for use in resensitising bacteria to an antibiotic or potentiating the therapeutic efficacy of an antibiotic to bacteria.

21. An antibiotic and a compound of formula (I), as defined in any one of claims 1 to 16, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or- 96 -polymorphic form thereof, or the pharmaceutical composition of claim 17 or claim 18, for use in treating, ameliorating or preventing a bacterial infection,22. The antibiotic and compound for use according to claim 21, wherein the5 bacterial infection is caused by Staphylococcus aureus (S, aureus).

23. The antibiotic and compound for use according to claim 21 or claim 22, wherein the antibiotic is a fluoroquinolone antibiotic.

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