Mycobacterial infections

Abstract

The present invention relates to mycobacterial infections, and in particular, to novel compounds, therapies and methods for treating mycobacterial infections. The invention also extends to pharmaceutical compositions comprising the compounds, and methods of making the pharmaceutical compositions.

Description

[0001] Mycobacterial Infections

[0002] The present invention relates to mycobacterial infections, and in particular, to novel compounds, therapies and methods for treating mycobacterial infections. The invention also extends to pharmaceutical compositions comprising the compounds, and methods of making the pharmaceutical compositions.

[0003] Tuberculosis (TB), an infectious disease resulting from infection by the bacterium Mycobacterium tuberculosis (Mtb), caused the deaths of 1.5 million people in 2022 making it the leading cause of mortality worldwide due to a single infectious agent that year. New diagnoses totalled 7.1 million, though the World Health Organisation notes in its Global Tuberculosis Report 2020 that under-reporting and underdiagnosis mean that this figure is likely to be nearer 10 million. More worryingly, cases of drugresistant TB continue to climb year on year, with 206,030 of the new diagnoses confirmed as either rifampicin-resistant or multidrug-resistant TB (MDR-TB). TB currently causes more than one third of all deaths attributable to AMR bacteria and this dire situation was further exacerbated by the COVID-19 pandemic which derailed control measures.

[0004] Existing treatments for TB all involve the combination of multiple agents as there is no monotherapy for this disease. For example, the regimen most commonly recommended for antibiotic sensitive TB is a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by isoniazid and rifampicin alone for a further four months. These drugs are continued for a further seven months in patients infected with HIV. For patients infected with multi-drug resistant strains of Mtb, the treatment is more challenging and until recently took two years or longer. The introduction of a short six-month treatment for drug resistant TB that includes combinations of bedaquiline, linezolid, pretomanid and moxifloxacin has had very promising results. However, this treatment comes with significant side effects and risk factors and therefore often fails, necessitating research into new treatments that are shorter, less toxic and target antibiotic resistant strains. Of the 28 antitubercular new chemical entities currently undergoing phase I and II clinical trials across the world, only five have novel biological targets and modes of action. Research into new antitubercular scaffolds with novel modes of action is thus of the utmost importance if humanity is to stay ahead in this antitubercular arms race. Accordingly, there remains an urgent unmet need in the art for improved therapies for treating mycobacterial infections. The inventors conducted a screening of 8,892 regulatory agency-approved drugs and molecules that have progressed to Phase II clinical trials. They employed ligand-based virtual screening using a homology model of Rvll27c as a novel drug target for TB. The top 25 hits were computationally validated through 100 ns molecular dynamic simulations of docked complexes. This method identified several compounds, including those from the oxicam family of non-steroidal anti-inflammatory drugs (NSAIDs). The inventors tested these compounds for Rvll27c-specific anti-TB activity and surprisingly found that droxicam exhibited the most promising results. Further experiments demonstrated that droxicam effectively inhibited the growth of Mycobacterium inside host macrophage cells without causing toxicity to mammalian cells. Building upon this work, the inventors then set out to explore the role of oxicam compounds as chemical tools in studying the role of Rvll27c in Mycobacterium metabolism and pathogenesis, as well as the druggability of Rvll27c as a novel target. In the course of medicinal chemistry optimization, 18 novel oxicam compounds were synthesised, with surprisingly improved MICs and superior drug-like properties that synergize with existing TB treatments (Figures 1 and 2). Additionally, the inventors have demonstrated that these compounds exhibit selective toxicity against mycobacteria while remaining non-toxic to eukaryotic cells (Figure 3). Moreover, the inventors have demonstrated the efficacy ex vivo of these compounds within macrophages (Figure 3), indicating their potential to eliminate both intracellular and extracellular TB.

[0005] Hence, in a first aspect of the invention, there is provided a compound of Formula (I) : wherein X1is CR1or N;

[0006] X2is CR2or N;

[0007] X3is CR3or N;

[0008] X4is CR4or N;

[0009] X5is CR5or N;

[0010] L is -CONH- or NH;

[0011] R1to R5are each independently H, a halogen, an optionally substituted Ci-e alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle, an optionally substituted 5 to 10 membered heteroaryl, OR7, SR7or NR7R8; or two adjacent R1to R5groups, together with the atoms to which they are joined, combine to form an optionally substituted C3- C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl;

[0012] R6is OH or halogen;

[0013] R7and R8are each H, an optionally substituted Ci-e alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; with the proviso that the compound of Formula (I) is not piroxicam; and

[0014] R12and R13, together with the atoms to which they are joined, combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof.

[0015] 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 six carbon atoms, i.e. Ci-Ce alkyl. Ci-Ce 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 and / sohexyl.

[0016] "Alkenyl" refers to olefinically unsaturated hydrocarbon groups which can be unbranched or branched. In certain embodiments, the alkenyl group has 2 to 6 carbons, i.e. it is a C2-C6 alkenyl. C2-C6 alkenyl includes for example vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl.

[0017] "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 C2-C6 alkynyl. C2-C6 alkynyl includes for example propargyl, propynyl, butynyl, pentynyl and hexynyl.

[0018] An alkyl, alkenyl or alkynyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OR18, NR18R19, oxo, optionally substituted Ce-Ci2 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl and optionally substituted 3 to 12 membered heterocycle. R18and R19may independently be H, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl. In one embodiment, an alkyl, alkenyl or alkynyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OH, NH2, Ce- C12 aryl, 5 to 10 membered heteroaryl, C3-C12 cycloalkyl and 3 to 12 membered heterocycle. In one embodiment, an alkyl, alkenyl or alkynyl group is unsubstituted or substituted with one or more halogens.

[0019] The term "halo" or "halogen" includes fluoro (-F), chloro (-CI), bromo (-Br) and iodo (- I).

[0020] "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 12 membered ring system. In one embodiment, the cycloalkyls defined herein are C3-C6 cycloalkyls. Representative examples of a C3- C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0021] "Aryl" refers to an aromatic 6 to 12 membered hydrocarbon group. 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. Examples of a C6-C12 aryl group include, but are not limited to, phenyl, a-naphthyl, g-naphthyl, biphenyl, tetrahydronaphthyl and indanyl.

[0022] "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. A heteroaryl group may contain 1, 2, 3, 4 or 5 ring atoms which are heteroatoms. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. 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, 1H- 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 6- membered monocyclic heteroaryl ring.

[0023] "Heterocycle" refers to 3 to 12 membered monocyclic, bicyclic or bridged molecules in which at least one ring atom is a heteroatom. A heterocyclic group may contain 1, 2, 3, 4 or 5 ring atoms which are heteroatoms. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. A heterocycle may be saturated or partially saturated. Exemplary 3 to 12 membered heterocycle 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, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane, oxazine.

[0024] A cycloalkyl, aryl, heteroaryl or heterocycle group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OH, NH2, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl and optionally substituted 3 to 12 membered heterocycle. In one embodiment, a cycloalkyl, aryl, heteroaryl or heterocycle group is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OR18, NR18R19, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-C12 aryl, 5 to 10 membered heteroaryl, C3-C12 cycloalkyl and 3 to 12 membered heterocycle. R18and R19are as defined above. In one embodiment, a cycloalkyl, aryl, heteroaryl or heterocycle group is unsubstituted or substituted with one or more halogens.

[0025] 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 latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.

[0026] 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-phenyl propionic, 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- benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, and the like.

[0027] 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.

[0028] 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. D2O, ds-acetone and de-DMSO.

[0029] L may be -NH-. In one embodiment, L is -CONH-. Accordingly, the compound may be a compound of formula la:

[0030] R12and R13, together with the atoms to which they are joined, may combine to form an optionally substituted 6 membered heteroaryl or an optionally substituted phenyl. In some embodiments, R12and R13, together with the atoms to which they are joined, combine to form an optionally substituted phenyl. Accordingly, the compound of formula I may be a compound of formula lb: , wherein R14to R17are H, halogen, OR18, NR18R19, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl or optionally substituted 3 to 12 membered heterocycle; and

[0031] R18and R19may independently be H, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl.

[0032] One or more of R14to R17may be halogen, OR18, NR18R19, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl or optionally substituted 3 to 12 membered heterocycle. In some embodiments, one or more of R14to R17may be halogen, OR18, NR18R19, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl. In some embodiments, one or more of R14to R17may be halogen, OR18, NR18R19, optionally substituted C1-3 alkyl, optionally substituted C2-3 alkenyl or optionally substituted C2-3 alkynyl. R18and R19may independently be H, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl. In some embodiments, R18and R19may independently be H, optionally substituted C1-3 alkyl, optionally substituted C2-3 alkenyl or optionally substituted C2-3 alkynyl. If one or more of R14to R19is an optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, the alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, NH2, oxo, optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl and optionally substituted 3 to 12 membered heterocycle. In some embodiments, the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of halogen, OH, NH2, oxo, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted 5 or 6 membered heterocycle. The or each optionally substituted aryl, optionally substituted heteroaryl, optionally substituted and optionally substituted heterocycle may be unsubstituted or substituted with one or more of halogen or C1-3 alkyl. In some embodiments, the or each optionally substituted aryl, optionally substituted heteroaryl, optionally substituted and optionally substituted heterocycle may be unsubstituted or substituted with methyl. Accordingly, in some embodiments, one or more of R14to R17may be OCH3, or In some embodiments, R14is H.

[0033] In some embodiments,

[0034] In some embodiments,

[0035] In some embodiments, R17is H.

[0036] In some embodiments, R14to R17are all H. Accordingly, the compound of formula lb may be a compound of formula Ibi :

[0037] In some embodiments, the compound may be a compound of formula Ic:

[0038] In some embodiments, the compound may be a compound of formula Ici :

[0039] In some embodiments, X1is N. X2may be CR2, X3may be CR3, X4may be CR4and X5may be CR5.

[0040] In some embodiments, X1is N. X2may be CR2, X3may be CR3, X4may be CR4and X5may be N.

[0041] In some embodiments, X1is N. X2may be CR2, X3may be CR3, X4may be N and X5may be CR5.

[0042] In some embodiments, X1is CR1. X2may be CR2, X3may be CR3, X4may be CR4and X5may be CR5.

[0043] In embodiments where X1is CR1, R1may be H, a halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl or an optionally substituted C2-6 alkynyl. In some embodiments, R1is H, a halogen, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl. In some embodiments, R1is H.

[0044] In embodiments where X2is CR2, R2may be H, a halogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl or an optionally substituted C2-6 alkynyl. In some embodiments, R2is H, a halogen, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl. In some embodiments, R2is H.

[0045] In embodiments where X3is CR3, R3may be H, a halogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle, an optionally substituted 5 to 10 membered heteroaryl, OR7, SR7or NR7R8. In some embodiments, R3is H, a halogen, an optionally substituted C1-3 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 3 to 6 membered heterocycle, an optionally substituted 5 or 6 membered heteroaryl or OR7. In some embodiments, R3is H, fluoro, a C1-3 alkyl, cyclopropyl, phenyl or OR7. R7and R8may each be H, an optionally substituted Ci-e alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 3 to 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R7and R8are each H, a C1-3 alkyl, a C3-C6 cycloalkyl, phenyl, a 3 to 6 membered heterocycle or a 5 or 6 membered heteroaryl. If R3, R7or R8is an optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, the alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, NH2, oxo, optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl and optionally substituted 3 to 12 membered heterocycle. In some embodiments, the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of halogen, OH, NH2, oxo, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted 5 or 6 membered heterocycle. The or each optionally substituted aryl, optionally substituted heteroaryl, optionally substituted and optionally substituted heterocycle may be unsubstituted or substituted with one or more of halogen or C1-3 alkyl. In some embodiments, the or each optionally substituted aryl, optionally substituted heteroaryl, optionally substituted and optionally substituted heterocycle may be unsubstituted or substituted with methyl. Accordingly, R7and R8may be methyl, phenyl, or . In some embodiments, R7is methyl or phenyl.

[0046] In alternative embodiments where X2is CR2and X3is CR3, R2and R3together with the atoms to which they are joined, may combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R2and R3together with the atoms to which they are joined, may combine to form an optionally substituted C4-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4 to 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R2and R3together with the atoms to which they are joined, may combine to form a Cs-Ce cycloalkyl, phenyl, a 5 or 6 membered heterocycle or a 5 or 6 membered heteroaryl. In some embodiments, R2and R3together with the atoms to which they are joined, may combine to form cyclopentene, phenyl, IH-pyrrole or pyridine.

[0047] In embodiments where X4is CR4, R4may be H, a halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl or an optionally substituted C2-6 alkynyl. In some embodiments, R4is H, a halogen, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl. In some embodiments, R4is H.

[0048] In alternative embodiments where X3is CR3and X4is CR4, R3and R4together with the atoms to which they are joined, may combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R3and R4together with the atoms to which they are joined, may combine to form an optionally substituted C4-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4 to 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R3and R4together with the atoms to which they are joined, may combine to form a Cs-Ce cycloalkyl, phenyl, a 5 or 6 membered heterocycle or a 5 or 6 membered heteroaryl. In some embodiments, R3and R4together with the atoms to which they are joined, may combine to form phenyl.

[0049] In embodiments where X5is CR5, R5may be H, a halogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl or an optionally substituted C2-6 alkynyl. In some embodiments, R5is H, a halogen, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl. In some embodiments, R5is H.

[0050] In alternative embodiments where X4is CR4and X5is CR5, R4and R5together with the atoms to which they are joined, may combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4and R5together with the atoms to which they are joined, may combine to form an optionally substituted C4-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4 to 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R4and R5together with the atoms to which they are joined, may combine to form a Cs-Ce cycloalkyl, phenyl, a 5 or 6 membered heterocycle or a 5 or 6 membered heteroaryl. In some embodiments, R4and R5together with the atoms to which they are joined, may combine to form phenyl. In some embodiments, R6is OH.

[0051] In alternative embodiments, R6is a halogen. R6may be chloro.

[0052] The compound of formula (I) may be: In one embodiment, the compound of formula (I) may be:

[0053] In another embodiment, the compound of formula (I) may be:

[0054] In another embodiment, the compound of formula (I) may be:

[0055] In another embodiment, the compound of formula (I) may be:

[0056] The inventors discovered that the compounds according to the first aspect of the invention, are particularly suitable for therapy against pathogenic mycobacteria. Hence, according to a second aspect of the invention, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use in therapy.

[0057] According to a third aspect of the invention, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use in treating, preventing or ameliorating a mycobacterial infection.

[0058] According to a fourth aspect, there is provided a method of treating, preventing or ameliorating a mycobacterial infection in a subject, the method comprising administering, or having administered, to a subject in need of such treatment, a therapeutically effective amount of a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof.

[0059] The mycobacterial infection may be caused by a bacterium selected from the group consisting of: M. tuberculosis, M. bovis, M. africanum, M. canettii, M. microtti, M. caprae, M. pinnipedii, M. avium complex, M. avium, M. intracellularae, M. abscessus, M. fortuitum, M. chimaera, M. gordonae, M. bochemicum, M. kansassii, M. kumatonence, M. xenopi, M. chelonae and M. leprae.

[0060] In some embodiments, the mycobacterial infection is caused by M. tuberculosis.

[0061] The inventors discovered that the compounds according to the invention not only exhibit efficacy in vitro but also effectively kill M. tuberculois within macrophages (Figure 3). Accordingly, in one embodiment, the compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, is capable of killing the mycobacteria within a macrophage. In some embodiments, the compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, is capable of killing M. tuberculosis within a macrophage.

[0062] The inventors also demonstrated that the compounds according to the invention are non-toxic towards human cells (Figure 4). Accordingly, in one embodiment, the compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, is non-toxic towards human cells. Furthermore, the inventors demonstrated that several known compounds, including those from the oxicam family of NSAIDs, exhibit surprising anti-TB activity. The inventors believe that they are the first to demonstrate that these known oxicam NSAIDs exhibit antitubercular activity.

[0063] Hence, in a fifth aspect of the invention, there is provided an oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use in treating, preventing or ameliorating a mycobacterial infection.

[0064] According to a sixth aspect, there is provided a method of treating, preventing or ameliorating a mycobacterial infection in a subject, the method comprising administering, or having administered, to a subject in need of such treatment, a therapeutically effective amount of an oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof.

[0065] The oxicam compound may be understood to be a compound of Formula (II) : wherein R9is an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; together form a linker with formula -C(O)-; and

[0066] R12and R13together with the atoms to which they are joined, combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl.

[0067] In some embodiments, R9is an optionally substituted Ce-io aryl or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R9is an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R9is an optionally substituted pyridinyl, an optionally substituted thiazolyl or an optionally substituted isoxazolyl. The optionally substituted aryl or optionally substituted heteroaryl may be unsubstituted or substituted with a halogen or a Ci-6 alkyl. In some embodiments, the substituted aryl or optionally substituted heteroaryl is unsubstituted or substituted with a methyl.

[0068] In some embodiments, R12and R13together with the atoms to which they are joined, combine to form an optionally substituted Ce-io aryl or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R12and R13together with the atoms to which they are joined, combine to form an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R12and R13together with the atoms to which they are joined, combine to form an optionally substituted phenyl or an optionally substituted thiophenyl. The optionally substituted aryl or optionally substituted heteroaryl may be unsubstituted or substituted with a halogen or a Ci-e alkyl. In some embodiments, the substituted aryl or optionally substituted heteroaryl is unsubstituted or substituted with a halogen. In some embodiments the substituted aryl or optionally substituted heteroaryl is unsubstituted or substituted with a chloro.

[0069] Accordingly, the oxicam compound may be: Lornoxicasi In one embodiment, the oxicam compound may be selected from the group consisting of: piroxicam; droxicam; meloxicam; isoxicam; and lornoxicam.

[0070] The mycobacterial infection may be caused by a bacterium selected from the group consisting of: M. tuberculosis, M. bovis, M. africanum, M. canettii, M. microtti, M. caprae, M. pinnipedii, M. avium complex, M. avium, M. intracellularae, M. abscessus, M. fortuitum, M. chimaera, M. gordonae, M. bochemicum, M. kansassii, M. kumatonence, M. xenopi, M. chelonae and M. leprae.

[0071] In some embodiments, the mycobacterial infection is caused by M. tuberculosis.

[0072] It will be appreciated that the compounds described herein, may be used in a medicament, which may be used as a monotherapy (i.e. use of the compound alone), for treatment against a mycobacterial infection. Alternatively, the compounds described herein may be used as an adjunct to, or in combination with, known therapies for treating, ameliorating, or preventing a mycobacterial infection.

[0073] Accordingly, in one embodiment, at least one additional therapeutic agent may be administered with the compounds described herein. In some embodiments, at least two, three or four additional therapeutic agents may be administered with the compounds described herein. In some embodiments, therefore, the compound (or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof), for use according to the second, third or fifth aspect, may be administered with at least one additional therapeutic agent. In some embodiments, the methods according to the fourth and sixth aspect, may comprise administering the compound (or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof), with additional therapeutic agents. The compounds according to the invention may be administered before, after, and / or together with the other therapeutic agent The therapeutic agents may be selected from a group consisting of for example: rifampicin, isoniazid, ethambutol, pyrazinamide, bedaquiline, linezolid, moxifloxacin, and pretomanid.

[0074] The compounds described herein 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, polyplex, emulsion, lipid nanoparticles (e.g. with peptide, DNA or RNA on the surface or encapsulated) or any other suitable form that may be administered to a person or animal in need of treatment. The lipid nanoparticle may comprise one or more components selected from a group consisting of: a cationic lipid (which in some embodiments is ionisable); phosphatidylcholine; cholesterol; and polyethylene glycol (PEG)-lipid. 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.

[0075] Medicaments comprising the compounds described herein may be used in a number of ways. For instance, oral administration may be required, in which case the agents may be contained within a composition that may, for example, be ingested orally in the form of a tablet, capsule or liquid. Compositions comprising agents and medicaments of the invention may be administered by inhalation (e.g. intranasally). Compositions may also be formulated for topical use. For instance, creams or ointments may be applied to the skin. Accordingly, suitable modes of administration include oral, intra- tumoral, parenteral, topical, inhaled / intranasal, rectal / intravaginal, and ocular / aural administration.

[0076] The compound of the invention may also be incorporated within a slow- or delayed- release device. Such devices may, for example, be inserted on or under the skin, and the medicament may be released over weeks or even months. The device may be located at least adjacent the treatment site. Such devices may be particularly advantageous when long-term treatment with the compound is required and which would normally require frequent administration (e.g. at least daily injection).

[0077] In one embodiment, however, medicaments according to the invention may be administered to a subject by injection into the blood stream, muscle, skin or directly into a site requiring treatment. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion), or intradermal (bolus or infusion), or intramuscular (bolus or infusion). In some embodiments, injections are intravenous.

[0078] It will be appreciated that the amount of 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 monotherapy or in a combined therapy. The frequency of administration will also be influenced by the half-life of the active agent 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 composition, the mode of administration, and the type and advancement of the mycobacterial infection. 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.

[0079] Generally, for administration to a human, the total daily dose of the compounds of the invention is typically in the range lOOpg to 10g, such as Img to 1g, for example lOmg to 500mg. For example, oral administration may require a total daily dose of from 25mg to 250mg. 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.

[0080] Daily doses may be given as a single administration (e.g. a single daily administration). Alternatively, the compound may require administration twice or more times during a day. As an example, the compound may be administered as an initial primer and a subsequent boost(s), or two boosts administered at between a week or monthly intervals. In some embodiments, the compound may be administered as an initial primer and a subsequent boost, administered between two to six weeks apart. 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 of the compound according to the invention and precise therapeutic regimes (such as daily doses of the agents and the frequency of administration).

[0081] 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). The inventors believe that they are the first to describe a pharmaceutical composition for treating a disease, based on the use of the compounds according to the first aspect.

[0082] Hence, according to a seventh aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

[0083] The invention also provides, in an eighth aspect, a process for making the composition according to the seventh aspect, the process comprising contacting a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

[0084] A "subject" may be a vertebrate, mammal, or domestic animal. Hence, 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. In some embodiments, however, the subject is a human being.

[0085] 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. treat the mycobacterial infection.

[0086] For example, the therapeutically effective amount of compound used may be from about 0.01 mg to about 800 mg, and optionally from about 0.01 mg to about 500 mg. In some embodiments, the amount of compound is an amount from about 0.1 mg to about 250 mg, and optionally from about 0.1 mg to about 20 mg.

[0087] 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.

[0088] 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 vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets, in some embodiments, 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, optionally 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.

[0089] 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.

[0090] The compounds of the invention may be administered orally in the form of a sterile solution 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 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 of the features described herein (including any accompanying claims, abstract and drawings), 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.

[0091] For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which :-

[0092] Figure 1 shows the minimum inhibitory concentration (MIC) for piroxicam and four novel oxicam compounds according to the invention (ML-185-013, ML-185-019, ML- 185-023 and ML-178-048) against Mycobacterium tuberculosis (Mtb) strain H37Rv.

[0093] Figure 2 shows the bactericidal activity of oxicam compounds according to the invention (ML-185-023 and ML5-185-019), compared to first line TB drugs isoniazid and rifampicin.

[0094] Figure 3 shows the intracellular activity of the lead compounds MIL-185-019 and ML- 185-023, in a macrophage model of TB.

[0095] Figure 4 shows eukaryotic cell survival following treatment with lead compounds ML- 185-019 and ML-185-023.

[0096] Figure 5 shows the minimum inhibitory concentration (MIC) for five oxicam compounds (droxicam, piroxicam, meloxicam, isoxicam and lornoxicam) against a Mycobacterium tuberculosis (Mtb) strain.

[0097] The inventors set out to identify improved compounds for the treatment of mycobacterial infections. The inventors conducted a screening of 8,892 regulatory agency-approved drugs and molecules that have progressed to Phase II clinical trials. They employed ligand-based virtual screening using a homology model of Rvll27c as a novel drug target for TB. The top 25 hits were computationally validated through 100 ns molecular dynamic simulations of docked complexes. This method identified several compounds, including those from the oxicam family of NSAIDs. Accordingly, the inventors then set out to identify and explore the role of oxicam compounds as chemical tools against Mycobacterium tuberculosis. Materials and Methods

[0098] In vitro and ex vivo testing

[0099] The minimum inhibitory concentration (MIC) of antibiotics in vitro was determined using the broth microdilution method. Briefly, a two-fold dilution series of the compound stock solution was set up in solid black nunc 96-well plates using complete Middlebrook 7H9 media (containing 0.2% glycerol and 0.2% tyloxopol) to generate a concentration range of compounds at a volume of 50pl per well. A culture of a GFP fluorescent strain of H37Rv M. tuberculosis was standardised to OD600nm : 0.01. To prevent evaporation during incubation, the outermost wells of the plate were filled with lOOpI of deionized water, and the plates then tape-sealed to prevent evaporation. The plates were incubated statically at 37°C for 7 days. Growth was determined by measuring GFP as an indicator of cell numbers: Relative fluorescent units (RFU535nm) were determined at day 7 using a plate reader (Hidex Sense, Hidex, Finland). A lOpg / ml rifampicin positive control, bacteria free wells as blanks and drug free negative controls were included in all assays.

[0100] For the macrophage TB model, THP1 monocytes were treated with 50ng / ml phorbol 12-myristate 13-acetate (PMA) for 72 h at 37 °C, 5% CO2, and 95% humidity. Cells were washed with PBS supplemented with 0.49 mm Mg2 and 0.68 mm Ca2+ and 1% FCS (PBS+). Macrophages were infected with a fluorescent strain of M. tuberculosis H37Rv mScarlet at a multiplicity of infection of 1 for 4 h at 37 °C. Extracellular bacteria were removed by washing twice with warm PBS+. A 2-fold drug dilution series of the compounds tested was applied to the plates containing infected macrophages and incubated for 7 days. After washing three times with pre-warmed PBS+ the fluorescence of each of the test wells was measured using a Hidex Sense plate reader. The assay also included positive controls (10pm rifampicin), blanks (media and compounds only) and drug free controls (media and bacteria only).

[0101] For kill curve experiments compounds were added to complete Middlebrook 7H9 media at 5 x MIC. Rifampicin and isoniazid were added at 0.5pg / ml as positive controls alone and with the compounds. The cultures were grown shaking at 37°C 150rpm and samples taken for viability testing using standard Miles and Misra methodology at day 0, 7 and 14 days. Samples were washed prior to plating out to prevent carry over of compounds.

[0102] Results The antimicrobial activity of piroxicam, and four novel oxicam compounds, ML-185- 013, ML-185-019, ML-185-023 and ML-178-048, was evaluated using M. tuberculosis strain H37Rv and all showed low micromolar minimum inhibitory concentrations (MICs), indicating antimicrobial activity. Figure 1 shows M. tuberculosis survival curves in the presence of piroxicam (the parent compound) and four of the novel oxicam compounds. Additionally, as shown in Figure 5, five known oxicam compounds (droxicam, piroxicam, meloxicam, isoxicam and lornoxicam) showed low micromolar minimum inhibitory concentrations against a Mycobacterium tuberculosis (Mtb) strain.

[0103] The lead compounds also show good bactericidal activity, with ML-185-023 causing a 6-log kill over a 14-day period (Figure 2). Notably, their bactericidal activity surpasses that of isoniazid and rifampicin, which are both first-line treatments currently used for TB.

[0104] In addition, the inventors have discovered that the lead compounds either synergize, or do not antagonise existing anti-TB drugs, isoniazid and rifampicin (Figure 2). This finding represents a significant advancement in the field, as combination therapy is a key strategy for combating TB. The ability of these compounds to work with current treatments (including rifampicin, isoniazid, ethambutol, pyrazinamide, bedaquiline, linezolid, moxifloxacin, pretominid) further underscores their potential as valuable additions to combination therapy regimens currently in use for drug sensitive and resistant Mtb and other mycobacterial infections.

[0105] Furthermore, the inventors' research demonstrates that the lead compounds not only exhibit efficacy in vitro but also effectively kill Mtb within macrophages (Figure 3) while being non-toxic towards human cells (Figure 4). This is a critical finding, as developing drugs that can penetrate human cells and the TB phagosome to then kill Mtb is a significant roadblock in anti-TB drug discovery. The ability of the lead compounds to target intracellular Mtb is therefore a significant milestone in the development of anti-TB drugs.

[0106] Conclusions

[0107] The inventors have demonstrated that several known compounds from the oxicam family of NSAIDs, exhibit surprising activity against M. tuberculosis. The inventors have also identified a series of novel oxicam-type compounds which possess activity against M. tuberculosis, as well as superior drug-like properties that synergise with existing TB treatments. These compounds exhibit selective toxicity against mycobacteria while remaining non-toxic to eukaryotic cells. Moreover, they demonstrate efficacy ex vivo within macrophages, indicating their potential to eliminate both intracellular and extracellular TB.

Claims

Claims1. A compound of Formula (I) :wherein X1is CR1or N;X2is CR2or N;X3is CR3or N;X4is CR4or N;X5is CR5or N;L is -CONH- or NH;R1to R5are each independently H, a halogen, an optionally substituted Ci-e alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle, an optionally substituted 5 to 10 membered heteroaryl, OR7, SR7or NR7R8; or two adjacent R1to R5groups, together with the atoms to which they are joined, combine to form an optionally substituted C3- C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl;R6is OH or halogen;R7and R8are each H, an optionally substituted Ci-e alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; with the proviso that the compound of Formula (I) is not piroxicam; andR12and R13, together with the atoms to which they are joined, combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof.

2. The compound according to claim 1, wherein L is -NH-, optionally wherein L is - CONH-.

3. The compound according to claim 1 or claim 2, wherein the compound is a compound of formula la:

4. The compound according to any preceding claim, wherein the compound is a compound of formula lb:, wherein R14to R17are H, halogen, OR18, NR18R19, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C12 cycloalkyl or optionally substituted 3 to 12 membered heterocycle; andR18and R19may independently be H, optionally substituted Ci-e alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl.

5. The compound according to claim 4, wherein the compound is a compound of formula Ibi:

6. The compound according to claim 4, wherein the compound is a compound of formula Ic:

7. The compound according to any preceding claim, wherein the compound is a compound of formula Ici :

8. The compound according to any preceding claim, wherein the compound is:

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use in therapy.

10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use in treating, preventing or ameliorating a mycobacterial infection.

11. The compound for use according to claim 10, wherein the mycobacterial infection is caused by a bacterium selected from the group consisting of: M. tuberculosis, M. bovis, M. africanum, M. canettii, M. microtti, M. caprae, M. pinnipedii, M. avium complex, M. avium, M. intracellularae, M. abscessus, M. fortuitum, M. chimaera, M. gordonae, M. bochemicum, M. kansassii, M. kumatonence, M. xenopi, M. chelonae and M. leprae.

12. The compound for use according to claim 10 or claim 11, wherein the mycobacterial infection is caused by M. tuberculosis.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

14. A process for making the composition according to claim 13, the process comprising contacting a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

15. An oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use in treating, preventing or ameliorating a mycobacterial infection.

16. The oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use according to claim 15, wherein the oxicam compound is a compound of Formula (II) :wherein R9is an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl;together form a linker with formula -C(O)-; andR12and R13together with the atoms to which they are joined, combine to form an optionally substituted C3-C12 cycloalkyl, an optionally substituted Ce-io aryl, an optionally substituted 3 to 12 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl.

17. The oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use according to either claim 15 or claim 16, wherein the oxicam compound is:

18. The oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use according to any one of claims 15 to 17, wherein the mycobacterial infection may be caused by a bacterium selected from the group consisting of: M. tuberculosis, M. bovis, M. africanum, M. canettii, M. microtti, M. caprae, M. pinnipedii, M. avium complex, M. avium, M. intracellularae, M. abscessus, M. fortuitum, M. chimaera, M. gordonae, M. bochemicum, M. kansassii, M. kumatonence, M. xenopi, M. chelonae and M. leprae.

19. The oxicam compound, or a pharmaceutically acceptable salt, solvate, tautomeric form, stereoisomer or polymorphic form thereof, for use according to any one of claims 15 to 18, wherein the mycobacterial infection is caused by M. tuberculosis.

20. The compound, for use according to any one of claims 9 to 12, or the oxicam compound, for use according to any one of claims 15 to 19, wherein the compound or oxicam compound is administered with at least one additional therapeutic agent.

21. The compound or the oxicam compound, for use according to claim 20, wherein the at least one additional therapeutic agent is selected from the group consisting of: rifampicin, isoniazid, ethambutol, pyrazinamide, bedaquiline, linezolid, moxifloxacin, and pretomanid.

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