Compounds

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof wherein X-Y is -NHSO2- or -SO2NH-; R1 is H, CN or alkyl; R2 is selected from COOH and a tetrazolyl group; R3 is selected from H, Cl and alkyl; R4 is selected from H and halo; R5 is selected from H, alkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R6 is H; R7 is selected from H, CN, haloalkyl, halo, SO2-alkyl, optionally substituted heteroaryl, SO2NR14R15, CONR10R11 and alkyl; R8 is selected from H, alkyl, haloalkyl and halo; R9 is H or halo; and R10, R11, R12, R14, and R15 are H or alkyl; R13 is selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; and m is 0-3. The compounds of formula (I) modulate ERAP1 (endoplasmic reticulum aminopeptidase 1) and are for use in treating proliferative, immune or inflammatory disorders, particularly cancer or leukemia. The compounds of formula (I) stimulate a neo-antigen directed immune response in the subject. A method for producing an antigen-presenting cell which presents a neo-antigen using compounds of formula (I) is disclosed. An immunogenic composition comprising an antigen-presenting cell is also disclosed. Exemplified compounds include 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid.

Description

The present invention relates to compounds that are capable of modulating ERAP1. The compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative, viral, immune and inflammatory disorders. BACKGROUND TO THE INVENTION ERAP1 (Endoplasmic Reticulum Aminopeptidase 1; also referred to as APPILS or ARTS1) is an aminopeptidase important in the generation of a proportion of antigens and neoantigens as part of the antigen presentation pathway1. The antigen presentation pathway starts with the breakdown of proteins by the proteasome into peptides. These peptides are transported into the endoplasmic reticulum where a proportion are processed by ERAP1 before binding to the Major Histocompatibility Complex Class I (MHC Class I)1. Antigens bound to MHC Class I are then transported to the surface of a cell and presented to CD8+ T-cells and recognised as either self or non-self. Neoantigens are antigens that are specific to cancer and can be recognised as foreign by the immune system leading to destruction of cancer cells. Neoantigens are created either as a direct result of somatic mutations in the DNA of cancer cells, leading to the generation of mutated proteins, or through the indirect consequences of somatic mutations on protein processing and expression. Those cancers with higher rates of mutation and correspondingly higher levels of neoantigens have much greater response rates to the checkpoint inhibitor immunotherapies anti-PD-1 (e.g. pembrolizumab, nivolumab), anti-PD-L1 (e.g. atezolizumab, avelumab, durvalumab) and anti-CTLA4 antibodies (e.g. ipilimumab, tremelimuab) compared with cancers harbouring lower numbers of neoantigens2’3. The role of ERAP1 in the antigen presentation pathway is to trim a proportion of peptides, via its aminopeptidase activity, to create antigens and neoantigens of the optimal length for binding to MHC Class I. ERAP1 also over-trims some neoantigens, preventing their binding to MHC Class I and presentation at the cell surface4. Ablation of ERAP1 activity has been shown to change the antigen and neoantigen repertoire, leading to an increase in presentation of certain antigens I neoantigens and the presentation of entirely novel antigens / neoantigens5. In addition, ERAP1 ablation causes CD8+ T cell dependent tumour rejection in mouse cancer models4. Accordingly, modulators of ERAP1 activity may be useful for cancer treatment, either used alone or in combination with current cancer immunotherapy agents, including checkpoint inhibitors, because they change the antigens and neoantigens presented on the surface of cancer cells and make them more visible to the immune system, leading to tumour attack and destruction. Knockdown of ERAP1 is also shown to reduce the levels of regulatory-1 ike T cells and enhance the killing of cancer cells by natural killer cells6 7. This suggests that modulators of ERAP1 activity might be effective cancer treatments by both modulating cancer cell visibility and creating a more anti-tumourogenic immune response. ERAPTs peptide processing role in antigen presentation is also applicable in infectious viral disease. Maben etal (J. Med. Chem. 2020; 63, 103-121) disclose compounds that selectively inhibit ERAP1 over its paralogues ERAP2 and I RAP. WO 2020 / 104822, WO 2020 / 225569, WO 2021 / 094763, WO2022 / 064187, and WO 2023 / 007188 (Grey Wolf Therapeutics Limited) disclose aryl sulfonamide compounds that are capable of modulating ERAP1. The present invention seeks to provide further compounds that are capable of modulating ERAP1. Such compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative disorders, immune disorders and inflammatory disorders. STATEMENT OF INVENTION A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, (Rnlm (I) wherein: the group X-Y is -NHSO2- or -SO2NH-; Ri is H, CN or alkyl; R2 is selected from COOH and a tetrazolyl group; R3 is selected from H, Cl and alkyl; R4 is selected from H and halo; Rs is selected from H, alkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; Re is H; R? is selected from H, CN, haloalkyl, halo, SO2-alkyl, heteroaryl, SO2NR14R15, CONR10R11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R8 is selected from H, alkyl, haloalkyl and halo; R9 is H or halo; and R10, Ri 1, R12, R14, and R15 are each independently H or alkyl; R^is selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; and m is 0, 1,2 or 3. The invention also encompasses enantiomers of compounds of formula (I), and mixtures of enantiomers, including racemic mixtures. Advantageously, the presently claimed compounds are capable of modulating ERAP 1, thereby rendering the compounds of therapeutic interest in the treatment of various disorders, for example, in the field of oncology and immuno-oncology. Compounds in accordance with the present invention advantageously exhibit significantly greater membrane permeability and reduced efflux than comparator compounds known in the art. This in turn can translate to improved in vivo pharmacokinetics. A second aspect of the invention relates to a pharmaceutical composition comprising at least one compound as described above and a pharmaceutically acceptable carrier, diluent or excipient. A third aspect of the invention relates to a compound as described above for use in medicine. A fourth aspect of the invention relates to a compound as described above for use in treating or preventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder. A fifth aspect of the invention relates to the use of a compound as described above in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder. A sixth aspect of the invention relates to a compound as described above for use in the prevention or treatment of a disorder caused by, associated with or accompanied by any abnormal ERAP1 activity. A seventh aspect of the invention relates to the use of a compound as described above in the preparation of a medicament for the prevention or treatment of a disorder caused by, associated with or accompanied by abnormal ERAP1 activity. An eighth aspect of the invention relates to a method of treating a mammal having a disease state alleviated by modulation of ERAP1, wherein the method comprises administering to a mammal a therapeutically effective amount of a compound as described above. A ninth aspect of the invention relates to a compound as described above for use in treating or preventing a disease state alleviated by modulation of ERAP1. A tenth aspect of the invention relates to the use of a compound as described above in the preparation of a medicament for treating or preventing a disease state alleviated by modulation of ERAP1. An eleventh aspect of the invention relates to a method of treating or preventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described above. DETAILED DESCRIPTION The present invention relates to bis-aryl sulfonamide compounds that are capable of modulating ERAP1. Studies by the applicant have shown that compounds in accordance with the present invention advantageously exhibit greater membrane permeability and lower efflux than certain reference compounds known in the art. Moreover, further studies have shown that compounds according to the invention exhibit improved in vivo pharmacokinetics, such as lower clearance and longer half life. Further details of these studies are described in the accompanying examples section. The compounds of the invention contain a chiral centre, denoted * in the example structure below: Thus, the compounds can exist as two different enantiomers: For the avoidance of doubt, the invention encompasses the compounds in either of the above configurations, as well as mixtures thereof, including racemic mixtures. The skilled person will understand that the absolute stereochemistry (R- and S-) at the 10 chiral centre denoted * will depend on the nature and position of any substituent(s) R12 and R13. In one preferred embodiment, the compound is in the form of a mixture of the R- and S-enantiomers. In one preferred embodiment, the mixture is a racemic mixture, i.e. a 15   50:50 mixture of a compound of the R- and S-enantiomers. Racemic mixtures can be used to prepare enantiomerically pure R- and S-forms by separating the enantiomers using standard methods, for example by chemical resolution using optically active acid or by the use of column chromatography or reverse-phase column chromatography using a substantially optically active (or “chiral”) stationary phase as known to those skilled in the art. Racemic mixtures can also be used to prepare enantiomerically enriched mixtures of the S- and R-forms. Mixtures enriched with either the R- or S-enantiomer can also be obtained from the appropriate enantiomerically enriched precursors. In one preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers wherein the weightweight ratio is at least approximately 2:1 or greater, preferably at least approximately 5:1 or greater, most preferably at least approximately 10:1 or greater in favour of the enantiomer that displays significant in vitro and / or in vivo activity (the eutomer). In one embodiment, the compound is in the form of a mixture comprising the S-enantiomer and the R-enantiomer, wherein the weightweight ratio of R-enantiomer to S-enantiomer is greater than 1.05:1, more preferably, greater than 2:1, even more preferably greater than 5:1, even more preferably greater than 10:1. In one embodiment, the compound is in the form of a mixture comprising the S-enantiomer and the R-enantiomer, which is substantially enriched with the R-enantiomer. In one embodiment, the compound is in the form of a mixture comprising the S-enantiomer and the R-enantiomer, wherein the weightweight ratio of S-enantiomer to R-enantiomer is greater than 1.05:1, more preferably, greater than 2:1, even more preferably greater than 5:1, even more preferably greater than 10:1. In one embodiment, the compound is in the form of a mixture comprising the S-enantiomer and the R-enantiomer, which is substantially enriched with the S-enantiomer. “Alkyl” is defined herein as a straight-chain or branched alkyl radical, preferably C1-20 alkyl, more preferably C1-12 alkyl, even more preferably C1-10 alkyl or C1-6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. “Cycloalkyl” is defined herein as a monocyclic alkyl ring, preferably, C3-7-cycloalkyl, more preferably Cs-e-cycloalkyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or a fused bicyclic ring system such as norbornane. “Halogen” is defined herein as chloro, fluoro, bromo or iodo. As used herein, the term “aryl” refers to a Ce-12 aromatic group, which may be benzocondensed, for example, phenyl or naphthyl. “Heteroaryl” is defined herein as a monocyclic or bicyclic C2-12 aromatic ring comprising one or more heteroatoms (that may be the same or different), such as oxygen, nitrogen or sulphur. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl etc and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl etc.; or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, etc. and benzo derivatives thereof, such as quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl etc. Particularly preferred heteroaryl groups include 1 / 7-imidazol-5-yl, 1 / 7-imidazol-4-yl, 1 / 7-imidazol-2-yl, 1 / 7-pyrrol-1-yl, 1 / 7-pyrrol-2-yl, 1 / 7-pyrrol-3-yl, 1 / 7-pyrrol-4-yl, 1 / 7-pyrrol-5-yl, 1 / 7-pyrazol-1-yl, 1 / - / -pyrazol-5-yl, 1 / 7-pyrazol-3-yl, 1 / - / -pyrazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1 / 7-1,2,4-triazol-3-yl, 1 / 7-1,2,4-triazol-5-yl, 1 / - / -1,2,4-triazol-1-yl, 1 / - / -1,2,3-triazol-4-yl, 1 / - / -1,2,3-triazol-5-yl, 1 / - / -1,2,3-triazol-1-yl, thiazol-5-yl, thiazol-4-yl, 1 / 7-1,2,3,4-tetrazol-4-yl, 2 / 7-1,2,3,4-tetrazol-5-yl, oxazol-5-yl, oxazol-4-yl, oxazol-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyradizin-3-yl, pyradizin-4-yl, pyrazinyl, 1,3,4-oxadizol-2-yl, 1,3,4-oxadizol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isoxazol-5-yl, isoxazol-4-yl and isoxazol-3-yl. “Heterocycloalkyl” refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionally interrupted by one or more -(CO)- groups in the ring and / or which optionally contains 8 one or more double bonds in the ring. Preferably, the heterocycloalkyl group is monocyclic or bicyclic. Preferably, the heterocycloalkyl group is a C3-7-heterocycloalkyl, more preferably a C3-6-heterocycloalkyl. Alternatively, the heterocycloalkyl group is a C4-7-heterocycloalkyl, more preferably a C4-6-heterocycloalkyl. Preferred 5 heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl. Compounds of formula (I) One aspect of the invention relates to compounds of formula (I) as described above. In one preferred embodiment, the invention relates to compounds of formula (la), and pharmaceutically acceptable salts and hydrates thereof: 15 In one preferred embodiment, the compound is of formula (la-1), or a pharmaceutically acceptable salt or hydrate thereof: R7 (la-1) wherein X, Y, R1’9, R12, R13 and m are as defined above. In one preferred 5 embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is of formula (la-2), or a pharmaceutically acceptable salt or hydrate thereof: 10                                   R7 (la-2) wherein X, Y, R1'9, R12, R13 and m are as defined above. In one preferred embodiment, the compound is in enantiomerically pure form. 15 In one preferred embodiment, m is 0, 1 or 2, more preferably 0 or 1, even more preferably 0. In one preferred embodiment, R12 is selected from H and Me, and is more preferably H. In one preferred embodiment, R^is selected from Me, Et, Pr, Cl, F, Br, MeO, CN, CF3 and OH. More preferably, R^is Me. In one preferred embodiment, Ri is H, CN or Me, more preferably H. In one preferred embodiment, R2 is COCH. In one particularly preferred embodiment, X-Y is NH-SO2. In another preferred embodiment, X-Y is SO2-NH. In one preferred embodiment, R4 is selected from H, Cl and F, more preferably H. In one preferred embodiment, Rs is selected from alkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy. In one preferred embodiment, Rs is selected from alkyl, alkoxy and cycloalkyl. More preferably, Rs is cycloalkyl. In one particularly preferred embodiment, R5 is selected from OMe, OEt, Me, Et, and cyclopropyl. In another preferred embodiment, R5 is selected from H, Me, CF3, CHF2, SO2-Me, Cl, MeO, OH, CH2OH, SMe, cyclopropyl, triazolyl, oxetanyl and CN. More preferably, Rs is selected from H, CN, Me, SO2-Me, CF3 and CHF2, CH2OH, SMe, cyclopropyl, 3,4-triazol-1-yl, oxetan-3-yl. In one particularly preferred embodiment, Rs is cyclopropyl. In one preferred embodiment, R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, CONR10R11, SO2NR16R17, heteroaryl and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH. In one preferred embodiment, R7 is a heteroaryl group optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH. In one preferred embodiment, R7 is a heteroaryl group selected from pyridinyl, thienyl, imidazolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyradizinyl, thiazolyl, isothiazolyl, triazinyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH. In one preferred embodiment, R7 is a heteroaryl group selected from imidazolyl, pyrazolyl, pyrazinyl, pyradizinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH. In one preferred embodiment, R7 is a heteroaryl group selected from 1H-imidazol-5-yl, 1 / 7-imidazol-4-yl, 1 / 7-imidazol-2-yl, 1 / - / -pyrrol-1 -yl, 1 / 7-pyrrol-2-yl, 1 / 7-pyrrol-3-yl, 1 / 7-pyrrol-4-yl, 1 / 7-pyrrol-5-yl, 1 / - / -pyrazol-1 -yl, 1 / - / -pyrazol-5-yl, 1 / - / -pyrazol-3-yl, 1 / 7-pyrazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1 / 7-1,2,4-triazol-3-yl, 1 / 7-1,2,4-triazol-5-yl, 1 / 7-1,2,4-triazol-1-yl, 1 / 7-1,2,3-triazol-4-yl, 1 / 7-1,2,3-triazol-5-yl, 1 / 7-1,2,3-triazol-1-yl, thiazol-5-yl, thiazol-4-yl, 1 / 7-1,2,3,4-tetrazol-4-yl, 2 / - / -1,2,3,4-tetrazol-5-yl, oxazol-5-yl, oxazol-4-yl, oxazol-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyradizin-3-yl, pyradizin-4-yl, pyrazinyl, 1,3,4-oxadizol-2-yl, 1,3,4-oxadizol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isoxazol-5-yl, isoxazol-4-yl and isoxazol-3-yl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, CN, alkoxy, haloalkyl and OH. In one highly preferred embodiment, R7 is a heteroaryl group selected from 1 / 7-pyrazol-5-yl, 1 / - / -pyrazol-3-yl, 1 / - / -pyrazol-4-yl, oxazol-2-yl, 1 / 7-1,2,3-triazol-4-yl, 1 / 7-12 1,2,3-triazol-5-yl, thiazol-5-yl, 1 / 7-1,2,3,4-tetrazol-4-yl, 2 / 7-1,2,3,4-tetrazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-5-yl, pyradizin-3-yl, pyradizin-4-yl, pyrazinyl and 1,3,4-oxadizol-2-yl, each of which is optionally substituted by one or more substituents selected from Me, F, Cl, CN and MeO. In one highly preferred embodiment, R7 is a heteroaryl group selected from 1 / 7-1,2,3,4-tetrazol-4-yl and 2 / 7-1,2,3,4-tetrazol-5-yl, each of which is optionally substituted by one or more substituents selected from Me, F, Cl, CN and MeO. In one preferred embodiment, R7 is selected from CN, haloalkyl, SO2-alkyl, SO2NR16R17, CONR10R11 and tetrazolyl. In one preferred embodiment, R7 is selected from CF3, CN, CONH2, 1 / 7-1,2,3,4-tetrazol-1-yl, SO2NH2 and SO2Me. In one preferred embodiment, R7 is selected from H, CN, CF3, CHF2, Cl, F, SO2-Me, CONH2, SO2NH2, heteroaryl and Me. More preferably, R7 is selected from H, CN, Me, SO2-Me, CONH2, SO2NH2, tetrazolyl, CF3 and CHF2. In another preferred embodiment, R7 is selected from CN, haloalkyl, SO2-alkyl, SO2NH2, CONR10R11 and tetrazolyl. More preferably for this embodiment, R7 is selected from CF3, CN, SO2NH2, 1 / 7-1,2,3,4-tetrazol-1-yl, CONH2 and SO2Me, more preferably from CF3, CN, 1 / 7-1,2,3,4-tetrazol-1-yl and SO2Me . In one preferred embodiment, R7 is haloalkyl or heteroaryl, more preferably tetrazolyl. In one preferred embodiment, R7 is haloalkyl, more preferably, CF3. In one preferred embodiment, R7 is CN. In one preferred embodiment, R7 is SO2-alkyl, more preferably SO2Me. In one preferred embodiment, R7 is SO2NR16R17, more preferably SO2NH2. In one particularly preferred embodiment, R? is CF3 or CN. In one preferred embodiment, Rs is selected from H, alkyl, haloalkyl and Cl. In one preferred embodiment, Rs is selected from H, Cl, F and Me. More preferably, Rs is selected from H, Cl and F. In one preferred embodiment, R9 is H or F, more preferably, H. In one preferred embodiment, Ri, R3, R4, Re, and R9 are all H. In one preferred embodiment: R2 is COOH; X-Y is NH-SO2; Rs is cyclopropyl; Ri, R3, R4, Re and R9 are all H; R? is selected from CN and haloalkyl, preferably CF3; Rs is selected from H, Cl and F; R12 is H; and m is 0. In one preferred embodiment, the compound of formula (I) is selected from the following: °Y0H hn,, J     A ‘fa H f| ] H | A' | 0 0 A cf3 (3) O^OH I 0            1 HN^J   XX P H ||| H T / ¾ | XX 0 0 A CN (4) p0 °yoh HN,,        / A ‘fa H H| AxN"sA^ fl T / % T AA 0 0 A CN (5) O^ / OH \      0              1 HN,A Ph f| 1 h T      T ji j 0 0 1 F j^     △ CN (6) O^OH < 0   X hn,, J ’fa H f| | H T T A J 0 0 1 F ^[      △ CN (7) O^,OH 1      0              1 HN^J    Ajs Ph f| J X.N Afa ft T / / % T AJ 00 1 cr y    △ CN (8) O^ / OH 1      0              1 HN,,       XX ■fa h r n AA AA H T '•% T A J 0 0 1 cr y    △ CN (9) and pharmaceutically acceptable salts and hydrates thereof. Examples are racemic at the single chiral centre unless indicated otherwise. 5 In one preferred embodiment, the compound of the invention exhibits an IC50 against Decapeptide WRVYEKC(Dnp)ALK-acid (where Dnp is Dinitrophenyl maleimide) (10-mer) of 100 nM to 500 nM, more preferably, less than 100 nM. Further details of this assay are detailed in the accompanying examples. 10 In one preferred embodiment, the compound of the invention is selected from compounds (1) and (3)-(9). THERAPEUTIC APPLICATIONS A further aspect of the invention relates to compounds as described herein for use in medicine. The compounds have particular use in the field of oncology and immunoncology, as described in more detail below. Yet another aspect of the invention relates to compounds as described herein for use in treating or preventing a disorder selected from a proliferative disorder, an immune disorder, an inflammatory disorder and a viral disorder. In a preferred embodiment, the compound of the invention modulates ERAP1. In one embodiment the compound inhibits the activity of ERAP1. In an alternative embodiment the compound increases the activity of ERAP1. In one embodiment the compound of the invention may change the repertoire of presented antigens. One aspect of the invention relates to a compound as described herein for use in treating a proliferative disorder. Preferably, the proliferative disorder is a cancer or leukemia. A cancer may be selected from: basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intraepithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. Without wishing to be bound by theory, it is understood that ERAP1 modulators are capable of changing at least 10% of the antigen and neoantigen repertoire of cancer cells, as measured using immunopeptidomics and mass spectrometry analysis. Approximately 50% of this change is an upregulation in the presentation of certain antigens and neoantigens, whilst the other 50% is the presentation of entirely novel antigens and neoantigens. Both changes lead to an increase in the visibility of the tumour to the immune system, leading to measurable changes in the CD8+ T cell repertoire and CD8+ T cell activation status. This change in CD8+ T cell response leads to immune-mediated tumour clearance, and can be potentially enhanced by combining with cancer therapeutics such as antibody checkpoint inhibitors (e.g. anti-PD-1). Without wishing to be bound by theory, it is understood that modulators of ERAP1 cause killing of cancer cells by natural killer (NK) cells due to disruption of the interaction between killer cell Ig-like receptors (KIR) or lectin-like receptor CD94-NKG2A on NK cells with classical or non-classical MHC-l-peptide (pMHC-l) complexes on cancer cells. In one preferred embodiment, the disorder is cancer, and the compound increases the visibility of cancer cells to the immune system by altering the repertoire of antigens and neoantigens presented to the immune system. A further aspect of the invention relates to a method of increasing the visibility of cancer cells to the immune system in a subject by altering the repertoire of antigens and neoantigens presented to the immune system, said method comprising administering to the subject a compound of formula (I). In one preferred embodiment, the compound increases the CD8+ T cell response to the cancer cell. In one preferred embodiment, the compound of the invention is for use in the treatment of a disease of uncontrolled cell growth, proliferation and / or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is modulated by the ERAP1 pathway. In one preferred embodiment, the disease of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is selected from a haematological tumour, a solid tumour and / or metastases thereof. More preferably, the compound is for use in treating a disorder selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and / or metastases thereof. The compound may kill cancer cells, reduce the number of proliferating cells in the cancer and / or reduce the volume or size of a tumour comprising the cancer cells. The compound may reduce the number of metastasising cancer cells. In one embodiment the compound may be used (or is for use) in treating cancer in a subject who has previously had cancer. The compound may be used to reduce the likelihood of the cancer recurring, or the likelihood of further cancer developing. The compound may induce a neoantigen in the recurring or further cancer to which the subject already possesses an existing immune response. As such, the compound may increase or boost an immune response against the cancer. In one embodiment the compound is for use in preventing cancer. The compound may be used for prophylaxis against the development of cancer. That is to say, the compound may stimulate an immune response, such as a vaccine response, against a future cancer. The compound may stimulate in a subject an immune response directed to a neoantigen. Once a cancer develops in the subject, they may be treated again with the compound (or a different compound) to stimulate development of the same neoantigen, thereby eliciting the subject’s pre-exisiting immune response to said neoantigen to treat or prevent the cancer. The same or a different compound may be used before and after the cancer develops in a subject. In one embodiment the compound may be used for the prevention of cancer. In one embodiment the subject may previously have had cancer, may have a familial history of cancer, may have a high risk for developing cancer, may have a genetic predisposition to developing cancer, or may have been exposed to a carcinogenic agent. In one embodiment the subject may be in remission from cancer. One embodiment provides ex vivo generated antigen-presenting cells, such as dendritic cells (DCs). The antigen-presenting cells may be produced ex vivo to present neo-antigens, such as those generated by a compound according to the present invention. The compound may be used in a method for producing ex vivo an antigen-19 presenting cell which presents a neo-antigen, and wherein the cell may be used as a vaccine against cancer. The antigen presenting cell such as a dendritic cell may be pulsed or loaded with the neo-antigen or genetically modified (via DNA or RNA transfer) to express one, two or more neo-antigens. Methods of preparing dendritic cell vaccines are known in the art. The neo-antigen may be generated from the subject's normal tissue in which ERAP1 is modulated with a compound according to the invention. Sources of normal tissue may be fibroblasts or B cells, for example, that can be readily expanded in vitro. Alternatively, RNA from the cancer, total or mRNA enriched poly A+ RNA may be used. Poly A+ RNA can be also amplified to generate sufficient antigen for DC loading and thereby limit the ex vivo culture step. In one embodiment a dendritic cell which has been treated with the compound as described above may be used to treat a subject. The dendritic cell may be contacted with the compound ex vivo, and then the dendritic cell may be administered to the subject. The compound may therefore be used in vitro or in vivo, for example either for in situ treatment or for ex vivo treatment followed by the administration of the treated cells to the subject. Another aspect of the invention relates to a compound as described above for use in treating an immune disorder. In one preferred embodiment, the immune disorder is an autoimmune disorder. Examples of the autoimmune disorders include, but are not limited to: rheumatoid arthritis (RA), myasthenia gravis (MG), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, inflammatory bowel disease, autoimmune uveoretinitis, polymyositis and certain types of diabetes, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's Syndrome, ankylosing spondylitis and related spondyloarthropathies, rheumatic fever, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis, inorganic dust pneumoconioses, sarcoidosis, autoimmune hemolytic anemia, immunological platelet disorders, cryopathies such as cryofibrinogenemia, psoriasis, Behget's disease, birdshot chorioretinopathy and autoimmune polyendocrinopathies. Polymorphisms in the ERAP1 gene that impact ERAP1 enzymatic activity are strongly associated with an increased risk of autoimmunity, including the diseases ankylosing spondylitis, psoriasis, Behget's disease and birdshot chorioretinopathy11. Variants of ERAP1 that reduce ERAP1 enzymatic activity are protective against disease, whilst those that reportedly elevate activity are associated with increased disease risk12. This suggests that modulation of ERAP1 activity could be an effective treatment for autoimmune diseases. Thus, in one preferred embodiment, the immune disorder is selected from ankylosing spondylitis, psoriasis, Behget's disease and birdshot chorioretinopathy. In one preferred embodiment, the immune disorder is ankylosing spondylitis. Ankylosing spondylitis (AS) is a type of arthritis in which there is long term inflammation of the joints of the spine. Typically, the joints where the spine joins the pelvis are also affected. Occasionally other joints such as the shoulders or hips are involved. Between 0.1% and 1.8% of people are affected and onset is typically in young adults. Although the cause of ankylosing spondylitis is unknown, it involves a combination of genetic and environmental factors. More than 90% of those affected have a specific human leukocyte antigen known as the HLA-B27 antigen.13 In addition, certain variants of ERAP1, in conjunction with HLA-B27, are clearly associated with either an elevated or reduced risk of disease, providing evidence of a clear role for modulated antigen presentation in disease.18 There is no cure for ankylosing spondylitis and current treatments serve only to improve symptoms and prevent worsening. Medications used to date include NSAIDs, steroids, DMARDs such as sulfasalazine, and biologic agents such as infliximab. In one preferred embodiment, the immune disorder is Behget's disease (BD). Behget's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful mouth sores, genital sores, inflammation of parts of the eye, and arthritis. The cause is not well-defined, and whilst environmental factors play a role, genetic studies have shown an increased risk of 21 disease in patients carrying HLA-B51 in conjunction with specific variants of ERAP1.19 The disease is primarily characterized by auto-inflammation of the blood vessels, hence it is sometimes characterised as an auto-inflammatory disease. There is currently no cure for Behget's disease, but the symptoms can be controlled with medicines that reduce inflammation in the affected parts of the body, for example, with corticosteroids, immunosuppressants or biological therapies that target the biological processes involved in the process of inflammation. In one preferred embodiment, the immune disorder is birdshot chorioretinopathy. Birdshot chorioretinopathy, also known as Birdshot Uveitis or HLA-A29 Uveitis, is a rare form of bilateral posterior uveitis affecting the eye. It causes severe, progressive inflammation of both the choroid and retina. Symptoms include floaters, blurred vision, photopsia (flashing lights in eyes), loss of color vision and nyctalopia. Birdshot chorioretinopathy is thought to be an autoimmune disease. The disease has strong association with the Human leukocyte antigen haplotype (HLA)-A29. This indicates a role for T-lymphocytes in the pathogenesis. Birdshot chorioretinopathy is associated with IL-17, a hallmark cytokine of TH17 cells that play an important role in autoimmunity.15’16 A genome-wide association study has ascertained HLA-A29:02 as the primary risk factor and identified that both ERAP1 and ERAP2 are associated with birdshot chorioretinopathy.17’20 Genetic variants within the ERAP1 and ERAP2 loci modulate enzyme activity and also mRNA and protein expression. ERAP2 is an aminopeptidase that, together with ERAP1, trims peptides in the endoplasmic reticulum and loads these peptides on HLA molecules for presentation to T cells of the immune system. In one preferred embodiment, the immune disorder is psoriasis. Psoriasis is a chronic skin disease in which skin cells rapidly build up on the surface of the skin forming scales and red patches that are itchy and sometimes painful. The cause is not well-defined but includes both environmental and genetic factors. HLA-C06 strongly associates with risk of disease and variants in ERAP1, possibly in conjunction with HLA-C06, are also strongly associated with disease.21 There is no cure for psoriasis and current treatments serve only to improve symptoms and prevent worsening. Medications used in therapy include steroids, methotrexate, sulfasalazine, and biologic agents such as etanercept. Another aspect of the invention relates to a compound as described above for use in treating or preventing a viral disorder. Modulators of ERAP1 such as the compounds described herein are capable of changing the antigen repertoire of multiple viruses, which leads to the recognition and destruction of viral infected cells. Accordingly, ERAP1 modulators have potential therapeutic applications in the treatment of viral infection and diseases. ERAP1 modulates certain viral antigens, including those from human papilloma virus (HPV), human cytomegalovirus (CMV) hepatitis C (HCV) and human immunodeficiency virus (HIV)8 9’10. In addition, knockdown of ERAP1 in HPV infected cells changes the repertoire of presented HPV antigens leading to greater recognition by CD8+T cells8. In one preferred embodiment, the viral disorder is a viral disease or viral infection selected from HIV, HPV, CMV and HCV. In one preferred embodiment, the viral disorder is HIV. In one preferred embodiment, the viral disorder is HPV. In one preferred embodiment, the viral disorder is CMV. In one preferred embodiment, the viral disorder is HCV. Another aspect relates to a compound as described herein for use in the prevention or treatment of a disorder caused by, associated with or accompanied by abnormal activity against ERAP1. Another aspect relates to a compound as described herein for use in the prevention or treatment of an ERAP1-associated disease or disorder. Yet another aspect relates to the use of a compound as described herein in the preparation of a medicament for the prevention or treatment of a disorder caused by, associated with or accompanied by any abnormal activity against ERAP1. As used herein the phrase “preparation of a medicament” includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament. Another aspect relates to the use of a compound as described above in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder. Yet another aspect relates to the use of a compound as described herein in the preparation of a medicament for the prevention or treatment of an ERAP1-associated disease or disorder. Another aspect of the invention relates to a method of treating an ERAP1-associated disease or disorder in a subject. The method according to this aspect of the present invention is effected by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, as described hereinabove, either perse, or, more preferably, as a part of a pharmaceutical composition, mixed with, for example, a pharmaceutically acceptable carrier, as is detailed hereinafter. Yet another aspect of the invention relates to a method of treating a subject having a disease state alleviated by modulation of ERAP1 wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to the invention. Another aspect relates to a method of treating a disease state alleviated by modulation of ERAP1, wherein the method comprises administering to a subject a therapeutically effective amount of a compound according to the invention. Preferably, the subject is a mammal, more preferably a human. The term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known 24 manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts. Herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease or disorder, substantially ameliorating clinical symptoms of a disease or disorder or substantially preventing the appearance of clinical symptoms of a disease or disorder. Herein, the term “preventing” refers to a method for barring an organism from acquiring a disorder or disease in the first place. The term “therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. For any compound used in this invention, a therapeutically effective amount, also referred to herein as a therapeutically effective dose, can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the ICsoorthe ICwoas determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data. Using these initial guidelines one of ordinary skill in the art could determine an effective dosage in humans. Moreover, toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LDsoand the ED5o. The dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LDsoand EDso. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell cultures assays and animal studies can be used in formulating a dosage range that is not toxic for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the EDso with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition, (see, e.g., Fingl etal, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1). Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain therapeutic effect. Usual patient dosages for oral administration range from about 50-2000 mg / kg / day, commonly from about 100-1000 mg / kg / day, preferably from about 150-700 mg / kg / day and most preferably from about 250-500 mg / kg / day. Preferably, therapeutically effective serum levels will be achieved by administering multiple doses each day. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. One skilled in the art will be able to optimize therapeutically effective local dosages without undue experimentation. As used herein, “ERAP1-related disease or disorder” refers to a disease or disorder characterized by inappropriate ERAP1 activity. Inappropriate activity refers to either an increase or decrease in ERAP1 activity relative to wildtype ERAP1 (Uniprot ID Q9NZ08), caused by variation in the ERAP1 protein sequence, as measured by enzyme or cellular assays. Inappropriate activity could also be due to overexpression of ERAP1 in diseased tissue compared with healthy adjacent tissue. Preferred diseases or disorders that the compounds described herein may be useful in preventing include proliferative disorders, viral disorders, immune disorders and inflammatory disorders as described hereinbefore. Thus, the present invention further provides use of compounds as defined herein for the manufacture of medicaments for the treatment of diseases where it is desirable to modulate ERAP1. Such diseases include proliferative disorders, viral disorders, immune disorders and inflammatory disorders as described hereinbefore. In one preferred embodiment, the compound activates ERAPTs conversion of (L)-leucine-7-amido-4-methylcoumarin (L-AMC) to (L)-leucine and the fluorescent molecule 7-amino-4-methylcoumarin. While the same assay can also identify inhibitors of ERAPTs cleavage of the amide bond in L-AMC, for the purposes of this application this assay is referred to as the “L-AMC activator assay”. The potency of any activator is calculated and expressed as the concentration of the activator required to increase the enzyme activity of ERAP1 by 50% over its baseline level (i.e. an ECso). In one preferred embodiment, the compound exhibits an ECso value in an L-AMC activator assay of less than about 25 pM. More preferably, the compound exhibits an ECso value in the L-AMC activator assay of less than about 10 pM, more preferably, less than about 5 pM, even more preferably, less than about 1 pM, even more preferably, less than about 0.1 pM, even more preferably, less than about 0.01 pM. In one preferred embodiment, the compound inhibits ERAPTs ability to hydrolyse the decapeptide substrate WRVYEKCdnpALK. This peptide has minimal fluorescence as the N-terminal tryptophan residue’s fluorescence is quenched by the dinitrophenol (DNP) residue within the peptide. However, as ERAP1 hydrolyses the N-terminal amide bond and tryptophan is released this internal quenching is lost and the reaction is monitored by the increase in tryptophan fluorescence over the course of the assay. For the purposes of this application this assay is referred to as the “10mer inhibition assay” and compound potencies are calculated and expressed as ICso as would be familiar to a person skilled in the art. In one preferred embodiment, the compound exhibits an ICso value in the 10mer assay of less than about 25 pM. More preferably, the compound exhibits an ICso value in the 10mer assay of less than about 10 pM, more preferably, less than about 5 pM, even more preferably, less than about 1 pM, even more preferably, less than about 0.1 pM, even more preferably, less than about 0.01 pM. In one preferred embodiment, the compound exhibits an ICso value in the 10mer assay of from about 100 nM to about 500 nM, more preferably, less than 100 nM. PHARMACEUTICAL COMPOSTIONS For use according to the present invention, the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, described herein, may be presented as a pharmaceutical formulation, comprising the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic and / or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A Wade and PJ Weller. The carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water. The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used. Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. An active compound may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion. Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release -controlling matrix or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use. Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles. Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use. An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use. Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient. As one possibility such formulations are in the form of finely comminuted powders which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling 30 formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and / or a solid diluent. Suitable liquid propellants include propane and the chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide. Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension. Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof. As a further possibility an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation. Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w / v of an active compound in aqueous or oily solution or suspension. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered 31 media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. Formulations suitable for topical formulation may be provided for example as gels, creams or ointments. Such preparations may be applied e.g. to a wound or ulcer either directly spread upon the surface of the wound or ulcer or carried on a suitable support such as a bandage, gauze, mesh or the like which may be applied to and over the area to be treated. Liquid or powder formulations may also be provided which can be sprayed or sprinkled directly onto the site to be treated, e.g. a wound or ulcer. Alternatively, a carrier such as a bandage, gauze, mesh or the like can be sprayed or sprinkle with the formulation and then applied to the site to be treated. According to a further aspect of the invention, there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above, the process comprising bringing the active compound(s) into association with the carrier, for example by admixture. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound as described herein into conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle. SALTS / ESTERS The compounds of the invention can be present as salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters. Pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge etal, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g. hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates. Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. More preferably, the salt is a hydrochloride salt. Esters are formed either using organic acids or alcohols / hydroxides, depending on the functional group being esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric 33 acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen). ENANTIOMERS / TAUTOMERS In all aspects of the present invention previously discussed, the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds of the invention. The person skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers may be isolated / prepared by methods known in the art. Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3rd edition, ed. March, J., John Wiley and Sons, New York, 1985). Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. STEREO AND GEOMETRIC ISOMERS Some of the compounds of the invention may exist as stereoisomers and / or geometric isomers - e.g. they may possess one or more asymmetric and / or geometric centres and so may exist in two or more stereoisomeric and / or geometric forms. The present invention contemplates the use of all the individual stereoisomers and geometric isomers of those compounds, and mixtures thereof. The terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree). The present invention also includes all suitable isotopic variations of the compound or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 180,31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. For example, the invention includes compounds of general formula (I) where any hydrogen atom has been replaced by a deuterium atom. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. ATROPISOMERS Some of the compounds of the invention may exist as atropisomers. Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. The invention encompasses all such atropisomers. PRODRUGS The invention further includes the compounds of the present invention in prodrug form, i.e. covalently bonded compounds which release the active parent drug in vivo. Such prodrugs are generally compounds of the invention wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo. Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out be an esterase etc. Other such systems will be well known to those skilled in the art. SOLVATES The present invention also includes solvate forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably the solvate is a hydrate. POLYMORPHS The invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds. ADMINISTRATION The pharmaceutical compositions of the present invention may be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration. Preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose. By way of example, the formulations may be in the form of tablets and sustained release capsules, and may be prepared by any method well known in the art of pharmacy. Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, gellules, drops, cachets, pills or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution, emulsion or a suspension of the active agent in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc. Preferably, these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose. For compositions for oral administration (e.g. tablets and capsules), the term “acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent. Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier. Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions. Injectable forms typically contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose. The pharmaceutical compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders. An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required. DOSAGE A person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. The dosage amount will further be modified according to the mode of administration of the compound. For example, to achieve an “effective amount” for acute therapy, parenteral administration of a compound is typically preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg / kg; preferably between 0.1 and 20 mg / kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to modulate ERAP1. The compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg / kg / day. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect. The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to achieve one or more of the therapeutic indications disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg / kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg / kg. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention. The compounds of this invention, which may have good bioavailability, may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect. COMBINATIONS A further aspect of the invention relates to a combination comprising a compound as described herein and one or more additional active agents. In a particularly preferred embodiment, the one or more compounds of the invention are administered in combination with one or more additional active agents, for example, existing drugs available on the market. In such cases, the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents. Drugs in general are more effective when used in combination. In particular, combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimum time intervals between such doses. The major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance. Beneficial combinations may be suggested by studying the activity of the test compounds with agents known or suspected of being valuable in the treatment of a particular disorder. This procedure can also be used to determine the order of administration of the agents, i.e. before, simultaneously, or after delivery. Such scheduling may be a feature of all the active agents identified herein. In one preferred embodiment, the additional active agent is an immunotherapy agent, more preferably a cancer immunotherapy agent. An “immunotherapy agent" refers to a treatment that uses the subject’s own immune system to fight diseases such as cancer. In one preferred embodiment the compound of the invention inhibits the activity of ERAP1, and the compound is administered in combination with an immunotherapy. The compound may increase the sensitivity of cancer cells to an immunotherapy. The immunotherapy may be mediated by T cells. In one embodiment the compound may increase the number of CD8+ T cells in a tumour. In one embodiment the compound may be used to treat cancers which are weakly responsive or not responsive to immunotherapies. In one preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention, a co-stimulatory antibody, a chemotherapy agent, a radiotherapy agent, a targeted therapy agent or an antibody, particularly a monoclonal antibody. In one preferred embodiment the additional active agent is a molecule capable of immune checkpoint intervention. Immune checkpoint molecules include CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRP, CD47, CD48, 2B4, B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, IDO, CD39, CD73, A2aR and butyrophilins. Immune checkpoint molecules include both inhibitory and activatory molecules, and interventions may apply to either or both types of molecule. Immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, BTLA inhibitors and CTLA-4 inhibitors, for example. Co-stimulatory antibodies deliver positive signals through immune-regulatory receptors including but not limited to ICOS, CD137, CD27 OX-40 and GITR. In one highly preferred embodiment, the the additional active agent is an antibody checkpoint inhibitor. Suitable examples of antibody checkpoint inhibitors, include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies and anti-CTLA4 antibodies. In one preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-1 antibody, more preferably selected from pembrolizumab, cemiplimab and nivolumab. In one preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-L1 antibody, more preferably selected from atezolizumab, avelumab and durvalumab. In one preferred embodiment, the antibody checkpoint inhibitor is an anti-CTLA4 antibody, more preferably selected from ipilimumab and tremelimumab. In one preferred embodiment the immunotherapy is an anti-cancer vaccine or virus, such as an oncolytic virus. In one preferred embodiment the immunotherapy is a cell-based therapy. In one embodiment the cell-based therapy may be a T cell therapy, such as adoptive T cell therapy, or therapy with CAR-T cells. Adoptive cell-based immunotherapy may include the following: Irradiated autologous or allogeneic tumor cells, tumor lysates or apoptotic tumor cells, antigen-presenting cell-based immunotherapy, dendritic cell-based immunotherapy, adoptive T cell transfer, adoptive CAR T cell therapy, autologous immune enhancement therapy (AIET), cancer vaccines, and / or antigen presenting cells. Such cell-based immunotherapies can be further modified to express one or more gene products to further modulate immune responses, for example expressing cytokines such as GM-CSF, and / or to express tumor-associated antigen (TAA) antigens, such as Mage-1, gp-100, patient-specific neoantigen vaccines, and the like. In a further embodiment, the immunotherapy may comprise non-cell-based immunotherapies. In one embodiment, compositions comprising antigens with or without vaccine-enhancing adjuvants may be used. Such compositions exist in many well-known forms, such as peptide compositions, oncolytic viruses, and recombinant antigen comprising fusion proteins. In an alternative embodiment, immunomodulatory interleukins, such as IL-2, IL-6, IL-7, IL-12, IL-17, IL-23, as well as modulators thereof (e.g., blocking antibodies or more potent or longer lasting forms) may be used. Immunomodulatory cytokines, such as interferons, G-CSF, imiquimod, T F alpha, and the like, as well as modulators thereof (e.g., blocking antibodies or more potent or longer lasting forms) may also be used. In another embodiment, immunomodulatory chemokines, such as CCL3, CCL26, and CXCL7, and the like, as well as modulators thereof (e.g., blocking antibodies or more potent or longer lasting forms) may be used. In a further embodiment, 42 immunomodulatory molecules targeting immunosuppression, such as STAT3 signaling modulators, FkappaB signaling modulators, and immune checkpoint modulators, may be used. In another embodiment, immunomodulatory drugs, such as immunocytostatic drugs, glucocorticoids, cytostatics, immunophilins and modulators thereof (e.g., rapamycin, a calcineurin inhibitor, tacrolimus, ciclosporin (cyclosporin), pimecrolimus, abetimus, gusperimus, ridaforolimus, everolimus, temsirolimus, zotarolimus, etc.), hydrocortisone (Cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate (doca) aldosterone, a non-glucocorticoid steroid, a pyrimidine synthesis inhibitor, leflunomide, teriflunomide, a folic acid analog, methotrexate, anti-thymocyte globulin, anti-lymphocyte globulin, thalidomide, lenalidomide, pentoxifylline, bupropion, curcumin, catechin, an opioid, an EVIPDH inhibitor, mycophenolic acid, myriocin, fingolimod, an NF-xB inhibitor, raloxifene, drotrecogin alfa, denosumab, an F-xB signaling cascade inhibitor, disulfiram, olmesartan, dithiocarbamate, a proteasome inhibitor, bortezomib, MG132, Prol, PI-0052, curcumin, genistein, resveratrol, parthenolide, thalidomide, lenalidomide, flavopiridol, non-steroidal anti-inflammatory drugs (NSAIDs), arsenic tri oxide, dehydroxymethylepoxyquinomycin (DHMEQ), l3C(indole-3-carbinol) / DIM(di-indolmethane) (13C / DIM), Bay 1 1-7082, luteolin, cell permeable peptide SN-50, IKBa -super repressor overexpression, FKB decoy oligodeoxynucleotide (ODN), or a derivative or analog of any thereto, may be used. In yet another embodiment, immunomodulatory antibodies or protein may be used. For example, antibodies that bind to CD40, Toll-like receptor (TLR), 0X40, GITR, CD27, or to 4-IBB, T-cell bispecific antibodies, an anti-IL-2 receptor antibody, an anti-CD3 antibody, OKT3 (muromonab), otelixizumab, teplizumab, visilizumab, an anti-CD4 antibody, clenoliximab, keliximab, zanolimumab, an anti-CDI I a antibody, efalizumab, an anti-CD 18 antibody, erlizumab, rovelizumab, an anti-CD20 antibody, afutuzumab, ocrelizumab, ofatumumab, pascolizumab, rituximab, an anti-CD23 antibody, lumiliximab, an anti-CD40 antibody, teneliximab, toralizumab, an anti-CD40L antibody, ruplizumab, an anti-CD62L antibody, aselizumab, an anti-CD80 antibody, galiximab, an anti-CD147 antibody, gavilimomab, a B-Lymphocyte stimulator (BLyS) inhibiting 43 antibody, belimumab, an CTLA4-lg fusion protein, abatacept, belatacept, an anti-CTLA4 antibody, ipilimumab, tremelimumab, an anti-eotaxin 1 antibody, bertilimumab, an anti-a4-integrin antibody, natalizumab, an anti-IL-6R antibody, tocilizumab, an anti-LFA-1 antibody, odulimomab, an anti-CD25 antibody, basiliximab, daclizumab, inolimomab, an anti-CD5 antibody, zolimomab, an anti-CD2 antibody, siplizumab, nerelimomab, faralimomab, atlizumab, atorolimumab, cedelizumab, dorlimomab aritox, dorlixizumab, fontolizumab, gantenerumab, gomiliximab, lebrilizumab, maslimomab, morolimumab, pexelizumab, reslizumab, rovelizumab, talizumab, telimomab aritox, vapaliximab, vepalimomab, aflibercept, alefacept, rilonacept, an IL-1 receptor antagonist, anakinra, an anti-IL-5 antibody, mepolizumab, an IgE inhibitor, omalizumab, talizumab, an IL12 inhibitor, an IL23 inhibitor, ustekinumab. In one embodiment, the subject may be undergoing or have previously undergone treatment with a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chern. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, 44 cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-Fll); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor 45 RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (Tykerb); inhibitors of PKC-a, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation and 5 pharmaceutically acceptable salts, acids or derivatives of any of the above. In addition, the methods of treatment can further include the use of radiation. In addition, the methods of treatment can further include the use of photodynamic therapy. PROCESS 10 Another aspect of the invention relates to processes for preparing compounds of formula (I) as described herein. In one embodiment, the invention relates to a process for preparing a compound of formula (la) wherein R2 is COOH, X is NH, Y is SO2, R12 is H, and Ri, R3, R4, R5-R9 are 15 as defined hereinabove, said process comprising the steps of: (i) providing an intermediate of formula (1-2), where PG is a protecting group; (ii) reacting said intermediate of formula (1-2) with a compound of formula (Ila), wherein Re-Rg are as defined herein above, to form a compound of formula (Hla); (iii) reacting said compound of formula (Illa) with a compound of formula (IVa), where Ri, R3, R4 and Rs are as defined hereinabove and R' is alkyl (preferably Me), to form a compound of formula (Va); (iv) removing the protecting group PG from said compound of formula (Va) to form a compound of formula (Via); (v)    converting said compound of formula (Via) to a compound of formula (Vila); and (vi) hydrolysing the ester group COOR' of said compound of formula (Vila) to form a compound of formula (la). For ease of reference in the above scheme, the substituent (Ri3)m is omitted for clarity. Preferred reagents and conditions for each step are set out in the accompanying examples. In one preferred embodiment, step (i) comprises preparing an intermediate of formula (I-2) by treating an intermediate of formula (1-1) with bis(pinacolato)diboran: Preferably, the protecting group PG is a Boc group. In one preferred embodiment, the process further comprises preparing intermediate (I-1) by the following steps: (1-4)                                      (1-3)                                         (1-1) (a) preparing an intermediate of formula (1-3) by protecting the NH group of a compound of formula (1-4) with a protecting group, PG; (b) treating said intermediate of formula (1-3) with 1,1,1 -trifluoro-A / -phenyl-A / -((trifluoromethyl)sulfonyl)methanesulfonamide in the presence of potassium bis(trimethylsilyl)amide and a suitable solvent to form an intermediate of formula (1-1). In one preferred embodiment, step (ii) comprises coupling an intermediate of formula (I-2) with a compound of formula (Ila) in the presence of Pd(amphos)Cl2 and tripotassium phosphate in a suitable solvent. Preferably the solvent is a water-dioxane mixture. The skilled person would understand that other solvents would also be suitable. In one preferred embodiment, step (iii) comprises reacting said compound of formula (Illa) with a compound of formula (IVa) in the presence of pyridine / dichloromethane. In one preferred embodiment, step (iv) comprises removing the protecting group PG from said compound of formula (Va), for example, by treating with TFA in dichloromethane, to form a compound of formula (Via). In one preferred embodiment, step (v) comprises treating said compound of formula (Via) with a reducing agent to form a compound of formula (Vila). In one preferred embodiment, step (v) comprises treating said compound of formula (Via) with NaBH4in a suitable solvent, for example, a mixture of THF and methanol. The skilled person would understand that other solvents and reducing agents would also be suitable. In one preferred embodiment, step (vi) comprises treating said compound of formula (Vila) with LiOH:H2O to form a compound of formula (la). Preferably, step (vi) is 48 carried out in a solvent mixture comprising THF and water. The skilled person would understand that other solvents would also be suitable. In an alternative embodiment, the invention relates to a process for preparing a 5 compound of formula (la) wherein R2 is COOH, X is NH, Y is SO2, R12 is H, and Ri, R3, R4, R5-R9 are as defined hereinabove, said process comprising the steps of: Ry Step (ii) Step (Hi) (Va) (Villa) 10   (i) providing a compound of formula (Villa), wherein R6-R9 are as defined above; (ii) reacting said compound of formula (Villa) with an intermediate of formula (1-1), where PG is a protecting group, to form a compound of formula (Illa); (iii) reacting said compound of formula (Illa) with a compound of formula (IVa), where Ri, R3, R4 and Rs are as defined hereinabove and R' is alkyl (preferably Me), to 15 form a compound of formula (Va); (iv) removing the protecting group PG from said compound of formula (Va) to form a compound of formula (Via); (v) converting said compound of formula (Via) to a compound of formula (Vila); and 20 (vi) hydrolysing the ester group COR' of said compound of formula (Vila) to form a compound of formula (la). In one preferred embodiment, the process comprises preparing said compound of formula (Villa), where Re-Rg are as defined hereinabove, by reacting a compound of formula (Xa) with bis(pinacolato)diboran: In one preferred embodiment, step (ii) comprises coupling said compound of formula (Villa) with said intermediate (1-1) in the presence of bis(triphenylphosphine)palladium (II) chloride in a suitable solvent. Preferably, the solvent is a mixture of water and THF. The skilled person would understand that other solvents would also be suitable. In one preferred embodiment, step (iii) comprises reacting said compound of formula (Illa) with a compound of formula (IVa) in the presence of pyridine / dichloromethane. In one preferred embodiment, step (iv) comprises removing the protecting group PG from said compound of formula (Va), for example, by treating with TFA in dichloromethane to form a compound of formula (Via). In one preferred embodiment, step (v) comprises treating said compound of formula (Via) with a reducing agent to form a compound of formula (Vila). In one preferred embodiment, step (v) comprises treating said compound of formula (Via) with NaBH4in a suitable solvent, for example, a mixture of THF and methanol. The skilled person would understand that other solvents and reducing agents would also be suitable. In one preferred embodiment, step (vi) comprises treating said compound of formula (Vila) with LiOH:H2O to form a compound of formula (la). Preferably, step (vi) is carried out in a solvent mixture comprising THF and water. The skilled person would understand that other solvents would also be suitable. In one embodiment, the invention provides a process for preparing an enantiomer of a compound of formula (la). In one preferred embodiment, the process comprises preparing a compound of formula (Vila) as described above, optionally re-protecting the NH group of said compound of formula (Vila) and subjecting the resulting mixture to chiral chromatography. Thus, in one preferred embodiment, the invention relates to a process for preparing an an enantiomer of a compound of formula (la), said process comprising preparing a compound of formula (Vila) as described above, and carrying out the following additional steps: Enantiomer 1                                 Enantiomer 1                                  tnantior (IXa)                                               (Vila)                                                 (la) (v') re-protecting said compound of formula (Vila) with a protecting group PG to form a compound of formula (IXa), where PG is preferably Boc; (vi1) subjecting the mixture formed in step (v’) to chiral chromatography and isolating an enantiomer of said compound of formula (IXa); (vii') removing the protecting group PG from the enantiomer of said compound of formula (IXa) to form an enantiomer of a compound of formula (Vila); (viii') hydrolysing the ester group COR' of the enantiomer of the compound of formula (Vila) to form an enantiomer of a compound of formula (la). Preferred features for protection step (v1), deprotection step (vii') and hydrolysis step (viii') correspond to those described hereinabove. In an alternative embodiment, compound (Vila) can be subjected to chiral chromatography directly (without re-protection) to isolate an enantiomer of said compound of formula (Vila). The present invention is further described by way of the following non-limiting examples. EXAMPLES Abbreviations aq: aqueous; cone.: concentrated; CPME: cyclopentyl methyl ether; DAD: diode array detector; DCM: dichloromethane; dioxane: 1,4-dioxane; DMAP: 4-Dimethylaminopyridine; ESI: electrospray ionisation; h: hour(s); HPLC: high performance liquid chromatography; LC: liquid chromatography; M: molar, molecular ion; min: minute(s); MS: mass spectrometry; MSD: mass spectrometry detector; m / z: mass to charge ratio; NMR: nuclear magnetic resonance; Pd(amphos)Cl2: Bis(di-ferf-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(ll); Pd(dppf)Ch: [1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium; PDA: photodiode array; ppm: parts per million; SFC: supercritical fluid chromatography; TBME: tert-butyl methyl ether; TIC: total ion current; TFA: trifluoroacetic acid; THF: tetrahydrofuran; RT: room temperature (ca. 20 °C); tR: retention time; UV: ultraviolet; UPLC: ultra performance liquid chromatography. Other abbreviations are intended to convey their generally accepted meanings. General Experimental Conditions All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Reaction mixtures were magnetically stirred, and reactions performed at room temperature (ca. 20 °C) unless otherwise indicated. Column chromatography was performed on an automated flash chromatography system, such as a CombiFlash Rf system or Biotage Isolera Rf system, using prepacked silica (40 pm) cartridges, unless otherwise indicated. 1H NMR spectra were recorded using a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, or a Bruker Avance 400 MHz spectrometer. Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. Peak multiplicities are reported as a combination of s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent, etc, with coupling constants (J) reported where appropriate. The spectra were recorded at 298 K unless otherwise indicated. Analytical IIPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY LIPLC® H-Class system, equipped with Binary Solvent Pump, SM-FTN, CMA, PDA, QDa, running one of the analytical methods described below. Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1260 HPLC system, Quaternery Pump, HiP Sampler, Column Compartment, DAD, G6150 MSD running one of the analytical methods described below. Nomenclature of structures was generated using ‘Structure to Name’ conversion from ChemDraw® Professional 21 (PerkinElmer). Analytical Methods Method 1 - UPLC Acidic 3 min method Column:     Waters ACQUITY UPLC®CSH C18, 1.7 pm, 2.1 x 30 mm at 40 °C Detection:    UV at 254 nm unless otherwise indicated, MS by electrospray ionisation Solvents:     A: 0.1% formic acid in water, B: MeCN Gradient: Time %A %B Flow rate (mL / min) 0.00 98 2 0.77 2.50 0 100 0.77 3.00 0 100 0.77 Method 2 - UPLC Basic Method Column:     Waters ACQUITY UPLC®BEH C18, 1.7 pm, 2.1 x 30 mm at 40 °C 5 Solvents:    A: 0.2% Ammonia in water, B: MeCN Other conditions as Method 1. Method 3 - LCMS Acidic Method Column: 10 Detection: Solvents: Gradient: Waters Cortecs C18, 30 x 2.1 mm, 2.7pm, at 40 °C UV at 254 nm unless otherwise indicated, MS by electrospray ionisation A: 0.1% formic acid in water, B: MeCN Time %A %B Flow rate (mL / min) 0.00 98 2 1.35 2.5 0 100 1.35 3 0 100 1.35 Method 4 - LCMS Basic Method 15 Column: Phenomenex Evo C18, 30 x 2.1 mm, 2.6pm, at 40 °C Solvents:    A: 0.2% Ammonia in water, B: MeCN Other conditions as Method 3. Intermediate 1: tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-4H-1,4- oxazine-4-carboxylate O BOC2O, DMAP Et3N, DCM Step 1 Step 2 Step 1: tert-butyl 3-oxomorpholine-4-carboxylate: morpholin-3-one (10.0 g, 98.9 mmol) was combined with DMAP (12.1 g, 98.9 mmol) in DCM (400 mL) and treated with triethylamine (14 mL, 100 mmol). The resultant solution was cooled in an ice bath for 10 min, then treated portionwise with di-ferf-butyl dicarbonate (32.4 g, 148 mmol). The resultant solution was allowed to warm to RT and stir for 18 h. The mixture was sequentially washed with saturated NaHCO3(aq) (400 mL), water (400 mL), and brine (400 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc / isohexane) to afford the title compound (17.3 g, 85.8 mmol, 87% yield) as a pale-yellow oil, which crystallised to a white solid upon standing. 1H NMR (500 MHz, CDCI3) 6 4.22 (s, 2H), 3.91 - 3.85 (m, 2H), 3.77 - 3.71 (m, 2H), 1.54 (s, 9H). Step 2: tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate: A solution of potassium bis(trimethylsilyl)amide (1 M in THF) (62.0 mL, 62.0 mmol) in THF (300 mL) was cooled to -78 °C under N2 and a solution of the product from Step 1 above (10.0 g, 49.6 mmol) in THF (100 mL) was added dropwise maintaining the temperature below -70 °C. The mixture was stirred at this temperature for 90 min, then a solution of 1,1,1-trifluoro-A / -phenyl-A / -((trifluoromethyl)sulfonyl) methanesulfonamide (21.3 g, 59.5 mmol) in THF (100 mL) was added dropwise maintaining the temperature below -70 °C. The mixture was stirred for 1 h and was then warmed to RT. 2 M NaOH(aq) (300 mL) was added and the mixture was concentrated in vacuo to ca. 500 mL. TBME (200 mL) was added, and the layers were separated. The aqueous layer was extracted with TBME (200 mL), and the organic layers were combined, washed with brine (100 mL) and dried over anhydrous K2CO3 overnight. The mixture was filtered, concentrated in vacuo onto Celite® and partially purified by chromatography on silica gel (220 g cartridge, 10-100% DCM / isohexane) into 50 mL test tubes pre-treated with Et3N (0.1 mL) to afford the title compound (5.69 55 g, 17 mmol, 33% yield, 97% purity) as a clear colourless oil. UPLC-MS (Method 1): m / z 331.9 (M-H)- at 1.80 min. 1H NMR(500 MHz, DMSO) 5 7.06 (s, 1H), 4.02 (dd, J = 5.0, 3.9 Hz, 2H), 3.56 - 3.51 (m, 2H), 1.44 (s, 9H). Note: Intermediate 2 is unstable and was prepared or re-analysed immediately prior to use. 5 Example 1:4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid LiOH(aq) THF, MeOH Step 6 Step 1: tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4- oxazine-4-carboxylate: A mixture of Intermediate 1 (918 mg, 2.62 mmol, 95% purity), 10 K2CO3 (540 mg, 3.91 mmol) and bis(pinacolato)diboron (1.00 g, 3.94 mmol) was sparged with N2 for 15 min. Triphenylphosphine (69 mg, 263 pmol) and Bis(triphenylphosphino)palladium(ll) chloride (46 mg, 65.5 pmol) were added and the mixture was sparged with N2 for 5 min and then heated to 90 °C and stirred overnight. 56 The mixture was filtered through Celite®, washing with EtOAc. The filtrate was diluted with EtOAc (150 mL) and sequentially washed with water (50 mL) and brine (50 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-25% EtOAc / isohexane) to afford the title compound (104 mg, 167 pmol, 6% yield, 50% purity) as a pale-yellow solid. 1H NMR (500 MHz, DMSO) 6 5.76 (s, 1H), 4.07 - 3.98 (m, 2H), 3.54-3.45 (m, 2H), 1.44 (s, 9H), 1.19 (s, 12H). This material was contaminated with bis(pinacolato)diboron and was used in the next step without further purification. Step 2: tert-butyl 5-(2-amino-4-(trifluoromethyl)phenyl)-2,3-dihydro-1,4-oxazine-4-carboxylate: A mixture of 2-bromo-5-(trifluoromethyl)aniline (25 pL, 0.17 mmol), the product from Step 1 above (104 mg, 167 pmol, 50% purity) and tripotassium phosphate (63.0 mg, 297 pmol) in dioxane (1 mL) and water (0.25 mL) was sparged with N2 for 10 min. Pd(amphos)Cl2 (5.0 mg, 7.1 pmol) was added, the mixture was sparged with N2 for 5 min and then heated to 80 °C and stirred overnight. The mixture was cooled to RT, diluted with water (5 mL) and extracted with EtOAc (3x15 mL). The organic extracts were combined, washed with brine (10 mL), dried (MgSO4), and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc / isohexane) to afford the title compound (34.1 mg, 89.1 pmol, 51% yield, 90% purity) as a yellow solid. UPLC-MS (Method 2): m / z 245.1 (M-Boc+H)+ at 1.72 min 1H NMR (500 MHz, DMSO) 6 7.04 (d, J = 7.9 Hz, 1H), 6.89 (d, J= 1.9 Hz, 1H), 6.79-6.73 (m, 1H), 6.16 (s, 1H), 5.14 (s, 2H), 4.12 (t, J= 4.4 Hz, 2H), 3.81 -3.73 (m, 2H), 1.16 (s, 3H), 1.03 (s, 6H). Step 3: tert-butyl 5-(2-((2-cyclopropyl-5-(methoxycarbonyl)phenyl)sulfonamido)-4-(trifluoromethyl)phenyl)-2,3-dihydro-1,4-oxazine-4-carboxylate: A mixture of the product from Step 2 above (34.1 mg, 89.1 pmol, 90% purity), methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (40.0 mg, 146 pmol, prepared according to WO2020 / 104822 Example 323 Step 2) and pyridine (24 pL, 298 pmol) in DOM (1 mL) was heated to 35 °C and stirred for 6 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to afford the title compound (18.9 mg, 26.0 pmol, 29% yield, 80% purity) as a yellow solid. UPLC-MS (Method 2): m / z 605.0 (M+Na)+, 581.3 (M-H)’, at 1.35 min. Step 4: methyl 4-cyclopropyl-3-(N-(2-(3,4-dihydro-1,4-oxazin-5-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 3 above (18.9 mg, 26.0 pmol, 80% purity) in TFA (120 pL, 1.56 mmol) and DCM (120 pL) was stirred at RT overnight. The mixture was diluted with DCM (5 mL), sequentially washed with saturated NaHCO3(aq) (5 mL) and brine (5 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (14.2 mg) as a brown solid. UPLC-MS (Method 1): m / z 483.4 (M+H)+, 481.2 (M-H)-, at 1.71 min. Step 5: methyl 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (14.2 mg) in THF (150 pL) and MeOH (150 pL) was treated with NaBH4 (5.00 mg, 132 pmol) and the mixture was stirred at RT for 1 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3*10 mL). The organic extracts were combined and washed with brine (10 mL), dried (MgSO4), filtered, and the concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-10% MeOH / DCM) to afford the title compound (12.0 mg, 24.8 pmol, 95% yield over two steps) as a light-yellow gum. UPLC-MS (Method 1): m / z 485.5 (M+H)+, 483.2 (M-H)-, at 1.01 min. Step 6: 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from Step 5 above (12 mg, 24.8 pmol) and LiOH H2O (5 mg, 119 pmol) in THF (0.5 mL) and water (0.1 mL) was stirred at RT overnight. The THF was removed in vacuo and the residue was acidified to pH 4 using 1 M HCI(aq). The resultant precipitate was collected by filtration and the filtrate was concentrated in vacuo. The combined residue was suspended in DCM (15 mL) and filtered. The collected solid was dissolved in MeOH (10 mL) and concentrated onto Celite®, then purified by chromatography (4 g reverse phase C18 cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to afford the title compound (5.8 mg, 12 pmol, 49% yield, 98% purity) as a yellow solid. UPLC-MS (Method 1): m / z 471.4 (M+H)+, 469.2 (M-H)-, at 0.86 min. 1H NMR (500 MHz, DMSO) 5 8.50 (d, J = 1.9 Hz, 1H), 8.15 (s, 1H), 7.82 (dd, J= 8.1,2.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 4.53 - 4.47 (m, 1H), 4.14-4.05 (m, 1H), 3.94-3.84 (m, 2H), 3.73-3.66 (m, 1H), 3.63-3.55 (m, 58 1H), 3.25-3.21 (m, 1H), 3.14-3.05 (m, 1H), 1.10-1.04 (m, 2H), 0.86-0.77 (m, 2H). Two exchangeable protons not observed. Example 2:4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid Enantiomer 1 Step 1: methyl 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate Enantiomer 1: The product from Example 1 Step 5 was dissolved in MeOH (5 mg / mL) with sonication, filtered, and then separated by chiral SFC (Waters prep 100 with a PDA and a QDa detectors, 40 °C, 120 bar, Phenomenex A1 column, 5 pM, 21 x 250 mm; flow rate 65 mL / min, 15% (0.03% ammonia / MeOH) / CO2). UPLC-MS (Method 1): m / z 485.3 (M+H)+, 483.3 (M-H)’, at 1.08 min. 1H NMR (500 MHz, DMSO) 5 9.43 (S, 1H), 8.52 (d, J= 2.0 Hz, 1H), 7.85 (dd, J = 8.1, 1.9 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.30 (d, J= 8.1 Hz, 1H), 6.96-6.89 (m, 2H), 4.51 (dd, J= 10.1, 3.9 Hz, 1H), 3.97-3.91 (m, 1H), 3.88 (dd, J = 12.0, 3.9 Hz, 1H), 3.84 (s, 3H), 3.83 - 3.73 (m, 1H), 3.57 (td, J = 12.0, 2.4 Hz, 1H), 3.30 (s, 1H), 3.27 -3.08 (m, 3H), 1.19-1.04 (m, 2H), 0.90-0.83 (m, 1H), 0.83-0.77 (m, 1H). Chiral SFC (Waters UPC2, Phenomenex A1 column, 5 pM, 4.6 x 250 mm, flow rate 4 mL / min, 15% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 1.75 min, 99% ee. Step 2: 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid Enantiomer 1: The title compound was prepared using a procedure analogous to Example 1 Step 6. Analytical data consistent with Example 1. Example 3:4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid Enantiomer 2 Step 1: methyl 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate Enantiomer 2: The title compound was obtained from the separation performed in Example 2 Step 1. Chiral SFC (Waters 5 UPC2, Phenomenex A1 column, 5 pM, 4.6 x 250 mm, flow rate 4 mL / min, 15% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 2.36 min, 98% ee. Other analytical data consistent with the product from Example 2 Step 1. Step 2: 4-cyclopropyl-3-(N-(2-(morpholin-3-yl)-5- 10 (trifluoromethyl)phenyl)sulfamoyl)benzoic acid Enantiomer 1: The title compound was prepared using a procedure analogous to Example 1 Step 6. Analytical data consistent with Example 1. Example 4: 3-(N-(5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 1 N Pd(dppf)CI2, KOAc Dioxane Pd(PPh3)2CI2 Na2CO3 THF, H2O Step 2 Step 1 Pyridine DCM Step 3 i) TFA, DCM ii) NaBH4 MeOH, THF Step 4 Chiral SFC Step 5 Step 1:3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: A mixture of 3-amino-4-bromobenzonitrile (1 g, 5.08 mmol), Bis(pinacolato)diboron (1.29 g, 5.08 5 mmol), potassium acetate (1.49 g, 15.2 mmol), Pd(dppf)Cl2 (0.371 g, 0.508 mmol) in dioxane (5 mL) was purged with N2. The mixture was heated at 80 °C for 16 h, then concentrated onto silica gel and purified by chromatography on silica gel (40 g cartridge, 0-30% EtOAc / isohexane) to afford the title compound (1.07 g, 4.30 mmol, 85% yield) as a light-orange solid. 1H NMR (500 MHz, DMSO) 5 7.49 (d, J= 7.6 Hz, 10    1H), 6.94 (d, J = 1.5 Hz, 1H), 6.82 (dd, J = 7.6, 1.5 Hz, 1H), 5.90 (br s, 2H), 1.31 (s, 12H). Step 2: tert-butyl 5-(2-amino-4-cyanophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate: The product from Step 1 above (450 mg, 1.75 mmol) was combined with bis(triphenylphosphine)palladium(ll) chloride (50 mg, 71.2 pmol) and sodium carbonate (890 mg, 8.40 mmol) and the vessel purged with N2. THF (10 mL) and water (4 mL) were added, followed by a solution of Intermediate 1 (600 mg, 1.80 mmol) in THF (1 mL). The resultant mixture was heated at 40 °C for 2 h. Additional Intermediate 1 (600 mg, 1.80 mmol) in THF (1 mL) was added and heating was continued for 4 h. Additional Intermediate 1 (600 mg, 1.80 mmol) in THF (1 mL) was added and heating was continued overnight. The mixture was cooled, diluted with TBME (10 mL) and the phases separated. The aqueous phase was extracted with TBME (5 mL), then the organic phases were combined and concentrated in vacuo. The residue was dissolved in DCM (5 mL), passed through a phase separator, and the filtrate purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to afford the title compound (349 mg, 1.13 mmol, 65% yield, 98% purity) as an off-white solid. UPLC-MS (Method 1): m / z 246.1 (M+H-C4H8)+, 202.2 (M+H-Boc)+, at 1.48 min. 1H NMR (500 MHz, DMSO) 5 7.02 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 6.87 (dd, J=7.7, 1.7 Hz, 1H), 6.20 (s, 1H), 5.18 (s, 2H), 4.14-4.09 (m, 2H), 3.78-3.73 (m, 2H), 1.05 (s, 9H). Step 3: tert-butyl 5-(4-cyano-2-((2-cyclopropyl-5-(methoxycarbonyl)phenyl)sulfonamido)phenyl)-2,3-dihydro-1,4-oxazine-4-carboxylate: The product from Step 2 above (169 mg, 550 pmol, 98% purity) was combined with methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (190 mg, 1.26 Eq, 692 pmol, prepared according to WO2020 / 104822 Example 323 Step 2) in DCM (4 mL) and treated with pyridine (140 pL, 1.73 mmol). The resultant solution was allowed to stand at RT over the weekend. Additional methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (50.3 mg, 183 pmol) was added and the resultant solution was allowed to stand at RT for a further 24 h. The solution was sequentially washed with 1 M HCI(aq) (5 mL), water (5 mL), and saturated NaHCO3(aq) (5 mL), dried (MgSO4) and directly purified by chromatography on silica gel (12 g cartridge, 0-60% EtOAc / isohexane) to afford the title compound (253 mg, 0.42 mmol, 77% yield, 90% purity) as an off-white foam. UPLC-MS (Method 1): m / z 440.0 (M+H-Boc)+, 538.3 (M-H)’, at 1.84 min. 1H NMR (500 MHz, DMSO) 5 9.89 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.03 (dd, J = 8.3, 1.9 Hz, 1H), 7.60 (dd, J= 8.0, 1.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.13 62 (d, J = 8.4 Hz, 1H), 6.09 (s, 1H), 4.14-4.06 (m, 2H), 3.85 (s, 3H), 3.72-3.67 (m, 2H), 2.72 - 2.63 (m, 1H), 1.07 - 0.98 (m, 2H), 1.02 (s, 9H), 0.86 - 0.80 (m, 2H). Step 4: methyl 3-(N-(5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: The product from Step 3 above (253 mg, 422 pmol, 90% purity) was treated with TFA (2 mL, 26.0 mmol) and the resultant solution allowed to stand at RT for 90 min. The mixture was concentrated in vacuo and the residue partitioned between DCM (5 mL) and saturated NaHCO3(aq) (5 mL). The phases were separated, and the aqueous phase extracted with DCM (2*1 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in THF (2.5 mL) and treated with NaBH4 (80 mg, 2.11 mmol). The resultant suspension was stirred for 5 min, then MeOH (0.5 mL) was added dropwise. Once the effervescence had subsided, the mixture was stirred at RT for 1 h. The resultant clear solution was quenched by dropwise addition of 1 M HCI(aq) (3 mL) to pH 1, then stirred for 5 min. The resultant biphasic mixture was neutralised with 2 M NaOH(aq) (0.5 mL) to pH 8-9. The mixture was extracted with EtOAc (5 mL, then 2*1 mL). The extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (12 g cartridge, 50-100% (2% cone. NH4OH(aq) in 3:1 EtOAc / EtOH, then flushed with (2% AcOH in 3:1 EtOAc / EtOH)) afforded the title compound (119 mg, 261 pmol, 62% yield, 97% purity) as a pale yellow oil. An additional component (77 mg) was also isolated from the chromatography. This was dissolved in EtOAc (1 mL) and treated with AcOH (0.1 mL). The resultant solution was allowed to stand at RT for 3 days. MeOH (1 mL) and 3 M HCI in CPME (0.25 mL, 83.3 pmol) were added and the solution allowed to stand at RT for 24 h. The mixture was concentrated in vacuo to afford a second batch of the title compound (91 mg, 190 pmol, 45%, 92% purity). Step 5: methyl 3-(N-(5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate Enantiomer 1: The product from Step 4 above (119 mg, 261 pmol, 97% purity) was dissolved in MeOH (3 mL), filtered and was then separated by chiral SFC (Waters prep 100 with a PDA and a QDa detectors, 40 °C, 120 bar, Phenomenex Lux A1 column, 5 pM, 21 mm x 250 mm; flow rate 65 mL / min, 30% MeOH / CO2) to afford the title compound (24 mg, 53 pmol, 20% yield, 98% purity) as a 63 colourless glass. UPLC-MS (Method 1): m / z 442.3 (M+H)+ at 0.97 min. Chiral SFC (Waters UPC2, Phenomenex Lux A1 column, 5 pM, 4.6 x 250 mm, flow rate 4 mL / min, 15% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 3.76 min. Step 6: 3-(N-(5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 1: A solution of the product from Step 5 above (24 mg, 53.3 pmol, 98% purity) in THF (1 mL) was treated with 1 M LiOH(aq) (269 pL, 269 pmol). The resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo to remove the THF, then acidified to pH 4 using 1 M HCI(aq). The resultant white suspension was extracted with EtOAc (3x2 mL). The extracts were combined, washed with brine (1 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (19.2 mg, 42 pmol, 79% yield, 94% purity) as a white solid. UPLC-MS (Method 1): m / z 428.4 (M+H)+, 426.4 (M-H)’, at 0.81 min. 1H NMR (500 MHz, MeOD) 6 8.62 (d, J = 1.8 Hz, 1H), 8.07 (dd, J = 8.2, 1.9 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.20 (dd, J= 7.9, 1.6 Hz, 1H), 7.08 (d, J= 8.2 Hz, 1H), 4.48 (dd, J = 10.4, 3.9 Hz, 1H), 4.11 -3.99 (m, 2H), 3.90 (dd, J = 12.2, 3.9 Hz, 1H), 3.78 (td, J = 11.9, 2.7 Hz, 1H), 3.31 (s, 1H), 3.25 (td, J = 12.0, 3.6 Hz, 1H), 3.12-3.03 (m, 1H), 1.51 - 1.28 (m, 1H), 1.24-1.14 (m, 2H), 1.05-0.87 (m, 2H). Two exchangeable protons not observed. The following examples were prepared by methods analogous to Example 4, substituting appropriate starting materials and intermediates where necessary: Example Structure Name 1 Analytical Data 5 °Y°H II N 3-(N-(5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 2 Analytical data consistent with Example 4. Step 5 Chiral SFC (Waters UPC2, Phenomenex Lux A1 column, 5 pM, 4.6 x 250 mm, flow rate 4 mL / min, 15% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 5.52 min, 98% ee. Example Structure Name / Analytical Data 3-(N-(5-cyano-4-fluoro-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 1 6 HN. I "° °1 H | r   °''° / 1 .OH UPLC-MS (Method 1): m / z 446.3 (M+H)+, 444.3 (M-H)-, at 0.86 min. 1H NMR (500 MHz, MeOD) 6 8.57 (d, J= 1.8 Hz, 1H), 8.09 (dd, J = 8.2, 1.9 Hz, 1H), 7.42 (d, J= 5.8 Hz, 1H), 7.31 (d, J= 9.7 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 4.39 (dd, J= 9.9, 4.0 Hz, 1H), 4.01 -3.80 (m, 3H), 3.73 (td, J= 11.6, 2.8 Hz, 1H), 3.27-3.12 (m, 2H), 3.09-2.97 (m, 1H), 1.44 - 1.29 (m, 1H), 1.21 (dd, J= 8.5, 2.4 Hz, 2H), 1.05 - 0.89 (m, 2H). Two exchangeable protons not observed. Step 5 Chiral SFC (Waters UPC2, ChiralPak IG column, 5 pm, 4.6 x 250 mm, flow rate 4 mL / min, 25% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 2.28, 100% ee. HN. '° °1 H | .OH 3-(N-(5-cyano-4-fluoro-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 2 7 r Vn"sA r $ / 1 Analytical data consistent with Example 6. Step 5 Chiral SFC (Waters UPC2, ChiralPak IG column, 5 pm, 4.6 x 250 mm, flow rate 4 mL / min, 25% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 2.80, 95% ee. Example Structure Name 1 Analytical Data 8 HNX I t O^OH 0 h \ i Zl o'0 I >l 3-(N-(4-chloro-5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 1 UPLC-MS (Method 1): m / z 462.3 (M+H)+, 420.1 (M-H)-, at 1.01 min. 1H NMR (500 MHz, MeOD) 5 8.61 (d, J= 1.8 Hz, 1H), 8.07 (dd, J = 8.2, 1.9 Hz, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.07 (d, J= 8.3 Hz, 1H), 4.48 (dd, J = 10.3, 3.9 Hz, 1H), 4.18-4.08 (m, 1H), 4.07-3.98 (m, 1H), 3.93 (dd, J= 12.2, 3.9 Hz, 1H), 3.79 (td, J = 12.0, 2.6 Hz, 1H), 3.26 (td, J = 12.0, 3.7 Hz, 1H), 3.12-3.03 (m, 1H), 1.36-1.25 (m, 1H), 1.20 (dd, J= 8.5, 2.8 Hz, 2H), 1.07-0.86 (m, 2H). Three exchangeable protons not observed. Step 5 Chiral SFC (Waters UPC2, ChiralPak IB-N column, 5 pm, 4.6 x 250 mm, flow rate 4 mL / min, 20% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 3.50 min, 100% ee. 9 HN. Cl I b -0 °y0H i h A r     A I 3-(N-(4-chloro-5-cyano-2-(morpholin-3-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Enantiomer 2 Analytical data consistent with Example 8. Step 5 Chiral SFC (Waters UPC2, ChiralPak IB-N column, 5 pm, 4.6 x 250 mm, flow rate 4 mL / min, 20% (0.1% ammonia / MeOH) / CO2, 120 bar) tR: 3.95 min, 95% ee. Biological Investigations The following assays can be used to illustrate the commercial utilities of the compounds according to the present invention. 5 Biological Assay 1: ERAP1 mediated hydrolysis of an amide substrate measured in a biochemical system Materials and Solutions 1X Assay buffer (AB): 25 mM Bis-tris propane, 0.05% w / v Hydroxypropylmethylcellulose pH 7.75 made with Optima grade water Decapeptide WRVYEKC(Dnp)ALK-acid (where Dnp is Dinitrophenyl maleimide) (10-mer) L-Leucine 7-amido-4-methylcoumarin (L-AMC) Purified ERAP1 (37-941 )-1 OHis (ERAP1) Assay procedure: 12.5 pL ERAP1 enzyme in 1X AB was combined with 250 nL test compound in DMSO. 12.5 pL of either 240 pM L-AMC in 1X AB or 100 pM 10-mer in 1X AB was added to the reaction and incubated at 23 °C for 1 h. For detection, plates were read at excitation 365 nm and emission 442 nm (L-AMC) or excitation 279 nm and emission 355 nm (10-mer). Compound IC50 was determined using a 4-parameter equation. The results for selected compounds according to the invention are shown in Table 1. OVA antigen presentation assay The cellular effect of representative compounds according to the invention on antigen presentation can be measured by assessing their effect on the presentation of an ovalbumin-specific peptide (SIINFEKL) to T-cells, as previously described [Reeves et al, (2014) Proc. Natl. Acad. Sci. USA 111; 17594-17599], Briefly, SiHa cells are transiently transfected with plasmids encoding mouse H2Kb and an ER-targeted N-terminally extended precursor peptide derived from ovalbumin (MRYMILGLLALAAVCSAAIVMKSIINFEHL) using Lipofectamine 3000. The cells are harvested 6 h post-transfection and transfected SiHa cells are plated compounds across a 12-point concentration response curve to quantify ERAP1 inhibitor ICso- SiHa cells are cultured in the presence of compound for 48 h. Subsequently, B3Z cells [Karttunen et al, (1992) Proc. Natl. Acad. Sci. USA 89; 6020-6024] are added to the cell culture for 4 h; the B3Z T-cell hybridoma encodes a TCR recognizing specifically the SIINFEHL / H2Kb complex at the cell surface, which upon activation, triggers a signalling cascade leading to the transcription of the LacZ gene that is under the control of the IL-2 promoter. Intracellular p-galactosidase activity as a readout of T-cell activation is measured by quantifying the conversion of chlorophenored- p -D-galacto-pyrannoside (CPRG) to chlorophenol red by measuring absorbance at 570 nm. Immunopeptidomics The effect of representative compounds according to the invention on global antigen processing can be determined using an unbiased proteomics pipeline as described by Purcell and colleagues [Purcell et al, (2019) Nat Protoc. 14; 1687-1707], Briefly, 500 million SiHa cells are treated with compound for 24 h or siRNA for 72 hours and then harvested, lysed and MHC-bound peptides isolated by immunoaffinity capture. The peptides are eluted using 10% (v / v) acetic acid and separated from the MHC-1 and p2-microglobulin proteins by HPLC before analysis by LC-MS / MS. Hepatocyte Stability (Human, mouse, rat, dog) Test compound (3pM) is incubated with cryopreserved hepatocytes in suspension. Samples are removed at 6 time points over the course of a 60 min experiment and test compound is analysed by LC-MS / MS. An intrinsic clearance value (CLint) with standard error and half-life (1½) are calculated. Cryopreserved pooled hepatocytes are stored in liquid nitrogen prior to use. Wiliams E media supplemented with 2mM L-glutamine and 25mM HEPES and test compound (final substrate concentration 3pM; final DMSO concentration 0.25 %) are pre-incubated at 37 C prior to the addition of a suspension of cryopreserved hepatocytes (final cell density 0.5x106 viable cel!s / mL in Williams E media supplemented with 2mM L-glutamine and 25mM HEPES) to initiate the reaction. The final incubation volume is 500pL A control incubation is included for each compound tested where lysed cells are added instead of viable cells. Two control compounds are included with each species. The reactions are stopped by transferring 50pL of incubate to 100pL methanol containing internal standard at the appropriate time points. The control (lysed cells) is incubated for 60min only. The termination plates are centrifuged at 2500rpm at 4°C for 30min to precipitate the protein. Following protein precipitation, the sample supernatants are combined in cassettes of up to 4 compounds and analysed using generic LC-MS / MS conditions. From a plot of In peak area ratio (compound peak area / internal standard peak area) against time, the gradient of the line is determined. Subsequently, half-life (1½) and intrinsic clearance (CLm) are calculated using the equations below: Elimination rate constant (k) = (- gradient) Half-life (1½) (min) = 0.693 / k Intrinsic clearance (CLint) (pL / min / million cells) = (V x 0.693) / ti / 2 where V = Incubation volume (pL)ZNumber of cells Two control compounds for each species are included in the assay and if the values for these compounds are not within the specified limits the results are rejected and the experiment repeated. Caco~2 Permeability The human colon epithelial cancer cell line, Caco-2, is used as a model of human intestinal absorption of drugs. This model is suitable to test compound suitability for oral dosing, predict intestinal permeability and investigate drug efflux. When cultured as a monolayer, Caco-2 cells differentiate to form tight junctions between cells to serve as a model of passive diffusion of compounds across the monolayer. Various uptake and efflux transporters are expressed in Caco-2 cells. Caco-2 Permeability was determined using the CacoReady™ Kit from ReadyCell S.L. (Barcelona, Spain), a ready-to-use cell-based assay for rapid in-vitro assessment of a drug’s permeability. Differentiated and polarized Caco-2 cells (21-day system) are plated on a 96-transwell permeable system as a single monolayer to allow for automated high throughput screening of compounds. Drug transport is assessed in both directions (apical to basolateral (A-B) and basolateral to apical (B-A)) across the cell monolayer (Figure 1). The buffer used for the assay does not include HEPES, so as to minimise the inhibitory effect on uptake transporters. Studies were run in HBSS buffer, with both the A and B compartments at pH7.4 and analytical analysis samples taken at 0 and 2hrs. Test compound concentrations are quantified using a calibration curve following analysis by LC-MS / MS, and the apparent permeability coefficient (Papp) and efflux ratio of the compound across the monolayer are calculated. The efflux ratio is used as an indicator of active efflux. The permeability coefficient (Papp) is calculated from the following equation: ~ / dQ / dt\ x A / Where dQ / dt is the amount of compound in basal (A-B) or apical (B-A) compartment as a function of time (nmol / s). Co is the initial concentration in the donor (apical or basal) compartment (mean of T=0) (nmol / mL) and A is the area of the transwell (cm2). The efflux ratio is then calculated as: Papp (BtoA) Papp (AtoB) Compounds of the invention are more permeable with lower efflux when compared to closely related literature comparisons (Table 2). For example, compare literature compound 1 with Examples 1 and 3; literature compound 2 with Example 7; literature compound 3 with Example 9. In Vivo Pharmacokinetics in Rat Pharmacokinetic parameters were determined in male Spague-Dawley rat (n=3 animals per administration route). Compounds were dose intravenously at 1mg / kg (5% DMSO195% 2-hydroxypropyl-p-cyclodextrin (25%w / v) in water) at 5mL / kg and oral at 3mg / kg (10% DMSO 110% TPGS110% PEG400165% HMPC (0.5% solution in water) at 10mL / kg, wherein TPGS is D-a-Tocopheryl polyethylene glycol 1000 succinate and HMPC is hydroxypropylmethylcellulose. For the iv route, blood was sampled via serial jugular vein cannulation (JVC) at 0.083, 0.25, 0.5, 1,2, 4, 8, 12 and 24hr. For the oral route, samples were taken at 0.25, 0.5, 1,2, 4, 6, 12 and 24hr. 100pL aliquots of blood were placed into K2 EDTA tubes and samples were gently mixed and placed on crushed ice immediately following collection. As soon as practically possible (within 30 mins of sampling), samples were centrifuged (1500 g, 10 min, 4 °C) and plasma collected. 40 pL plasma was diluted 1:1 with 100mM phosphoric acid and gently mixed and stored on ice. The concentrations of compound in the plasma samples were determined by protein precipitation with ice cold acetonitrile followed by LC-MS / MS analysis. Compounds of the invention have improved in vivo pharmacokinetics (such as lower clearance and longer half-life) when compared to closely related literature comparisons (Table 3). For example, compare literature compound 1 with Example 3 ; literature compound 2 with Example 7. Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the 5 invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims. Table 1: Activity of selected compounds according to the invention 1 MEDIUM 2 LOW 3 MEDIUM 4 LOW 5 HIGH 6 LOW 7 HIGH 8 LOW 9 HIGH IC50 vs Decapeptide WRVYEKC(Dnp)ALK-acid (where Dnp is Dinitrophenyl maleimide) (10-mer); High (<1nM), Medium (>1nM to <10nM), Low (>10nM to <250nM). Table 2: Caco-2 permeability and efflux for selected compounds according to the invention and comparison to literature comparisons Compound A to B (x 10-6 cm / s) Efflux ratio HN r Literal (W O^O H h \ i vSrV °''° A ture comparison 1 Example 16 02021094763) 0.9 2.1 HN 1 b Literal (W O^OH r h \ i r    '° △ i ture comparison 2 Example 21 02021094763) 0.4 1.7 HNX / Cl Literal (W 0^0 H l h ril T    '° A I N ture comparison 3 Example 22 02021094763) 0.1 6.8 Example 1 2.4 1.5 Example 3 2.7 1.5 Example 7 0.6 0.1 Example 9 1.0 0.3 Table 3: Rat pharmacokinetics for selected compounds according to the invention and comparison to literature comparisons Compound IV Clearance (mL / min / kg) IV T1 / 2 (h) Vd (L / kg) Oral Cmax (liM) Oral AUCO-t (gM.h) Literature comparison 1 Example 16 (WO2021094763) 24 0.9 3.2 0.5 1.8 Literature comparison 2 Example 21 (WO2021094763)* 72 0.2 0.57 0.075 0.11 Example 3 1.7 1.8 0.31 6 23 Example 5 6 2.3 0.38 ND ND Example 7 3.7 4.5 0.25 ND ND Example 9 6.4 3.6 0.34 0.59 1.3 Calculated from blood analysis applying a blood:plasma correction factor of 0.6 REFERENCES 1. Serwold et al, (2002), ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum; Nature: 419, p480. 2. Snyder et al, (2014), Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma; NEJM: 371, p2189. 3. Van Allen et al, (2015), Genomic correlates of response to CTLA-4 blockade in metastatic melanoma; Science: 348, p124. 4. James et al, (2013), Induction of Protective Antitumor Immunity through Attenuation of ERAAP Function; J Immunol: 190, p5839. 5. Niranjana et al, (2016), ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules; J Immunol: 197, p1035. 6. Pepelyayeva et al, (2018), ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis; Sci. Reports: 8: p12464. 7. Cifaldi et al, (2015), ERAP1 Regulates Natural Killer Cell Function by Controlling the Engagement of Inhibitory Receptors, Cancer Res.: 75, p824. 8. Steinbach et al, (2017), ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism, Oncoimmunol: 6, e1336594. 9. Kim et al, (2011), Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1, Nat. Immunol.: 12, p984. 10. Tenzer et al, (2009), Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance, Nat. Immunol.: 10, p636. 11. Reeves etal, (2018), The role of polymorphic ERAP1 in autoinflammatory disease, Biosci. Rep.: 29, p38. 12. Chen et al, (2014), Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis, Ann Rheum Dis: 75, p916. 13. Sheehan, NJ (January 2004). "The ramifications of HLA-B27". Journal of the Royal Society of Medicine. 97 (1): 10-4. 14. Smith, JA (January 2015). "Update on ankylosing spondylitis: current concepts in pathogenesis". Current allergy and asthma reports. 15 (1): 489. 15. Kuiper JJW, Mutis T, de Jager W, de Groot-Mijnes JD, RothovaA (2011). "Intraocular interleukin-17 and proinflammatory cytokines in HLA-A29-associated birdshot chorioretinopathy". Am J Ophthalmol. 152 (2): 177-182 16. Kuiper JJW, EmmelotME, RothovaA, Mutis T (2013). "Interleukin-17 production and T helper 17 cells in peripheral blood mononuclear cells in response to ocular lysate in patients with birdshot chorioretinopathy". Mol Vis. 19: 2606-14 17. Kuiper JJW, van Setten J, Ripke S, Van't Slot R, Mulder F, Missotten T, Baarsma GS, Francioli LC, Pulit SL, de Kovel CG, Ten Dam-van Loon N, den Hollander Al, Huis In Het Veld P, Hoyng CB, Cordero-Coma M, Martin J, Lloreng V, Arya B, Thomas D, Bakker SC, Ophoff RA, Rothova A, de Bakker PI, Mutis T, Koeleman BP (2014). "A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy". Hum Mol Genet. 23 (22): 6081-6087 18. Evans et al (2011), Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 10;43(8):761-7 19. Conde-Jaldon et al (2014), Epistatic interaction of ERAP1 and HLA-B in Behget disease: a replication study in the Spanish population. PLoS One. 14;9(7) 20. Kuiper et al (2018), Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis. Hum Mol Genet, doi: 10.1093 / hmg / ddy319 21. Strange et al (2010), A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet.;42(11):985-90.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or hydratethereof,(I)wherein:the group X-Y is -NHSO2- or -SO2NH-;Ri is H, CN or alkyl;R2 is selected from COOH and a tetrazolyl group;R3 is selected from H, Cl and alkyl;R4 is selected from H and halo;Rs is selected from H, alkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; Re is H;R7 is selected from H, CN, haloalkyl, halo, SO2-alkyl, heteroaryl, SO2NR14R15, CONR10R11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH;Rs is selected from H, alkyl, haloalkyl and halo;R9 is H or halo; andR10, Ri 1, R12, R14, and R15 are each independently H or alkyl;Risis selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; and m is 0, 1,2 or 3.

2. A compound according to claim 1, which is of formula (la), or a pharmaceutically acceptable salt or hydrate thereof,(la)wherein R1-9, R12, R13, X, Y and m are as defined in claim 1.

3. A compound according to any preceding claim wherein Ri is H.

4. A compound according to any preceding claim wherein R2 is COOH.

5. A compound according to any preceding claim wherein X-Y is NH-SO2.

6. A compound according to any preceding claim wherein R4 is H.

7. A compound according to any preceding claim wherein Rs is selected fromalkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy, and is more preferably selected from alkyl, alkoxy and cycloalkyl.

8. A compound according to claim 7 wherein Rs is selected from OMe, OEt, Me, Et, and cyclopropyl, more preferably, OMe, Etand cyclopropyl, more preferably, Rs is cyclopropyl.

9. A compound according to any preceding claim wherein R3 is H.

10. A compound according to any preceding claim wherein R7 is selected from CN, haloalkyl, SO2-alkyl, SO2NR16R17, CONR10R11 and tetrazolyl.

11. A compound according to any preceding claim wherein R7 is selected from CF3, CN, CONH2, SO2NH2, 1 / 7-1,2,3,4-tetrazol-1-yl and SO2Me, more preferably, R7 is selected from CF3, CN, 1 / 7-1,2,3,4-tetrazol-1-yl and SO2Me, and most preferably, R7 is selected from CF3 or CN.

12. A compound according to any preceding claim wherein Rs is selected from H, Cl, F and Me, more preferably, wherein Rs is selected from H, Cl and F.

13. A compound according to any preceding claim wherein R9 is H.

14. A compound according to any preceding claim wherein Ri, R3, R4, Rs, and R9are all H.

15. A compound according to any preceding claim wherein R12 is H.

16. A compound according to any preceding claim wherein m is 0.

17. A compound according to claim 1 wherein:R2 is COOH;X-Y is NH-SO2;R5 is cyclopropyl;Ri, R3, R4, Rs and R9 are all H;R7 is selected from CN and haloalkyl, preferably CF3;Rs is selected from H, Cl and F;R12 is H; andm is 0.

18. A compound according to claim 1 which is selected from the following:O^ / OH 1      0              1 HN^J t h n A / AV h T T lYY 0 0 A cf3 (1) °y0H hnvA A-A'sA=< h T z / % T 0 0 A cf3 (2) <o  Y hn,A    A^ Y h [i n / An AA H T T xA 0 0 A cf3 (3) 0<^ / 0H [ o y hn«A P H fl I A^n AA kA ° ° A CN (4) ~   O^o H < 0   Y HN,,         A. p H f| ] AaAA h T <% T o ° ° A CN (5) O^OH I 0             I hn^A a. A H f| | AAsA^ h T , / ^ T A^A ool f       △ CN (6) 0^ / OH 1      0              1 HN,, A rs; h (| | AaAA JI   ool F y    △ CN (7) Ao °v0H hn«A a. Ph III AaAa h T T JI    ool cry   △ CN (8) O. .OH I 0             1 hn,, J rs; h (| j AaAA fl T '>% T A J ool cr y    △ CN (9)and pharmaceutically acceptable salts and hydrates thereof.

19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 18 admixed with a pharmaceutically acceptable excipient, diluent or carrier, and optionally one or more additional active agents.

20. A compound as defined in any one of claims 1 to 18 for use in medicine.

21. A compound as defined in any one of claims 1 to 18 for use in treating orpreventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.

22. A compound for use according to claim 21, wherein the compound modulates ERAP1.

23. A compound for use according to claim 21 or claim 22, wherein the disorder is a proliferative disorder, preferably a cancer or leukemia.

24. A compound for use according to any one of claims 21 to 23, wherein the compound kills cancer cells, reduces the number of proliferating cells in the cancer, reduces the volume or size of a tumour comprising the cancer cells, and / or reduces the number of metastasising cancer cells.

25. A compound for use according to any one of claims 21 to 24, wherein the compound is used for preventing cancer, wherein preferably the compound induces a neo-antigen to which the subject has an existing immune response.

26. A compound for use according to claim 25, wherein said compound is used in a subject who has cancer or who is susceptible to developing cancer, wherein the compound stimulates a neo-antigen directed immune response in the subject, and wherein a second compound (which may be the same or different to the first compound), is used subsequently to stimulate the same neo-antigen as the first compound, thereby directing the subjects immune response against said cancer.

27. A compound for use according to any one of claims 21 to 26, wherein the subject has previously had cancer, has a familial history of cancer, has a high risk for 81developing cancer, has a genetic predisposition to developing cancer, has been exposed to a carcinogenic agent, and / or is in remission from cancer.

28. An in vitro or in vivo method for producing an antigen-presenting cell which presents a neo-antigen, comprising inducing with a compound of formula (I) as defined in any one of claims 1 to 18 a neo-antigen in said antigen-presenting cell, wherein preferably the antigen-presenting cell is a dendritic cell.

29. An immunogenic composition comprising an antigen-presenting cell obtained or obtainable by the method according to claim 28.

30. An immunogenic composition according to claim 29 for use in treating or preventing cancer in a subject, wherein preferably the immunogenic composition is a vaccine.

31. A compound for use according to any one of claims 21 to 27, wherein said compound is used in combination with an immunotherapy, wherein preferably the subject has cancer and the compound increases the sensitivity of cancer cells to an immunotherapy.

32. A compound for use according to claim 31 wherein said immunotherapy is an immune checkpoint intervention, preferably an antibody checkpoint inhibitor.

33. A compound for use according to claim 32 wherein said antibody checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA4 antibody.

34. A compound for use according to claim 21 or claim 22, wherein the disorder is an immune disorder, and is preferably selected from ankylosing spondylitis, Behcet’s disease, psoriasis and birdshot chorioretinopathy.

35. A compound for use according to claim 21 or claim 22, wherein the disorder is an inflammatory disorder, more preferably an auto-inflammatory disorder.

36. A compound for use according to claim 21 or claim 22, wherein the viral disorder is an infectious viral disease selected from HIV, HPV, CMV and HCV.

37. A compound for use according to any one of claims 21 to 27 or 31 to 33, wherein the disorder is cancer, and wherein the compound increases the visibility of cancer cells to the immune system by altering the repertoire of antigens and neoantigens presented to the immune system.

38. A compound for use according to claim 37, wherein the compound increases the CD8+ T cell response to the cancer cell.

39. A combination comprising a compound according to any one of claims 1 to 18 and a further active agent.