ERAP inhibitor

Abstract

The present invention relates to novel compounds useful as inhibitors of endoplasmic reticulum aminopeptidase (ERAP), particularly as inhibitors of ERAP 2. The present invention also relates to therapeutic applications of these compounds, particularly the use of these compounds in the treatment or prevention of proliferative disorders, autoinflammatory disorders, and autoimmune disorders.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to novel compounds useful as inhibitors of endoplasmic reticulum aminopeptidase (ERAP), particularly as inhibitors of ERAP 2. The present invention also relates to therapeutic uses of these compounds. [Background technology]

[0002] 2. Background of the Invention The component task of the adaptive immune system is to fight disease by recognition of infected or abnormal cells. For this, the immune system detects antigenic peptides (epitopes) on the cell surface using blood cells that mount a specialized cytotoxic response. Antigenic peptides are produced by proteolytic hydrolysis of intracellular proteins or extracellular proteins previously internalized inside the cell. The composition of the pool of presented peptides (repertoire) is key for the immune system to function well, and alterations in peptide processing promote disease. For example, tumor cells typically stop antigenic peptide production, while hyperactive processing produces epitopes that lead the immune system to cause autoimmune, autoinflammatory diseases.

[0003] A significant proportion of precursor peptides are processed by the endoplasmic reticulum (ER) aminopeptidase ERAP enzymes (ERAP1, ERAP2, and the ERAP1,2 heterodimer; referred to as ERAP), which cleave N-terminally extended precursors into mature epitopes. 1,2 These epitopes are loaded onto HLA class I molecules (MHC-I) and presented on the surface of antigen-presenting and tumor cells to instruct the immune system to mount an immune response. Importantly, some antigenic epitopes are also destroyed by ERAP into peptides that can no longer bind to MHC class I molecules. The overall composition of the antigen repertoire can have a profound effect on the cytotoxic response of the immune system, and the ERAP enzyme has emerged as a key protein influencing its formation (and regulation of the cytotoxic response of T cells and NK cells). 3,4 .

[0004] Polymorphisms in ERAP1 and ERAP2 are associated with predisposition to various human diseases 5 In particular, these diseases include viral infections, cancer and proliferative diseases, and autoimmune diseases. 6,7 .

[0005] Examples of related autoimmune diseases include, but are not limited to, MHC class I inflammatory diseases spondyloarthritis, Behcet's disease, uveitis scatter, psoriasis, and type 1 diabetes. These correlations are associated with changes in the activity and specificity of ERAP.

[0006] It has been shown that ERAP is a key target for boosting the cytotoxic responses of T cells and NK cells in cancer 8,9,10 ERAP genotype is associated with tumor and immune infiltration and strongly predicts overall cancer survival. Recent studies have revealed that low levels of ERAP2 may be associated with improved response to anti-PD-L1 (immunotherapy) in patients with luminal subtype bladder cancer. 11 Along the same lines, an in vivo loss-of-function CRISP genetic screen showed that deletion of ERAP1 in a mouse transplantable tumor model increased the efficacy of anti-PD-1 immunotherapy. 12 Finally, ERAP regulates responses to infections (HCV, HCMV, influenza virus, HPV, HIV, SARS-CoV-2, tuberculosis). 13,14 .

[0007] ERAP inhibitors have been shown to regulate antigen presentation and immune responses 15,16,17 The inhibitor was shown to suppress Th17 responses in a cell model of spondyloarthritis. 18 The compound modulates the immunopeptidome of cancer cells in patients. 19 .

[0008] These clinical and preclinical results teach that the ERAP enzyme has important functions in vivo and support that it is a target for therapeutic targeting of these diseases. Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there is a demand for an efficient ERAP inhibitor, particularly a selective ERAP inhibitor.More specifically, it is advantageous to provide a selective and efficient ERAP inhibitor for use in treating or preventing disorders involving the recognition of MHC-1-loaded antigenic peptides by T cells and / or NK cells, such as proliferative, autoimmune and autoinflammatory disorders. [Means for solving the problem]

[0010] Summary of the Invention The present invention relates to a compound represented by formula (I) [ka] [During the ceremony, n is 0 or 1; R 1 is selected from the group consisting of phenyl, naphthalenyl, indolyl and benzodioxolyl, where the phenyl, naphthalenyl, indolyl and benzodioxolyl may be substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy; R 3 is a 5- or 6-membered heteroaryl containing one sulfur atom and optionally one further nitrogen, sulfur or oxygen atom, wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl; R2 is hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl; and R 4 is hydrogen, C1-C6-alkyl, -CH2-OR a4 , -CH2-C(=O)R b4 and -CH2-NH-C(=O)R c4 wherein R a4 is hydrogen or C1-C6-alkyl, R b4 is hydroxyl, C1-C6-alkoxy, amino or C1-C6-alkylcarbonylamino, R c4 is C1-C6-alkoxy or R 2 and R 4 together with the nitrogen and carbon atom to which they are attached form a 5- or 6-membered heteroaryl selected from pyrrolidinyl, morpholinyl, thiazolidinyl, and piperidinyl. or a hydrate, solvate or salt thereof, and a pharmaceutical composition comprising same.

[0011] The present invention also relates to compounds of formula (I) for use in medicine, in particular for use in the treatment or prophylaxis of proliferative, autoinflammatory and autoimmune disorders.

[0012] Further aspects of the invention are disclosed herein and in the claims. [Brief description of the drawings]

[0013] [Figure 1] Figure 1 shows the cellular effects of increasing concentrations of representative compounds of the invention, 23 and 24, on antigen presentation of the model antigen ovalbumin-specific peptide SIINFEKL. Data were normalized to control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Description of the invention Compounds of formula (I) The present invention relates to a compound represented by formula (I) [ka] [During the ceremony, n is 0 or 1; R 1 is selected from the group consisting of phenyl, naphthalenyl, indolyl and benzodioxolyl, where the phenyl, naphthalenyl, indolyl and benzodioxolyl may be substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy; R 3 is a 5- or 6-membered heteroaryl containing one sulfur atom and optionally one further nitrogen, sulfur or oxygen atom, wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl; R 2 is hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl; and R 4 is hydrogen, C1-C6-alkyl, -CH2-OR a4 , -CH2-C(=O)R b4 and -CH2-NH-C(=O)R c4 wherein R a4 is hydrogen or C1-C6-alkyl, R b4 is hydroxyl, C1-C6-alkoxy, amino or C1-C6-alkylcarbonylamino, R c4 is C1-C6-alkoxy or R2 and R 4 together with the nitrogen and carbon atom to which they are attached form a 5- or 6-membered heteroaryl selected from pyrrolidinyl, morpholinyl, thiazolidinyl, and piperidinyl. or a hydrate, solvate or salt thereof.

[0015] Preferred salts according to the invention are physiologically acceptable salts of the compounds of formula (I). However, the invention also encompasses salts which are not themselves suitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds of the invention.

[0016] The term "physiologically acceptable salts" refers to relatively non-toxic, inorganic or organic acid addition salts of the compounds of formula (I). Suitable pharma- ceutically acceptable salts of the compounds of formula (I) include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, phosphoric acid or nitric acid, or, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, cinnamic acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, , sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid or other organic acids.

[0017] Solvates in the sense of the invention are described as forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination is with water.

[0018] The present invention includes all possible stereoisomers of the compounds of formula (I) as single stereoisomers or any mixture of said stereoisomers in any ratio. Isolation of a single stereoisomer of a compound of formula (I), such as a single enantiomer or a single diastereomer, can be achieved by any suitable condition of a method in the art, such as, for example, chromatography, in particular chiral chromatography.

[0019] The term "substituted with one or more" means that one or more hydrogen atoms of the specified atom or group are replaced with one selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom in the circumstances present. Combinations of substituents are permissible.

[0020] The term "C1-C6-alkyl" as used herein refers to a straight or branched, saturated aliphatic chain of 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.

[0021] The term "C1-C6-hydroxyalkyl" as used herein refers to a C1-C6-alkyl, as defined herein, substituted with one or more hydroxyl groups. Examples of C1-C6-hydroxyalkyl groups include 2-hydroxy-ethyl.

[0022] The term "C1-C6-halogenoalkyl" as used herein refers to C1-C6-alkyl, as defined herein, substituted with one or more halogens. Examples of C1-C6-halogenoalkyl include trifluoromethyl.

[0023] As used herein, the term "halogen" refers to chlorine, bromine, iodine and fluorine.

[0024] The term "C3-C6-cycloalkyl" as used herein refers to a monocyclic ring system containing 3 to 6 carbon atoms, where the group may be saturated or unsaturated, but is not aromatic. In some embodiments, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] The term "C1-C6-alkoxy" as used herein refers to a radical of the formula -O-C1-C6-alkyl, where C1-C6-alkyl is as defined herein.

[0026] The term "C1-C6-halogenoalkoxy" as used herein refers to a radical of the formula -O-C1-C6-halogenoalkyl, where C1-C6-halogenoalkyl is as defined herein.

[0027] The term "C1-C6-hydroxyalkoxy" as used herein refers to a radical of the formula -O-C1-C6-hydroxyalkyl, where C1-C6-hydroxyalkyl is as defined herein.

[0028] The term "C1-C6-alkoxy-C1-C6-alkoxy" refers to a radical of the formula -O-C1-C6-alkyl-O-C1-C6-alkyl, where C1-C6-alkyl is as defined herein.

[0029] The term "carbamoyl" as used herein refers to a group of formula -C(=O)-NH2.

[0030] The term "C1-C6-alkylcarbamoyl" as used herein refers to a radical of the formula -C(=O)NH-C1-C6-alkyl.

[0031] The term "C1-C6-alkylcarbonylamino" as used herein refers to a radical of the formula -NH-C(=O)-C1-C6-alkyl, where C1-C6-alkyl is as defined herein.

[0032] As used herein, the term "C1-C6-aminoalkyl" refers to a compound of the formula -(CH2) n -NH2 (n ranges from 1 to 6) group.

[0033] The term "amidoxime" or "hydroxycarbamimidoyl" includes the radical -C(=NH)NHOH or -C(=NOH)NH2.

[0034] As used herein, "indolyl" includes indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl.

[0035] As used herein, "pyridyl" includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.

[0036] As used herein, "benzodioxolyl" includes 1,3-benzodioxol-5-yl and 1,4-benzodioxan-6-yl.

[0037] In the above formula (I), R 1 is phenyl, R 1 may be mono-, di- or tri-substituted. The substituents may be at any position on the phenyl ring (i.e. ortho, meta and / or para). The substituents may be as described above. Typically, R 1 may be substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, and phenoxy. 1 is phenyl monosubstituted at the ortho, meta or para position. 1 is ortho- and para-substituted phenyl. In some embodiments, R 1 is a para- and di-ortho-substituted phenyl.

[0038] In one embodiment, R 1 teeth [ka] where R a , R b and R c are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy.

[0039] In one embodiment, R 1 teeth [ka] where R a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, and phenoxy. a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, C-C-alkyl, C-C-alkoxy, C-C-halogenoalkoxy and phenoxy. ais hydroxyl, cyano, C-C-alkoxy (e.g. methoxy, t-butoxy), C-C-halogenoalkoxy (e.g. trifluoromethoxy), C-C-alkoxy-C-C-alkoxy (e.g. methoxyethoxy), amidoxime or phenoxy, typically hydroxyl, C-C-alkoxy (e.g. methoxy, t-butoxy), C-C-halogenoalkoxy (e.g. trifluoromethoxy) or phenoxy, R b is hydrogen. In some embodiments, R a is hydroxyl or C1-C6-alkoxy (e.g. methoxy), R b is halogen (e.g. chlorine or fluorine) or C1-C6-alkoxy (e.g. methoxy).

[0040] R 1 In the above formula (I) where R is indolyl, 1 is preferably indol-3-yl, which may be substituted with one or more substituents as described above. In certain embodiments, R 1 is an unsubstituted indol-3-yl.

[0041] R 1 In the above formula (I) which is naphthalenyl, R 1 is preferably naphthalen-2-yl, which may be substituted with one or more substituents as described above. In certain embodiments, R 1 is unsubstituted naphthalen-2-yl.

[0042] R 1 In the above formula (I) where R is benzodioxolyl, 1 is preferably 1,3-benzodioxol-5-yl, which may be substituted with one or more substituents as described above. In certain embodiments, R 1 is unsubstituted 1,3-benzodioxol-5-yl.

[0043] In the above formula (I), R 2may be hydrogen, C1-C3-alkyl (eg methyl), cyclopropyl, typically hydrogen or C1-C3-alkyl (eg methyl).

[0044] In the above formula (I), R 3 can be a 5- or 6-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl, isothiazolyl, thiopyranyl, dithiynyl, and thiazinyl, wherein said 5- or 6-membered heteroaryl can be substituted as described herein.

[0045] In one embodiment, in the above formula (I), R 3 can be a 5-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl, and isothiazolyl, where said thiophenyl, thiazolyl, and isothiazolyl can be substituted as described herein.

[0046] In one embodiment, in the above formula (I), R 3 is thiophenyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl.

[0047] In one embodiment, R 3 teeth [ka] where R 5 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, phenyl and pyridyl, where the phenyl and pyridyl may be substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl.

[0048] In one embodiment, R 3 teeth [ka] where R 5 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, phenyl and pyridyl (e.g. pyrid-2-yl, pyrid-3-yl and pyrid-4-yl), where the phenyl and pyridyl may be substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl.

[0049] In one embodiment, R 3 teeth [ka] where R 6 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl.

[0050] In one embodiment, R 3 is thiazolyl, where the thiazolyl may be substituted as described herein.

[0051] In the above formula (I), R 4 may be hydrogen, C1-C3-alkyl (eg methyl) or C3-C6-alkyl (eg cyclopropyl), typically hydrogen or C1-C3-alkyl (eg methyl).

[0052] In certain embodiments, the compounds of the present invention have the formula (I): [ka] [During the ceremony, n is 0 or 1; R 1is indol-3-yl, naphthalen-2-yl, 1,3-benzodioxol-5-yl or substituted phenyl as disclosed herein, in particular: [ka] where R a , R b and R c are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy, or [ka] where R a and R b are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy, typically hydrogen, hydroxyl, halogen, cyano, C1-C6-alkyl, C1-C6-halogenoalkyl, C1-C6-alkoxy, C1-C6-halogenoalkoxy, C1-C6-hydroxyalkoxy, ethynyl, carbamoyl, C1-C6-alkylcarbamoyl, polyoxyethylenyl and phenoxy; R 2 is hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, preferably hydrogen or C1-C3-alkyl; R 3is a 5-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl and isothiazolyl, wherein the thiophenyl, thiazolyl and isothiazolyl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl, preferably R 3 is thiophenyl, which may be substituted as described herein, more preferably R 3 teeth [ka] where R 5 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, phenyl and pyridyl, where the phenyl and pyridyl may be substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl; and R 4 is hydrogen, C1-C6-alkyl, -CH2-OR a4 , -CH2-C(=O)R b4 and -CH2-NH-C(=O)R c4 wherein R a4 is hydrogen or C1-C6-alkyl, R b4 is hydroxyl, C1-C6-alkoxy, amino or C1-C6-alkylcarbonylamino, R c4 is C1-C6-alkoxy, preferably R 4 is hydrogen or C1-C6-alkyl. It is a compound of the formula:

[0053] In some of these particular embodiments, R 1 teeth [ka] where R a and R b is independently selected from the group consisting of hydrogen, cyano, hydroxyl, halogen, C-C-alkyl, C-C-alkoxy, C-C-halogenoalkoxy and phenoxy. a is hydroxyl, cyano, C-C-alkoxy (e.g. methoxy, t-butoxy), C-C-halogenoalkoxy (e.g. trifluoromethoxy), C-C-alkoxy-C-C-alkoxy (e.g. methoxyethoxy), amidoxime or phenoxy, typically hydroxyl, C-C-alkoxy (e.g. methoxy, t-butoxy), C-C-halogenoalkoxy (e.g. trifluoromethoxy) or phenoxy, R b is hydrogen. In some embodiments, R a is hydroxyl or C1-C6-alkoxy (e.g. methoxy), R b is halogen (e.g. chlorine or fluorine) or C1-C6-alkoxy (e.g. methoxy).

[0054] In some of these particular embodiments, R 3 teeth [ka] where R 5 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, phenyl and pyridyl (e.g. pyrid-2-yl, pyrid-3-yl and pyrid-4-yl), where the phenyl and pyridyl may be substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl.

[0055] In some of these particular embodiments, R 3 teeth [ka] where R6 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, phenyl, pyridyl, C1-C6-aminoalkyl and C1-C6-alkylcarbamoyl.

[0056] In certain embodiments, the compound of the present invention has formula (I): [ka] [In the formula, n, R 1 , R 2 , R 3 and R 4 is as set forth herein.] or a hydrate, solvate or salt thereof.

[0057] The present invention includes any of the compounds of formula (I) described in the Examples section (ie, any of compounds 1-48 described herein and mixtures thereof).

[0058] Synthesis of compounds of formula (I) Compounds of formula (I) can be synthesized according to the following schemes (Schemes 1, 2, 3 and 4). The following schemes and procedures illustrate synthetic routes to compounds of the invention of formula (I) and are not intended to be limiting. In the following, n, R 1 , R 2 ,R 3 and R 4 has the same meaning as set forth above unless otherwise specified.

[0059] Route A [ka] Scheme 1 A route for preparing a compound of formula (I) from a compound of formula (VIII), wherein n, R 1 , R 2 , R 3 and R 4has the meaning as defined above. Compounds of formula (VIII) can be readily prepared from commercially available precursors by known methods, such as those described in the Examples section.

[0060] Reagents and conditions: (a) KCN, NH2OH / H2O (1 / 1:w / w), methanol, room temperature, overnight; (b) sulfonamide-alkyne (compound of formula (V)), CuSO4.5H2O, sodium ascorbate, dimethylformamide / H2O or dioxane / H2O, room temperature, overnight.

[0061] If the reaction sequence requires protection of an amino group, the amino protecting group can be cleaved at the final stage by any conventional method. For example, the tert-butyloxycarbonyl group (Boc) can be cleaved by adding hydrochloric acid to the compound of formula (I) (HCl 4N in dioxane, 1 day, room temperature). The compound can then be isolated as the potassium salt by the addition of aqueous potassium carbonate (pH 10).

[0062] As used herein, a "sulfonamide-alkyne" is a compound of formula (V) [ka] where R 2 , R 3 and R 4 is as described herein. Compounds of formula (V) can be readily prepared from commercially available precursors by known methods, such as those described in the Examples section.

[0063] In one aspect, the present invention provides a method for preparing a compound of formula (I), comprising the steps of: (1) reacting a methanol solution of a compound of formula (VIII) with an aqueous solution of hydroxylamine to obtain a compound of formula (IX); (2) reacting a compound of formula (IX) with a compound of formula (V) in the presence of copper sulfate pentahydrate and sodium ascorbate to obtain a compound of formula (I); (3) If the compound of formula (I) contains an amino group protected with an amino-protecting group (e.g., Boc), cleaving the amino group and recovering the compound of formula (I) as a potassium salt. The present invention relates to a method comprising the steps of:

[0064] Route B [ka] Scheme 2 A route for preparing a compound of formula (I) from a compound of formula (VIII), wherein n, R 1 , R 2 , R 3 and R 4 has the meaning as defined above. Compounds of formula (VIII) can be readily prepared from commercially available precursors by known methods, such as those described in the Examples section.

[0065] Reagents and conditions: (b) sulfonamide-alkyne (compound of formula (V), see above), CuSO4.5H2O, sodium ascorbate, dimethylformamide / H2O or dioxane / H2O, room temperature, overnight; (a) KCN, NH2OH / H2O (1 / 1:w / w), methanol, room temperature, overnight.

[0066] As mentioned above, if the reaction sequence requires protection of the amino group, the amino protecting group can be cleaved at the final stage by any conventional method. For example, the tert-butyloxycarbonyl group (Boc) can be cleaved by adding hydrochloric acid to the compound of formula (I) (HCl 4N in dioxane, 1 day, room temperature). The trimethylsilyl group can be cleaved by a solution of TBAF in THF. The compound can then be converted to the potassium salt by adding an aqueous solution of potassium carbonate (pH 10).

[0067] In one aspect, the present invention provides a method for preparing a compound of formula (I), comprising the steps of: (1) reacting a compound of formula (VIII) with a compound of formula (V) in the presence of copper sulfate pentahydrate and sodium ascorbate to obtain a compound of formula (X); (2) Reacting a methanol solution of the compound of formula (X) with an aqueous solution of hydroxylamine to obtain the compound of formula (I) The present invention relates to a method comprising the steps of:

[0068] Route C [ka] Scheme 3 A route for preparing a compound of formula (I) from a compound of formula (VIII), wherein n, R 1 , R 2 , R 3 and R 4 has the meaning as defined above. Compounds of formula (VIII) can be readily prepared from commercially available precursors by known methods, such as those described in the Examples section.

[0069] Reagents and conditions: (b) sulfonamide-alkyne (compound of formula (V)), CuSO4.5H2O, sodium ascorbate, dimethylformamide / H2O or dioxane / H2O, room temperature, overnight; (c) boronic acid (R 5 -B(OH)2, where R 5 is phenyl or pyridyl, optionally substituted as described herein), Pd(PPh3)4, Cs2CO3, dioxane / H2O (4 / 1:v / v), 70°C, 1h 45min to 4h; (a) KCN, NH2OH / H2O (1 / 1:w / w), methanol, room temperature, overnight. (x) If Boc deprotection is required: HCl 4N dioxane, 1 day, room temperature; then aqueous potassium carbonate (pH 10).

[0070] As mentioned above, if the reaction sequence requires protection of the amino group, the amino protecting group can be cleaved at the final stage by any conventional method. For example, the tert-butyloxycarbonyl group (Boc) can be cleaved by adding hydrochloric acid to the compound of formula (I) (HCl 4N in dioxane, 1 day, room temperature). The compound can then be converted to the potassium salt by adding an aqueous solution of potassium carbonate (pH 10).

[0071] In one aspect, the present invention provides a method for preparing a compound of formula (I), comprising the steps of: (1) Reacting a compound of formula (VIII) with a compound of formula (V) 3 is a bromine substituted thiophenyl) in the presence of copper sulfate pentahydrate and sodium ascorbate to give a compound of formula (X); (2) Compound of formula (X) and R 5 -B(OH)2 (wherein, R 5 is optionally substituted phenyl or pyridyl as described herein) in the presence of palladium tetrakis with cesium carbonate and a boronic acid to give a compound of formula (XI) [ka] to obtain a compound of; (3) reacting a methanol solution of the compound of formula (XI) with an aqueous solution of hydroxylamine to obtain the compound of formula (I); (4) If the compound of formula (I) contains an amino group protected with an amino-protecting group (e.g., Boc), cleaving the amino group and recovering the compound of formula (I) as a potassium salt. The present invention relates to a method comprising the steps of:

[0072] Route D [ka] Scheme 4 A route for preparing a compound of formula (I) from a compound of formula (VII), wherein n, R 1 , R 2 and R 3 has the meaning as defined above. Compounds of formula (VII) can be readily prepared from commercially available precursors by known methods, such as those described in the Examples section.

[0073] Reagents and conditions: (i) R 2-N-propargylamine, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), triethylamine, dimethylformamide, room temperature and overnight; (j) dimethylformamide, reflux, overnight; (k) HCl, H2O, 85°C, MW, 3 hours; (l) SOCl2, methanol, 0°C to room temperature, overnight; (m) R 3 -Sulfonyl chloride (R 3 –SO2Cl), N,N-diisopropylethylamine (DIPEA), dimethylformamide, 0°C to room temperature, overnight; (p) KCN, NH2OH / H2O (1 / 1:w / w), methanol, room temperature, overnight.

[0074] In one aspect, the present invention provides a method for preparing a compound of formula (I), comprising the steps of: (1) A compound of formula (VII) and R 2 - N-propargylamine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and triethylamine to obtain a compound of formula (XII); (2) cyclizing a compound of formula (XII) to obtain a compound of formula (XIII); (3) ring-opening a compound of formula (XIII) to obtain a compound of formula (XIV); (4) reacting a compound of formula (XIV) with thionyl chloride to obtain a compound of formula (XV); (5) Compound of formula (XV) and R 3 -sulfonyl chloride to obtain a compound of formula (XVI); (6) Reacting a methanol solution of the compound of formula (XVI) with an aqueous solution of hydroxylamine to obtain the compound of formula (I) The present invention relates to a method comprising the steps of:

[0075] The compounds of formula (I) may be converted into any salt, in particular a pharma- ceutically acceptable salt, as described herein, by any method known to those skilled in the art.Similarly, any salt of the compounds of formula (I) may be converted into the free compound by any method known to those skilled in the art.

[0076] The present invention includes all possible salts of the compounds of the present invention, either as single salts or any mixture of said salts in any ratio.

[0077] Intermediates The present invention also relates to any intermediates described above and in the Examples section.

[0078] therapeutic application Hereinafter, the phrase "compound of formula (I)" refers to any compound of formula (I) described herein, including any compound of formula (I) described in the "Examples" section, as well as salts, hydrates, solvates, isomers, mixtures of isomers in any ratio, and any combination thereof. Thus, the term "compound of formula (I)" may refer to a single compound of formula (I) or a combination of two or more compounds of formula (I) or their salts, hydrates, solvates, isomers, or mixtures of isomers.

[0079] The compound of formula (I) was found to be an efficient inhibitor of ERAP, particularly an efficient ERAP2 inhibitor. "Inhibitor" refers to a molecule capable of reducing or suppressing enzyme activity. The compound of formula (I) affects the antigenic peptide repertoire presented to cytotoxic T cells and / or NK cells. As a result, the compound of formula (I) is useful in medicine. In particular, the compound of formula (I) may be useful for regulating adaptive immune responses in humans and animals. More specifically, the compound of formula (I) may be useful for treating or preventing disorders involving recognition of antigenic peptides loaded on MHC-1 by T cells and / or NK cells, such as proliferative disorders, autoinflammatory disorders, and autoimmune disorders. In other words, the compound of formula (I) may be useful for treating or preventing disorders involving ERAP2 activity. The compound of formula (I) may also be useful for treating or preventing infectious disorders.

[0080] As used herein, the term "disorder" refers to a disease, condition, or illness.

[0081] As used herein, the term "treating" refers to combating, alleviating, reducing, ameliorating, suppressing, combating, curing or ameliorating the condition of a disorder.

[0082] As used herein, the term "prevention" refers to avoiding or reducing the risk of developing, experiencing, contracting or having a disorder.

[0083] The treatment or prevention of a disorder may be partial or complete.

[0084] In one embodiment, the present invention relates to a compound of formula (I) for use as a medicament.

[0085] According to a further aspect, the present invention relates to a compound of formula (I) for use in the treatment or prevention of a disorder in which recognition of antigenic peptides loaded on MHC-1 by T cells and / or NK cells is involved / has a role.In other words, the present invention relates to a compound of formula (I) for use in the treatment or prevention of a disorder in which ERAP2 activity is involved.

[0086] In another aspect, the present invention relates to a compound of formula (I) for use in the treatment or prevention of a disorder in which an abnormal activity of ERAPS is observed.

[0087] In another embodiment, the present invention relates to compounds of formula (I) for modulating the antigenic peptide repertoire presented by MHC-1.

[0088] In another aspect, the present invention relates to a compound of formula (I) for use as an ERAP2 inhibitor.

[0089] In another embodiment, the present invention relates to a compound of formula (I) for use in the treatment or prevention of proliferative disorders, autoinflammatory disorders and autoimmune disorders. In other words, the present invention relates to the use of a compound of formula (I) for the treatment or prevention of proliferative disorders, autoinflammatory disorders and autoimmune disorders.

[0090] In some embodiments, the present invention relates to the compound of formula (I) for use in the treatment or prevention of proliferative disorders such as cancer.Cancer includes, but is not limited to, colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, bladder cancer, glioblastoma, lung cancer (e.g. non-small cell lung cancer), neuroblastoma, inflammatory myofibroblastic tumor, leukemia (e.g. acute myeloid leukemia, myelodysplastic syndrome or chronic myelomonocytic leukemia), melanoma and lymphoma (e.g. diffuse B-cell lymphoma or anaplastic large cell lymphoma).In particular, cancer includes melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma and malignant pleural mesothelioma.

[0091] In particular, the compounds of formula (I) may be useful in cancer immunotherapy and / or radiotherapy.

[0092] In certain embodiments, the present invention relates to a compound of formula (I) for use in the treatment or prevention of autoimmune disorders such as spondyloarthritis (e.g. ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis), psoriasis, shotgun chorioretinopathy or type 1 diabetes.

[0093] In certain embodiments, the present invention relates to a compound of formula (I) for use in the treatment or prevention of an autoimmune disorder, such as Behcet's disease or psoriasis.

[0094] According to a further aspect, the present invention relates to a method for treating or preventing disorders, in particular proliferative disorders, inflammatory disorders and immune disorders, in particular cancer, spondyloarthritis (e.g. ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis), shotgun chorioretinopathy, type 1 diabetes, Behcet's disease or psoriasis, using a therapeutically effective amount of a compound of formula (I). In other words, the present invention relates to a method for treating disorders, in particular proliferative disorders, autoimmune and autoinflammatory disorders, in particular cancer, spondyloarthritis (e.g. ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis), shotgun chorioretinopathy, type 1 diabetes, Behcet's disease or psoriasis in a subject, which comprises administering to the subject, which may be a human or animal, a therapeutically effective amount of at least one compound of formula (I).

[0095] As used herein, a "therapeutically effective amount" refers to an amount that (i) treats or prevents a particular disorder, (ii) attenuates, alleviates or eliminates one or more symptoms of a particular disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disorder described herein. The amount of a compound that constitutes a therapeutically effective amount varies depending on many factors, such as the compound and its biological activity, the composition used for administration, the route of administration, the type of disorder to be treated and its severity, drugs used in combination or simultaneously with the compound, and the age, weight, general health, sex and dietary habits of the patient. Such effective amounts can be routinely determined by those skilled in the art based on their knowledge.

[0096] In another embodiment, the present invention relates to a compound of formula (I) for use in a method for treating a disorder, particularly a proliferative disorder, an autoinflammatory disorder and an autoimmune disorder, particularly cancer, spondyloarthritis (e.g. ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis), shotcretinopathy, type 1 diabetes, Behcet's disease or psoriasis.

[0097] According to a further aspect, the present invention relates to a compound of formula (I) for the manufacture of a pharmaceutical composition, preferably a medicament, for the prevention or treatment of disorders, in particular proliferative disorders, autoinflammatory and autoimmune disorders, more in particular cancer, spondyloarthritis (e.g. ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis), shotcretinopathy, type 1 diabetes, Behcet's disease or psoriasis.

[0098] Pharmaceutical Compositions The present invention also relates to pharmaceutical compositions, especially medicaments, comprising a compound of formula (I) and one or more excipients, especially one or more pharma- ceutically acceptable excipients, and to the use thereof for the above-mentioned purposes.

[0099] In one embodiment, the present invention relates to a pharmaceutical composition, particularly a medicament, comprising a therapeutically effective amount of a compound of formula (I) and a pharma- ceutical acceptable additive.The pharmaceutical composition is particularly useful for the treatment or prevention of disorders, particularly proliferative disorders, autoinflammatory disorders and autoimmune disorders, particularly cancer, spondyloarthritis (e.g. ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis), shotgun chorioretinopathy, type 1 diabetes, Behcet's disease or psoriasis.

[0100] Pharmaceutically acceptable excipients include fillers and carriers, ointment bases, suppository bases, solvents, surfactants, emulsifiers, dispersing or wetting agents, buffers, acids and bases, isotonicity agents, adsorbents, viscosity enhancers, gel forming agents, thickening agents and / or binders, disintegrants, coating materials for films or diffusion membranes and film formers, encapsulating materials, natural or synthetic polymers, plasticizers, penetration enhancers, stabilizing agents, preservatives, colorants, flavoring agents, sweetening agents, flavor and / or odor masking agents.

[0101] The pharmaceutical compositions may further comprise one or more additional pharma- ceutical active agents, such as anti-cancer agents, particularly anti-cancer agents useful in immunotherapy or radiotherapy, disease-modifying anti-rheumatic drugs (DMARDs) and current immunotherapies for immune disorders.

[0102] The pharmaceutical composition may further comprise one or more anti-viral or anti-bacterial agents.

[0103] The pharmaceutical composition may further contain other ERAP1 or ERAP2 or IRAP inhibitors.

[0104] Pharmaceutical Combinations One or more compounds of formula (I) may be administered in therapeutically effective amounts in combination therapy with one or more pharma- ceutical active agents (pharmaceutical combinations).

[0105] Therefore, the present invention also relates to such pharmaceutical combinations.For example, the compound of the present invention can be combined with anticancer drugs, particularly anticancer drugs useful in immunotherapy or radiotherapy, disease-modifying antirheumatic drugs (DMARDs), current immunotherapy for immune disorders or other ERAP1 or ERAP2 or IRAP inhibitors.

[0106] The compounds may be administered simultaneously (either in a single formulation or in separate formulations), sequentially or separately.

[0107] In certain embodiments of the invention, a compound of formula (I) is administered prior to the administration of one or more other pharma- ceutical active agents.

[0108] In another embodiment of the invention, the compounds of formula (I) are administered simultaneously with the administration of one or more other pharma- ceutical active agents.

[0109] In yet another embodiment of the present invention, the compounds of formula (I) according to the present invention are administered immediately following administration of one or more other pharma- ceutical active agents.

[0110] The single pharma- ceutical active agents (the compound of formula (I) and the other pharma- ceutical active agent) may be packaged in the kit or separately.

[0111] Route of administration The compounds of formula (I) may have systemic and / or local activity and for this purpose may be administered in any suitable manner, for example by the oral, cutaneous, transdermal or parenteral route.

[0112] Dosage forms suitable for oral administration include, for example, tablets (plain or coated, e.g. with a delayed-dissolving or insoluble enteric or controlled release coating), orally disintegrating tablets, films / wafers, films / lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0113] Suitable administration forms for parenteral administration are injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0114] Dosage forms suitable for the dermal or transdermal administration route are, for example, pharmaceutical forms for aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (eg patches), milks, pastes, foams or dusting powders.

[0115] Embodiments of the present invention will now be described by way of the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the invention. EXAMPLES

[0116] synthesis I. Preparation of 1,4-disubstituted 1,2,3-triazoles of formula (I) I.1 Preparation of amino acid derivatives (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-phenoxyphenyl)propanoate [ka] A flask was charged with methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (50 mg, 0.169 mmol, 1 equiv.) phenylboronic acid (41 mg, 0.339 mmol, 2 equiv.), copper diacetate (31 mg, 0.169 mmol, 1 equiv.) and molecular sieves. Dichloromethane and pyridine were added and the mixture was stirred at room temperature for 2 days. The mixture was diluted with water (5 mL) and extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography eluting with cyclohexane / ethyl acetate (100 / 0 to 90 / 10) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-phenoxyphenyl)propanoate. Description: Colorless oil. Yield: 40%. Purity: 100%. LC tR = 3.33 minutes. MS (ESI-): m / z = 372 [MH] - 1 H NMR, 300 MHz, MeOD-d4, δ (ppm): 7.36-7.28 (m, 2H), 7.22-7.17 (m, 1H), 7.08 (td, J = 7.4 and 0.9 Hz, 2H), 6.96-6.88 (m, 4H), 4.35 (dd, J = 5.5 and 9.0 Hz, 1H), 3.70 (s, 3H), 3.09 (dd, J = 5.5 and 13.8 Hz, 1H), 2.87 (dd, J = 9.0 and 13.8 Hz, 1H), 1.39 (s, 9H) 13 C NMR, 75 MHz, MeOD-d4, δ (ppm): 174.1, 158.9, 157.8, 157.5, 133.4, 131.7, 130.8, 124.2, 119.9, 119.7, 80.6, 56.6, 52.6, 38.1 and 28.7

[0117] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-phenoxyphenyl)propanoic acid. [ka] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-phenoxyphenyl)propanoate (300 mg, 0.808 mmol, 1 equiv.) in methanol (4 mL) and water (3 mL) was added sodium hydroxide (129 mg, 3.23 mmol, 4 equiv.) and the mixture was stirred overnight at room temperature. The mixture was acidified to pH=2 using 1N HCl, the product was extracted three times with ethyl acetate, and the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give (2S)-2-(tert-butoxycarbonylamino)-3-(4-phenoxyphenyl)propanoic acid. Appearance: Blue foam. Yield: 91%. Purity: 100%. LC tR = 2.78 minutes. MS (ESI-): m / z = 356 [MH] - 1 H NMR, 300 MHz, MeOD-d4, δ (ppm): 7.34-7.28 (m, 2H), 7.21 (m, 2H), 7.08 (tt, J = 1.0 and 7.4 Hz, 1H), 6.96-6.87 (m, 4H), 4.34 (br, 1H), 3.16 (br, 1H), 2.89 (br, 2H), 1.38 (s, 9H) 13 C NMR, 75 MHz, MeOD-d4, δ (ppm): 158.9, 157.9 (br, 2C), 157.4, 134.0, 131.8, 130.8, 124.2, 119.8, 119.6, 80.5, 38.3, 28.7

[0118] (S)-2-Amino-3-(4-phenoxyphenyl)propanoic acid, hydrochloride To an ice-cold solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-phenoxyphenyl)propanoic acid (254 mg, 0.711 mmol) in dichloromethane (2.8 mL) was added a solution of HCl in dioxane (1.8 mL, 10 equiv.). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give (S)-2-amino-3-(4-phenoxyphenyl)propanoic acid, hydrochloride salt. [ka] Description: Yellow solid. Yield: 93%. Purity: 97%. LC tR = 1.92 minutes. MS (ESI+): m / z = 258 [M+H] + 1 H NMR, 300 MHz, DMSO-d6, δ (ppm): 13.82 (br, 1H), 8.50 (br, 3H), 7.42-7.35 (m, 2H), 7.33-7.28 (m, 2H), 7.15-7.10 (m, 1H), 7.01-6.94 (m, 4H), 4.13 (t, J = 6.1Hz, 1H), 3.14 (d, J = 6.1Hz, 1H) 13 C NMR, 75 MHz, DMSO-d6, δ (ppm): 170.3, 156.8, 155.7, 131.2, 130.1, 130.0, 123.3, 118.9, 118.4, 53.2, 34.9

[0119] I.2 Preparation of compounds of formula (V) Propargylamine or R 2 -N-propargylamine (1.1-1.5 equiv.) and N,N-diisopropylethylamine or triethylamine (1.2-3 equiv.) were solubilized in dichloromethane or dimethylformamide (0.08-0.34 M). The reaction medium was cooled to 0 °C and R 3-sulfonyl chloride (1-1.2 equiv.) was added. The mixture was allowed to reach room temperature and stirred for 1 h to overnight. The product was then washed twice with 0.5 M or 1 M HCl (aq), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then filtered through silica gel (4 g cartridge) or purified by flash chromatography to give the compound of formula (V): [ka] [In the formula, R 2 and R 3 is as described herein, and R 4 is hydrogen. of the desired product was obtained.

[0120] R 4 Compounds of formula (V) where is other than hydrogen have the formula NH-CHR 4 -CCH or NHR 2 -CHR 4 -CCH compounds and R 3 -sulfonyl chloride. An exemplary procedure is described below.

[0121] N-[(1S)-1-Methylprop-2-ynyl]-5-(2-pyridyl)thiophene-2-sulfonamide (V-10) To a stirring solution of tert-butyl N-[(1S)-1-methylprop-2-ynyl]carbamate (176 mg, 0.96 mmol, 1.0 equiv) in methanol (4 mL, 0.25 M) was added HCl (1.2 mL of a 4 M solution in 1,4-dioxane, 4.81 mmol, 5.0 equiv). The resulting mixture was stirred at room temperature for 3 h and then evaporated to dryness. The resulting residue was dissolved in CHCl (5.2 mL), NEt (0.26 mL, 2.12 mmol, 2.1 equiv) and DMAP (1 crystal) were added, and the resulting mixture was cooled to 0 °C. 5-(2-pyridyl)thiophene-2-sulfonyl chloride (250 mg, 0.96 mmol, 1.0 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 4 h and then quenched with water. The two layers were separated and the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give N-[(1S)-1-methylprop-2-ynyl]-5-(2-pyridyl)thiophene-2-sulfonamide (224 mg, 80%) as a beige powder that was used directly as is.

[0122] N-[(1R)-1-methylprop-2-ynyl]-5-(2-pyridyl)thiophene-2-sulfonamide (V-11) To a stirring solution of tert-butyl N-[(1S)-1-methylprop-2-ynyl]carbamate (141 mg, 0.77 mmol, 1.0 equiv) in methanol (3.2 mL, 0.25 M) was added HCl (0.96 mL of a 4 M solution in 1,4-dioxane, 3.88 mmol, 5.0 equiv). The resulting mixture was stirred at room temperature for 3 h and then evaporated to dryness. The resulting residue was dissolved in CHCl (4.10 mL), NEt (0.23 mL, 1.69 mmol, 2.1 equiv) and 4-dimethylaminopyridine (DMAP) (1 crystal) were added, and the resulting mixture was cooled to 0 °C. 5-(2-pyridyl)thiophene-2-sulfonyl chloride (200 mg, 0.77 mmol, 1.0 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 4 h and then quenched with water. The two layers were separated and the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (cyclohexane / ethyl acetate 1:0 to 1:1 (v / v)) to give N-[(1R)-1-methylprop-2-ynyl]-5-(2-pyridyl)thiophene-2-sulfonamide (150 mg, 67%) as a beige powder.

[0123] I.3 Preparation of compounds of formula (VIII) The compound of formula (VIII) was prepared according to the following scheme: Protocol VIII-a [ka] Reagents and conditions: (a1) (i) ZnCl2, K2CO3, methanol, 0 °C, (ii) hydrogen sulfate 1H-imidazole-1-sulfonyl azide, N,N-diisopropylethylamine (DIPEA), methanol, 0 °C to room temperature, overnight; (a2) SOCl2, methanol, 0 °C to room temperature, overnight.

[0124] or Protocol VIII-b [ka] Reagents and conditions: A: Boc2O, TEA, 1:1 1,4-dioxane / water overnight, room temperature; B: K2CO3, DMF, MeI (1 or 2 eq), overnight, room temperature; if necessary, E: 4 eq bromine derivative, 0.1 eq NaI, dry DMF, K2CO3 85°C, overnight; C: DCM, 6 eq TFA, room temperature, overnight; D: (i) ZnCl2, K2CO3, methanol, 0°C, (ii) 1H-imidazole-1-sulfonyl azide hydrogen sulfate, N,N-diisopropylethylamine (DIPEA), methanol, 0°C to room temperature, overnight;

[0125] or Protocol VIII-c [ka] Reagents and conditions: A: dry MeOH, thionyl chloride (4 eq), 0 °C then rt; B: Boc2O, TEA, 1:1 1,4-dioxane / water overnight, rt; if required F: Sonogashira cross coupling CuI (0.2 eq); PdCl2(PPH3)2 (0.1 eq); TEA; ethynyl derivative (1.2 eq), 6 h, rt; C: DCM, TFA 6 eq, rt, overnight; D(i) ZnCl2, K2CO3, methanol, 0 °C, (ii) 1H-imidazole-1-sulfonyl azide hydrogen sulfate, N,N-diisopropylethylamine (DIPEA), methanol, 0 °C to rt, overnight.

[0126] I.3.1 Protocol VIII-a I.3.1.1 Preparation of compounds of formula (VII) R of formula (VI) under an inert atmosphere 1A mixture of -α or β amino acid (1 eq.), ZnCl2 (0.06 eq.) and K2CO3 (4 eq.) in anhydrous methanol (0.6 M) was cooled to 0° C. in an ice bath. Further, anhydrous N,N-diisopropylethylamine (1.1 eq.) was slowly added to a solution of 1H-imidazole-1-sulfonyl azide hydrogen sulfate (1.2 eq.) solubilized in anhydrous methanol (0.3 M) under inert atmosphere (solution A). The azide-containing solution was added immediately by dropwise addition to the first mixture at 0° C. The cooling bath was then removed and the white mixture was stirred at room temperature overnight. The mixture was then cooled to 0° C., diluted with water (10 mL) and carefully acidified to pH=2 with dilute aqueous HCl (1N). It was extracted with ethyl acetate and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were concentrated under reduced pressure to give the compound of formula (VII).

[0127] I.3.1.2 Preparation of compounds of formula (VIII) The compound of formula (VII) (1 equiv.) was dissolved in methanol (0.07-0.48M), cooled to 0°C, and thionyl chloride (2.0 equiv.) was added dropwise. The resulting solution was stirred overnight in a melting ice bath. The solvent was then evaporated under reduced pressure to give the desired product, or the residue was dissolved in a mixture of ethyl acetate and saturated aqueous NaHCO3 and extracted twice. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired product of formula (VIII).

[0128] I.3.2 Protocol VIIIb or c I.3.2.1 Preparation of compounds of formula (XX) Protocol XXa To a solution of an amino acid of formula (VI) (1.0 equiv.) and TEA (1.5 equiv.) in a 1:1 (v / v) mixture of 1,4-dioxane / water (15 mL) cooled to 0° C., Boc2O (1.2 equiv.) was added. After 30 min at 0° C., the solution was warmed to room temperature and stirred overnight. 1,4-dioxane was then removed under reduced pressure and the remaining aqueous mixture was cooled in an ice bath. If necessary, the pH was adjusted to 2 by dropwise addition of 1M HCl. The product was then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the protected amino acid as a light oil.

[0129] To a stirred solution of N-Boc protected amino acid (1.0 equiv.) and K2CO3 (1.3 equiv.) in DMF was added MeI (2.2 equiv. or 1 equiv.). The resulting mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was partitioned between water and EtOAc. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with brine and dried over MgSO4. 、 After filtration and concentration under reduced pressure, the crude mixture was purified by flash column chromatography on silica gel (cyclohexane / EtOAc 1:0 to 0:1 (v / v)) to give the compound of formula (XX).

[0130] Protocol XXb Thionyl chloride (1.0 mL, 13.7 mmol, 4.0 equiv.) was added slowly to a solution of (2S)-2-amino-3-(4-iodophenyl)propanoic acid (VI) (1.00 g, 3.44 mmol, 1 equiv.) in dry methanol (9.0 mL) cooled to 0° C. The reaction mixture was allowed to reach room temperature and then concentrated under reduced pressure to give [(1S)-1-[(4-iodophenyl)methyl]-2-methoxy-2-oxo-ethyl]ammonium chloride (1.20 g, quantitative) as a yellowish salt.

[0131] The amine functionality is then protected. To a solution of amine (1.0 equiv.) and TEA (1.5 equiv.) in a 1:1 (v / v) mixture of 1,4-dioxane / water (15 mL) cooled to 0° C., Boc2O (1.2 equiv.) was added. After 30 min at 0° C., the solution was allowed to warm to room temperature and stirred overnight. 1,4-dioxane was then removed under reduced pressure and the remaining aqueous mixture was cooled in an ice bath. The product was then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the Boc-protected compound (XX).

[0132] I.3.2.2 Preparation of compounds of formula (VIII) If necessary, the phenol group may be alkylated: To a solution of compound XX (1 eq.), brominated compound (4 eq.) and NaI (0.1 eq.) in dry DMF was added K2CO3 (2.7 eq.). The reaction vessel was fitted with a condenser and the reaction mixture was stirred at 85° C. overnight. It was then cooled to rt and evaporated to dryness. The resulting oil was suspended in a mixture of CH2Cl2 and saturated aqueous NH4Cl. The aqueous layer was extracted twice with CH2Cl2 and the combined organic layers were washed several times with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the alkylated compound.

[0133] The Boc group is then deprotected using dropwise addition of TFA (6 eq.) in dry DCM or HCl (4 M solution in 1,4-dioxane, 1 eq.) in dry MeOH. The resulting solution is stirred overnight and evaporated to dryness to give the amine as the TFA or HCl salt. The amino group is then converted to the corresponding azide (VIII) using conditions described in Protocol VIII-a.

[0134] A solution of the amine (1 eq.), ZnCl2 (0.06 eq.) and K2CO3 (4 eq.) in anhydrous methanol (0.6 M) was then cooled to 0° C. in an ice bath under inert atmosphere. Further, anhydrous N,N-diisopropylethylamine (1.1 eq.) was slowly added to a solution of 1H-imidazole-1-sulfonyl azide hydrogen sulfate (1.2 eq.) solubilized in anhydrous methanol (0.3 M) under inert atmosphere. The azide-containing solution was immediately added dropwise to the amine solution at 0° C. The cooling bath was then removed and the white mixture was stirred at room temperature overnight. The mixture was then cooled to 0° C., diluted with water (10 mL) and carefully acidified to pH=2 with dilute aqueous HCl (1N). It was extracted with ethyl acetate and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were concentrated under reduced pressure to give the compound of formula (VIII).

[0135] or If necessary, the iodo-aromatic group may be subjected to Sonogashira coupling: To a stirred and degassed solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-iodophenyl)propanoate (250 mg, 0.62 mmol, 1.0 equiv.), CuI (24 mg, 0.12 mmol, 0.2 equiv.) and PdCl2(PPh3)2 (45 mg, 0.06 mmol, 0.1 equiv.) in TEA (7 mL) was added ethynyl(trimethyl)silane (0.10 mL, 0.74 mmol, 1.2 equiv.). The resulting solution was stirred at rt for 6 h, then quenched with water and diluted with Et2O. After filtration through a pad of Celite, the two layers were separated. The aqueous layer was extracted with Et2O and the combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (cyclohexane / EtOAc 1:0 to 1:1 (v / v)) to afford methyl (2S)-2-(tert-butoxycarbonylamino)-3-[4-(2-trimethylsilylethynyl)phenyl]propanoate (166 mg, 72%) as a light oil.

[0136] The Boc group is then deprotected using dropwise addition of TFA (6 eq.) in dry DCM or HCl (4 M solution in 1,4-dioxane, 1 eq.) in dry MeOH. The resulting solution is stirred overnight and evaporated to dryness to give the amine as the TFA or HCl salt. The amino group is then converted to the corresponding azide (VIII) using conditions described in Protocol VIII-a.

[0137] I.4 Preparation of compounds of formula (I) I.4.1 Route A (Scheme 1) Preparation of Compounds of Formula (IX) To a solution of compound of formula (VIII) (1 equiv.) in methanol (0.04-0.35 M), aqueous hydroxylamine (50% w / w in water, 0.04-0.35 M) and KCN (0.1-0.5 equiv.) were added. The mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was purified on a flash silica gel column or a C18 gel column.

[0138] Preparation of Compounds of Formula (I) - Huisgen cycloaddition Compounds of formula (IX) (0.9-1 equiv.) and compounds of formula (V) (1.0-1.1 equiv.) were mixed in dioxane / HO (2 / 1, 0.07 M) or dimethylformamide / water (2 / 1 or 1 / 0.8, 0.02-0.11 M) and then copper sulfate pentahydrate (0.1 or 0.2 equiv.) was added followed by sodium ascorbate (0.5 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate, and the organic layers were combined and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give the desired 1,4-triazole.

[0139] I.4.2 Route B (Scheme 2) Preparation of Compounds of Formula (X) - Huisgen cycloaddition Compounds of formula (VIII) (0.9-1 equiv.) and compounds of formula (V) (1.0-1.1 equiv.) were mixed in dioxane / HO (2 / 1, 0.07 M) or dimethylformamide / water (2 / 1 or 1 / 0.8, 0.02-0.11 M) and then copper sulfate pentahydrate (0.1 or 0.2 equiv.) was added followed by sodium ascorbate (0.5 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate, and the organic layers were combined and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give the desired 1,4-triazole.

[0140] Preparation of Compounds of Formula (I) To a solution of compound of formula (X) (1 equiv.) in methanol (1 equiv.), aqueous hydroxylamine (50% w / w aqueous solution, 18-300 equiv.) and KCN (0.1-0.5 equiv.) were added at room temperature or 0°C. The mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was purified on a flash silica gel column or a C18 gel column.

[0141] I.4.3 Route C (Scheme 3) Preparation of Compounds of Formula (X) A compound of formula (VIII) (0.9 to 1 equivalent) and a compound of formula (V) (wherein R3 is a bromine-substituted thiophenyl) (1.0-1.1 equiv.) was mixed in dioxane / HO (2 / 1, 0.07 M) or dimethylformamide / water (2 / 1 or 1 / 0.8, 0.02-0.11 M) and then copper sulfate pentahydrate (0.1 or 0.2 equiv.) was added followed by sodium ascorbate (0.5 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate, and the organic layers were combined and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give the desired 1,4-triazole.

[0142] Preparation of compounds of formula (XI) - Suzuki Coupling A flask was charged with a compound of formula (X) (1 equivalent), a boronic acid (R 5 -B(OH)2, where R 5 is phenyl or pyridyl, optionally substituted as described herein (1.5-2.1 equiv.), palladium tetrakis (0.15 equiv.) and cesium carbonate (1.05 equiv.). The flask was degassed and flushed with argon three times. Degassed dioxane and water (3.5 / 1, 0.15-022 M) were added and the mixture was warmed to 70° C. and stirred for 1 h 45 min to 4 h. The mixture was diluted with water, treated with 1N HCl solution (pH=1-2) and extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography eluting with cyclohexane / ethyl acetate / methanol to give the desired intermediate of formula (XI).

[0143] Preparation of Compounds of Formula (I) To a solution of compound of formula (XI) (1 equiv.) in methanol (0.04-0.35 M), aqueous hydroxylamine (50% w / w in water, 0.04-0.35 M) and KCN (0.1-0.5 equiv.) were added. The mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was purified on a flash silica gel column or a C18 gel column.

[0144] If deprotection of an amino protecting group is necessary to reach the compound of formula (I), the deprotection can be carried out by known methods. For example, a Boc group can be cleaved by adding 4N HCl in dioxane. A trimethylsilyl group can be cleaved with TBAF in THF. If appropriate, the compound of formula (I) can be isolated as a salt, for example the potassium salt.

[0145] II. Preparation of 1,5-disubstituted 1,2,3-triazoles of formula (I) (Route D - Scheme 4) Preparation of compounds of formula (XII) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.1 equivalents) and triethylamine (3 equivalents) were reacted with the azidoamino acid compound (formula VII) and R 2 -N-propargylamine (1.1-1.3 equiv.) was added to a mixture of dimethylformamide (0.24-0.30 M). The mixture was stirred at room temperature overnight, ethyl acetate was added, and the organic phase was washed with aqueous HCl (0.1 or 1 M), NaHCO3, saturated NaCl, and H2O. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give the azide-alkyne (compound of formula (XII)).

[0146] Preparation of compounds of formula (XIII) - Intramolecular Huisgen cycloaddition Compound of formula (XII) was dissolved in dimethylformamide (0.009-0.04M), heated to reflux temperature, and stirred overnight to allow cyclization. After cooling, the mixture was diluted with ethyl acetate and washed with water (3 times). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was then purified by flash silica gel chromatography column to give compound of formula (XIII).

[0147] Preparation of compound of formula (XIV) Compound of formula (XIII) (1 eq) was diluted with 6M aqueous HCl (0.35-0.8M) and heated in a microwave at 85° C. for 1-3 h. The solvent was then evaporated under reduced pressure to give compound of formula (XIV) as the hydrochloride salt, which was used in the next step without further purification.

[0148] Preparation of compounds of formula (XV) The crude intermediate of formula (XIV) was dissolved in methanol (0.09-0.25M) and the mixture was cooled to 0° C., after which thionyl chloride (2 equiv.) was added. The solution was stirred at room temperature overnight and the solvent was evaporated to give the desired compound as the hydrochloride salt.

[0149] Preparation of compounds of formula (XVI) The compound of formula (XV) (1.1-1.5 equivalents) and N,N-diisopropylethylamine or triethylamine (1.2-3 equivalents) were solubilized in dichloromethane or dimethylformamide (0.08-0.34 M). The reaction medium was cooled to 0° C. and R 3 -sulfonyl chloride (1-1.2 equiv.) was added. The mixture was allowed to reach room temperature and stirred for 1 h-overnight. The product was then washed twice with 0.5 M or 1 M HCl (aq), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then filtered through silica gel (4 g cartridge) or purified by flash chromatography to give the desired product.

[0150] Preparation of Compounds of Formula (I) To a solution of compound of formula (XVI) (1 equiv.) in methanol (0.04-0.35 M), aqueous hydroxylamine (50% w / w in water, 0.04-0.35 M) and KCN (0.1-0.5 equiv.) were added. The mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was purified on a flash silica gel column or a C18 gel column.

[0151] III. Working Examples III.1 Starting materials and intermediate compounds III.1.1 Compound of formula (V) [Table 1] [Table 2] [Table 3]

Table 4

Table 5

Table 6

[0152] III.1.2 Compound of formula (VII)

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

[0153] III.1.3 Compound of formula (VIII)

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

[0154] III.1.4 Compounds of formula (IX)

Table 25

[0155] III.1.5 Compounds of formula (X)

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

[0156] III.1.6 Compounds of formula (XI)

Table 64

Table 65

Table 66

Table 67

Table 68

[0157] III.1.7 Compounds of formula (XII)

Table 69

Table 70

Table 71

[0158] III.1.8 Compounds of formula (XIII)

Table 72

Table 73

Table 74

[0159] III.1.9 Compounds of formula (XV)

Table 75

Table 76

Table 77

[0160] III.1.10 Compounds of formula (XVI)

Table 78

Table 79

Table 80

Table 81

Table 82

Table 83

Table 84

Table 85

Table 86

[0161] III.1.11 Compounds of formula (XX)

Table 87

Table 88

[0162] III.2 Compounds of formula (I)

Table 89

Table 90

Table 91

Table 92

Table 93

Table 94

Table 95

Table 96

Table 97

Table 98

Table 99

Table 100

Table 101

Table 102

Table 103

Table 104

Table 105

Table 106

Table 107

Table 108

Table 109

Table 110

Table 111

Table 112

Table 113

Table 114

Table 115

Table 116

Table 117

Table 118

Table 119

Table 120

Table 121

Table 122

Table 123

Table 124

Table 125

Table 126

Table 127

Table 128

Table 129

Table 130

Table 131

Table 132

Table 133

Table 134

Table 135

Table 136

Table 137

Table 138

Table 139

Table 140

Table 141

[0163] Biological Data I. In vitro ERAP activity assay The enzymatic activity of ERAP1 or 2 was assayed using L-AMC (L-leucine-7-amido-4-methylcoumarin hydrochloride) or R-AMC (L-arginine-7-amido-4-methylcoumarin hydrochloride), respectively. 50 mM Hepes at pH 7 and 100 mM NaCl were used as buffers. Briefly, 60 nL of test compound was acoustically dispensed into a 384-well plate (dark, non-binding surface) with a nanoacoustic dispenser Echo (Labcyte) and pre-incubated with 10 μL of ERAP 0.8 μg / mL or 1 μg / mL or vehicle at ambient temperature for 30 min. The reaction was then initiated by adding 10 μL of substrate at 10 μM. The final concentrations of ERAP, substrate and DMSO were 0.5 μg / mL, 5 μM and 0.4%, respectively. For dynamic readout a Victor 3V (Perkin-Elmer) was used with excitation at 380 nm and emission at 450 nm. Fluorescence was measured every 3 min for 1 h.

[0164] Z and Z' coefficients were calculated according to J.-H. Zhang, TDY Chung, KR Oldenburg, A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays, J. Biomol. Screen., 4 (1999) 67-73. Data analysis was performed using Xlfit® v 5.0 or GraphPad Prism® v 4.0.

[0165] The percentage of inhibition at various concentrations was obtained as above and IC 50 were performed as 8-point dose-response curves and reported as the average of at least three independent experiments. Bestatin was used as a reference inhibitor (100% inhibition at 2 mM). Data analysis was performed using Xlfit® v 5.0 or GraphPad Prism® v 4.0. Nonlinear curve fitting and statistical analysis were performed using built-in functions.

[0166] The results are shown in Tables 1 and 2. [Table 142] ERAP2 IC 50 uses R-AMC as a substrate +++(<500nM);++(<5μM);+(>5μM)

[0167] [Table 143] IC of ERAP1 or ERAAP 50 uses L-AMC as a substrate +++(<500nM);++(<5μM);+(>5μM)

[0168] II. Hydrolysis of nanomer-peptides The enzymatic reaction was carried out using the KSIINFEKL peptide (Proteogenix, Schiltigheim, FR). The enzymatic reaction was stopped at the desired time points using ice-cold acetonitrile (×100 dilution) and then injected into the LC-MS / MS to measure the AUC. LC-MS / MS analysis was performed using a triple quadrupole mass spectrometer Xevo TQD (Waters (登録商標) ) combined with a UPLC Acquity I Class (Waters (登録商標) The column was an Acquity BEH C18 50×2.1 mm, 1.7 μm column (Waters (登録商標)) with the following mobile phases: 5 mM ammonium formate pH 3.75 buffer for solvent (A) and 5 mM ammonium formate pH 3.75 in acetonitrile for solvent (B). Flow rate 600 μL / min, analytical method started at 98% (A) for 10 s, then percentage of B was gradually increased to 98% in 2 min, held at 98% (B) for 30 s, then returned to initial conditions and held for 1.5 min. Injection volume was 1 μL. MS analysis was performed under MRM detection using parameters optimized for each peptide (capillary voltage, product ion, collision energy, desolvation temperature). Instrument control as well as reprocessing of chemical analyses were performed using MassLynx software (Waters (登録商標) ) was performed. For XSIINFEKL, 100% corresponds to the AUC of the peptide at t=0 in the absence of enzyme. Dose-response curves of the compounds were performed at t=60 min.

[0169] The results are shown in Table 3. [Table 144]

[0170] III. Antigen Presentation Assay Examples HEK293 cells are transiently transfected with a single plasmid encoding i) a 14 amino acid HiBiT tag (part of nanoluciferase) fused to the N-terminus of mouse H2kB, ii) an ER-targeted N-terminally extended antigenic precursor peptide for L-SIINFEKL, and iii) a TAP inhibitor (protein UL49.5) using Jetprime according to the manufacturer's recommendations. Cells are harvested 4 hours after transfection and seeded in a 96-well plate format with pre-dispensed test compounds. The amount of HiBiT-tagged H2kB protein present on the cell surface is determined 24 hours later using the Nano-Glo® HiBiT Extracellular Detection System (Promega). The results are shown in Figure 1.

[0171] List of references 1 Serwold T, Gonzalez F, Kim J, Jacob R, & Shastri N (2002) ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419 (6906): 480-483 2 Saveanu L, et al. (2005) Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol 6 (7): 689-697 3 J.A. Lopez de Castro, How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins, Front Immunol, 9 (2018) 2463 4 Hammer GE, Gonzalez F, James E, Nolla H, & Shastri N (2007) In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nat Immunol 8 (1): 101-108 5 Y. Yao, N. Liu, Z. Zhou, L. Shi, Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations, Hum. Immunol., 80 (2019) 325-334 6A.L. Hanson, T. Cuddihy, K. Haynes, D. Loo, C.J. Morton, U. Oppermann, P. Leo, G.P. Thomas, K.-A. Le Cao, T.J. Kenna, M.A. Brown, Genetic Variants in ERAP1 and ERAP2 Associated With Immune-Mediated Diseases Influence Protein Expression and the Isoform Profile, Arthritis & Rheumatology, 70 (2018) 255-265 7 M. Compagnone, L. Cifaldi, D. Fruci, Regulation of ERAP1 and ERAP2 genes and their disfunction in human cancer, Hum. Immunol., 80 (2019) 318-324 8 Cifaldi, E. Lo Monaco, M. Forloni, E. Giorda, S. Lorenzi, S. Petrini, et al., Natural killer cells efficiently reject lymphoma silenced for the endoplasmic reticulum aminopeptidase associated with antigen processing, Cancer Res. 71 (2011) 1597 9 L. Cifaldi, P. Romania, M. Falco, S. Lorenzi, R. Meazza, S. Petrini, et al., ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors, Cancer Res. 75 (2015) 824 10E. James, I. Bailey, G. Sugiyarto, T. Elliott, Induction of protective antitumor immunity through attenuation of ERAAP function, J. Immunol. 190 (2013) 5839 11 Y.W. Lim, H. Chen-Harris, O. Mayba, S. Lianoglou, A. Wuster, T. Bhangale, et al., Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration, Proc. Natl. Acad. Sci. U.S.A. 115 (2018) E11701 12 R.T. Manguso, H.W. Pope, M.D. Zimmer, F.D. Brown, K.B. Yates, B.C. Miller, et al., In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target, Nature 547 (2017) 413 13 Saulle, I., et al. An overview on erap roles in infectious diseases. Cells 2020, 9 14[ PubMed ] [ Cross Ref ] Saulle I., Vanetti C., Goglia S., Vicentini C., EA-O. Tombetti, M. Garziano, M. Clerici, MA-O. Biasin, A New ERAP2 / Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection? LID - E1951 15 E. Zervoudi, E. Saridakis, JR Birtley, SS Seregin, E. Reeves, P. Kokkala, YA Aldhamen, A. Amalfitano, IM Mavridis, E. James, D. Georgiadis, E. Stratikos, Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses, Proc. Natl. Acad. Sci. USA, 110 (2013) 19890–19895 16 [ PubMed ] Maben Z, Arya R, Rane D, WF An, Metkar S, Hickey M, Bender S, Ali, TT Nguyen, Evnouchidou R, Schilling R, Stratikos E, Stratikos J Golden, LJ Stern, J. Med. Chem., 63(2020) 103–121 17Patent application GR 20130100582; Patent application WO 2020 / 104822 A1 18 Chen, L., et al Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis. Ann. Rheum. Dis., 2016, 75, 916-23 19 Koumantou, D et al Editing the Immunopeptidome of Melanoma Cells Using a Potent Inhibitor of Endoplasmic Reticulum Aminopeptidase 1. Cancer Immunol. Immunother. 2019, 68, 1245-1261

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, n is 0 or 1; R １ is selected from the group consisting of phenyl, naphthalenyl, indolyl and benzodioxolyl, wherein the phenyl, naphthalenyl, indolyl and benzodioxolyl are selected from the group consisting of hydroxyl, halogen, cyano, C １ -C ６ -Alkyl, C １ -C ６ -Halogenoalkyl, C １ -C ６ -Alkoxy, C １ -C ６ - halogenoalkoxy, C １ -C ６ -hydroxyalkoxy, C １ -C ６ -Alkoxy-C １ -C ６ -alkoxy, ethynyl, carbamoyl, C １ -C ６ - optionally substituted with one or more substituents selected from the group consisting of alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy; R ３ is a 5- or 6-membered heteroaryl containing one sulfur atom and optionally one further nitrogen, sulfur or oxygen atom, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, C １ -C ６ - optionally substituted with one or more substituents selected from the group consisting of alkyl, phenyl and pyridyl, wherein the phenyl and pyridyl are selected from the group consisting of halogen, C １ -C ６ -Alkyl, phenyl, pyridyl, C １ -C ６ -aminoalkyl and C １ -C ６ - optionally substituted with one or more substituents selected from the group consisting of alkylcarbamoyl; R ２ is hydrogen, C １ -C ６ -Alkyl or C ３ -C ６ -cycloalkyl; and R ４ is hydrogen, C １ -C ６ -Alkyl, -CH ２ -O-R ａ４ , -CH ２ -C(=O)R ｂ４ and -CH ２ -NH-C(=O)R ｃ４ wherein R ａ４ is hydrogen or C １ -C ６ -alkyl, R ｂ４ is hydroxyl, C １ -C ６ -alkoxy, amino or C １ -C ６ -alkylcarbonylamino, R ｃ４ is C １ -C ６ -alkoxy or R ２ and R ４ together with the nitrogen and carbon atom to which they are attached form a 5- or 6-membered heteroaryl selected from pyrrolidinyl, morpholinyl, thiazolidinyl, and piperidinyl. or a hydrate, solvate or pharma- ceutically acceptable salt thereof.

2. R １ is selected from the group consisting of phenyl, indol-3-yl, naphthalen-2-yl and 1,3-benzodioxol-5-yl, wherein the phenyl, indol-3-yl, naphthalen-2-yl and 1,3-benzodioxol-5-yl are hydroxyl, halogen, cyano, C １ -C ６ -Alkyl, C １ -C ６ -Halogenoalkyl, C １ -C ６ -Alkoxy, C １ -C ６ - halogenoalkoxy, C １ -C ６ -hydroxyalkoxy, C １ -C ６ -Alkoxy-C １ -C ６ -alkoxy, ethynyl, carbamoyl, C １ -C ６ The compound of formula (I) of claim 1, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents selected from the group consisting of alkylcarbamoyl, polyoxyethylenyl amidoxime and phenoxy.

3. R １ but 【Chemistry 2】 where R ａ , R ｂ and R ｃ is hydrogen, hydroxyl, halogen, cyano, C １ -C ６ -Alkyl, C １ -C ６ -Halogenoalkyl, C １ -C ６ -Alkoxy, C １ -C ６ - halogenoalkoxy, C １ -C ６ -hydroxyalkoxy, C １ -C ６ -Alkoxy-C １ -C ６ -alkoxy, ethynyl, carbamoyl, C １ -C ６ 3. The compound of formula (I) of claim 1 or 2, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, wherein the aryl group is independently selected from the group consisting of alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy.

4. R ３ is a 5- or 6-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl, isothiazolyl, thiopyranyl, dithiynyl and thiazinyl, wherein said 5- or 6-membered heteroaryl may be substituted as described in claim 1, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, of the compound of formula (I) of any one of claims 1 to 3.

5. R ３ is a 5-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl and isothiazolyl, wherein said thiophenyl, thiazolyl and isothiazolyl are optionally substituted as defined in claim 1, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, of the compound of formula (I) of any one of claims 1 to 4.

6. R ３ but 【Chemistry 3】 where R ５ is hydrogen, halogen, C １ -C ６ - selected from the group consisting of alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl are halogen, C １ -C ６ -Alkyl, phenyl, pyridyl, C １ -C ６ -aminoalkyl and C １ -C ６ -alkylcarbamoyl, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents selected from the group consisting of:

7. R ３ but 【Chemistry 4】 where R ５ is hydrogen, halogen, C １ -C ６ - selected from the group consisting of alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl are halogen, C １ -C ６ -Alkyl, phenyl, pyridyl, C １ -C ６ -aminoalkyl and C １ -C ６ -alkylcarbamoyl, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents selected from the group consisting of:

8. The compound of formula (I) has the following formula: 【Chemistry 5】 where n, R １ , R ２ , R ３ and R ４ 8. A compound of formula (I) according to any one of claims 1 to 7, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, wherein:

9. 2. A compound of formula (I) of claim 1, or a hydrate, solvate or pharma- ceutically acceptable salt thereof: (R)—N-hydroxy-4-(1H-indol-3-yl)-3-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide; (R)-N-hydroxy-3-(1H-indol-3-yl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)—N-hydroxy-3-(1H-indol-3-yl)-2-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)—N-hydroxy-3-(1H-indol-3-yl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)-2-(4-((5-bromothiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxy-3-(1H-indol-3-yl)propenamide; (R)—N-hydroxy-4-(naphthalen-2-yl)-3-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide; (S)—N-hydroxy-4-(4-hydroxyphenyl)-3-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide; (R)-N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)—N-hydroxy-4-(4-hydroxyphenyl)-3-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide; (S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)-4-(5-(N-((1-(1-(hydroxyamino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-1H-1,2,3-triazol-4-yl)methyl)sulfamoyl)thiophen-2-yl)-N-methylbenzamide; (S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)-2-(4-((5-bromothiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxy-3-(4-hydroxyphenyl)propenamide; (S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (2S)-3-(4-hydroxyphenyl)-2-[4-[(3-thienylsulfonylamino)methyl]triazol-1-yl]propanehydroxamic acid; (2S)-2-[4-[[(3-bromo-2-thienyl)sulfonylamino]methyl]triazol-1-yl]-3-(4-hydroxyphenyl)propanehydroxamic acid; (2S)-3-(4-hydroxyphenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (R)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propanamide; (S)—N-hydroxy-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-3-(4-(trifluoromethoxy)phenyl)propanamide; (S)—N-hydroxy-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-3-(4-(trifluoromethoxy)phenyl)propenamide; (S)—N-hydroxy-3-(4-phenoxyphenyl)-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)—N-hydroxy-3-(4-methoxyphenyl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (S)—N-hydroxy-3-(4-methoxyphenyl)-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (2S)-3-(4-tert-butoxyphenyl)-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-tert-butoxyphenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (S)-4-(5-(N-((1-(1-(hydroxyamino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)-1H-1,2,3-triazol-4-yl)methyl)sulfamoyl)thiophen-2-yl)-N-methylbenzamide; (S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-(pyridin-3-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide; (3R)-4-(1H-indol-3-yl)-3-[5-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]butanehydroxamic acid; (3S)-4-(4-hydroxyphenyl)-3-[5-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]butanehydroxamic acid; (S)—N-hydroxy-4-(4-hydroxyphenyl)-3-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide; (3S)-4-(4-hydroxyphenyl)-3-[5-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]butanehydroxamic acid; (2S)-3-(4-hydroxyphenyl)-2-[5-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2R)-3-(4-hydroxyphenyl)-2-[5-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[[[5-(4-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(1,3-benzodioxol-5-yl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[[[5-(3-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3-chloro-4-hydroxy-phenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3-chloro-4-hydroxy-phenyl)-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3,4-dimethoxyphenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3,4-dimethoxyphenyl)-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; 3-[5-[[1-[(1S)-2-(hydroxyamino)-1-[(4-methoxyphenyl)methyl]-2-oxo-ethyl]triazol-4-yl]methylsulfamoyl]-2-thienyl]-N-methyl-benzamide; (2S)-3-(3-fluoro-4-hydroxy-phenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3-fluoro-4-hydroxy-phenyl)-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[[methyl-[[5-(2-pyridyl)-2-thienyl]sulfonyl]amino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[(1S)-1-[[5-(2-pyridyl)-2-thienyl]sulfonylamino]ethyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[(1R)-1-[[5-(2-pyridyl)-2-thienyl]sulfonylamino]ethyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3-methoxyphenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(2-methoxyphenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-[4-(2-methoxyethoxy)phenyl]-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3-fluoro-4-methoxy-phenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(3-chloro-4-methoxy-phenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-ethynylphenyl)-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-[4-(N-hydroxycarbamimidoyl)phenyl]-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[[(2-phenylthiazol-5-yl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid; (2S)-2-[4-[[cyclopropyl-[[5-(2-pyridyl)-2-thienyl]sulfonyl]amino]methyl]triazol-1-yl]-3-(4-methoxyphenyl)propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[1-[(5-phenyl-2-thienyl)sulfonyl]-2-piperidyl]triazol-1-yl]propanehydroxamic acid; (2S)-3-(4-methoxyphenyl)-2-[4-[(2S)-1-[(5-phenyl-2-thienyl)sulfonyl]pyrrolidin-2-yl]triazol-1-yl]propanehydroxamic acid; or (2S)-3-(4-cyanophenyl)-2-[4-[[(5-phenyl-2-thienyl)sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid.

10. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 9 or a hydrate, solvate or pharma- ceutically acceptable salt thereof and one or more excipients.

11. 11. The pharmaceutical composition of claim 10 for the treatment or prevention of a proliferative disorder, an autoinflammatory disorder or an autoimmune disorder.

12. The pharmaceutical composition of claim 11 for the treatment or prevention of cancer, spondyloarthritis, shotcretinopathy, type 1 diabetes, Behcet's disease or psoriasis.

13. A pharmaceutical combination comprising at least one compound of formula (I) according to any of claims 1 to 9, or a hydrate, solvate or pharma- ceutically acceptable salt thereof, and one or more additional pharma- ceutical active agents.

14. 14. The pharmaceutical combination of claim 13, wherein said additional pharma- ceutical active agent is an anti-cancer agent, a disease-modifying anti-rheumatic drug (DMARD), an anti-viral or anti-bacterial agent or another ERAP1 or ERAP2 or IRAP inhibitor.

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