Traf2 inhibitors for the treatment of cancer and other diseases

Abstract

The present invention relates to novel TRAF2 inhibitors for use in the treatment of cancer and use of novel TRAF2 inhibitors in biochemical assays, cell culture systems, or animal models.

Description

TRAF2 inhibitors for the treatment of cancer and other diseasesTECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to novel TRAF2 inhibitors for use in the treatment of cancer and other TRAF2-related disease, and use of novel TRAF2 inhibitors in biochemical assays, cell culture systems, or animal models.BACKGROUND ART

[0002] Epstein-Barr virus (EBV) is a human gammaherpesvirus that has been classified as a class I carcinogen by the World Health Organization (WHO). A global burden of about 143,000 deaths per year is associated with EBV-associated cancer1. EBV primarily infects human B cells and transforms them into indefinitely profilerating tumor cells2. The EBV oncoprotein latent membrane protein 1 (LMP1 ) acts like a constitutively active receptor of the tumor necrosis factor (TNF) receptor family that is critical for cell transformation and pathogenesis of most EBV- associated cancers2, 3. EBV-associated cancers and lymphoproliferative diseases expressing LMP1 include, among others, post-transplant lymphoproliferative disease (PTLD), Hodgkin’s lymphoma (HL), EBV-associated NK-cell and T-cell lymphoma, diffuse large B cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and infectious mononucleosis (IM)4"8. EBV infection is also associated with the development of multiple sclerosis (MS), and EBV-induced infectious mononuleceosis has been indentified as a risk factor for the development of MS9'11. The invention is further directed to the compound or the pharmaceutical composition for use in the treatment of an EBV associated neuronal disease such as multiple sclerosis (MS), retinopathies induced by diabetes and ischemia / reperfusion, skin inflammation, cardiovascular inflammation, inflammatory bowel diseases, liver inflammation, autoimmune inflammatory diseases, rheumatoid arthritis, acute and chronic lung disease, acute respiratory distress syndrome (ARDS), and diabetes

[0003] LMP1 mediates tumor cell survival by activating NF-KB and MAPK pathway signaling through the direct recruitment of TNF receptor-associated factor 2 (TRAF2) to the P204xQxT TRAF2 interaction motif within the C-terminal activator region 1 (CTAR1), which is located within LMPTs cytoplasmic signaling domain3, 12'19. EBV virions harboring LMP1 with a mutated TRAF2 interaction site show a drastically reduced potential of B cell transformation17. The RNAi- mediated knockdown of TRAF2 in EBV-transformed cells inhibits LMP1 activation of NF-KB20.

[0004] The direct interaction of TRAF2 with cellular TNF receptors such as CD40, TNF receptor 2, lymphotoxin-beta receptor, RANK, or the BAFF receptors TACI and BCMA, or RIG-I like receptors such as MAVS is the basis for NF-KB and MAPK signaling by these receptors21'27.1005] There is a high medical need for novel anti-EBV therapies. Currently, no drug or vaccine targeting EBV is available to the patient. Standard treatment of EBV-associated cancer includes antibody- (rituximab), chemo- or radiotherapy, which are often ineffective or cause severe side effects28, 29.SUMMARY OF THE INVENTION

[0006] The present invention is related to a compound according to formula (I),(i) whereinA and B are independently selected from the group consisting of -(CrCs)alkyl,and H, preferably methyl, or ; more preferably methyl or -CH2CH2OH;G is — O-, -NR1-CH2-, preferably -O-;L is selected from the group consisting of -OR2, -NR3R4, -CONR5R6, -COOR7, - Ph, -PhO(CrC5)alkyl; p is an integer between 0 and 4; preferably 0 and 1 ; more preferably 1 ; k is an integer between 0 and 2; preferably 0 and 1 ; more preferably 0;V, D, E, and W are independently selected from the group consisting of.-F, -Cl, -(CrC5)alkyl, - (C3-C5)cycloalkyl, -CD3, -O(C1-C5)alkyl, -NR8R9, -NO2-CONR10R11, -C(O)R12, hydrogen and deuterium, preferably hydrogen, -Cl, -F, deuterium, -OCH3, -NRSR9, -C(O)R12, -CH3, -CD3;R1, R2, R3, and R4are independently selected from the group consisting of -(C1C5)alkyl, C(O)alkyl and hydrogen, preferably -(C1-C5)alkyl, C(O)alkyl and hydrogen;R5, R®, R7, R8, R9, R10, R11and R12are independently selected from the group consisting of -(Ci- C5)alkyl and hydrogen, preferably -(C1-C5)alkyl and hydrogen;X and Y are independently selected from the group consisting of -S-, NH-, -CH2S-, -CH2O-, - OCH2-, CH2NH-, -S-CH2-, -NHCH2-, and -C=C-, preferably -S-;Z1and Z2are independently selected from the group consisting of CH, and N; wherein in -(C1C5)alkyl and -C(O)alkyl, one or more hydrogens may be substituted by a substituent selected from the group consisting of F, deuterium, -OH; wherein the compound is nor a pharmaceutically acceptable salt, solvate or hydrate thereof.1007] The invention is further directed to a pharmaceutical composition comprising the compounds of the present invention and at least one pharmaceutically acceptable carrier.

[0008] The invention is further directed to the compound or the pharmaceutical composition for use in medicine and as TRAF2 inhibitor.

[0009] The invention is further directed to the compound and to the pharmaceutical composition for use in the treatment of cancer.

[0010] The compounds of the present invention inhibit LMP1-TRAF2 protein-protein interaction (Fig. 1). Thereby, they disrupt the virus-host cell interface of EBV formed by LMP1 and TRAF2 to interfer with LMP1 signal transduction and to cause cell death of EBV transformed cells expressing LMP1.BRIEF DESCRIPTION OF THE FIGURES AND TABLES

[0011] Fig. 1: Principle of action of small molecule TRAF2 inhibitors (IH). The inhibitors block the interaction between LMP1 and TRAF2 and thereby uncouple LMP1 from its cellular signaling network.

[0012] Fig. 2: Setup of the LMP1-TRAF2 protein-protein-interaction assay based upon Alphascreen technology (Perkin Elmer).

[0013] Fig. 3: Biological assay in EBV-transformed human B cells demonstrating the specific effect of the inhibitors (here: compound 59) on LMP1 -induced JNK and NF-KB signaling. LCL.NGFR-LMP1 cells are EBV-transformed human B cells which express NGFR-LMP1, a fusion protein of the NGF receptor extracellular and transmembrane domains and the signaling domain of LMP1, instead of wildtype LMP1. LMP1 -specific signaling can be triggered in these cells by antibody-mediated crosslinking of NGFR-LMP1 molecules at the cell surface. The compound 59 inhibits JNK and NF-KB activation by NGFR-LMP1 in the nanomolar range.

[0014] Table 4 Range of EC50values of the listed TRAF2 inhibitor compounds on the viability of PTLD880 and LCL877 cells as measured by the MTT cell viability assay.DETAILED DESCRIPTION OF THE INVENTION

[0015] The solution of the present invention is described in the following, exemplified in the appended examples, illustrated in the Figures and reflected in the claims.

[0016] Definitions

[0017] It is noted that as used herein, the singular forms “a”, “an”, and “the", include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a reagent” includes one or more of such different reagents and reference to “the method” includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.

[0018] Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0019] The term "and / or" wherever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by said term".

[0020] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises" and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising" can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”.

[0021] When used herein “consisting of’ excludes any element, step, or ingredient not specified.

[0022] All publications cited throughout the text of this specification (including all patents, patent application, scientific publications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admissionthat the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

[0023] The content of all documents and patent documents cited herein is incorporated by reference in their entirety.

[0024] A beter understanding of the present invention and of its advantages will be had from the following examples, offered for illustrative purposes only. The examples are not intended to limit the scope of the present invention in any way.

[0025] The term "alkyl" refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 5 carbon atoms, i.e., 1, 2, 3, 4, 5, carbon atoms, more preferably 1 to 3 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1 ,2-dimethyl- propyl, iso-amyl, and the like.

[0026] The term "cycloalkyl" represents cyclic non-aromatic versions of "alkyl” and "alkenyl" with preferably 3 to 5 carbon atoms, i.e., 3, 4, 5 carbon atoms, more preferably 3 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl.

[0027] “Ph” means phenyl. “-PhO(CrC6)alkyl means a phenyl group substituted with a “-0(C1 C6)alkyl” group. The “-O(C1C6)alkyl” substituent may be in ortho, meta or para position.

[0028] As used herein and throughout the entire description, the term "solvate" as used herein refers to an addition complex of a dissolved material in a solvent (such as an organic solvent (e.g., an aliphatic alcohol (such as methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, and the like), water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A "hydrate" is a solvate wherein the solvent is water.

[0029] As used herein and throughout the entire description, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66: 1-19). Physiologically acceptable salts of the compounds of the present invention are in particular salts with a nontoxic salt component and preferably arepharmaceutically utilizable salts. They can contain inorganic or organic salt components. Such salts can be formed, for example, from compounds of the present invention which contain an acidic group, for example a carboxylic acid group (HO-CO-) or a sulfonic acid group (HO-S(O)2-) and nontoxic inorganic or organic bases. Suitable bases are, for example, alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia, organic amino compounds and quaternary ammonium hydroxides. Reactions of compounds of the present invention with bases for the preparation of the salts are in general carried out according to customary procedures in a solvent or diluent On account of the physiological and chemical stability, advantageous salts of acidic groups are in many cases sodium, potassium, magnesium or calcium salts or ammonium salts which can also carry one or more organic groups on the nitrogen atom. Compounds of the present invention which contain a basic, i.e. protonatable, group, for example an amino group or another basic heterocycle, can be present in the form of their acid addition salts with physiologically acceptable acids, for example as salt with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which in general can be prepared from the compounds of the present invention by reaction with an acid in a solvent or diluent according to customary procedures. As usual, in particular in the case of acid addition salts of a compound containing two or more basic groups, in an obtained salt the ratio of the salt components can deviate upward or downward from the stoichiometric ratio, such as the molar ratio 1 :1 or 1:2 in the case of the acid addition salt of a compound of the present invention containing one or two basic groups with a monovalent acid, and vary depending on the applied conditions. The present invention comprises also salts containing the components in a non-stoichiometric ratio, and an indication that an acid addition salt of a compound of the present invention contains an acid in equimolar amount, for example, also allows for a lower or higher amount of acid in the obtained salt, for example about 0.8 or about 1.1 mol of acid per mol of compound of the present invention. If the compounds of the present invention simultaneously contain an acidic and a basic group in the molecule, the invention also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned. The present invention also comprises all salts of the compounds of the present invention which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange. A subject of the present invention also are solvates of the compounds of the present invention and their salts, such as hydrates and adducts with alcohols like (CrC4)-alkanols, in particular physiologically acceptable solvates, as well as active metabolites of compounds of the present.

[0030] As used herein and throughout the entire description, the term “pharmaceutically acceptable” may in particular mean approved by a regulatory agency or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0031] The invention is directed to a compound according to formula (I),wherein

[0032] A and B are independently selected from the group consisting of -(C1C5)alkyl,and H; preferably methyl, o ; more preferably methyl or -CH2CH2OH.

[0033] G is -O-, -NR1-CH2-; preferably -O-.

[0034] L is selected from the group consisting of -OR2, -NR3R4, -CONRSR6, -COOR7, -Ph, - PhO(C1-C5)alkyl.

[0035] p is an integer between 0 and 4; preferably 0 and 1 ; more preferably 1.

[0036] k is an integer between 0 and 2; preferably 0 and 1 ; more preferably 0.

[0037] V, D, E, and W are independently selected from the group consisting of.-F, -Cl, -(C1 C5)alkyl, -(C3-C5)cycloalkyl, -CD3, -O(C1-C5)alkyl, -NR8R9, -NO2-CONR10R11, -C(O)R12, hydrogen and deuterium, preferably hydrogen, -Cl, -F, deuterium, -OCH3, -NR8R9, -C(O)R12, - CH3, -CD3.

[0038] R1, R2, R3, and R4are independently selected from the group consisting of -(C1C5)alkyl, C(O)alkyl and hydrogen, preferably -(C1C5)alkyl, C(O)alkyl and hydrogen;

[0039] R5, R6, R7, R8, R9, R10, R11and R1Zare independently selected from the group consisting of -(C1-C5)alkyl and hydrogen, preferably -(C1C5)alkyl and hydrogen;

[0040] In one embodiment R1, R2, R3, R4, R8, R9, and R12are independently selected from the group consisting of -(C1C5)alkyl, and hydrogen.

[0041] X and Y are independently selected from the group consisting of -S-, NH-, -CH2S-, - CH2O-, -OCH2O-, CH2NH-(-S-CH2-, -NH-CH2-, and -C=C-, preferably -S-.

[0042] Z1and Z2are independently selected from the group consisting of CH, and N; in -(CrC5)alkyl and -C(O)(CrC5)alkyl, one or more hydrogens may be substituted by a substituent selected from the group consisting of F, deuterium, -OH; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0043] Preferably, the compound is no

[0044] In one embodiment, A and B are independently selected from the group consisting of -(C1C5)alkyl , preferably methyl and CH2CH2OH;p is 0 or 1 ; k is 0;G is O, -NR1, -CH2-;C, D, E, and W are independently selected from the group consisting of hydrogen, -F, deuterium, -OCH3, -NR8R9, -C(O)R12, -CH3, CD3;R1, R5, R8, R9, and R12are independently selected from the group consisting of -(C1Cs)alkyl, and hydrogen;X and Y are independently selected from the group consisting of S.

[0045] In one embodiment A and B are independently selected from the group consisting of -(C1C5)alkyl, -CH2CH2OH, , preferably methyl;p is 1; k is 0;G is O; wherein in -(G1-C3)alkyl and -C(O)alkyl, one or more hydrogens may be substituted by a substituent selected from the group consisting of -OH;C, D, E, and W are independently selected from the group consisting of hydrogen, -F, -Cl deuterium, -CH3and -CD3;Z1and Z2are independently selected from the group consisting of CH, and N;X and Y are S;

[0046] The compound may be selected from the group consisting of :100 101 102

[0047] In one embodiment the compound is selected from the group consisting ofSynthesis of the compounds1. Synthesis of 2,3-dichloroquinoxalines from phenyldiamines

[0048] V, D, E, and W are independently selected from the group consisting of -F, -Cl, -(CrC5)alkyl, -(C3-C5)cycloalkyl -O(C1C5)alkyl, -NR7R8, -NO2, -CONR9R10, -C(O)R11, hydrogen and deuterium, preferably hydrogen, -Cl, -F, deuterium, -OCH3, -NR12R13, -C(O)R14, -CH3; wherein in -(C1-C3)alkyl, one or more hydrogens may be substituted by a substituent selected from the group consisting of F, deuterium, -OH.

[0049] In a first step an aromatic diamine is converted with oxalic acid and POCI3in a suitable solvent, preferably a nonpolar aprotic solvent, such as toluene at reflux temperature, for example 110°C in case of toluene. Further modficiation of the quinoxaline (III) before the final synthetic step can be performed. The procedures are further exemplified and described in more detail for specific examples.2. Sythesis of target compounds

[0050] A and B are independently selected from the group consisting of -(C1-C5Jalkyl, ^, and H; preferably methyl, or more preferably methyl or -CH2CH2OH;G is -O-, -NR1, -CH2-;L is selected from the group consisting of -OR2, -NR3R4, -CONR5R6, -COOR7, - Ph, -PhO(C,- Cs)alkyl; p is an integer between 0 and 4; preferably 0 or 1 ; k is an integer between 0 and 2; preferably 0 or 1 ; more preferably 0;V, D, E, and W are independently selected from the group consisting of -F, -Cl, -(C1-C3)alkyl, - (C3-C5)cycloalkyl, -CD3, -O(C1-C5)alkyl, -NR8R9, -NO2-CONR10R11, -C(O)R12, hydrogen and deuterium, preferably hydrogen, -Cl, -F, deuterium, -OCH3, -NR®R9, -C(O)R12, -CH3, -CD3;R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12are independently selected from the group consisting of -(C-i-C5)alkyl, -C(O)alkyl and hydrogen, preferably -(C1-C5)alkyl, -C(O)alkyl and hydrogen;X and Y are independently selected from the group consisting of -S-, NH-, -CH2S-, -CH2O-, - OCH2-, CH2NH-, -S-CH2-, -NH-CH2-, preferably -S-;X1and Y1are independently selected from the group consisting of -SH, -NH2)-CH2SH, - CH2OH, -CH2NH2, HS-CH2-, and -NH2-CH2-, preferably -SH;Z1and Z2are independently selected from the group consisting of CH, and N; wherein in -(C1C5)alkyl and -C(O)alkyl one or more hydrogens may be substituted by a substituent selected from the group consisting of F, deuterium, -OH.

[0051] Compound (III) has been converted with (IV) and / or (V) in a suitable solvent, preferably a polar aprotic solvent, such as DMF, in the presence of a weak base, such as DI PEA, or triethylamine, at a temperature of 80 to 120°C, preferably 100°C. The procedures are further exemplified and described in more detail for specific examples.

[0052] The invention further comprises a pharmaceutical composition comprising the compound as described above and at least one pharmaceutically acceptable carrier.

[0053] Pharmaceutically acceptable "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of weting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington’s Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0054] The invention is further directed to the compound or the pharmaceutical composition for use in medicine.

[0055] The invention is further directed to the compound of the pharmaceutical composition for use as TRAF2 inhibitor.

[0056] The invention is further directed to the compound or the pharmaceutical composition for use in the treatment of a disease caused by an infection with the Epstein-Barr virus and / or a disease which is associated with TRAF2.

[0057] The invention is further directed to the compound or the pharmaceutical composition use in the treatment of cancer, preferably the cancer is selected from the group consisting of i) Epstein-Barr virus (EBV) associated cancers and lymphoproliferations expressing LMP1, preferably post-transplant lymphoproliferative disease (PTLD), EBV-positive Hodgkins’slymphoma (HL), EBV-associated NK-cell and T-cell lymphoma, EBV-positive diffuse large B cell lymphoma (DLBCL), nasopharyngeal carcinoma, and infectious mononucleosis (IM); ii) primary effusion lymphoma (PEL), Kaposi’s sarcoma, and multicentric Castleman's disease; ABC-DLBCL (activated B cell-type diffuse large B cell lymphoma); classical EBV-negative Hodgkin’s lymphoma, MALT-lymphoma, and multiple myeloma.

[0058] The invention is further directed to the compound or the pharmaceutical composition for use in the treatment of an EBV associated neuronal disease such as multiple sclerosis (MS), retinopathies induced by diabetes and ischemia / reperfusion, skin inflammation, cardiovascular inflammation, inflammatory bowel diseases, liver inflammation, autoimmune inflammatory diseases, rheumatoid arthritis, acute and chronic lung disease, acute respiratory distress syndrome (ARDS), and diabetes.

[0059] Post-transplant lymphoproliferative disease (PTLD), EBV-positive Hodgkin’s lymphoma (HL), EBV-associated NK-cell and T-cell lymphoma, EBV-positive diffuse large B cell lymphoma (DLBCL), nasopharyngeal carcinoma, and infectious mononucleosis (IM) are EBV-associated cancers and lymphoproliferations expressing LMP14’8.

[0060] Primary effusion lymphoma (PEL), Kaposi's sarcoma, and multicentric Castleman’s disease induced by the Kaposi’s Sarcoma herpesvirus (KSHV). The KSHV-derived protein vFLIP contains a PxQxT TRAF2 interaction motif30. vFLIP directly binds TRAF2 via this motif to activate NF-KB, which is crucial for KSHV-associated PEL survival and lymphomagenesis30. Moreover, the KSHV protein K12 interacts with TRAF2 and thereby regulates the MAPK pathway31.

[0061] ABC-DLBCL (activated B cell-type diffuse large B cell lymphoma). TRAF2 correlates with poor progression of ABC-DLBCL24132.

[0062] Classical EBV-negative Hodgkin’s lymphoma. Hodgkin-Reed-Sternberg (HRS) tumor cells receive CD30 and CD40 survival signals from eosinophils and mast cells, which express CD30 ligand, or from activated T cells, which express CD40 ligand. Such signals from the inflammatory microenvironment of the tumor cause NF-KB activation and survival of the tumor cells24, 33. Several immune cells present in the HL microenvironment further secrete the ligands BAFF and APRIL to stimulate the TNF receptor family members BCMA and TACI on HRS cells33. Both, BCMA and TACI directly interact with TRAF2231 34. Further, HRS cells express RANK-ligand and its receptor RANK to stimulate NF-KB activation in an autocrine loop33. The TNFR family member RANK directly recruits TRAF2, 5 and TRAF635.

[0063] MALT lymphoma. In MALT lymphoma the CIAP2-MALT1 fusion protein induces NF-KB via MALT1-TRAF6 interaction. TRAF2, which interacts with the clAP2 portion of the fusion, is also required for CIAP2-MALT1 activity24. A potential synergy between MALT1 inhibitors and TRAF2 inhibitors might exist

[0064] Multiple Myeloma derived from plasma cells in the bone marrow depends on the activity of the NF-KB pathway, which is induced in the stromal-dependent multiple myeloma stage by BAFF and APRIL ligands present in the myeloma microenvironment in the bone marrow. Multiple myeloma cells retain their BAFF / APRIL receptors BCMA and TACI, and some multiple myelomas even harbor amplifications of CD40, lymphotoxin-beta receptor, or TACI24.

[0065] Multiple sclerosis (MS) is associated with Epstein-Barr Virus (EBV)9'11.

[0066] The cell surface receptor CD40 is required for the development of retinopathies induced by diabetes and ischemia / reperfusion. Inhibition of CD40-TRAF2 interaction is a target for such retinopathies36.

[0067] Modulation of inflammatory and autoimmune diseases. Inflammatory processes mediated by, for instance, receptors of the TNF receptor family, RIG-I and cytokine receptors are regulated by TRAF226. Thereby, TRAF2 is involved in the regulation of skin inflammation, cardiovascular inflammation, inflammatory bowel diseases, liver inflammation, and autoimmune inflammatory diseases27. Moreover, CD40 and TRAF2 rescue auto-reactive Th40 T cells from FAS-induced cell death in autoimmunity37.

[0068] Rheumatoid arthritis. BAFF ligand levels correlate with the disease activity and bone destruction of rheumatoid arthritis. The BAFF pathway, which depends on TRAF2, has been suggested as target for the treatment of rheumatoid arthritis due to its role in NF-KB activation, differentiation, proliferation, and activation of B cells in rheumatoid arthritis38.

[0069] Acute and chronic lung disease associated with alveolar hypoventilation leading to CO2 accumulation in the acute respiratory distress syndrome (ARDS). TRAF2 has been identified as the E3 ubiquitin ligase responsible for ubiquitination of the Na,K-ATPase beta-subunit upon hypercapnia and, thus, suggested as novel target for the treatment of acute or chronic hypercapnic respiratory failure39.

[0070] Type 1 Diabetes (T 1 D). In T1 D, auto-reactive T cells destroy the insulin-producing beta cells in the pancreas. Islets susceptible to destruction by such autoreactive T cells upregulate the death receptor Fas via TNF receptor 2, which is TRAF2-dependent40. In addition, IL-1 beta and IFNgamma induce cell death of insulin-producing beta cells in T1D. Both cytokines upregulate TRAF2, which is involved in JNK and STAT3 activation and the induction of apoptotic beta cell death in response to IL-1 beta and IFNgamma41. TRAF2 is, thus, a target to block beta cell death in T1 D.

[0071] Type 2 diabetes (T2D). Obesity is associated with intrahepatic inflammation that promotes insulin resistance and T2D. Hepatic TRAF2 cell autonomously promotes hepatic gluconeogenesis by enhancing the hyperglycemic response to glucagon and other factors that increase cAMP levels, thus contributing to hyperglycemia in obesity42.

[0072] The invention is further directed to the use of the compound as TRAF2 inhibitor in biochemical assays, cell culture systems, or animal models.

[0073] A better understanding of the present invention and of its advantages will be had from the following examples, offered for illustrative purposes only. The examples are not intended to limit the scope of the present invention in any way.EXAMPLES OF THE INVENTION1. General information1.1 Reagents and equipment

[0074] When using reagents sensitive to air or moisture, the corresponding reaction was carried out in an inert gas atmosphere (argon or nitrogen) and / or with dry solvents. Tetrahydrofuran (THF) was dried over sodium wire with benzophenone as an indicator. Dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene (PhMe), dichloromethane (CH2CI2), 1,2- dichloroethane (DCE) and methanol were purchased from ACROS or SIGMA-ALDRICH. The glassware used to carry out the reaction was previously baked out in a vacuum. Unless otherwise stated, a magnetic stirrer was used. For the removal of solvents under reduced pressure, rotary evaporators from BUCHI were used. For lyophilization, the freeze-drying Alpha 1 - 4 LDplus from CHRIST was used. Syntheses in the microwave were carried out using the BIOTAGE Initiator-!- device.1.2 NMR spectroscopy

[0075] The1H and13C NMR spectra were recorded with the Avance-400, Ascend-400, Avance- 500 and -600 instruments from BROKER at 25°C. 1 H spectra were recorded at 400 MHz, 500 MHz and 600 MHz, respectively, and 13C spectra at 101 MHz, 125 MHz and 151 MHz, respectively. CDCI3, CD3OD, DMSO-d6 were used as solvents. The calibration of the 1 H-NMR spectra was carried out with respect to the signal of the solvent.

[0076] Table 1. Solvent signals in 1H and 13C-spectra

[0077] The spliting of the signals is given as follows: singlet (s), doublet (d), doublet of doublet (dd), triplet (t), wide singlet (bs) and multiplet (m). The chemical shift 6 = is given in parts per million (ppm) and the coupling constant J is given in hertz (Hz). For a complete interpretation, 1H-1H correlation spectra (COSY) as well as 1H-13C correlation spectra (HSQC, HMBC) and spatial correlation spectra (1D-NOE, NOESY) were also used. The numbering of the assigned cores was arbitrary.Thin-layer chromatography

[0078] For thin-layer chromatography, glass plates of the type TLC silica gel 60 F254 from MERCK and aluminum-coated plates from Macherey-Nagel were used. Detection was performed using UV light of the wavelength A = 254 nm, as well as the staining reagents potassium permanganate, bromocresol green and ninhydrin with subsequent heat treatment.Liquid Chromatography-Mass Spectrometry (LCMS)

[0079] The mass spectrometric data for reaction control were taken on a WATERS Acquity H UPLC CLASS system with a WATERS 515 HPLC® pump and a WATERS 2767 Sample Manager. A WATERS Acquity UPLC® BEH C18 column (1.7 pm, 2.1 x 50 mm) was used for chromatographic separation. It was measured in a mass range of 50 - 800 with a total runtime of 3.0 and 3.5 min, respectively. A flow rate of 0.8 mL / min and a standard injection volume of 2 pL were chosen. A water-acetonitrile mixture with 0.1% methanic acid (FA) was used as a solvent, the gradient can be found in the following table.

[0080] Table 2. LCMS-Gradient.High-resolution mass spectrometry (HRMS)

[0081] High-resolution mass spectrometry (HRMS) was performed using a MICROMASS LCT with lock-spray unit. The injection was carried out in loop mode of an HPLC system from WATERS (Alliance 2695). Ionization was xxrried out by electron spray ionization (ESI). Electron ionization spectra were recorded with a micromass GCT spectrometer with direct inlet at 70 eV. The calculated and found masses are given in atomic units. Column chromatography The column chromatographic purification was carried out with a Reveleris flash system from Buchi with a variable flow rate. Silica and C18 columns of different sizes from the companies BUCHI, AXEL SEMRAU and MACHEREY-NAGEL were used for normal and reversed phase separation. The pore size of the columns was 40 pm. The normal phase gradient was composed of several isocratic stages, between which the polarity of the solvent mixture waslinearly increased. The solvents used and the eluent ratio are given in the respective reaction procedure.2. Reaction control and conditions2.1 General proceduresI: Synthesis of 2,3-dichloroquinoxalines from phenyldiamines

[0082] la: The phenyldiamine (1.0 eq.), oxalic acid dihydrate (1.45 eq.) and silica gel (0.04- 0.063 mm, 3.0 mass eq.) were suspended in PhMe (8 mL). The reaction mixture was heated to 110°C and stirred at this temperature for 5 hours. POCI3(10.0 eq.) and DMF (2.5 mL) were carefully added and stirred for 1 hour at the same temperature. The reaction mixture was taken up in cold water and extracted with EtOAc. The combined organic phases were washed with saturated NaCI solution, dried over Na2SO4and filtered. The solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography (PE / EtOAc 0-25%).

[0083] lb: The phenyldiamine (1.0 eq.), oxalic acid dihydrate (1.45 eq.) and silica gel (0.04- 0.063 mm, 3 mass eq.) were suspended in PhMe (5 mL). The reaction mixture was heated to 110°C and stirred at this temperature for 6 hours. POCI3(10.0 eq.) and DMF (1.5 mL) were carefully added and stirred for 1 hour at the same temperature. The reaction mixture was taken up in cold water and extracted with EtOAc. The organic phases were combined, dried and filtered over Na2SO4. The solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography (PE / EtOAc 0-50%).II: Synthesis of symmetrical target compounds

[0084] Ila: The 2,3-dichloroquinoxaline (1.0 eq.), the tetrazole (2.50 eq.) and DIPEA (5.0 eq.) were dissolved in DMF and stirred for 2-16 hours at 100°C. The reaction mixture was cooled to room temperature and taken up in water. The obtained suspension was filtered and the residue washed with MeOH and water. The product was dried by lyophilization.

[0085] lib: The chloroquinoxaline (1.0 eq.), the tetrazole or triazole (2.50 eq.) and DIPEA (4.0 eq.) were dissolved in DMF and stirred for 2-16 hours at 100°C. The reaction mixture was cooled to room temperature, taken up in water and a few drops of AcOH were added. If the product precipitated, it was filtered and washed with water to yield the crude product. Otherwise, the aqueous phase was extracted three times with EtOAc, the organic phases were combined,washed with saturated NaCI solution, dried over Na2SO4and filtered. In both cases, the crude product was purified by column chromatography (PE / EtOAc 0-100%).

[0086] He: The 2,3-dichloroquinoxaline (1.0 eq.), the tetrazole or triazole (2.50 eq.) and DIPEA (5.0 eq.) were dissolved in DMF and stirred for 2-16 hours at a temperature of 60-100°C. The reaction mixture was cooled to room temperature, taken up in water and lyophilized. The residue was purified by column chromatography.

[0087] lid: The 2,3-dichloroquinoxaline (1.0 eq.), the tetrazole or triazole (2.50 eq.) and DIPEA (5.0 eq.) were dissolved in DMF and stirred for 2-16 hours at a temperature of 60-100°C. The reaction mixture was cooled to room temperature, taken up in water and extracted three times with EtOAc, then the combined the organic phases were washed with saturated NaCI solution, dried over Na2SO4and filtered. The solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography.

[0088] HI: Synthesis of 5-mercaptotetrazoles from isothiocyanates The isothiocyanate (500 mg, 1.0 eq.) was dissolved in isopropyl alcohol (2.5 mL). NaN3(1.0 eq.) was dissolved in water (10 mL) and stirred under reflux. The dissolved isothiocyanate was added drop by drop to the aqueous solution and the reaction mixture was refluxed overnight. Subsequently, the mixture was cooled in an ice bath, cone. HCI (1 mL) was added and concentrated under reduced pressure. It was cooled again in the refrigerator for at least 4 hours and filtered. The resulting solid was dried under reduced pressure.2.2 Synthesis of Tetrazoles5-Mercapto-1 -methyltetrazole (1)

[0089] The synthesis of 1 was carried out by the reaction of methyl isothiocyanate based on the general procedure III. In this case, 200 mg of isothiocyanate was used and the amount of other reagents and solvents was reduced accordingly. The product (205 mg, 1.77 mmol, 65%) was obtained as a beige solid.1H-NMR (400 MHz, CDCI3) 5 = 3.92 (s, 3H). Rf(CH2CI2+ 1% MeOH) = 0.05.5-Mercapto-1 -cyclopropyltetrazole (2)

[0090] The synthesis of 2 was carried out by the reaction of cyclopropyl isothiocyanate according to general procedure III. The product (670 mg, 4.71 mmol, 69%) was obtained as a beige solid.1H-NMR (400 MHz, CDCI3) 5 = 3.69 (tt, J = 7.5, 3.7 Hz, 1 H), 1.38 - 1.20 (m, 4H).13C-NMR (101 MHz, CDCI3) <5 = 165.2, 29.7, 7.1. Rf(CH2CI2+ 10% MeOH) = 0.10.5-Mercapto-1 -ethyltetrazole (3)

[0091] The synthesis of 3 was carried out by the reaction of ethyl isothiocyanate according to general procedure III. The product (567 mg, 4.36 mmol, 76%) was obtained as a yellowish oil that crystallized in the freezer.’H-NMR (400 MHz, CDCI3) 6 = 4.35 (q, J = 7.3 Hz, 2H), 1.53 (t, J = 7.3 Hz, 3H). Rf(CH2CI2+ 10% MeOH) = 0.10. LC-MS (ESI; LRMS; tR= 0.77 min) m / z calculated for [M+Hf: 131.1 , found: 131.1.5-Mercapto-1 -butyltetrazole (4)

[0092] The synthesis of 4 was carried out by the reaction of butyl isothiocyanate based on general procedure III. In this case, the aqueous acidic phase was not filtered, but extracted with EtOAc. The product (653 mg, 4.13 mmol, 95%) was obtained as a yellow oil that crystallized in the freezer.1H-NMR (400 MHz, CDCI3) 6 = 4.29 (t, J = 7.3 Hz, 2H), 1.97 - 1.85 (m, 2H), 1.45 - 1.37 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). Rf(CH2CI2+ 10% MeOH) = 0.10. LC-MS (ESI; LRMS; tR= 1.00 min) m / z calculated for [M+H]+: 159.1, found: 159.1.5-Mercapto-1-benzyltrazole (5)

[0093] The synthesis of 5 was carried out by the reaction of benzyl isothiocyanate according to general procedure III. The product (372 mg, 1.94 mmol, 58%) was obtained as a white solid.’H-NMR (400 MHz, CDCI3) 6 = 7.53 - 7.42 (m, 2H), 7.42 - 7.33 (m, 3H), 5.46 (s, 2H). Rf(CH2CI2+ 10% MeOH) = 0.05. LC-MS (ESI; LRMS; tR= 1.05 min) m / z calculated for [M+Hf: 193.1, found: 193.1.5-Mercapto-1 -(4-methoxybenzyl)tetrazole (6)

[0094] The synthesis of 6 was carried out by the reaction of 4-methoxybenzyl isothiocyanate according to general procedure III. The product (460 mg, 2.07 mmol, 74%) was obtained as a white solid solid.1H-NMR (400 MHz, CDCI3) 6 = 7.44 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.39 (s, 2H), 3.80 (s, 4H). Rf(CH2CI2+ 10% MeOH) = 0.05.5-Mercaptotetrazole (7)

[0095] 6 (444 mg, 2.00 mmol) was dissolved in anisole (0.7 mL) and TFA (3.3 mL) and stirred for 2 hours at 100°C in a closed microwave vessel. The reaction mixture was cooled and the precipitate was dissolved in EtOAc. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (10 mL) and H2O (5 mL). NaOH (1120 mg, 28 mmol, 14 eq.)was added and the mixture was stirred for 30 min. The phases were separated and the aqueous phase was adjusted to pH 1-2 by means of cone. HCI. The aqueous-acidic phase was extracted several times with EtOAc and the combined organic phases were dried over Na2SO4. The solvent was removed under reduced pressure. The product (190 mg, 1.86 mmol, 93%) was obtained as a white solid. For safety reasons, the product was stored as a solution in DMF (1.9 mL). It was used without further purification.2-(5-Mercapto-1 H-tetrazole-1 -yl)-W-methylacetamide (8)

[0096] 2-(5-mercapto-1H-tetrazol-1-yl)acetic acid (500 mg, 3.12 mmol) was dissolved in THF (8 mL) and DMF (1.5 mL). CDI (532 mg, 3.28 mmol, 1.05 eq.) was also dissolved in THF (8 mL) and DMF (1.5 mL) and added drop by drop to the solution of the tetrazole. Subsequently, methylamine in THF (2N, 3.1 mL, 6.24 mmol, 2.00 eq.) was added to the reaction mixture and stirred for 12 hours at room temperature. The solvent was removed under reduced pressure and the residue was taken up in water. The pH was adjusted to 2-3 by means of 4 N HCI and the aqueous phase was extracted with EtOAc, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The product (380 mg, 2.19 mmol, 70%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-d6) S = 4.91 (s, 1 H), 2.63 (d, J = 4.6 Hz, 2H). Rf(CH2CI2+ 5% MeOH + TEA) = 0.25. LC-MS (ESI; LRMS; tR= 0.28 min) m / z calculated for [M+H]+: 174.0, found: 174.1.3-lsothiocyanatooxetane (9)

[0097] 3-Aminooxetane (2.00 g, 27.36 mmol, 1.00 eq.) was dissolved in CHCI3and added to a suspension of NaHCO3(15.40 g, 183.31 mmol, 6.70 eq.) in water (29.4 mL). A solution of thiophosgene (2.62 mL, 34.20 mmol, 1.25 eq.) in CHCI3was added dropwise into the suspension and stirred for 18 hours at room temperature. Subsequently, the solid was filteredoff and the phases were separated. The aqueous phase was extracted with CHCI3and the combined organic phases were washed with a saturated NaCI solution, dried over Na2SO4and the solvent was removed under reduced pressure. The temperature of the water bath was maintained at 40°C and the pressure did not fall below 20 mbar. The product (2.62 g, 22.72 mmol, 83%) was immediately used in the following step.1H-NMR (400 MHz, DMSO-d6) 6 = 5.10 - 4.98 (m, 1H), 4.81 - 4.71 (m, 2H), 4.62 - 4.54 (m, 2H).13C-NMR (101 MHz, DMSO-d6) 5 = 130.6, 76.5, 48.8.1 >(Oxetan-3-yl)-1 H-tetrazol-5-thiole (10)

[0098] NaN3(423 mg, 6.51 mmol, 1.5 eq.) in water (49.4 mL) was heated to 65°C. 9 (500 mg, 4.34 mmol) was dissolved in CHCI3(74 mL) and added to the solution drop by drop. Subsequently, the mixture was stirred for 3.5 hours at 70°C. It was cooled to 15°C, filtered and adjusted to pH 1-2 by addition of cone. HCI. The mixture was extracted several times with EtOAc, the combined organic phases were washed with a saturated NaCI solution, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was washed with Et2O and purified by column chromatography (CH2CI2 / MeOH +0.5% TEA, 0-5%). The product (203 mg, 0.78 mmol, 18%) was obtained as a yellow solid.1H-NMR (400 MHz, CDCI3) 6 = 5.93 (tt, J = 7.8, 6.6 Hz, 1H), 5.20 - 4.93 (m, 4H).1H-NMR (400 MHz, DMSO-d6) 6 = 5.71 (tt, J = 7.6, 6.1 Hz, 1 H), 5.02 - 4.93 (m, 2H), 4.95 - 4.86 (m, 2H).13C- NMR (101 MHz, DMSO-d6) 6 = 163.6, 74.9 (C8+C10), 50.4 (C7). Rf(CH2CI2+ TEA) = 0.25. LC- MS (ESI; LRMS; tR= 0.29 min) m / z calculated for [M+H]+: 159.0, found: 159.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 181.0160, found: 181.0161.W,1 -Dimethyl-1 H-tetrazole-5-amine (11)

[0099] 5-Amino-1 -methyltetrazole (500 mg, 5.05 mmol, 1.00 eq.) was dissolved in MeOH (10 mL). Para-formaldehyde (227 mg, 7.57 mmol, 1.5 eq.) and NaOMe (273 mg, 5.05 mmol, 1.00eq.) were added to the solution. The reaction mixture was stirred for 1 hour under reflux, cooled, NaBH4(572 mg, 15.14 mmol, 3.00 eq.) was added and the reaction was stirred again for 2 hours under reflux. The reaction was terminated by adding water, the mixture was taken up in EtOAc and concentrated under reduced pressure. The organic phase was washed with a saturated NaCI solution, dried over Na2SO4, filtered and dried under reduced pressure. The residue was purified by column chromatography (CH2CI2 / 7N NH3in MeOH, 0-5%). The product (434 mg, 3.84 mmol, 76%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 6.79 - 6.75 (bs, 1H), 3.68 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H).13C-NMR (101 MHz, DMSO-d6) 5 = 156.5, 31.4, 29.9. Rf(CH2CI2+ 5% MeOH) = 0.18. LC-MS (ESI; LRMS; tR= 0.26 min) m / z calculated for [M+H]+: 114.1 , found: 114.0. HR-MS (ESI; LOT) m / z calculated for [M+Naf : 136.0599, found: 136.0599((1-Methyl-1H-tetrazol-5-yl)methyl)triphenylphosphoniumchloride (12)

[0100] 1-Methyl-5-(chloromethyl)-1H-tetrazole (250 mg, 1.89 mmol) and PPh3(495 mg, 1.89 mmol) were dissolved in PhMe (2.8 mL) and stirred for 17 hours at 90°C. The reaction mixture was cooled and the precipitate was filtered and washed with PhMe. The product (700 mg, 1.77 mmol, 94%) was obtained as a grayish solid.1H-NMR (400 MHz, CDCI3) 6 = 8.02 - 7.90 (m, 6H), 7.83 - 7.73 (m, 3H), 7.71 - 7.60 (m, 6H),6.34 (d, J 14.8 Hz, 2H), 4.22 (s, 3H). Rr(CH2CI2+ TEA) 0.20. LC-MS (ESI; LRMS; tR0.86 min) m / z calculated for [M-CI]+: 359.1 , found: 359.3Cyclobutylisothiocyanate (13)

[0101] Cyclobutylamine (416 mg, 5.85 mmol, 1.00 eq.), dissolved in THF (11 mL), was cooled to 0°C. Thiophosgene (0.47 mL, 6.14 mmol, 1.05 eq.) was carefully added and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was taken up in saturated Na2CO3solution and extracted with EtOAc. The solvent was removed underreduced pressure and the product (483 mg) was obtained as a light brown liquid. It was used without further purification.5-Mercapto-1 -cyclobutyltetrazole (14)

[0102] NaN3(133 mg, 2.04 mmol, 1.05 eq.) was dissolved in water (4.5 mL) and stirred under reflux. 13 (220 mg, 1.94 mmol, 1.00 eq.) was dissolved in i-PrOH (1 mL) and added dropwise to the refluxing solution. The reaction mixture was stirred overnight under reflux and then cooled in an ice bath. Cone. HCI (0.8 mL) was added. The precipitating solid was filtered off, washed with water and dried under reduced pressure. The product was obtained as a cream-colored crystalline solid (68 mg, 0.44 mmol, 17% over two steps).1H-NMR (400 MHz, DMSO-d6) 5 = 5.07 (p, 1H), 2.58 - 2.35 (m, 4H), 1.94 - 1.84 (m, 2H).13C- NMR (101 MHz, DMSO-d6) S = 163.1, 50.1, 28.8, 14.6. GC-MS: m / z calculated: 156.0470, found 156.0471W-(2-(5-thioxo-4,5-dihydro-1 H-tetrazol-1 -yl)ethyl)acetamide (105)

[0103] Methyl (2-acetamidoethyl)dithiocarbamate (1000 mg, 5.21 mmol, 1.00 eq) was dissolved in dioxane (3 mL). NaN3(443 mg, 6.82 mmol, 1.31 eq) was dissolved in water (2.5 mL) and added to the first solution, the reaction was then refluxed for 4 hours. The organic solvent was removed under reduced pressure and the aqueous phase was washed with diethyl ether. It was then acidified to pH 1 by addition of 1M HCI and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%) and the product obtained as a white solid (120 mg, 0.64 mmol, 12 %).1H NMR (400 MHz, DMSO) 58.00 (t, J = 6.1 Hz, 1H), 4.31 - 4.16 (m, 2H), 3.52 - 3.42 (m, 2H), 1.74 (s, 3H). MS m / z calculated for [M+H]+: 188.05 , found: 188.05 .N-(3-(5-thioxo-4,5-dihydro-1 H-tetrazol-1 -yl)propyl)acetamide (106)

[0104] Methyl (3-acetamidpropyl)dithiocarbamate (1000 mg, 4.85 mmol, 1.00 eq) was dissolved in dioxane (3 mL). NaN3(413 mg, 6.36 mmol, 1.31 eq) was dissolved in water (2.5 mL) and added to the first solution, the reaction was then refluxed for 4 hours. The organic solvent was removed under reduced pressure and the aqueous phase was washed with diethyl ether. It was then acidified to pH 1 by addition of 1M HCI and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%) and the product obtained as a white solid (722 mg, 3.59 mmol, 74 %).1H NMR (400 MHz, DMSO) 5 7.92 (s, 1H), 4.21 (t, J = 7.2 Hz, 2H), 3.07 (q, J = 6.7 Hz, 2H), 1.98 - 1.86 (m, 2H), 1.79 (s, 3H). MS m / z calculated for [M+H]+: 202.25 , found: 202.08.N-(4-(5-thioxo-4,5-dihydro-1 H-tetrazol-1 -yl)butyl)acetamide (107)(00105] Methyl (4-acetamidebutyl)dithiocarbamate (1000 mg, 4.85 mmol, 1.00 eq) was dissolved in dioxane (3 mL). NaN3(386 mg, 5.95 mmol, 1.31 eq) was dissolved in water (2.5 mL) and added to the first solution, the reaction was then refluxed for 4 hours. The organic solvent was removed under reduced pressure and the aqueous phase was washed with diethyl ether. It was then acidified to pH 1 by addition of 1 M HCI and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%) and obtained as a white solid (624 mg, 2.91 mmol, 64 %).1H NMR (400 MHz, DMSO) 5 7.84 (s, 1H), 4.21 (t, J = 7.0 Hz, 2H), 3.21 - 2.90 (m, 2H), 1.77 (s, 3H), 1.38 (t, J = 7.6 Hz, 2H). MS m / z calculated for [M+H]+: 216.08 , found: 216.06.1 -(3-aminopropyl)-1 ,4-dihydro-5H-tetrazole-5-thione (108)

[0106] 106 (140 mg, 0.70 mmol) was dissolved in 6N HCI (1.8 mL) and refluxed for 75 min. After neutralization the aqueous phase was lyophilized. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%) and obtained as a white solid (70 mg, 0.44 mmol, 63 %).1H NMR (400 MHz, DMSO) 54.31 (t, J = 6.9 Hz, 2H), 2.86 (q, J = 7.1 Hz, 2H), 2.11 (p, J = 7.1 Hz, 2H). MS m / z calculated for [M+H]+: 160.06 , found: 160.04.1 -(4-aminobutyl)-1 ,4-dlhydro-5H-tetrazole-5-thion (109)

[0107] 107 (178 mg, 0.83 mmol) was dissolved in 6N HCI (2.2 mL) and refluxed for 75 min. After neutralization the aqueous phase was lyophilized. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%) obtained as a white solid (78 mg, 0.45 mmol, 54 %).1H NMR (400 MHz, DMSO) 5 7.84 (s, 1H), 4.21 (t, J = 7.0 Hz, 2H), 3.21 - 2.90 (m, 2H), 1.77 (s, 3H), 1.38 (t, J = 7.6 Hz, 2H). MS m / z calculated for [M+H]+: 174.07, found: 174.06.2.3 Synthesis of 2,3-Dichloroquinoxalines2,3,4>5-Tetrafluoro-6-nitrobenzeneamine (15)

[0108] Pentafluoronitrobenzene (2.00 g, 9.39 mmol) was dissolved in Et2O (100 mL). Gaseous ammonia was slowly introduced into the mixture for 90 min, then the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (PE / EtOAc 20%). The product (1136 mg, 5.41 mmol, 58%) was obtained as a yellow solid.1H-NMR (400 MHz, CDCI3) 6 = 5.79 (s, 2H). Rf(PE / EtOAc 5:1) = 0.27.Tetrafluoro-1,2-diaminobenzene (16)

[0109] SnCI2(7.00 g, 36.95 mmol, 9.7 eq.) was dissolved in a mixture of cone. HCI (7.6 mL) and EtOH (5.8 mL) and heated to reflux. 15 (800 mg, 3.81 mmol, 1.0 eq.) was carefully added and the mixture was further refluxed for 30 min. The reaction mixture was cooled, water (12 mL) was added and the mixture was neutralized with NaHCO3. The mixture was filtered and the residue was washed with CH2CI2. The filtrate was extracted with CH2CI2, filtered again and washed with a saturated NaHCO3solution. The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The product (579 mg, 3.22 mmol, 84%) was obtained.1H-NMR (400 MHz, CDCI3) 6 = = 3.41 (s, 4H). Rf(CH2CI2) = 0.33. LC-MS (ESI; LRMS; tR= 1.01 min) m / z calculated for [M+H]+: 181.0, found: 181.3.2,3-Dichloro-5,6,7,8-tetrafluoroquinoxaline (17)

[0110] The synthesis of 17 was carried out starting from 16 (100 mg, 0.56 mmol) according to general procedure la. The product (82 mg, 0.35 mmol, 63%) was obtained as a white solid.13C-NMR (101 MHz, CDCI3) 5 = 147.9, 143.5 (q, J = 11.4 Hz), 142.4 - 142.1 (m), 141.1 - 140.6 (m), 139.8 - 139.5 (m), 127.7 - 127.4 (m). Rf(PE / EtOAc 20:1) = 0.40. GC-MS: tR: 9.84 min; m / z calculated: 269.9375, found: 269.9375.2,3-Dichloro-5-fluoroquinoxaline (18)

[0111] The synthesis of 18 was carried out starting from 2,3-diaminofluorobenzene (500 mg, 3.96 mmol) according to general procedure la. The product (481 mg, 2.22 mmol, 56%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = 7.86 - 7.81 (m, 1H), 7.80 - 7.72 (m, 1H), 7.54 - 7.47 (m, 1H).13C-NMR (101 MHz, CDCI3) 5 = 156.3 (d, J = 263.3 Hz), 146.8 (d, J = 1.1 Hz), 146.0 (d, J = 2.2 Hz), 141.5 (d), 131.1 (d, J = 8.2 Hz), 131.1 (d, J = 12.5 Hz), 124.1 (d, J = 4.7 Hz), 115.7 (d, J = 17.9 Hz). Rf(PE / EtOAc 20:1) = 0.25. GC-NIS: tR: 9.84 min; calculated: 215.9657, found 215.9653.2,3-Dichloro-6-fluoroquinoxaline (19)

[0112] The synthesis of 19 was carried out starting from 3,4-diaminofluorobenzene (500 mg, 3.96 mmol) a according to general procedure la. The product (245 mg, 1.13 mmol, 29%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = 8.03 (ddd, J = 9.2, 5.5, 0.5 Hz, 1H), 7.65 (ddd, J = 8.7, 2.8, 0.5 Hz, 1H), 7.57 (ddd, J = 9.2, 8.0, 2.8 Hz, 1H).13C-NMR (101 MHz, CDCI3) 6 = 163.5 (d, J = 254.9 Hz), 146.8, 144.9 (d, J = 3.7 Hz), 141.5 (d, J = 13.5 Hz), 137.8 (d, J = 1.4 Hz), 130.4 (d, J = 10.2 Hz), 121.6 (d, J = 25.9 Hz), 112.4 (d, J = 22.6 Hz). Rf(PE / EtOAc 20:1) = 0.33. GC-MS: tR: 9.42 min; calculated: 215.9657, found: 215.9660.2,3-Oichloro-6,7*difluoroquinoxaline (20)

[0113] The synthesis of 20 was carried out starting from 4,5-diamino-1 ,2- difluorobenzene (500 mg, 3.47 mmol) according to general procedure la. The product (166 mg, 0.71 mmol, 20%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = = 7.79 (t, J=8.9, 2H).13C-NMR (101 MHz, CDCI3) 5 = 153.2 (dd, J = 261.3, 17.6 Hz), 146.2, 138.0 (t, J = 6.4 Hz), 115.0 - 114.1 (m). Rr(PE / EtOAc 20:1) = 0.40. LC-MS (ESI; LRMS; tR= 1.32 min) m / z calculated for [M+H]+: 235.0 / 237.0, not found. GC-MS: tR: 9.18 min; calculated: 233.9563, found: 233.9570.2,3-Dichloro-6,7-difluoroquinoxaline (21 )

[0114] The synthesis of 21 was carried out starting from 4,5-diamino-1 ,3- difluorobenzene (500 mg, 3.47 mmol) according to general procedure la. The product (601 mg, 2.56 mmol, 74%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = 7.51 (ddd, J = 8.5, 2.6, 1.7 Hz, 1H), 7.34 (ddd, J = 9.4, 8.7, 2.7 Hz, 1H).13C-NMR (101 MHz, CDCI3) S = 162.9 (dd, J = 255.4, 12.0 Hz), 157.0 (dd, J = 266.4, 14.6 Hz), 148.3, 145.5 (dd, J = 3.7, 2.2 Hz), 141.7 (dd, J = 15.1, 1.9 Hz), 128.6 (dd, J = 12.5, 2.3 Hz), 108.7 (dd, J = 22.9, 5.2 Hz), 107.4 (dd, J = 29.6, 21.7 Hz). Rf(PE / EtOAc 20:1) = 0.33. GC-MS: tR: 9.30 min; calculated: 233.9563, found: 233.9562.2,3-Dichloro-6,7-difluoroquinoxaline (22)

[0115] The synthesis of 22 was carried out starting from 3,4-diamino-1 ,2- difluorobenzene (500 mg, 3.47 mmol) according to general procedure la. The product (507 mg, 2.16 mmol, 62%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = 7.89 - 7.78 (m, 1H), 7.77 - 7.62 (m, 1H).13C-NMR (101 MHz, CDCI3) 6 = 150.3 (dd, J = 255.1, 10.3 Hz), 147.2 (d, J = 2.5 Hz), 146.0 (d, J = 3.7 Hz), 143.3 (dd, J = 264.5, 13.5 Hz), 137.5, 132.1 (dd, J = 9.2, 4.8 Hz), 124.3 (dd, J = 8.0, 5.1 Hz), 121.7 (d, J = 21.3 Hz). Rf(PE) = 0.28. GC-MS: tR: 9.63 min; calculated: 233.9563, found: 233.95612,3,5-trichloroquinoxaline (23)

[0116] The synthesis of 23 was carried out starting from 3-chlorophenyl-1 ,2-diamine (1000 mg, 7.01 mmol) based on general procedure la. In this case, 15 mL PhMe and 5 mL DMF were used. The product (950 mg, 4.07 mmol, 58%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = = 8.07 - 8.00 (m, 1H), 7.97 (d, J=8.9, 1H), 7.75 (dd, J=8.9, 2.3, 1H). Rf(PE) = 0.20.Tetradeutero-1 ,2-benzenediamine (24)

[0117] 1 ,2-Benzenediamine (400 mg, 3.70 mmol) and Pt / C (10%, 80 mg) were suspended in a Schlenk flask in D20 (17 mL) and stirred in a closed system for 24 hours at 80°C under a hydrogen atmosphere. The mixture was filtered over Celite and it was washed several times with EtOAc. The phases were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with a saturated NaCI solution, driedover Na2SO4, and filtered. By removing the solvent under reduced pressure, the product (264 mg, 2.35 mmol, 64%) was obtained as a brown solid.1H-NMR (400 MHz, DMSOd 6 = 6.49 (s, 0.06H), 6.36 (s, 0.06H), 4.37 (bs, 4H). Rf(PE / EtOAc 1 :1) = 0.17. LC-MS (ESI; LRMS; tR= 0.17 min) m / z calculated for [M+Hf: 113.1 , found: 113.1.2,3-Dichloro-5,6,7,8-tetradeuteroquinoxaline (25)

[0118] The synthesis of 25 was carried out starting from 24 (100 mg, 0.90 mmol) according to general procedure lb. The product (104 mg, 0.51 mmol, 57%) was obtained as a white solid.13C-NMR (101 MHz, CDCI3) 6 = 145.5, 140.6, 131.2 - 130.5 (m), 128.3 - 127.6 (m). Rf(PE / EtOAc 20:1) = 0.30. GC-MS: tR: 9.72 min; calculated: 202.0003, found: 202.0001.Tetradeutero-1 ,2-benzenediamine (26)

[0119] 3-fluoro-1 ,2-diaminobenzene (500 mg, 3.96 mmol) and Pt / C (10%, 100 mg) were suspended in D20 (17 mL) in a Schlenk flask and stirred in a closed system for 24 hours at 80°C in a hydrogen atmosphere. The mixture was filtered over Celite and washed several times with EtOAc. The phases were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with a saturated NaCI solution, dried over Na2SO4, and filtered. By removing the solvent under reduced pressure, the product (371 mg, 2.87 mmol, 72%) was obtained as a brown solid.1H-NMR (400 MHz, DMSO-d6) 6 = 6.45 - 6.03 (m, 0.07H), 4.76 (s, 2.00H), 4.32 (s, 2.00H).13C- NMR (101 MHz, DMSO-d6) <5 = 151.6 (d, J = 231.7 Hz), 137.4 (d, J = 6.7 Hz), 122.1 (d, J = 14.9 Hz), 117.4 - 114.3 (m), 110.8 - 108.8 (m), 104.2 - 101.4 (m). Rr(PE / EtOAc 1 :1) = 0.40. LC-MS (ESI; LRMS; tR= 0.16 min) m / z calculated for [M+H]+: 130.1 , found: 130.1.2,3-Dichloro-5,6,7,8-tetradeuteroquinoxaline (27)

[0120] The synthesis of 27 was carried out starting from 26 (125 mg, 0.97 mmol) according to general procedure lb. The product (186 mg, 0.85 mmol, 87%) was obtained as a white solid.13C-NMR (101 MHz, CDCI3) 5 = 156.3 (d, J = 263.2 Hz), 146.8 (d, J = 1.0 Hz), 146.0 (d, J = 2.1 Hz), 141.4, 131.1 (d, J = 12.4 Hz), 131.0 - 130.2 (m), 124.1 - 123.2 (m), 115.8 - 114.9 (m). Rf(PE / EtOAc 20:1) = 0.28. GC-MS: tR: 9.84 min; calculated: 218.9846, found: 218.9841.2,3>DichIoro-6-methyl-7-fluorquinoxaline (28)

[0121] The synthesis of 28 was carried out starting from 4-fluoro-5-methylphenyl-1 ,2- diamine (250 mg, 1.78 mmol) according to general procedure lb. The product (220 mg, 0.95 mmol, 53%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = 7.84 (dd, J = 7.6, 1.1 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 2.52 (dd, J = 2.2, 1.1 Hz, 3H).13C-NMR (101 MHz, CDCI3) 6 = 162.9 (d, J = 255.3 Hz), 145.7, 144.7 (d, J = 3.5 Hz), 140.4 (d, J = 13.6 Hz), 138.0 (d, J = 1.4 Hz), 132.6 (d, J = 21.5 Hz), 129.8 (d, J = 6.8 Hz), 111.6 (d, J = 23.8 Hz), 15.8 (d, J ~ 3.8 Hz). Rf(PE / EtOAc 20:1) = 0.45. GG-MS: tR: 10.26 min; calculated: 229.9814, found: 229.9819.2,3-Dichloro>6-methoxyquinoxaline (29)

[0122] The synthesis of 29 was carried out starting from 4-methoxyphenyl-1 ,2-diamine (250 mg, 1.81 mmol) according to general procedure lb. The product (194 mg, 0.85 mmol, 47%) was obtained as a light-yellow solid.1H-NMR (400 MHz, CDCI3) S = 7.89 (d, J = 9.2 Hz, 1 H), 7.43 (dd, J = 9.2, 2.8 Hz, 1 H), 7.29 (d, J = 2.8 Hz, 1H), 3.96 (s, 3H).13C-NMR (101 MHz, CDCI3) 6 = 161.9, 145.7, 142.6, 142.5, 136.7, 129.2, 124.5, 106.0, 56.1. Rf(PE / EtOAc 20:1) = 0.33. GC-MS: tR: 11.34 min; calculated: 227.9857, found: 227.98522,3-Dichloro-5-methylquinoxaline (30)

[0123] The synthesis of 30 was carried out starting from 3-methyl-1 ,2-diamine (500 mg, 4.09 mmol) based on the general procedure la. However, in this case, 10 mL of PhMe and 5 mL of DMF were used. The product (672 mg, 3.15 mmol, 77%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 5 = 7.90 - 7.82 (m, 1H), 7.73 - 7.64 (m, 1H), 7.67 - 7.59 (m, 1 H), 2.76 (s, 3H). Rf(PE) = 0.27.2,3-Dichloro-6-methoxy-7-fluoroquinoxaline (31 )

[0124] The synthesis of 31 was carried out starting from 3-methoxy-4-fluorophenyl-1 ,2- diamine (250 mg, 1.60 mmol) according to general procedure lb. The product (228 mg, 0.92 mmol, 58%) was obtained as a lightyellow solid.1H-NMR (400 MHz, CDCI3) 6 = 7.23 (dd, J = 8.8, 2.6 Hz, 1H), 6.92 (dd, J = 10.5, 2.6 Hz, 1H), 4.08 (s, 3H).13C-NMR (101 MHz, CDCI3) 5 = 164.2 (d, J = 253.1 Hz), 156.1 (d, J = 12.9 Hz), 147.5, 143.6 (d, J = 3.7 Hz), 142.2 (d, J = 16.0 Hz), 130.2 (d, J = 1.4 Hz), 103.9 (d, J = 23.3 Hz), 101.1 (d, J = 30.1 Hz), 57.0. Rr(PE / EtOAc 5:1) = 0.38. GC-MS: tR: 11.34 min; calculated: 245.9763, found: 245.9751.2,3-dichloro-6-aminoquinoxaiine (32)

[0125] 2,3-dichloro-6-nitroquinoxaline (500 mg, 2.01 mmol) and tin (II) chloride dihydrate (2330 mg, 10.30 mmol, 5.0 eq.), were refluxed in EtOAc (200 mL) for 1 h. The reaction mixture was cooled and washed with aqueous NaOH (1N). The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the solvent removed under reduced pressure. The product (363 mg, 1.71 mmol, 83%) was obtained as an orange solid.1H-NMR (600 MHz, DMSO-d6) 6 = 10.58 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 9.1, 0.5 Hz, 1H), 7.93 (dd, J = 9.1 , 2.2 Hz, 1 H), 2.15 (s, 3H). Rf(CH2CI2+ 1% MeOH) = 0.50. LC-MS (ESI; LRMS; tR= 1.07 min) m / z calculated for [M+Hf: 214.0, found: 214.0. / V-(2,3-Dichloroqulnoxaline-6-yl)acetamlde (33)

[0126] 32 (100 mg, 0.47 mmol), AcO2(1 mL), pyridine (1 mL) and CH2CI2(1 mL) were stirred for 1 hour at 0°C. Subsequently, the mixture was taken up in water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The product (91 mg, 0.36 mmol, 76%) was obtained as a yellow solid.1H-NMR (600 MHz, DMSO-d6) 6 = 10.58 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 9.1 , 0.5 Hz, 1H), 7.93 (dd, 9.1, 2.2 Hz, 1H), 2.15 (s, 3H).13C-NMR (151 MHz, DMSO-d6) 5 = 169.4, 144.8, 142.3, 141.8, 141.1 , 136.6, 128.4, 124.7, 113.6, 24.2. Rf(PE / EtOAc 1:1) = 0.17. LC-MS (ESI; LRMS; tR= 1.05 min) m / z calculated for [M+H]+: 256.0 / 258.0, found: 256.0 / 258.0. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 277.9864, found: 277.9872.2,3-Dichloro-6-(trifluoromethyl)quinoxaline (103)

[0127] The synthesis of 103 was carried out starting from 4-methyltrifluoro-1 ,2-diamine (500 mg, 4.09 mmol) based on the general procedure la. In this case, however, 8 mL PhMe and 2.5 mL DMF were used. The product (398 mg, 1.50 mmol, 53 %) was obtained as a white solid.1H NMR (400 MHz, CDCI3) 58.42 - 8.33 (m, 1H), 8.24 - 8.15 (m, 1H), 8.06 - 7.96 (m, 1 H). Rf(PE / EE 20:1) 0.232,3-Dichloro-5-(trifluoromethyl)quinoxaline (104)

[0128] The synthesis of 104 carried out starting from 3-methyltrifluoro-1 ,2-diamine (500 mg, 4.09 mmol) based on the general procedure la. In this case, however, 8 mL PhMe and 2.5 mL DMF were used. The product (482 mg, 1.81 mmol, 64 %) was obtained as a white solid.1H NMR (400 MHz, CDCI3) 58.26 (ddd, J = 8.5, 1.4, 0.6 Hz, 1H), 8.17 (dt, J = 7.4, 0.7 Hz, 1 H), 7.90 (ddd, J = 8.3, 7.5, 0.8 Hz, 1H). Rf(PE / EE 20:1) 0.242.4 Synthesis of TRAF2-lnhibitors2,3-Bis((1*methyltetrazole“5-yl)thio)quinoxaline (34)

[0129] The synthesis of 34 was carried out by the reaction of 2,3-dichloroquinoxaline (300 mg, 1.52 mmol) and 1 (442 mg, 3.81 mmol) in DMF (10 mL) over 16 hours according togeneral procedure Ila. In this case, the residue was additionally washed with DMSO. The product (404 mg, 1.13 mmol, 74%) was obtained as a beige solid.1H-NMR (500 MHz, DMSO-d6) 5 = 7.80 - 7.75 (m, 4H), 4.13 (s, 6H).13C-NMR (126 MHz,DMSO-d6) <5 = 148.8, 147.3, 140.1, 131.2, 128.0, 34.7. Rf(CH2CI2+ 10% MeOH) = 0.40. LC-MS(ESI; LRMS; tR= 1.16 min) m / z calculated for [M+Na]+: 381.0, found: 381.5. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 381.0429, found: 381.04302,3-Bis((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (35)

[0130] The synthesis of 35 was carried out by the reaction of 2,3-dichloroquinoxaline (470 mg, 2.39 mmol) and 2 (848 mg, 5.96 mmol) in DMF (10 mL) over 12 hours at 80°C according to general procedure lie. In this case, the crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 5-95%). The product (280 mg, 0.78 mmol, 33%) was obtained as a beige solid.1H-NMR (500 MHz, DMSO-d6) 5 = 7.84 - 7.82 (m, 4H), 3.85 - 3.77 (m, 2H), 1.30 - 1.28 (m, 4H), 1.16 - 1.13 (m, 4H).13C-NMR (126 MHz, DMSO-d6) S = 149.0, 148.8, 140.1, 131.4, 127.9, 29.1, 6.6. Rf(CH2CI2+ 10% MeOH) = 0.50. LC-MS (ESI; LRMS; tR= 1.29 min) m / z calculated for [M+Na]+: 433.1, found: 433.5. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 433.0742, found: 433.0745.2,3-Bis((1-ethyltetrazol-5-yl)thio)quinoxaline (36)

[0131] The synthesis of 36 was carried out by the reaction of 2,3-dichloroquinoxaline (50 mg, 0.25 mmol) and 3 (83 mg, 0.63 mmol) in DMF (10 mL) over 16 hours according to general procedure lib. The product (29 mg, 0.08 mmol, 30%) was obtained as a yellow solid.1H-NMR (400 MHz, CDCI3) 6 = 7.75 - 7.65 (m, 4H), 4.51 (q, J = 7.3 Hz, 4H), 1.65 (t, J = 7.3 Hz, 6H).13C-NMR (101 MHz, CDCI3) 5 = 148.1, 146.1, 141.0, 131.5, 128.4, 44.0, 15.0. Rf(CH2CI2) = 0.15. LC-MS (ESI; LRMS; tR= 1.19 min) m / z calculated for [M+Na]+: 409.1 , found: 409.2. FIRMS (ESI; LCT) m / z calculated for [M+Na]+: 409.0742, found: 409.0746.2,3-Bis((1-benzyltetrazol-5-yl)thio)quinoxaline (37)

[0132] The synthesis of 37 was carried out by the reaction of 2,3-dichloroquinoxaline(40 mg, 0.20 mmol) and 5 (98 mg, 0.51 mmol) in DMF (5 mL) over 16 hours according to general procedure lib. The product (64 mg, 0.13 mmol, 62%) was obtained as a yellowish solid.1H-NMR (400 MHz, CDCI3) 6 = 7.62 - 7.54 (m, 2H), 7.52 - 7.44 (m, 2H), 7.29 - 7.20 (m, 4H), 7.16 - 7.07 (m, 4H), 7.10 - 7.01 (m, 2H), 5.63 (s, 4H).13C-NMR (101 MHz, CDCI3) 6 = 147.5, 146.7, 140.7, 132.5, 131.0, 128.9, 128.8, 128.3, 128.3, 52.3. Rf(CH2CI2) = 0.25. LC-MS (ESI; LRMS; tR= 1.34 min) m / z calculated for [M+Naf: 533.1, found: 533.2. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 533.1055, found: 533.1038.2,3-Bis((1-(4-methoxybenzyl)tetrazol-5-yl)thio)quinoxaline (38)

[0133] The synthesis of 38 was carried out by the reaction of 2,3-dichloroquinoxaline (100 mg, 0.51 mmol) and 6 (282 mg, 1.27 mmol) in DMF (5 mL) over 16 hours according to general procedure lib. The product (283 mg, 0.50 mmol, 98%) was obtained as a yellow solid.1H-NMR (400 MHz, CDCI3) 5 = 7.64 - 7.56 (m, 2H), 7.52 - 7.44 (m, 2H), 7.17 (d, J = 8.7 Hz, 4H), 6.57 (d, J = 8.7 Hz, 4H), 5.57 (s, 4H), 3.57 (s, 6H).13C-NMR (101 MHz, CDCI3) 6 = 159.9, 147.5, 146.3, 140.7, 130.9, 129.9, 128.3, 124.3, 114.3, 55.2, 52.1. Rf(CH2CI2) = 0.20. LC-MS (ESI; LRMS; tR= 1.32 min) m / z calculated for [M+Na]+: 593.1 , calculated: 593.2. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 593.1266, found: 593.1271.2,3-Bis((1-(4-methoxybenzyl)tetrazol-5-yl)thio)quinoxaline (39)

[0134] The synthesis of 39 was carried out by the reaction of 2,3-dichloroquinoxaline (50 mg, 0.25 mmol) and 4 (100 mg, 0.63 mmol) in DMF (5 mL) over 16 hours according to general procedure lib. The product (55 mg, 0.12 mmol, 49%) was obtained as a yellowish solid.1H-NMR (400 MHz, CDCI3) S = 7.82 - 7.56 (m, 4H), 4.45 (t, J = 7.2 Hz, 4H), 2.10 - 1.90 (m, 4H), 1.51 - 1.28 (m, 4H), 0.92 (t, J = 7.4 Hz, 6H).13C-NMR (101 MHz, CDCI3) 6 = 148.2, 146.5, 141.1 , 131.4, 128.4, 48.5, 31.5, 19.8, 13.5. Rf(CH2CI2) = 0.20. LC-MS (ESI; LRMS; tR= 1.38 min) m / z calculated for [M+H]*: 443.2, found: 443.2. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 465.1368, found: 465.1366.2,3-Bis((1-(tert-butyl)tetrazol-5-yl)thio)quinoxaline (40)

[0135] The synthesis of 40 was carried out by the reaction of 2,3-dichloroquinoxaline (25 mg, 0.13 mmol) and 5-mercapto-1-(tert-butyl)tetrazole (50 mg, 0.32 mmol) in DMF (3 ml) for 16 hours according to general procedure lib. The product (21 mg, 0.05 mmol, 37%) was obtained as a yellowish solid.1H-NMR (400 MHz, CDCI3) 6 = 7.84 - 7.76 (m, 2H), 7.75 - 7.65 (m, 2H), 1.82 (s, 18H).13C- NMR (101 MHz, CDCI3) 5 = 149.3, 146.1 , 141.4, 131.5, 128.7, 63.2, 29.8. Rf(CH2CI2) = 0.25. LC-MS (ESI; LRMS; tR= 1.28 min) m / z calculated for [M+Na]+: 465.1 , found: 465.2. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 465.1368, calculated: 465.1360.6-Chloro-2,3-bis((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (41)

[0136] The synthesis of 41 was carried out by the reaction of 2,3,6-trichloroquinoxaline (50 mg, 0.19 mmol) and 2 (55 mg, 0.39 mmol) in DMF (1 mL) over 8 hours based on general procedure lib. In this case, only 2.1 eq. tetrazole were used. The product (56 mg, 0.18 mmol, 97%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.96 (d, J = 2.2 Hz, 1 H), 7.91 - 7.80 (m, 2H), 3.82 (tt, J = 7.4, 3.8 Hz, 2H), 1.33 - 1.25 (m, 4H), 1.18 - 1.10 (m, 4H).13C-NMR (101 MHz, DMSO-d6) <5 = 150.6, 149.1 , 148.9, 148.6, 140.5, 138.9, 135.7, 131.8, 129.8, 126.9, 29.3, 29.3, 6.8, 6.8. Rr(CH2CI2+ 2% MeOH) = 0.33. LC-MS (ESI; LRMS; tR= 1.29 min) m / z calculated for [M+Na]+: 467.0 / 469.0, found: 467.1 / 469.1. HR-MS (ESI; LCT) m / z calculated for [M+N<: 467.0352, found: 467.0345.6-Chloro-2,3-bis((1 -methyltetrazol-5-yl)thio)quinoxaline (42)

[0137] The synthesis of 42 was carried out by the reaction of 2,3,6-trichloroquinoxaline (50 mg, 0.19 mmol) and 1 (45 mg, 0.39 mmol) in DMF (1 mL) over 8 hours based on general procedure lib. In this case, only 2.1 eq. tetrazole were used and the product was purified by normal phase column chromatography. The product (28 mg, 0.09 mmol, 48%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.94 - 7.86 (m, 1 H), 7.82 - 7.72 (m, 2H), 4.14 (s, 6H).13C- NMR (101 MHz, DMSO-d6) 6 = 150.4, 149.1 , 147.0, 146.8, 140.4, 138.7, 135.4, 131.5, 129.7, 126.8, 34.8, 34.7. Rf(CH2CI2+ 2% MeOH) = 0.40. LC-MS (ESI; LRMS; tR= 1.18 min) m / z calculated for [M+Na]+: 415.0 / 417.0, found: 415.1 / 417.0. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 415.0039, found: 415.0036.5-Fluoro-2,3-bis((1 -methyltetrazol-5-yl)thio)quinoxaline (43)

[0138] The synthesis of 43 was carried out by the reaction of 18 (25 mg, 0.13 mmol) and 1 (33 mg, 0.29 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (30 mg, 0.08 mmol, 69%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.80 - 7.72 (m, 1 H), 7.67 - 7.61 (m, 1H), 7.61 - 7.57 (m, 1H), 4.14 (s, 3H), 4.13 (s, 3H).13C-NMR (101 MHz, DMSO-d6) δ = 155.4 (d, J = 258.8 Hz),123.9 (d, J = 4.2 Hz), 115.3 (d, J = 17.8 Hz), 34.7, 34.7. Rf(PE / EtOAc 1:1) = 0.15. LC-MS (ESI;LRMS; tR= 1.06 min) m / z calculated for [M+H]+: 377.1, found: 377.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 399.0335, found: 399,0316.6-Fluoro-2,3-bis((1 -methyltetrazol-5-yl)thio)quinoxaline (44)

[0139] The synthesis of 44 was carried out by the reaction of 19 (20 mg, 0.09 mmol) and1 (27 mg, 0.23 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (24 mg, 0.06 mmol, 69%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.92 - 7.84 (m, 1H), 7.76 - 7.66 (m, 1H), 7.67 - 7.59 (m,1H), 4.14 (s, 3H), 4.13 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 5 = 162.5 (d, J = 251.5 Hz),150.6, 147.8 (d, J = 3.4 Hz), 147.3, 146.9, 141.0 (d, J = 13.8 Hz), 137.5 (d, J = 1.1 Hz), 130.6 (d, J = 10.5 Hz), 120.9 (d, J = 26.0 Hz), 112.0 (d, J = 22.6 Hz), 34.7, 34.7. Rf(PE / EtOAc 1 :1) = 0.15. LC-MS (ESI; LRMS; tR= 1.13 min) m / z calculated for [M+Hf: 377.1, found: 377.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 399.0335, found: 399.0337.

[0140] The synthesis of 45 was carried out by the reaction of 20 (25 mg, 0.11 mmol) and 1 (31 mg, 0.27 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie.The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (29 mg, 0.08 mmol, 72%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-d6) δ = 7.96 (t, J = 9.5 Hz, 2H), 4.14 (s, 6H).13C-NMR (101 MHz, DMSO-d6) 5 = 151.7 (dd, J = 256.6, 17.8 Hz), 149.4, 147.0, 137.7, 114.6 (dd, J = 12.8, 7.2 Hz), 34.7. Rf(PE / EtOAc 1:1) = 0.15. LC-MS (ESI; LRMS; tR= 1.15 min) m / z calculated for [M+H]+: 395.0, found: 395.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 417.0241 , found: 417.0222.5,7-Difluoro-2,3-bjs((1-methyltetrazol-5-yl)thio)quinoxaline (46)

[0141] The synthesis of 46 was carried out by the reaction of 21 (20 mg, 0.09 mmol) and1 (25 mg, 0.21 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (23 mg, 0.06 mmol, 68%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-d6) δ = 7.82 (ddd, J = 10.2, 9.3, 2.7 Hz, 1 H), 7.55 - 7.48 (m, 1H), 4.15 (s, 3H), 4.13 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 5 = 161.7 (dd, J = 250.9, 12.6 Hz), 156.5 (dd, J = 260.6, 14.8 Hz), 151.9, 148.4, 146.9, 146.5, 141.0 (d, J = 15.5 Hz), 128.1 (d, J = 12.1 Hz), 109.1 - 108.2 (m), 106.8 (dd, J = 30.5, 22.2 Hz), 34.8, 34.7. Rf(PE / EtOAc 1:1) = 0.18. LC-MS (ESI; LRMS; tR= 1.14 min) m / z calculated for [M+Hf: 395.0, found: 395.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 417.0241 , found: 417.0229.5,6-Difluoro-2,3-bis((1-methyltetrazol-5-yl)thio)quinoxaline (47)

[0142] The synthesis of 47 was carried out by the reaction of 22 (20 mg, 0.09 mmol) and 1 (25 mg, 0.21 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (23 mg, 0.06 mmol, 69%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.95 - 7.83 (m, 1H), 7.74 - 7.65 (m, 1H), 4.14 (s, 3H), 4.13 (s, 3H).13C-NMR (101 MHz, DMSO-d6) δ = 150.9 (d, J = 2.3 Hz), 149.1 (dd, J = 250.9, 9.9 Hz), 149.0 (d, J = 3.2 Hz), 146.8, 146.6, 142.2 (dd, J = 259.4, 13.5 Hz), 137.2, 131.2 (dd, J = 9.0, 4.6 Hz), 124.6 (dd, J = 8.3, 4.6 Hz), 120.8 (d, J = 21.3 Hz), 34.7, 34.7. Rf(PE / EtOAc 1:1) = 0.13. LC-MS (ESI; LRMS; tR= 1.13min) m / z calculated for [M+H]+: 395.0, found: 395.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 417.0241, found: 417.0229.5*Fluoro-2,3-bis((1-cyclopropyltetrazol*5-yl)thio]quinoxaline (48)

[0143] The synthesis of 48 was carried out by the reaction of 18 (50 mg, 0.23 mmol) and 2 (82 mg, 0.58 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (59 mg, 0.14 mmol, 60%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 8 = 7.84 - 7.75 (m, 1H), 7.72 - 7.62 (m, 2H), 3.94 - 3.76 (m, 2H), 1.35 - 1.25 (m, 4H), 1.21 - 1.11 (m, 4H).13C-NMR (101 MHz, DMSO-d6) S = 155.4 (d, J = 259.6 Hz), 150.3, 149.4 (d, J = 2.3 Hz), 148.8, 148.7, 141.0, 131.2 (d, J = 8.5 Hz), 130.4 (d, J = 12.3 Hz), 124.0 (d, J = 4,1 Hz), 115.6 (d, J = 17.7 Hz), 29.3, 29.3, 6.8, 6.7. Rr(PE / EtOAc 1:1) = 0.33. LC-MS (ESI; LRMS; tR= 1.23 min) m / z calculated for [M+Hf: 429.1, found: 429.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 451.0648, found: 451.0633.6-fluoro-2,3-bis((1-cyclopropyltetrazol-5-yl)thio)qulnoxaline (49)

[0144] The synthesis of 49 was carried out by the reaction of 19 (50 mg, 0.23 mmol) and 2 (82 mg, 0.58 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (60 mg, 0.06 mmol, 61%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.95 (dd, J = 9.2, 5.7 Hz, 1H), 7.79 - 7.69 (m, 1H), 7.72 - 7.64 (m, 1 H), 3.89 - 3.74 (m, 2H), 1.38 - 1.27 (m, 4H), 1.24 - 1.08 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 5 = 162.8 (d, J = 252.0 Hz), 150.9, 149.3, 148.6, 147.7 (d, J = 3.4 Hz), 141.1 (d, J = 13.9 Hz), 137.6 (d, J = 1.1 Hz), 130.7 (d, J = 10.5 Hz), 121.2 (d, J = 25.8 Hz), 112.1 (d, J = 22.7 Hz), 29.4, 29.2, 6.8, 6.8. Rf(PE / EtOAc 1:1) = 0.38. LC-MS (ESI; LRMS; tR= 1.24 min) m / z calculated for [M+H]+: 429.1, found: 429.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 451.0648, found: 451.0643.6,7-Difluoro-2,3-bis((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (50)

[0145] The synthesis of 50 was carried out by the reaction of 20 (50 mg, 0.21 mmol) and 2 (76 mg, 0.53 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (32 mg, 0.06 mmol, 34%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.02 (t, J = 9.5 Hz, 2H), 3.87 - 3.78 (m, 2H), 1.36 - 1.28 (m, 4H), 1.19 - 1.11 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 5 = 151.9 (dd, J = 257.3, 17.8 Hz), 149.5 (d, J = 1.5 Hz), 148.9, 137.9 (dd, J = 6.5 Hz), 115.1 - 114.3 (m), 29.3, 6.8. R, (PE / EtOAc 1 :1) = 0.40. LC-MS (ESI; LRMS; tR= 1.26 min) m / z calculated for [M+H]+: 447.0, found: 447.0. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 469.0554, found: 469.0549.5,7-Difluoro-2,3-bis((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (51)

[0146] The synthesis of 51 was carried out by the reaction of 21 (25 mg, 0.11 mmol) and 2 (38 mg, 0.27 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure He. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (41 mg, 0.09 mmol, 86%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.91 - 7.81 (m, 1H), 7.60 - 7.53 (m, 1 H), 3.89 - 3.78 (m, 2H), 1.35 - 1.27 (m, 4H), 1.22 - 1.11 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 5 = 162.0 (dd, J = 251.7, 13.0 Hz), 156.3 (dd, J = 261.9, 15.5 Hz), 152.3, 148.9, 148.3, 141.2 (dd, J = 15.6, 2.0 Hz), 128.3 (dd, J = 12.6, 2.1 Hz), 108.6 (dd, J = 23.2, 4.8 Hz), 107.1 (dd, J = 30.4, 22.4 Hz), 29.5, 29.3, 6.8, 6.8. Rf(PE / EtOAc 1:1) = 0.40. LC-MS (ESI; LRMS; tR= 1.25 min) m / z calculated for [M+Hf: 447.0, found: 447.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 469.0554, found: 469.0554.5,6-Difluoro-2,3-bis((1-methyltetrazol-5-yl)thio)quinoxaline (52)

[0147] The synthesis of 52 was carried out by the reaction of 22 (25 mg, 0.11 mmol) and 2 (38 mg, 0.27 mmol) in DMF (3 mL) over 2 hours at 100°C according to general procedure lie. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (37 mg, 0.06 mmol, 78%) was obtained as an orange solid.1H-NMR (400 MHz, DMS0-d6) 5 = 8.00 - 7.88 (m, 1H), 7.80 - 7.72 (m, 1H), 3.88 - 3.79 (m,2H), 1.34 - 1.24 (m, 4H), 1.20 - 1.13 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 6 = 151.3 (d, J2.2 Hz), 149.3 (dd, J = 251.1 , 10.0 Hz), 148.9 (d, J = 3.3 Hz), 148.8, 148.3, 142.3 (dd, J259.6, 13.7 Hz), 137.3, 131.4 (dd, J = 8.8, 4.7 Hz), 124.8 (dd, J = 8.3, 4.6 Hz), 121.2 (d, J = 21.2 Hz), 29.4, 29.3, 6.8, 6.8. Rf(PE / EtOAc 1:1 ) = 0.33. LC-MS (ESI; LRMS; tR= 1.25 min) m / z calculated for [M+H]+: 447.1, found: 447.0. HR-MS (ESI; LCT) m / z calculated for [M+N<:469.0554, found: 469.0551.5,6,7,8-Tetradeutero-2,3-bis((1-methyltetrazol-5-yl)thio)quinoxaline (53)

[0148] The synthesis of 53 was carried out by the reaction of 25 (25 mg, 0.12 mmol) and 1 (36 mg, 0.31 mmol) in DMF (3 mL) over 2 hours at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (PE / EtOAc 0-100%). The product (33 mg, 0.09 mmol, 74%, 97% deuterated) was obtained as a white solid.1H-NMR (500 MHz, DMSO-d6) S = 7.80 - 7.77 (m, 0.13H), 4.13 (s, 6.00H).13C-NMR (126 MHz,DMSO-d6) 5 = 148.8, 147.3, 140.1, 131.1 - 130.5 (m), 127.9 - 127.3 (m), 34.7. Rf(PE / EtOAc1 :1 ) = 0.22. LC-MS (ESI; LRMS; tR= 1.60 min) m / z calculated for [M+H]+: 385.1 , found: 385.2 HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 385.0680, found: 385.0670.6,7,8-Trideutero-5-fluoro-2,3-bis((1-methyltetrazol-5-yl)thio)quinoxallne (54)

[0149] The synthesis of 54 was carried out by the reaction of 27 (25 mg, 0.11 mmol) and 1 (33 mg, 0.28 mmol) in DMF (3 mL) over 4 hours at 80°C according to general procedure lid.The crude product obtained (40 mg) was already relatively clean, but was purified by column chromatography (PE / EtOAc 0-100%).1H-NMR 600 MHz, DMSO-d6) S = 7.77 - 7.73 (m, 0.18H), 7.66 - 7.62 (m, 0.20H), 7.61 - 7.57 (m, 0.16H), 4.14 (s, 3H), 4.13 (s, 3H).13C-NMR (151 MHz, DMSO-d6) 6 = 155.3 (d, J = 258.6 Hz), 150.2, 149.2 (d, J = 1.7 Hz), 146.9, 146.8, 140.8, 130.3 (d, J = 12.4 Hz), 129.6, 123.5, 115.0 (d, J = 17.8 Hz), 34.7, 34.7. R, (PE / EtOAc 1 :1) = 0.15. LC-MS (ESI; LRMS; tR= 1.10 min) m / z calculated for [M+Na]+: 402.1, found: 402.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 402.0523, found: 402.0514.2,2*-((Quinoxaline-2,3-diylbis(sulfanecliyl))bis(tetrazol-5,1-diyl))bis(ethan-1-ol) (55)

[0150] The synthesis of 55 was carried out by the reaction of 2,3-dichloroquinoxaline (50 mg, 0.25 mmol) and 5-mercapto-1-(2-hydroxyethyl)tetrazole (92 mg, 0.63 mmol) in DMF (3 mL) for 4 hours at 80°C based on the general procedure llc. In this case, 2 eq. DIPEA were used. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 5-95%). The product (55 mg, 0.13 mmol, 52%) was obtained as a yellowish-white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.80 (s, 1H), 5.13 (t, J = 5.5 Hz, 1H), 4.55 (t, J = 5.4 Hz, 1H), 3.83 (q, J = 5.4 Hz, 1H).13C-NMR (101 MHz, DMSO-d6) 6 = 149.2, 148.0, 140.2, 131.4, 128.1 , 59.2, 50.7. R, (CH2CI2+ 5% MeOH) = 0.20. LC-MS (ESI; LRMS; tR= 0.86 min) m / z calculated for [M+Na]+: 441.1, found: 441.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 441.0640, found: 441.0638.2,3-Bis((1-cyclobutyltetrazol-5-yl)thio)quinoxaline (56)

[0151] 2,3-Dichloroquinoxaline (25 mg, 0.13 mmol, 1.00 eq.), 14 (49 mg, 0.31 mmol, 2.50 eq.) and DIPEA (0.11 mL, 0.63 mmol, 5.00 eq.) were dissolved in DMF (1 mL) and stirred for 6 hours at 80°C. The mixture was cooled to room temperature and taken up in water. The product was extracted with EtOAc, the combined organic phases were washed with saturated NaCI solution, and then dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (CH2CI2 / MeOH 0-5%). A second column chromatographic purification (H2O / MeCN +0.05% TFA, 1-95%) was required. The product (4 mg, 0.01 mmol, 7%) was obtained as a white solid.1H-NMR (600 MHz, DMSO-d6) 6 = 7.77 (dt, J = 6.5, 3.3 Hz, 2H), 7.70 (dt, J = 6.4, 3.4 Hz, 2H), 5.36 - 5.04 (m, 2H), 2.71 - 2.62 (m, 4H), 2.39 (dtt, J = 9.2, 8.0, 2.6 Hz, 4H), 1.94 - 1.78 (m, 4H).13C-NMR (151 MHz, DMSO-d6) 6 = 148.7, 145.9, 140.0, 131.2, 127.8, 51.7, 30.1 , 14.5. Rr(CH2CI2+ 1% MeOH) = 0.30. LC-MS (ESI; LRMS; tR= 1.67 min) m / z calculated for [M+Naf: 461.1 , found: 461.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 461.1055, found 461.1057.5-Methyl-2,3-bis((1 -methyltetrazol-5-yl)thio)quinoxaline (57)

[0152] 30 (100 mg, 0.47 mmol, 1.00 eq.), 1 (164 mg, 1.41 mmol, 3.00 eq.) and DIPEA(0.41 mL, 2.35 mmol, 5.00 eq.) were dissolved in dry DMF (7 mL) and stirred for 4 hours at 80°C. The mixture was cooled to room temperature and taken up in water. The precipitated solid was filtered off and washed with EtOAc. The solvent of the organic phase of the filtrate was removed under reduced pressure and the solid was taken up in MeOH. The insoluble residue was filtered off and washed with MeOH. Both filter cakes were dried under reduced pressure and the product (166 mg, 0.45 mmol, 95%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.71 - 7.58 (m, 2H), 4.14 (s, 3H), 4.12 (s, 3H), 2.24 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 6 = 148.2, 147.5, 147.2, 140.2, 139.1 , 135.7, 131.1 , 130.8, 125.8, 34.7, 34.5, 15.8. Rf(PE / EtOAc 3:1) = 0.30. LC-MS (ESI; LRMS; tR= 1.36 min) m / z calculated for [M+H]+: 373.1 , found: 373.4. HR-MS (ESI; LCT) m / z calculated for [M+Na]*: 395.0586, found 395.0585.2,3-Bis((1-cyclopropyltetrazol-5-yl)thio)-5-methylquinoxaline (58)

[0153] 30 (100 mg, 0.47 mmol, 1.00 eq.), 2 (200 mg, 1.41 mmol, 3.00 eq.) and DIPEA(0.41 ml_, 2.35 mmol, 5.00 eq.) were dissolved in DMF (7 mL) and stirred for 4 hours at 80°C. The mixture was cooled to room temperature and taken up in water. The product was extracted with EtOAc, the combined organic phases were washed with saturated NaCI solution, and then dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was taken up in DMF and column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (103 mg, 0.24 mmol, 52%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.73 - 7.64 (m, 3H), 3.85 - 3.77 (m, 2H), 2.27 (s, 3H), 1.36 - 1.05 (m, 8H).13C-NMR (101 MHz, DMSO-d6) 5 = 149.5, 148.8, 148.8, 147.3, 140.3, 139.3, 135.9, 131.4, 131.0, 125.9, 29.2, 15.9, 6.8, 6.8. Rf(PE / EtOAc 5:2) = 0.31. LC-MS (ESI; LRMS; tR= 1.36 min) m / z calculated for [M+H]+: 425.1, found: 425.4. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 447.0899, found 447.0902.6-Methyl-2,3-bis((1 -methyltetrazol-5-yl)thio)quinoxaline (59)

[0154] 2,3-Dichloro-6-methylquinoxaline (100 mg, 0.47 mmol, 1.00 eq.), 1 (164 mg, 1.41 mmol, 3.00 eq.), and DIPEA (0.41 mL, 2.35 mmol, 5.00 eq.) were dissolved in dry DMF (7 mL) and stirred for 4 hours at 80°C. The mixture was cooled to room temperature and taken up in water. The precipitated solid was filtered off and washed with EtOAc. The solvent of the organic phase of the filtrate was removed under reduced pressure and the solid was taken up in MeOH. The insoluble residue was filtered off and washed with MeOH. Both filter cakes were dried under reduced pressure and the product (139 mg, 0.37 mmol, 80%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.72 - 7.68 (m, 1H), 7.65 - 7.61 (m, 1H), 7.57 (bs, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 2.48 (s, 3H).13C-NMR (101 MHz, DMSO-d6) <5 = 149.1, 147.7, 147.3, 147.1, 142.1, 140.3, 138.7, 133.2, 127.6, 126.7, 34.7, 34.7, 21.1. Rr(PE / EtOAc 3:1) = 0.30. LC- MS (ESI; LRMS; tR= 1.40 min) m / z calculated for [M+H]+: 373.1, found: 373.4. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 395.0586, found 395.0573.2,3-Bis((1-cyclopropyltetrazol-5-yl)thio)-6-methylquinoxaline (60)

[0155] 2,3-Dichloro-6-methylquinoxaline (100 mg, 0.47 mmol, 1.00 eq.), 2 (200 mg, 1.41 mmol, 3.00 eq.), DIPEA (0.41 mL, 2.35 mmol, 5.00 eq.) were dissolved in DMF (7 mL) and stirred for 4 hours at 80°C. The mixture was cooled to room temperature and taken up in water. The product was extracted with EtOAc, the combined organic phases were washed with saturated NaCI solution, and then dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (PE / EtOAc 0-50%). Asecond column chromatographic purification (H2O / MeCN +0.05% TFA, 1-95%) was required. The product (74 mg, 0.17 mmol, 37%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.80 - 7.73 (m, 1H), 7.71 - 7.63 (m, 1H), 7.63 (s, 1 H), 3.87 - 3.73 (m, 2H), 2.50 (s, 3H), 1.32 - 1.10 (m, 8H).13C-NMR (101 MHz, DMSO-d6) 5 = 149.6, 149.4, 149.1 , 147.1 , 142.4, 140.4, 138.8, 133.5, 127.7, 126.8, 29.2, 29.2, 21.1 , 6.8, 6.7. Rf(PE / EtOAc 5:2) = 0.29. LC-MS (ESI; LRMS; tR= 1.50 min) m / z calculated for [M+Na]+: 425.1, found: 425.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 447.0899, found 447.0889.2,3*Bis(((1-methyltetrazol-5-yl)thio)methyl)quinoxaline (61)

[0156] 2,3-bis(bromomethyl)quinoxaline (100 mg, 0.32 mmol, 1.0 eq.), 1 (92 mg, 0.79 mmol, 2.5 eq.) and DIPEA (0.275 ml, 1.58 mmol, 5.0 eq.) were dissolved in DMF (3 mL) and stirred for 90 min at 50°C. The reaction mixture was cooled, taken up in water and filtered. The residue was purified by column chromatography (CH2CI2 / MeOH 0-50%). The product (31 mg, 0.08 mmol, 25%) was obtained as a beige solid. SO-d6) 5 = 8.06 - 7.97 (m, 2H), 7.91 - 7.81 (m, 2H), 5.14 (s, 4H), 4.02 MHz, DMSO-d6) δ = 153.1 , 149.9, 139.9, 130.6, 128.2, 37.3, 33.8. Rf0.20. LC-MS (ESI; LRMS; tR= 1.00 min) m / z calculated for [M+Naf: 409.1 , found: 409.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 409.0742, found: 409.0745.3-Chloro-IV-(1 -methyltetrazol-5-yl)quinoxalin-2-amine (62)

[0157] 2,3-Dichlorquinoxaline (100 mg, 0.50 mmol, 1.00 eq.), 5-amino-1 -methyltetrazole (75 mg, 0.75 mmol, 1.50 eq.) and K2CO3(139 mg, 1.01 mmol, 2.00 eq.) were suspended in dry DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was taken up in water,volatiles removed under reduced pressure and the resulting crude product was taken up in DMF and purified by 'column chromatograpy (H2O / MeCN +0.05% TFA, 5-95%). The product (75 mg,0.29 mmol, 57%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 5 = 10.37 (s, 1H), 8.24 - 7.37 (m, 4H), 3.92 (s, 3H). Rf(PE / EtOAc 1:1) = 0.22. LC-MS (ESI; LRMS; tR= 1.08 min) m / z calculated for [M+H]+:262.1 / 264.1, found: 262.1 / 264.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 284.0427, found 284.0425.N-(1 -Methyltetrazol-5-yl)-3-((1 -methyltetrazol-5-yl)thio)quinoxalin-2-amine (63)

[0158] 62 (40 mg, 0.15 mmol, 1.00 eq.), 1 (27 mg, 0.23 mmol, 1.50 eq.), and DIPEA(0.13 mL, 0.76 mmol, 5.00 eq.) were dissolved in dry DMF (1 mL) and stirred for 5 hours at 80°C. The mixture was taken up in water and the product was extracted with EtOAc. The combined organic phases were washed with saturated NaCI solution and dried over Na2SO4, The product was obtained as a yellow solid (48 mg, 0.14 mmol, 94%).1H-NMR (400 MHz, DMSO-d6) 6 = 7.96 (dd, J = 8.3, 1.3 Hz, 1 H, 1), 7.59 (ddd, J = 8.4, 7.1 , 1.5 Hz, 1H, 2), 7.45 (dd, J = 8.1 , 1.5 Hz, 1H, 4), 7.41 - 7.33 (m, 1H, 3), 4.09 (s, 3H, 12), 4.05 (s, 3H, 11).13C-NMR (101 MHz, DMSO-d6) 5 = 155.5, 155.5, 147.6, 142.7, 133.2, 130.2, 129.0, 127.5, 125.3, 117.8, 34.6, 32.2. Rf(CH2CI2+ 1% MeOH) = 0.50. LC-MS (ESI; LRMS; tR= 1.41 min) m / z calculated for [M+Naf: 364.1 , found: 364.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 364.0817, found 364.0817.3-Chloro-W-methyl-A / -(1-methyItetrazol-5-yl)quinoxalin-2-amine (64)

[0159] 2,3-Dichloroquinoxaline (50 mg, 0.25 mmol), 11 (25 mg, 0.25 mmol) and K2CO3(35 mg, 0.25 mmol) were suspended in dry DMF (3 ml_) and stirred for 4 hours at 100°C. The reaction mixture was taken up in water and extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EtOAc 0-50%). The product (64 mg, 0.25 mmol, 97%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 5 = 8.07 - 7.97 (m, 2H), 7.92 - 7.86 (m, 1H), 7.86 - 7.76 (m, 1H), 4.01 (s, 3H), 3.53 (s, 3H).13C-NMR (101 MHz, DMSO-de) 6 = 156.2, 147.9, 140.3, 138.8, 138.5, 131.4, 129.5, 127.6, 127.3, 38.5, 33.5. Rf(PE / EtOAc 1:1 ) = 0.50. LC-MS (ESI; LRMS; tR= 1.05 min) m / z calculated for [M+H]+: 276.1 / 278.1, found: 276.1 / 278.0. HR-MS (ESI; LOT) m / z calculated for [M+Naf: 298.0584, found 298.0594. / V-Methyl- / V-(1 -methyltetrazol-5-yl)-3-((1 -methyltetrazol-5-yl)thio)quinoxalin-2-amine (65)

[0160] 64 (25 mg, 0.09 mmol, 1.00 eq.), 1 (13 mg, 0.11 mmol, 1.20 eq.), and DIPEA(0.03 mL, 0.18 mmol, 2.00 eq.) were dissolved in dry DMF (1.5 ml_) and stirred for 4 hours at 80°C. The reaction mixture was taken up in water and the solvent was removed under reduced pressure. The crude product was taken up in DMF and was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (11 mg, 0.03 mmol, 33%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.00 - 7.94 (m, 1H), 7.84 - 7.78 (m, 1H), 7.76 - 7.67 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.61 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 6 = 155.9, 147.8, 146.9, 146.6, 139.3, 138.3, 130.8, 129.9, 127.6, 127.5, 38.7, 34.6, 33.9. Rf(CH2CI2+ 1% MeOH) = 0.15. LC-MS (ESI; LRMS; tR= 0.99 min) m / z calculated for [M+Naf: 378.1, found: 378.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 378.0974, found 378.0981.2,3-Bis((1-methyltetrazol-5-yl)thio)-6-nitroquinoxaline (66)

[0161] The synthesis of 66 was carried out by the reaction of 2,3-dichloro-6- nitroquinoxaline (50 mg, 0.21 mmol) and 1 (60 mg, 0.52 mmol) in DMF (2 mL) over 4 hours based on the general procedure Ila. In this case, 4 eq. DIPEA and the temperature was 80°C instead of 100°C. The product (16 mg, 0.04 mmol, 19%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-cfc) 5 = 8.63 - 8.52 (dd, J = 2.5, 0.5 Hz, 1 H), 8.52 - 8.33 (dd, J = 9.2, 2.5 Hz, 1 H), 8.02 - 7.86 (dd, J = 9.2, 0.5 Hz, 1H), 4.21 - 4.16 (s, 3H), 4.16 - 4.13 (s, 3H).13C- NMR (101 MHz, DMSO-d6) 6 = 153.0, 151.5, 147.5, 146.4, 146.3, 142.3, 138.8, 129.6, 124.1, 123.9, 34.8, 34.8. Rf(CH2CI2) = 0.20. LC-MS (ESI; LRMS; tR= 1.04 min) m / z calculated for [M+H]+: 426.0, found: 426.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 426.0280, found: 426.0277.6-Fluoro-7-methyl-2,3-bis((1-methyltetrazol-5-yl)thio)quinoxaline (67)

[0162] The synthesis of 67 was carried out by the reaction of 28 (25 mg, 0.11 mmol) and 1 (32 mg, 0.27 mmol) in DMF (1.5 mL) for 4 hours at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (13 mg, 0.03 mmol, 31%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) S = 7.77 (dd, J = 7.8, 1.2 Hz, 1H), 7.60 (d, J = 10.1 Hz, 1 H), 4.13 (s, 3H), 4.12 (s, 3H), 2.39 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 6 = 161.8 (d, J = 252.0 Hz), 148.9, 148.0 (d, J = 3.3 Hz), 147.3, 147.2, 139.8 (d, J = 13.8 Hz), 137.5 (d, J = 0.9 Hz), 131.5 (d, J = 21.4 Hz), 129.8 (d, J = 6.6 Hz), 111.3 (d, J = 23.7 Hz), 34.7, 34.7, 14.8 (d, J = 3.3 Hz). R, (CH2CI2+ 2% MeOH) = 0.33. LC-MS (ESI; LRMS; tR= 1.10 min) m / z calculated for [M+Naf: 413.0, found: 413.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 413.0491 , found: 413.0492.6-Fluoro-7-methyl-2,3-bis((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (68)

[0163] The synthesis of 68 was carried out by the reaction of 28 (25 mg, 0.11 mmol) and 2 (39 mg, 0.27 mmol) in DMF (1.5 mL) over 4h at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (15 mg, 0.03 mmol, 31%) was obtained as an orange solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.83 (dd, J = 7.8, 1.2 Hz, 1 H), 7.65 (d, J = 10.0 Hz, 1 H), 3.84 - 3.76 (m, 2H), 2.41 (s, 3H), 1.33 - 1.25 (m, 4H), 1.18 - 1.10 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 5 = 162.0 (d, J = 252.8 Hz), 149.2, 149.1 , 149.0, 148.1 (d, J = 3.3 Hz), 139.9 (d, J = 14.0 Hz), 137.7 (d, J = 0.8 Hz), 131.9 (d, J = 21.5 Hz), 129.9 (d, J = 6.7 Hz), 111.4 (d, J = 23.6 Hz), 29.3, 29.2, 14.8 (d , J = 3.2 Hz), 6.8, 6.7. Rr(CH2CI2 + 2% MeOH) = 0.48. LC-MS (ESI; LRMS; tR= 1.21 min) m / z calculated for [M+Naf: 465.1 , found: 465.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 465.0804, found: 465.0793.6-Methoxy-2,3-bls((1 -methyltetrazol-5-yl)thio)quinoxaline (69)

[0164] The synthesis of 69 was carried out by the reaction of 29 (25 mg, 0.11 mmol) and 1 (32 mg, 0.27 mmol) in DMF (1.5 mL) over 4 hours at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (17 mg, 0.04 mmol, 40%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.75 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1 H), 7.13 (d, J = 2.8 Hz, 1H), 4.14 (s, 3H), 4.11 (s, 3H), 3.89 (s, 3H).13C-NMR (101 MHz, DMSO<) 6 = 161.5, 150.0, 148.3, 147.3, 144.1 , 142.3, 136.4, 129.3, 123.7, 106.1, 56.2, 34.7, 34.7. Rf(CH2CI2+ 2% MeOH) = 0.40. LC-MS (ESI; LRMS; tR= 1.04 min) m / z calculated for [M+Naf: 411.1 , found: 411.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 411.0535, found: 411.0523.6-Methoxy-2,3-b«s((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (70)

[0165] The synthesis of 70 was carried out by the reaction of 29 (25 mg, 0.11 mmol) and 2 (39 mg, 0.27 mmol) in DMF (1.5 mL) over 4h at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (15 mg, 0.03 mmol, 31%) was obtained as an orange solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.82 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.3, 2.8 Hz, 1 H), 7.17(d, J = 2.7 Hz, 1H), 3.91 (s, 3H), 3.86 - 3.80 (m, 1H), 3.80 - 3.73 (m, 1 H), 1.33 - 1.24 (m, 4H),1.23 - 1.08 (m, 4H).13C-NMR (101 MHz, DMSO<) 5 = 161.7, 150.6, 150.4, 149.0, 143.8,142.5, 136.5, 129.5, 124.0, 106.1, 56.3, 29.3, 29.0, 6.8, 6.7. Rf(CH2CI2+ 1% MeOH) = 0.30.LC-MS (ESI; LRMS; tR= 1.18 min) m / z calculated for [M+Na]+: 463.1 , found: 463.1. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 463.0848, found: 463.0842.2,3-Bis((4H-1 ,2,4-triazol-3-yl)thio)quinoxaline (71 )

[0166] The synthesis of 71 was carried out by the reaction of 29 (25 mg, 0.11 mmol) and 3-mercapto-1 ,2,4-triazole (39 mg, 0.27 mmol) in DMF (1.5 mL) over 4 hours at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (15 mg, 0.03 mmol, 31%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 8.74 (s, 2H), 7.72 (s, 4H).13C-NMR (101 MHz, DMSO-d6) 6 = 151.9, 147.0, 140.1, 130.4, 127.9. Rf(CH2CI2+ 5% MeOH) = 0.15. LC-MS (ESI; LRMS; tR= 0.78 min) m / z calculated for [M+H]+: 329.0, found: 329.1. HR-MS (ESI; LCT) m / z calculated for [M+Na: 351.0211 , found: 351.0218.7-Fluoro-5-methoxy-2,3-bis((1 -methyl-1 H-tetrazol-5-yl)thio)quinoxaline (72)

[0167] The synthesis of 72 was carried out by the reaction of 31 (50 mg, 0.20 mmol) and 1 (59 mg, 0.27 mmol) in DMF (2 mL) for 4 hours at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (CH2CI2 / MeOH +0.5% TEA, 0-5%). The product (15 mg, 0.03 mmol, 31%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.28 (dd, J = 11.2, 2.6 Hz, 1 H), 7.10 (dd, J = 9.3, 2.6 Hz, 1H), 4.16 (s, 3H), 4.09 (s, 3H), 3.92 (s, 3H).13C-NMR (101 MHz, DMSO-d6) <5 = 164.9, 162.4, 156.2, 156.1 , 151.8, 148.0, 146.9, 144.8, 144.8, 141.7, 141.5, 129.9, 103.2, 103.0, 101.4, 101.1, 57.1, 34.8, 34.7. Rf(CH2CI2+ 5% MeOH + TEA) = 0.66. LC-MS (ESI; LRMS; tR= 1.05 min) m / z calculated for [M+N<: 429.0, found: 429.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 429.0440, found: 429.0419. / V-(2,3-Bis((1-methyltetrazol-5-yl)thio)quinoxalin-6-yl)acetamide (73)

[0168] The synthesis of 73 was carried out by the reaction of 33 (20 mg, 0.08 mmol) and 1 (23 mg, 0.20 mmol) in DMF (2 mL) over 4 hours at 80°C according to general procedure lid. The crude product obtained was purified by column chromatography (H2O / MeCN +0.05% TFA, 5-95%). The product (15 mg, 0.04 mmol, 46%) was obtained as a yellowish solid.1H-NMR (400 MHz, DMSO-de) 6 = 10.46 (s, 1H), 8.10 (dd, J = 2.1, 0.7 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 0.7 Hz, 1H), 4.14 (s, 3H), 4.09 (s, 3H), 2.10 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 5 = 169.3, 150.1 , 148.0, 147.3, 145.3, 141.6, 141.2, 136.9, 128.7, 124.1 , 113.6, 34.7, 34.6, 24.2. Rf(CH2CI2+ 5% MeOH + TEA) = 0.34. LC-MS (ESI; LRMS; tR= 0.93 min) m / z calculated for [M+Na]+: 438.1 , found: 438.1. HR-MS (ESI; LOT) m / z calculated for [M+Na]+: 438.0644, found: 438.0639.2,3-Bis((1-(oxetan-3-yl) tetrazol-5-yl)thio)quinoxaline (74)

[0169] 2,3-Dichloroquinoxaline (10 mg, 0.04 mmol, 1.0 eq.), 10 (30 mg, 0.12 mmol, 3.0 eq.) and DIPEA (0.02 mL, 0.12 mmol, 3.0 eq.) were dissolved in DMF (2 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude product was purified by column chromatography (CH2CI2+ 2% (7N NH3in MeOH)). The product (9 mg, 0.02 mmol, 53%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.82 - 7.64 (m, 4H), 5.99 - 5.91 (m, 2H), 5.06 (t, J = 6.5 Hz, 4H), 4.86 (t, J = 7.3 Hz, 4H).13C-NMR (101 MHz, DMSO-d6) 5 = 148.3, 146.6, 139.9, 131.2, 127.6, 76.3, 51.9. Rf(CH2CI2+ 5% MeOH + TEA) = 0.50. LC-MS (ESI; LRMS; tR= 1.02 min) m / z calculated for [M+Na]+: 465.1 , found: 465.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]*: 465.0640, found: 465.0638.

[0170] 2,3-Dichloroquinoxaline (two batches of 250 mg, 1.26 mmol, 1.00 eq.), 1 (2x 149 mg, 1.26 mmol, 1.00 eq.) and DIPEA (2x 0.44 mL, 2.00 eq.) were dissolved in DMF (2x 7.5 mL each) and stirred for 7 hours at 80°C. After cooling to room temperature, the mixture was taken up in water and the product was extracted with EtOAc. The combined organic phases were washed with saturated NaCI solution and dried over Na2SO4. The crude product was purified by column chromatography (PE / EtOAc 0-30%) and the product (199 mg, 0.71 mmol, 28% yield) was obtained as an orange solid.1H-NMR (400 MHz, DMSO-d6) δ = 8.07 - 8.01 (m, 1 H), 7.90 - 7.78 (m, 2H), 7.74 - 7.68 (m,1H), 4.09 (s, 3H).13C-NMR (101 MHz, DMSO-d6) δ 150.2, 146.7, 142.9, 140.3, 139.6, 131.4,130.9, 130.8, 127.9, 127.7, 34.6. Rf(PE / EtOAc 3:1) = 0.30. LC-MS (ESI; LRMS; tR= 1.16 min) m / z calculated for [M+H]+: 279.0, found: 279.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+:301.0039, found 301.0050.Procedure 1

[0171] 75 (40 mg, 0.14 mmol, 1.00 eq.), 2 (31 mg, 0.22 mmol, 1.50 eq.), and DIPEA(0.13 mL, 0.72 mmol, 5.00 eq.) were dissolved in DMF (1 mL) and stirred for 15 hours at room temperature. Then the temperature was increased to 52°C. The mixture was taken up in water and the product was extracted with EtOAc. The combined organic phases were washed with saturated NaCI solution and dried over Na2SO4. The crude product was purified by column chromatography (PE / EtOAc 0-50%). The product (7 mg, 0.02 mmol, 13%) was obtained as a white solid. In the purification process, 35% of the starting material was recovered.Procedure 2

[0172] 2,3-Dichloroquinoxaline (500 mg, 2.51 mmol, 1.00 eq.), 1 (292 mg, 2.51 mmol, 1.00 eq.), 2 (357 mg, 2.51 mmol, 1.00 eq.), DIPEA (1.75 mL, 10.05 mmol, 4.00 eq.) were dissolved in DMF (15 mL) and stirred for 6 hours at 80°C. After cooling to room temperature, the mixture was taken up in water and the product was extracted with EtOAc. The combined organic phases were washed with saturated NaCI solution and dried over Na2SO4. The residue was extensively purifdied by normal and reverse phase chromatography to obtain the desired product as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.93 - 7.74 (m, 4H), 4.12 (s, 3H), 3.83 (ft, J = 7.4, 3.8 Hz, 1H), 1.42 - 1.09 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 6 = 149.7, 149.3, 148.1, 147.3, 140.2, 140.2, 131.5, 131.3, 128.1, 128.0, 34.7, 29.2, 6.8. Rf(PE / EtOAc 2:1) = 0.15. LC-MS (ESI; LRMS; tR= 1.10 min) m / z calculated for [M+Na]+: 407.1, found: 407.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 407.0576, found 407.0583.2-(5-((3-((1 -Methyltetrazol-5-yl)thio)quinoxalin-2-yl)thio)-tetrazol-1 -yl)ethan-1 -ol (77)

[0173] 2,3-Dichloroquinoxaline (40 mg, 0.20 mmol, 1.0 eq.), 1 (29 mg, 0.25 mmol, 1.25 eq.), 5-mercapto-1-(2hydroxyethyl)tetrazole (37 mg, 0.25 mmol, 1.25 eq.) and DIPEA (0.176 mL, 1.01 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified twice by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (28 mg, 0.07 mmol, 36%) was obtained as a light orange solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.87 - 7.71 (m, 4H), 5.15 (s, 1H), 4.61 - 4.54 (m, 2H), 4.11(s, 3H), 3.84 (t, J = 5.4 Hz, 2H).13C-NMR (101 MHz, DMSO-d6) 6 = 149.9, 148.2, 148.2, 147.3,140.2, 140.1, 131.5, 131.1 , 128.1, 127.9, 59.2, 50.7, 34.6. Rf(CH2CI2+ 2% MeOH + TEA)0.33. LC-MS (ESI; LRMS; tR= 0.96 min) m / z calculated for [M+Naf: 411.1 , found: 411.2. HR- MS (ESI; LCT) m / z calculated for [M+Naf: 411.0535, found: 411.0523.

[0174] 2,3-Dichloroquinoxaline (40 mg, 0.20 mmol, 1.0 eq.), 1 (29 mg, 0.25 mmol, 1.25 eq.), 8 (44 mg, 0.25 mmol, 1.25 eq.) and DIPEA (0.175 mL, 1.01 mmol, 5. eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product mixture was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). 78 (13 mg, 0.03 mmol, 11%) was obtained as a yellowish solid. 79 (26 mg, 0.06 mmol, 31%) was obtained as a yellowish solid.Product 78:1H-NMR (400 MHz, DMSO-d6) 6 = 8.27 (d, J = 5.0 Hz, 2H), 7.81 (d, J = 1.5 Hz, 4H), 5.25 (s, 4H), 2.52 (d, J = 5.2 Hz, 6H).13C-NMR (101 MHz, DMSO-d6) <5 = 164.2, 148.8, 148.3, 140.2, 128.1 , 122.1 , 49.7, 25.6. R, (CH2CI2+ 2% MeOH + TEA) = 0.40. LC-MS (ESI; LRMS; tR= 0.89 min) m / z calculated for [M+Na]+: 495.1, found: 495.3. HR-MS (ESI; LOT) m / z calculated for [M+Naf: 495.0858, found: 495.0871.Product 791H-NMR (400 MHz, DMSO-d6) 5 = 8.31 (d, J = 4.8 Hz, 1H), 7.84 - 7.74 (m, 4H), 5.29 (s, 2H),147.8, 147.2, 140.3, 140.1 , 131.6, 131.1, 128.2, 127.9, 49.7, 34.6, 25.6. Rf(CH2CI2+ 2% MeOH + TEA) = 0.35. LC-MS (ESI; LRMS; tR= 0.95 min) m / z calculated for [M+Na]+: 438.1 , found: 438.2. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 438.0644, found: 438.0641.2,3-Bis((4-methyl-1 ,2,4-triazol-3-yl)thio)quinoxaline (80)

[0175] 2,3-Dichloroquinoxaline (15 mg, 0.08 mmol, 1.0 eq.), 3-mercapto-4-methyl-1 ,2,4- triazole (22 mg, 0.19 mmol, 2.50 eq.), and DIPEA (0.066 mL, 0.38 mmol, 5 eq.) were dissolved in DMF (1 mL) and stirred for 6 hours at 90°C. The reaction mixture was cooled, taken up in water and filtered. The residue was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (16 mg, 0.05 mmol, 60%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 = 8.94 (s, 2H), 7.72 (s, 4H), 3.69 (s, 6H).13C-NMR (101 MHz, DMSO-d6) 5 = 149.8, 148.1 , 142.3, 140.0, 130.5, 127.8, 31.5. Rf(CH2CI2+ 3% MeOH + TEA) = 0.45. LC-MS (ESI; LRMS; tR= 0.82 min) m / z calculated for [M+H]+: 357.1, found: 357.2. HR-MS (ESI; LCT) m / z calculated for [M+Naf: 379.0524, found: 379.0510.2-(( 1 -Methyltetrazol-5-yl)thio)-3-((4-methyl-1 ,2,4-triazol-3-yl)thio)quinoxaline (81 )

[0176] 2,3-Dichloroquinoxaline (40 mg, 0.20 mmol, 1.0 eq.), 1 (47 mg, 0.40 mmol, 2.00 eq.), 3-mercapto-4-methyl-1 ,2,4-triazole (29 mg, 0.25 mmol, 1.25 eq.) and DIPEA (0.175 mL, 1.01 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The residue was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (8 mg, 0.02 mmol, 11%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.93 (s, 1 H), 7.87 - 7.60 (m, 2H), 4.14 (s, 3H), 3.69 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 6 = 150.3, 148.3, 148.1, 147.2, 140.2, 139.9, 131.0, 130.7,127.9, 127.8, 34.7, 31.5. R, (CH2CI2+ 3% MeOH + TEA) 0.40. LC-MS (ESI; LRMS; tR=0.96 min) m / z calculated for [M+H]+: 358.1, found: 358.2. HR-MS (ESI; LOT) m / z calculated for[M+Naf : 380.0477, found: 380.0473.

[0177] 75 (45 mg, 0.16 mmol, 1.00 eq.), 7 (0.98 M in DMF, 330 pL, 0.32 mmol, 2.00 eq.), and DIPEA (140 pL, 0.81 mmol, 5.00 eq.) were dissolved in DMF (3 mL) and stirred for 50 hours at 50°C. The mixture was cooled to room temperature and taken up into water. The solvent was removed under reduced pressure and the crude product was taken up in DMF and subjected to column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (10 mg, 0.03 mmol, 18%) was obtained as a slightly yellowish solid.’H-NMR (400 MHz, DMSO-d6) 6 = 7.90 - 7.85 (m, 1H), 7.85 - 7.79 (m, 2H), 7.78 - 7.74 (m, 1H), 4.10 (s, 3H).13C-NMR (101 MHz, DMSO-d6) 5 = 151.1 , 148.4, 147.7, 140.8, 140.7, 132.1, 131.5, 128.7, 128.3, 35.1. LC-MS (ESI; LRMS; tR= 1.23 min) m / z calculated for [M+H]+: 345.0, found: 345.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 367.0273, found 367.0272.2-Chloro-3-((1 -cyclopropyl-1 H-tetrazol-5-yl)thio)quinoxaline (83)

[0178] 2,3-Dichloroquinoxaline (50 mg, 0.25 mmol), 2 (25 mg, 0.18 mmol, 0.70 eq.) and DIPEA (49 mg, 0.38 mmol, 1.5 eq.) were dissolved in DMF (3 mL) and stirred for 2 hours at 80°C. The reaction mixture was taken up in EtOAc, washed with water and a saturated NaCIsolution. The organic phase was dried over Na2SO4, filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography. The product (30 mg, 0.11 mmol, 42%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 5 = 8.03 - 7.96 (m, 1H), 7.78 - 7.67 (m, 3H), 3.68 (tt, J = 7.5, 3.8 Hz, 1H), 1.50 - 1.42 (m, 2H), 1.20 - 1.10 (m, 2H).13C-NMR (101 MHz, CDCI3) <5 = 150.0, 147.6, 143.1 , 140.9, 140.3, 131.2, 130.8, 128.4, 128.0, 29.9, 7.6. Rf(PE / EtOAc 4:1) = 0.17. LC-MS (ESI; LRMS; tR= 1.22 min) m / z calculated for [M+H]+: 305.0, found: 305.1. HR-MS (ESI, UPLC - QTof) m / z calculated for [M+N<: 327.0196, found: 327.0196.2-((Tetrazol-5-yl)thio)-3-((1-cyclopropyltetrazol-5-yl)thio)quinoxaline (84)

[0179] 83 (20 mg, 0.07 mmol, 1.00 eq.), 7 (0.98 M in DMF, 100 pL, 0.10 mmol, 1.50 eq.), and DIPEA (0.23 mL, 0.13 mmol, 2.00 eq.) were dissolved in DMF (1 mL) and stirred at 50°C. After 6 hours, the same amounts of 7 and DIPEA were added again, which was repeated after a total of 23 hours. After 28 hours the implementation was complete and the reaction was terminated. The mixture was cooled to room temperature and taken up in water. The solvent was removed under reduced pressure and the crude product was taken up in DMF and subjected to column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (2 mg, 0.01 mmol, 8% yield) was obtained as a slightly yellowish solid.1H-NMR (400 MHz, DMSO-d6) 6 = 7.80 (s, 4H), 3.78 (tt, J = 7.4, 3.8 Hz, 1H), 1.30 - 1.08 (m, 4H).13C-NMR (101 MHz, DMSO-d6) 5 = 150.0, 148.9, 140.3, 140.3, 131.5, 131.2, 128.2, 127.9, 29.3, 6.8. LC-MS (ESI; LRMS; tR= 1.01 min) m / z calculated for [M+H]+: 393.0, found: 393.0. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 393.0429, found 393.0423.Ethyl 3-oxo-3,4-dihydroquinoxaline-2-carboxylate (85)

[0180] 1 ,2-phenyldiamine (1400 mg, 12,946 mmol, 1.0 eq.), diethyl-2-oxomalonate(2300 mg, 12,946 mmol, 1.0 eq.), and citric acid (76 mg, 0.388 mmol, 0.03 eq.) were dissolved in ethanol (30 mL) and stirred for 30 min at room temperature. The reaction mixture was cooled to 0°C and vacuum-filtered. The residue was washed with water and dried under reduced pressure. The product (2655 mg, 12,167 mmol, 94%) was obtained as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 12.88 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.74 - 7.54 (m, 1H), 7.37 (t, J = 7.6 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). Rf(PE / EtOAc 5:1) = 0.35. LC-MS (ESI; LRMS; tR= 0.89 min) m / z calculated for [M+Hf: 219.1, found: 219.3.Ethyl 3-chloroquinoxaline-2-carboxylate (86)

[0181] 85 (350 mg, 1.60 mmol) was suspended in POCI3(2 mL) and stirred under reflux for 5 hours. The reaction mixture was cooled and taken up in ice water. The aqeous phase was neutralized with NaHCO3and extracted with EtOAc. The combined organic phases werde dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The product (250 mg, 1.06 mmol, 66%) was obtained as yellowish solid.1H-NMR (400 MHz, DMSO-d6) 5 = 7.87 - 7.79 (m, 1H), 7.69 - 7.59 (m, 1H), 7.41 - 7.31 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). Rf(PE / EtOAc 10:1) = 0.25.3-Chloroquinoxaline-2-carbaldehyde (87)

[0182] 86 (1000 mg, 4.23 mmol, 1.00 eq.) was dissolved in THF (15 ml) and cooled to -78°C. DIBAI-H (1M in THF, 12.7 mL, 12.7 mmol, 3.00 eq.) was added dropwise and the mixture stirred at -78°C until complete conversion of the starting material could be observed by TLC. A small amount of water and dilute HCI were carefully added to the reaction mixture, thenit was allowed to warm to room temperature and was extracted with several times EtOAc. The combined organic phases were dried over Na2SO4)filtered and the solvent was removed under reduced pressure. The crude product (800 mg) was used without further purification.(E)-2-Chloro-3-(2-(1-methyltetrazol-5-yl)vinyl)quinoxaline (88)

[0183] 12 (205 mg, 0.52 mmol, 1.25 eq.) was dissolved in THF (2.5 mL) and cooled to -78°C. After addition of KOfBu (180 mg, 0.46 mmol, 1.10 eq.), the mixture was removed from the cold bath and stirred until a clear yellow solution was obtained. It was then cooled to -78°C again, 87 (80 mg, 0.42 mmol, 1.00 eq.) in THF (2.5 mL) was added dropwise and the reaction mixture was stirred for 1 hour at this temperature. Subsequently, the reaction mixture was taken up in water, extracted with EtOAc, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (CH2CI2 / EtOAc 0 - 50%). The product (52 mg, 0.19 mmol, 45% over 2 steps) was obtained as a yellowish solid.1H-NMR (400 MHz, CDCI3) 5 = 8.52 (d, J = 15.4 Hz, 1H), 8.16 - 8.11 (m, 1H), 8.07 - 8.02 (m, 1H), 7.91 (d, J = 15.4 Hz, 1H), 7.87 - 7.80 (m, 2H), 4.25 (s, 3H).13C-NMR (101 MHz, CDCI3) 6 = 152.0, 147.2, 146.2, 142.2, 141.2, 132.9, 131.9, 131.1, 129.4, 128.6, 116.0, 34.0. R, (CH2CI2+ 2% MeOH + TEA) = 0.55. LC-MS (ESI; LRMS; tR= 1.06 min) m / z calculated for [M+H]+: 273.1 / 275.1, found: 273.1 / 275.1. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 295.0475, found: 295.0469.(E)-2-((1 -methyltetrazol-5-yl)thio)-3-(2-(1 -methyltetrazol-5-yl)vinyl)quinoxaline (89)

[0184] 88 (20 mg, 0.07 mmol, 1.00 eq.), 1 (43 mg, 0.37 mmol, 5.00 eq.) and DIPEA(0.13 mL, 0.73 mmol, 10.00 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and filtered. The residue was washed withH2O / DMF (10:1), H2O / MeOH (1 :1) and H2O and dried under reduced pressure. The product (17 mg, 0.05 mmol, 66%) was obtained as a yellow solid.1H-NMR (600 MHz, CDCI3) 5 = 8.31 (d, J = 15.0 Hz, 1H), 8.10 - 8.07 (m, 1H), 7.94 (d, J = 15.0 Hz, 1H), 7.79 - 7.70 (m, 3H), 4.27 (s, 3H), 4.17 (s, 3H).13C-NMR (151 MHz, CDCI3) 6 = 151.8, 150.0, 147.1, 145.4, 142.4, 140.8, 131.9, 131.5, 131.0, 129.5, 128.4, 116.4, 34.9, 34.0. R,(CH2CI2+ 2% MeOH + TEA) = 0.45. LC-MS (ESI; LRMS; tR= 1.01 min) m / z calculated for[M+Naf: 375.1, found: 375.2. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 375.0865, found:375.0860

[0185] 89 (25 mg, 0.07 mmol, 1.00 eq.) and Pd / C (10%, 5 mg) were dissolved in THF (5 mL) and EtOAc (5mL) and stirred at room temperature. H2gas was introduced into the mixture for 30 min, then the reaction mixture was filtered and the residue was washed with EtOAc. The volatiles were removed under reduced pressure and the resulting crude product was purified by column chromatography (H2O / MeCN +0.05% TEA, 1-95%). The product (3 mg, 0.01 mmol, 12%) was obtained as a yellow solid.1H-NMR (500 MHz, DMS0-d6) 5 = 7.98 (dd, J = 8.1 , 1.5 Hz, 1H), 7.82 - 7.70 (m, 2H), 7.66 (dd,J = 8.2, 1.5 Hz, 1H), 4.15 (s, 3H), 4.07 (s, 3H), 3.66 - 3.60 (m, 2H), 3.58 - 3.54 (m, 2H).13C-NMR (151 MHz, DMSOO 5 = 154.9, 152.0, 151.0, 147.0, 140.2, 139.3, 130.4, 130.1 , 128.3,127.6, 34.6, 33.4, 30.8, 19.0. R, (CH2CI2+ 2% MeOH + TEA) = 0.30. LC-MS (ESI; LRMS; tR= 1.00 min) m / z calculated for [M+Na]+: 377.1 , found: 377.2. HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 377.1021, found: 377.1037.3,4,6-trideutero-5-(trideuteromethyl)benzene-1 ,2-diamine (91 )

[0186] 3,4-Diaminotoluene (400 mg, 3.27 mmol) and Pt / C (10%, 80 mg) were suspended in a microwave vessel in D2O (15 mL) and stirred in a closed system for 24 hours at 180°C under a hydrogen atmosphere. The mixture was filtered over Celite and it was washed several times with EtOAc. The phases were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with a saturated NaCI solution, dried over Na2SO41and filtered. By removing the solvent under reduced pressure, the product (255 mg, 1.99 mmol, 61%) was obtained as a brown solid. According to NMR analysis, the aromatic ring was deuterated almost entirely, while the methyl group was only converted partially, approximately around 50%.1H-NMR (400 MHz, DMSO-d6) 6 = 6.39 (s, 0.02H), 6.33 (s, 0.02H), 6.19 (s, 0.02H), 4.28 (s, 2H), 4.20 (s, 2H), 2.06 (s, 0.80H), 2.06 - 2.04 (m, 0.55H), 2.03 (m, 0.20H).13C-NMR (101 MHz, DMSO-ofe) 6 = 135.0, 132.3, 125.4, 117.7 - 116.7 (m), 115.4 - 114.7 (m), 114.7 - 113.9 (m), 20.4, 20.3 - 19.7 (m).2,3-Dlchloro-5,7,8-trldeutero-6-(trideuteromethyl)quinoxaline (92)

[0187] The synthesis of 92 was carried out starting from 91 (500 mg, 3.90 mmol) according to general procedure la. The product (581 mg, 2.65 mmol, 68%) was obtained as a white solid.1H-NMR (400 MHz, CDCI3) 6 = 7.87 - 7.80 (m, 0.04H), 7.71 (s, 0.14H), 7.57 (s, 0.33H), 2.59 - 2.49 (m, 1.50H).13C-NMR (101 MHz, CDCI3) 6 = 145.2, 144.3, 142.1 (d, J = 7.9 Hz), 140.6, 139.0, 133.5 - 132.7 (m), 127.8 - 127.0 (m), 127.2 - 126.5 (m).5,6,7,8-Tetradeutero-2-((1-methyltetrazol-5-yl)thio)-3-((4-methyl-4H-1,2,4-triazol-3- yl)thio)quinoxaline (93)

[0188] 25 (50 mg, 0.25 mmol, 1.0 eq.), 1 (36 mg, 0.31 mmol, 1.25 eq.), 3-mercapto-4- methyl-1 ,2,4-triazole (43 mg, 0.37 mmol, 1.50 eq.) and DIPEA (0.215 mL, 1.23 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (18 mg, 0.05 mmol, 20%) was obtained as a lightyellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.94 (s, 1H), 4.15 (s, 3H), 3.70 (s, 3H). HR-MS (ESI; LCT) m / z calculated for [M+Naf: 384.0728, found: 384.0717.2-(5-((3-((4-methyl-4H-1,2,4-triazol-3-yl)thio)quinoxalin-2-yl-5,6,7,8-d4)thio)tetrazol-1- yl)ethan-1-ol (94)

[0189] 25 (50 mg, 0.25 mmol, 1.0 eq.), 5-mercapto-1-(2-hydroxyethyl)tetrazole (45 mg,0.31 mmol, 1.25 eq.), 3-mercapto-4-methyl-1 ,2,4-triazole (35 mg, 0.31 mmol, 1.25 eq.) and DIPEA (0.215 mL, 1.23 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (24 mg, 0.06 mmol, 25%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.95 (s, 1H), 4.58 (t, J = 5.3 Hz, 2H), 3.84 (t, J = 5.3 Hz, 2H), 3.66 (s, 3H). HR-MS (ESI; LCT) m / z calculated for [M+Naf: 414.0833, found: 414.0818.2-(5-((3-((1 -methyltetrazol-5-yl)thio)quinoxalln-2-yl-5,6,7,8-d4)thio) tetrazol-1 -yl)ethan-1 -ol(95)

[0190] 25 (50 mg, 0.25 mmol, 1.0 eq.), 5-mercapto-1-(2-hydroxyethyl)tetrazole (45 mg,0.31 mmol, 1.25 eq.), 1 (36 mg, 0.31 mmol, 1.25 eq.) and DIPEA (0.215 mL, 1.23 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (30 mg, 0.08 mmol, 31%) was obtained as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 4.58 (t, J = 5.4 Hz, 2H), 4.11 (s, 3H), 3.85 (t, J = 5.4 Hz, 2H). HR-MS (ESI; LOT) m / z calculated for [M+Na]+: 415.0786, found: 415.0766.6-(Methyl-d3)«3-((1-methyltetrazol-5-yl)thio)-2-((4-methyl-4H-1,2,4-triazol-3- yl)thio)quinoxaline-5,7,8-d3(96) and 6-(Methyl-d3)-2-((1-methyltetrazol-5-yl)thio)-3-((4- methyl-4H-1 ,2,4-triazol-3-yl)thio)quinoxaline-5,7,8-d3(97)

[0191] 92 (50 mg, 0.23 mmol, 1.0 eq.), 1 (33 mg, 0.29 mmol, 1.25 eq.), 3-mercapto-4- methyl-1 ,2,4-triazole (33 mg, 0.29 mmol, 1.25 eq.) and DIPEA (0.200 mL, 1.14 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (8 mg, 0.02 mmol, 10%) was obtained as a 1 :1 mixture of isomers as a white solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.93 (s, 1H), 8.92 (s, 1H), 4.14 (s, 3H), 4.13 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H). LC-MS (ESI; LRMS; tR= 1.07 min) m / z calculated for [M+H]+: 378.1 , found: 378.0.2-(5-((7-(Methyl-d3)-3-((4-methyl-4M-1,2J4-trlazol-3-yl)thlo)quinoxalin-2-yl-5,6,8.d3)thio) tetrazol-1-yl)ethan-1-ol (98) and 2-(5-((6-(Methyl-d3)-3-((4-methyl-4H-1,2,4-triazol-3- yl)thio)quinoxalin-2-yl-5,7,8-d3)thio) tetrazol-1 -yl)ethan-1 -ol (99)

[0192] 92 (50 mg, 0.23 mmol, 1.0 eq.), 5-mercapto-1-(2-hydroxyethyl)tetrazole (42 mg,0.29 mmol, 1.25 eq.), 3-mercapto-4-methyl-1 ,2,4-triazole (33 mg, 0.29 mmol, 1.25 eq.) and DIPEA (0.200 mL, 1.14 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (15 mg, 0.04 mmol, 16%) was obtained as a 1:1 mixture of isomers as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 6 = 8.93 (s, 1H), 8.92 (s, 1H), 4.60 - 4.54 (m, 4H), 4.47 - 4.43 (m, 1H), 3.84 (t, J = 5.4 Hz, 4H), 3.81 - 3.78 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H). LC-MS (ESI; LRMS; tR= 0.98 min) m / z calculated for [M+Hf: 408.1, found: 408.0.2-(5-((7-(Methyl-d3)-3-((1-methyltetrazol-5-yl)thio)quinoxalin-2-y!-5,6,8-d3)thio)tetrazol-1- yl)ethan-1-ol (100) and 2-(5-((6-(Methyl-d3)-3-((1-methyltetrazol-5-yl)thio)quinoxalin-2-yl- 5,7,8-d3)thio)tetrazol-1-yl)ethan-1-ol (101)

[0193] 92 (50 mg, 0.23 mmol, 1.0 eq.), 5-mercapto-1-(2-hydroxyethyl)tetrazole (42 mg,0.29 mmol, 1.25 eq.), 1 (33 mg, 0.29 mmol, 1.25 eq.) and DIPEA (0.200 mL, 1.14 mmol, 5 eq.) were dissolved in DMF (3 mL) and stirred for 4 hours at 80°C. The reaction mixture was cooled, taken up in water and dried under reduced pressure. The crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (15 mg, 0.04 mmol, 16%) was obtained was obtained as a 1 :1 mixture of regioisomers as a colorless amorphous solid.HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 428.0879, found: 428.0873.MS (ESI; LRMS; tR= 1.09 min) m / z calculated for [M+Naf: 431.1 , found: 431.0.6-(Methyl-cf3)-2,3-bis((1-methyltetrazol-5-yl)thio)quinoxaline-5,7,8-cf3(102)

[0194] The synthesis of 35 was carried out by the reaction of 2,3-dichloroquinoxaline (470 mg, 2.39 mmol) and 2 (848 mg, 5.96 mmol) in DMF (10 mL) over 12 hours at 80°C according to general procedure lie. In this case, the crude product was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (20 mg, 0.05 mmol, 23%) was obtained as a white solid.LC-MS (ESI; LRMS; tR= 1.19 min) m / z calculated for [M+Na]+: 401.1, found: 401.0.2,3-Bis((1-methyl-1H*tetrazol-5-yl)thio)-5-(trifluoromethyl)quinoxaline (110)

[0195] 104 (200 mg, 0.75 mmol, 1.00 eq.), 1 (218.3 mg, 1.88 mmol, 2.50 eq.) andDIPEA (0.48 mL, 3.56 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred for 4 h at 80 °C. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (81 mg, 0.19 mmol, 25 %) was obtained as a yellow solid.1H NMR (400 MHz, DMSO) 5 8.14 (d, J = 7.4 Hz, 1H), 8.04 (dd, J = 8.6, 1.3 Hz, 1H), 7.85 (t, J = 7.9 Hz, 1H), 4.16 (s, 3H), 4.06 (s, 3H). HR-MS (ESI; LCT) m / z calculated for [M+Naf: 449.0303, found: 449.0310.2,3-Bis((1-methyl-1H-tetrazol-5-yl)thio)-6-(trifluoromethyl)quinoxaline (111)

[0196] 103 (200 mg, 0.75 mmol, 1.00 eq.), 1 (218.3 mg, 1.88 mmol, 2.50 eq.) andDIPEA (0.48 mL, 3.56 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred for 4 h at 80 °C. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (107 mg, 0.25 mmol, 33 %) was obtained as a yellow solid.1H NMR (400 MHz, DMSO) 6 8.20 - 8.16 (m, 1H), 8.01 (dd, J = 8.8, 2.1 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 4.16 (s, 3H), 4.14 (s, 3H). MS m / z calculated for [M+H]+: 427.04, found: 427.02. HR- MS (ESI; LCT) m / z calculated for [M+Na]+: 449.0303, found: 449.0291.N-(3-(5-((3-((1 -methyl-1 H-tetrazol-5-yl)thio)quinoxalin-2-yl)thio)-1 H-tetrazol-1 - y / )propyl)acetamide (112)

[0197] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 1 (73 mg, 0.63 mmol, 1.25 eq.), 106 (127 mg, 0.63 mmol, 1.25 eq.), and DIPEA (0.36 mL, 2.52 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred for 4 h at 80 °C. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (45 mg, 0.12 mmol, 20 %) was obtained as a white solid.1H NMR (400 MHz, DMSO) 67.81 - 7.70 (m, 4H), 4.48 (t, J = 7.2 Hz, 2H), 4.14 (s, 3H), 3.07 (q, J = 6.5 Hz, 2H), 2.05 (p, J = 7.0 Hz, 2H), 1.71 (s, 3H). HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 466.0957, found: 466.0936.IV-(4-(5-((3-((1 -methyl-1 H-tetrazol-5-yl)thio)quinoxalin-2-yl)thio)-1 H-tetrazol-1 - yl)butyl)acetamide (113) and W,N’-(((quinoxaline-2,3-diylbis(sulfanediyl))bis(1H-tefrazo / e- 5,1-diyl))bis(butane-4,1-diyl))diacetamide (114)

[0198] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 1 (73 mg, 0.63 mmol, 1.25 eq.), 107 (135 mg, 0.63 mmol, 1.25 eq.), and DIPEA (0.36 mL, 2.52 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred at 80 °C for 4 h. The reaction mixture was cooled. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The products (113: 50 mg, 0.11 mmol, 21 %, 114: 64 mg, 0.11 mmol, 22 %) was obtained as a white solid.113:1H NMR (400 MHz, DMSO) 6 7.86 - 7.68 (m, 4H), 4.49 (t, J = 7.0 Hz, 2H), 4.14 (s, 3H), 2.98 (q, J = 6.6 Hz, 2H), 1.88 (p, J = 7.2 Hz, 2H), 1.69 (s, 3H), 1.39 (p, J = 7.1 Hz, 2H). HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 480.1115, found: 480.1094.N-(2-(5-((3-((1-methyl-1 H-tetrazol-5-yl)thio)quinoxalin-2-yl)thio)-1H-tefrazoM- y / )ethyl)acetamide (115)

[0199] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 1 (73 mg, 0.63 mmol, 1.25 eq.), 105 (118 mg, 0.63 mmol, 1.25 eq.), and DIPEA (0.36 mL, 2.52 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred at 80 °C for 4 h. The reaction mixture was cooled. The reaction mixture was cooled, taken up in water and lyophilized. The residue was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (72 mg, 0.17 mmol, 33 %) was obtained as a white solid.1H NMR (400 MHz, DMSO) 5 8.07 (t, J = 5.9 Hz, 1H), 7.85 - 7.73 (m, 4H), 4.56 (dd, J = 6.5, 5.2 Hz, 2H), 4.12 (s, 3H), 3.55 (q, J = 5.9 Hz, 2H), 1.76 (s, 3H).13C NMR (101 MHz, DMSO) 5 170.30, 149.95, 148.70, 148.07, 147.66, 140.72, 140.59, 131.92, 131.66, 128.56, 128.40, 48.11, 38.57, 35.15, 22.91. MS m / z calculated for [M+H]+: 430.09, found: 430.06.N,N*-(((quinoxaline-2,3-diylbis(sulfanediyl))bis( 1H-tetrazole-5, 1-diyl))bis(propane-3,1- diyl))diacetamide (116)

[0200] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 106 (254 mg, 1.26 mmol, 2.50 eq.), and DIPEA (0.36 mL, 2.52 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred for 4 h at 80 °C. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (28 mg, 0.05 mmol, 10 %) was obtained as a white solid.HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 551.1484, found: 551.1472.2-(5-((3-((1 -methyl-tetrazol-5-yl)thio)quinoxaline-2-yl)thio)-1H-tetrazo / -1-y / ) acid (117)

[0201] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 1 (73 mg, 0.63 mmol, 1.25 eq.), 2-(5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)acid (101 mg, 0.63 mmol, 1.25 eq.), and DIPEA (0.36 mL, 2.52 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred at 80 °C for 4 h. The reaction mixture was cooled. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1- 95%). The product (80 mg, 0.18 mmol, 35 %) was obtained as a white solid.1H NMR (400 MHz, DMSO) 5 7.94 - 7.60 (m, 4H), 5.54 (s, 2H), 4.11 (s, 3H). MS m / z calculated for [M+H]+: 403.04, found: 403.02.2,2*-((quinoxaline-2,3-diylbis(sulfanediyl))bis(1H-tetrazole-5,1-diyl))cliacetic acid (118)

[0202] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 2-(5-thioxo-4,5-dihydro- 1H-tetrazol-1-yl)acid (202 mg, 0.63 mmol, 2.50 eq.), and DIPEA (0.36 mL, 2.52 mmol, 5.00 eq.) were dissolved in DMF (4 mL) and stirred for 4 h at 80 °C. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H2O / MeCN +0.05% TFA, 1-95%). The product (86 mg, 0.19 mmol, 38 %) was obtained as a white solid.’H NMR (400 MHz, DMSO) 6 7.80 (dd, J = 1.6, 0.9 Hz, 4H), 5.51 (s, 4H). MS m / z calculated for [M+H]+: 447.03, found: 447.99.N,N-dimethyl-2-(5-((3-((1 -methyl-1 H4etrazol-5-yl)thio)quinoxalin>2>yl)thio)-1 H-tetrazol-1 - yl)acetamide (119)

[0203] 117 (50 mg, 0.12 mmol, 1.00 eq.) was dissolved in DMF (1 mL). CDI (20.2 mg,0.12 mmol, 1 eq.) was also dissolved in DMF (1 mL) and then added to the first solution. Dimethylamine (24 mg, 0.25 mmol, 2 eq.) was then added slowly. After complete addition, DIPEA (0.1 mL, 0.6 mmol, 5.00 eq.) was added to the reaction and it was stirred overnight. The reaction mixture was taken up in water and extracted with EtOAc. The organic phase was washed with water and brine, dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (HzO / MeCN +0.05% TFA, 1-95%) and the product was obtained as a yellowish solid (21 mg, 0.05 mmol, 39 %).HR-MS (ESI; LCT) m / z calculated for [M+Na]+: 452.0800, found: 452.0779.2-((4H-1,2,4-triazol-3-yl)thio)-3-((1-methyl-1H-tetrazol-5-yl)thio)chlnoxalin (120)

[0204] 2,3-Dichloroquinoxaline (100 mg, 0.51 mmol, 1.00 eq.), 1 (73.7 mg, 0.63 mmol, 1.25 eq.), 2,4-dihydro-3H-1,2,4-triazole-3-thione (64.2 mg, 0.63 mmol, 1.25 eq.) and DIPEA (0.32 mL, 2.53 mmol, 5.00 eq.) were dissolved in DMF (2 mL) and stirred at 80 °C for 4 h. The reaction mixture was cooled, taken up in water and lyophilized. The solid was purified by column chromatography (H20+0.05% TFA / MeCN+0.05% TFA, 5-95%). The product (64 mg, 0.19 mmol, 37 %) was obtained as a yellow solid.1H NMR (400 MHz, DMSO) 5 8.77 (s, 1H), 7.91 - 7.85 (m, 1H), 7.81 - 7.73 (m, 2H), 7.73 - 7.66 (m, 1 H), 4.06 (s, 3H). HR-MS (ESI; LCT) m / z calculated for [M+Naf : 366.0320, found: 366.0306.Biochemical and biological assays1. Alphascreen-based LMP1 -TRAF2 protein-protein-interaction (PPI) assay

[0205] Alphascreen-system (Perkin Elmer)-based assay technology was established to detect and quantify the direct protein-protein-interaction of LMP1 with TRAF2 (Figure 2). The assay consisted of the following protein components: the recombinant GST-tagged C-terminal signaling domain of LMP1 (amino acids 181 to 386), which contains the TRAF2 interaction site P204XQXT of CTAR1 , and the recombinant 6xHis-tagged TRAF domain of human TRAF2 (amino acids 311 to 501). GST-LMP1 and His-TRAF2 were mixed in PBS supplemented with 0.5% BSA and 0.1% Tween-20 for 1 hour at room temperature in the presence of the test compound dissolved in DMSO, or DMSO alone as a negative control. GSH-donor beads (Perkin Elmer) binding to GST-LMP1 and Ni-NTA-acceptor beads (Perkin Elmer) binding to His-TRAF2 were added and the reaction mix was incubated for 1 hour at room temperature in the dark. Alphascreen PPI signals indicating LMP1-TRAF2 interaction were subsequently measured in a reader.Table 3: Alphascreen Results: Range of ICSOvalues of the listed TRAF2 inhibitor compounds on the LMP1-TRAF2 interaction as measured by the Alphascreen LMP1-TRAF2 interaction assay. IC50are classified as follows: IC50<30pM: +; IC50<10pM: ++, IC50<3pM: +++; IC50<1pM: ++++; IC50 <300 nM: +++++2. MTT cell viability assay

[0206] The effects of TRAF2 inhibitor compounds on cell survival and proliferation of EBV-transformed human B cells was assessed by MTT cell viability assays. The following cells lines were used: the patient-derived EBV-positive post-transplant lymphoma (PTLD) cell line PTLD880 and the EBV-transformed lymphoblastoid cell line, which was established from the same patient as PTLD880 LCL87743. At day zero, the cells were seeded in RPMI full medium in 96-well plates in the presence of compound dissolved in DMSO, or DMSO alone. The cells were incubated at 37° C and 5% CO2. At day four, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) was added. After 4 h, MTT turnover was analyzed by adding 200 pL of HChisopropanol (ratio 1 :24). The blue reaction product was measured at 550 nm with a reference filter at 690 nm.

[0207] Table 4: Range of EC50values of the listed TRAF2 inhibitor compounds on the viability of PTLD880 and LCL877 cells as measured by the MTT cell viability assay.EC5O are classified as follows: EC50<30pM: +; EC50<10pM: ++, EC50<3pM: +++; EC50<1pM:3. Analysis of LMP1 -induced signaling pathways in LCL.NGFR-LMP1 cells

[0208] LCL.NGFR-LMP1 cells and the stimulation of LMP1 signaling activity in these cells by antibody-mediated crosslinking of the NGFR-LMP1 fusion protein have been described43. LCL.NGFR-LMP1 cells are EBV-transformed human B cells, which were established byinfection of primary human B cells with a recombinant EBV carrying a fusion of the extracellular and transmembrane domains of human p75 nerve growth factor-receptor (NGFR) and the intracellular signaling domain of LMP1 instead of LMP1 wildtype. In these cells, LMP1 activity can be triggered at will by crosslinking of NGFR-LMP1 at the cell surface with antibodies (Figure 3). LCL.NGFR-LMP1 cells were deprived from antibodies for one week before restimulation to silence NGFR-LMP1 activity. The cells were incubated in the presence of the indicated concentrations of compound or DMSO as a control for 4 hours prior to antibody stimulation. Subsequently, NGFR-LMP1 activity was stimulated with crosslinking antibodies for 30 min. 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Claims

CLAIMS1. A compound according to formula (I),whereinA and B are independently selected from the group consisting of -(C1-C5alkyl,and H; preferably methyl, or .morepreferabiy methyl or -CH2CH2OH;G is -O-, -NR1, -CH2-; preferably -O-;L is selected from the group consisting of -OR2, -NR3R4, -CONR5R6, -COOR7, -Ph, -PhO(C1C5)alkyl; p is an integer between 0 and 4; preferably 0 and 1 ; more preferably 1 ; k is an integer between 0 and 2; preferably 0 and 1 ; more preferably 0;V, D, E, and W are independently selected from the group consisting of.-F, -Cl, -(Ci-C5)alkyl, - (C3-C5)cycloalkyl, -CD3, -O(C1C5)alkyl, -NR8R9, -NO2-CONR10R11, -C(O)R12, hydrogen and deuterium, preferably hydrogen, -Cl, -F, deuterium, -OCH3, -NR8R9, -C(O)R12, -CH3, -CD3;R1, R2, R3, and R4are independently selected from the group consisting of -(C1C5)alkyl, C(O)alkyl and hydrogen, preferably -(Ci-C5)alkyl, C(O)alkyl and hydrogen;R5, R6, R7, R8, R9, R10, R11and R12are independently selected from the group consisting of -(C1- C5)alkyl and hydrogen, preferably -(C1C5)alkyl and hydrogen;X and Y are independently selected from the group consisting of -S-, NH-, -CH2S-, -CH2O-, - OCH2-, CH2NH-, -S-CH2-, -NH-CH2-, and -C=C-, preferably -S-;Z1and Z2are independently selected from the group consisting of CH, and N; wherein in -(C1C5)alkyl, one or more hydrogens may be substituted by a substituent selected from the group consisting of F, deuterium, -OH;wherein the compound is notor a pharmaceutically acceptable salt, solvate or hydrate thereof.

2. The compound of claim 1 , whereinA and B are independently selected from the group consisting of -(C1C5)alkyl,preferably methyl and CH2CH2OH; p is 0 or 1 ; k is 0;G is O, -NR1, -CH2-;C, D, E, and W are independently selected from the group consisting of hydrogen, -F, deuterium, -OCH3>-NR®R9, -C(O)R12, -CH3, CD3;R1, R5, R8, R9, and R12are independently selected from the group consisting of -(C1-C5)alkyl, and hydrogen;X and Y are independently selected from the group consisting of S.

3. The compound according to claim 1 or 2, whereinA and B are independently selected from the group consisting of -(C1-C5)alkyl, -CH2CH2OH,, preferably methyl; p is 1; k is 0;G is O; wherein in -(CrC5)alkyl and -C(O)alkyl, one or more hydrogens may be substituted by a substituent selected from the group consisting of -OH;C, D, E, and W are independently selected from the group consisting of hydrogen, -F, -Cl deuterium, -CH3and -CD3;Z1and Z2are independently selected from the group consisting of CH, and N;X and Y are S.

4. The compound according to claim 1 or 2 wherein the compound is selected from the group consisting of100 101 102 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

5. The compound according to claim 1 or 2, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate or hydrate thereof.

6. A compound according the formular use in medicine.

7. A pharmaceutical composition comprising the compound of claims 1 to 6 and at least one pharmaceutically acceptable carrier.

8. The compound of claims 1 to 5 or the pharmaceutical composition of claim 7 for use in medicine.

9. The compound of claims 1 to 6 or the pharmaceutical composition of claim 7 for use as TRAF2 inhibitor.

10. The compound of claims 1 to 6 or the pharmaceutical composition of claim 7 for use in the treatment of a disease caused by an infection with the Epstein-Barr virus and / or a disease which is associated with TRAF2.

11. The compound of claims 1 to 6 or the pharmaceutical composition of claim 7 for use in the treatment of cancer, preferably the cancer is selected from the group consisting of i) Epstein-Barr virus (EBV) associated cancers and lymphoproliferations expressing LMP1, preferably post-transplant lymphoproliferative disease (PTLD), EBV-positive Hodgkins’s lymphoma (HL), EBV-associated NK-cell and T-cell lymphoma, EBV-positive diffuse large B cell lymphoma (DLBCL), nasopharyngeal carcinoma, and infectious mononucleosis (IM); and / or ii) primary effusion lymphoma (PEL), Kaposi's sarcoma, and multicentric Castleman’s disease; ABC-DLBCL (activated B cell-type diffuse large B cell lymphoma); classical EBV-negative Hodgkin’s lymphoma, MALT-lymphoma, and multiple myeloma.

12. The compound of claims 1 to 6 or the pharmaceutical composition of claim 7 for use in the treatment of an EBV associated neuronal disease such as multiple sclerosis (MS), retinopathies induced by diabetes and ischemia / reperfusion, skin inflammation, cardiovascular inflammation, inflammatory bowel diseases, liver inflammation, autoimmune inflammatory diseases, rheumatoid arthritis, acute and chronic lung disease, acute respiratory distress syndrome (ARDS), and diabetes.

13. Use of the compound of claims 1 to 6 as TRAF2 inhibitor in biochemical assays, cell culture systems, or animal models.

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