Compounds

Abstract

The present invention relates to [3-(sulphonyl or sulfonimidoyl)prop-2-en-1-yl]carboxamide derivatives having the formula (I) or the pharmaceutical acceptable salt or prodrug thereof. The present invention further relates to the compound according to the invention for use in therapy, particularly for the treatment of cancer. The present invention further relates to a method for inhibiting Met1-linked ubiquitination. The present invention also relates to a pharmaceutical composition comprising the compound of the present invention.

Description

[0001] Compounds FIELD OF THE INVENTION The present invention relates to [3-(sulphonyl or sulfonimidoyl)prop-2-en-1-yl]carboxamide derivatives, or pharmaceutically acceptable salts thereof. The present invention further relates to the compound according to the invention for use as a medicament and also for use in the treatment of cancer. The present invention further relates to a method for inhibiting Met1-linked ubiquitination. The present invention also relates to a pharmaceutical composition comprising the compound of the present invention. BACKGROUND OF THE INVENTION Cellular homeostasis depends on adaptation to the environment through numerous signalling cascades that translate extrinsic and intrinsic cues and stresses into appropriate responses. Signalling is most commonly propagated through rapid and specific post-translational modifications (PTMs) of signalling proteins, resulting in adaptive changes at the transcriptional and translational levels. Failure to adapt can cause cell damage or cell death and may lead to disease. Methionine 1 (Met1)-linked ubiquitin (also referred to as linear ubiquitin) is a PTM that over the past decade has emerged as critically important for controlling vital signalling cascades and preventing cell death. Consequently, dysregulation of Met1-linked ubiquitin modifications is associated with severe pathologies, including immune disorders, cancer, and neurodegeneration, emphasising that the balance of one single subtype of PTM can be essential for maintaining homeostasis, preventing and treating life-threatening diseases. The linear ubiquitin (Ub) chain assembly complex (LUBAC) is the only known mammalian ubiquitin ligase that makes Met1-linked ubiquitin. Consequently, by controlling the function of LUBAC, the role and regulation of the Met1-linked ubiquitin can be controlled. LUBAC is composed of three proteins, HOIL-1-interacting protein (HOIP; also known as RNF31), Heme-Oxidised IRP2 Ub Ligase-1 (HOIL-1; also known as RBCK1), and SHANK-Associated RH Domain-Interacting Protein (SHARPIN). It was discovered that of these three proteins, HOIP (RNF31) has remarkable specificity and exclusively assembles Met1-Ub, whereas HOIL-1 and SHARPIN function as co-factors in LUBAC and are critical for HOIP activation. LUBAC was first described to regulate signalling in response to activation of tumour necrosis factor (TNF) receptor 1 (TNF-R1) and has since been found to regulate signal transduction by a wide range of NF-κB- activating immune receptors, including cytokine receptors, Toll-like receptors (TLRs), NOD-like receptors (NLRs), and antigen receptors. Therefore, LUBAC can be considered one of the core components of NF-κB-activating signalling pathways. Further detailed information about the mechanisms and pathways involved in the Met1-linked ubiquitin PTM and subsequent control of vital signalling cascades and preventing cell death is described by, for example, Hrdinka and Gyrd-Hansen ("The Met1-linked ubiquitin machinery: emerging themes of (De) regulation." Molecular cell 68.2 (2017): 265-280), Ning et al. ("Structures, functions, and inhibitors of LUBAC and its related diseases." Journal of Leukocyte Biology (2022)), Jahan et al. ("Met1-linked ubiquitin signalling in health and disease: inflammation, immunity, cancer, and beyond." Cell Death & Differentiation 28.2 (2021): 473- 492) and Oikawa et al. ("Cellular and Mathematical Analyses of LUBAC Involvement in T Cell Receptor-Mediated NF-ΚB Activation Pathway." Frontiers in immunology (2020): 3042). Given the above, by controlling the function of LUBAC, the role and regulation of the Met1-linked ubiquitin can be controlled, and, consequently, the development of diseases like cancers can be controlled. It is believed that by providing Met1-linked ubiquitination inhibitors, in particular LUBAC associated HOIP (RNF31) inhibitors, promising candidates for the treatment of cancers can be identified. The earlier patent application PCT / NL2023 / 050347 (which is incorporated in its entirety into the present application), filed by the same applicant and inventors, discloses 3-(sulphonyl or sulfonimidoyl)prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives for use in the treatment of cancer. Compounds of the present invention have been further developed from compounds of this earlier application by the present inventors. SUMMARY OF THE INVENTION The inventors have surprisingly found that compounds of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, are expected to have a therapeutic benefit for the treatment of cancers. As will be evident from the in vitro data presented below, compounds of formula (I) are expected to provide therapeutic options in treating cancer. A first aspect of the present invention is a compound having the formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein R1is: wherein: m is 0 or 1; R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C0- C6)alkyl(C3-C6)cycloalkyl, (C0-C6)alkyl(C3-C6)aryl, (C0-C6)alkyl(C2-C5)heterocycloalkyl and SR10, wherein the (C1-C6)alkyl, cycloalkyl, aryl and heterocycloalkyl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; A is O or N; when A is O, m is 0; Y is C or N; when Y is N, R6is not present; each t is independently selected from the group consisting of 1, 2 or 3; when t is 1, n is 0; R2and R3are each independently selected from the group consisting of H, (C1-C4)alkyl and wherein R2and R3together with the carbon to which they are attached form (C3- C6)cycloalkyl; R4is selected from the group consisting of H, Hal and (C1-C6)alkyl; R5is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl(Hal0-4), (C2-C9)heterocycloalkyl(Hal0-4), (C3-C6)cycloalkoxy, (C6-C10)aryl(Hal0-4), (C6-C10)aryloxy, CN, primary, secondary and tertiary amino; R6and R7are each independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C6)cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one to four substituents selected from Hal, and (C1-C6)alkyl; R8is selected from the group consisting of H, OH, Hal, (C1-C6)alkyl and O(C1-C6)alkyl; n is 0 or 1; R9, when present, is CH2bonded to two independent carbon atoms of the cyclic ring, forming a methylene bridge between the two carbon atoms of the cyclic ring; R10is CH3 or CHal(1-3); when n is 0, i) R8is not H or ii) A is N and R11is not H; and when Y is C, at least one of R6, R7or R8is not H. A second aspect of the present invention is a compound having the formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein R1is: wherein: m is 0 or 1; R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C3-C6)aryl and SR10; A is O or N; when A is O, m is 0; Y is C or N; when Y is N, R6is not present; each t is independently selected from the group consisting of 1, 2 or 3; when t is 1, n is 0; R2and R3are each independently selected from the group consisting of H, (C1-C4)alkyl or wherein R2and R3together with the carbon to which they are attached form (C3-C6)cycloalkyl; R4is selected from the group consisting of H, Hal and (C1-C6)alkyl; R5is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, CN, primary, secondary and tertiary amino; R6and R7are independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C6)cycloalkyl wherein the alkyl or cycloalkyl is optionally substituted with one to four substituents selected from Hal and (C1-C6)alkyl; n is 0 or 1; R8is selected from the group consisting of H, OH, Hal, (C1-C6)alkyl and O(C1-C6)alkyl; R9, when present, is CH2bonded to two independent carbon atoms of the cyclic ring, forming a methylene bridge between the two carbon atoms of the cyclic ring; R10is CH3 or CHal(1-3); when n is 0, i) R8is not H or ii) A is N and R11is not H; and when Y is C, at least one of R6, R7or R8is not H. A third aspect of the present invention is a compound having formula (II): or a pharmaceutically acceptable salt or prodrug thereof, wherein: m is 0 or 1; R11, when present, is H; A is O or N; when A is O, m is 0; and R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy. A fourth aspect of the present invention is a compound having formula (III): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R6and R7are independently selected from H and (C1-C3)alkyl; and R8is selected from the group consisting of OH, (C1-C4)alkyl and O(C1-C4)alkyl. A fifth aspect of the present invention is a compound having formula (IV): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R11is selected from the group consisting of H, (C1-C6)alkyl, (C0-C6)alkyl(C3- C6)cycloalkyl, (C0-C6)alkyl(C3-C6)aryl, (C0-C6)alkyl(C2-C5)heterocycloalkyl and SR10, wherein the (C1-C6)alkyl, cycloalkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy or CN; R8is H or OH; n is 0 or 1; R9, when present, is CH2bonded to two independent carbons atoms of the cyclic ring, forming a methylene bridge between the two carbon atoms of the cyclic ring; R10is CHal(1-3); and when n is 0, i) R8is not H or ii) A is N and R11is not H. A sixth aspect of the present invention is a compound having formula (VIII): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R11is selected from the group consisting of H, (C1-C6)alkyl and (C0-C6)alkyl(C3-C6)aryl, wherein the (C1-C6)alkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R5is (C6-C10)aryl, wherein the aryl group is optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C2- C9)heterocycloalkyl(Hal0-4), (C6-C10)aryloxy, CN and secondary amino; and t is 1, 2 or 3. A seventh aspect of the present invention relates to a composition comprising the compound of the present invention, or pharmaceutically acceptable salt or prodrug thereof, wherein the composition further comprises at least one carrier. An eighth aspect of the present invention relates to a pharmaceutical composition comprising the compounds of the present invention, or a pharmaceutically acceptable salt or prodrug thereof. A nineth aspect of the present invention relates to a method for inhibiting Met1-linked ubiquitination, wherein the method comprises the administration of a compound of the present invention. A tenth aspect of the present invention relates to a method of treating cancer comprising administering to the patient in need thereof with a compound of the present invention, or a pharmaceutically acceptable salt thereof. An eleventh aspect of the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION In the present invention, and as demonstrated by the below in vitro data, compounds of formula (I) have been shown to exhibit promising RNF31 inhibiting properties (in a cell-free HTRF-based HOIP inhibition assay), thus providing a promising candidate as Met1-linked ubiquitination inhibitor. It was further found that compounds of the present invention downregulate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway and / or upregulate necrosis factor alpha (TNFα) induced cytotoxicity and are therefore, expected to offer therapeutic options for treating cancer. Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skills in the art to which this invention pertains. The term “comprises” or “comprising” will take its usual meaning in the art, namely indicating that the component includes but is not limited to the relevant features (i.e. including, among other things). As such, the term “comprises” will include references to the component consisting essentially of (such as consisting of) the relevant features. The term “consists of” or “consisting of” will take its usual meaning in the art, namely indicating that the component includes and is limited to the relevant features. The symbol “-” at the end of a group will take its usual meaning in the art, namely indicating the point of attachment of the group to the rest of a molecule. For example, a carbon substituted with -NH-C(O)-, will be interpreted as a carbon atom with a bond formed between the carbon and the nitrogen or oxygen of the -NH-C(O)- group. The expression “optionally substituted” as used herein means that the group may be unsubstituted or substituted by one or more substituents. Typically, such groups will be unsubstituted, or “one or more” means the group is substituted by one, two or three substituents, in particular one or two substituents, such as one substituent. Variations to the number and types of substituents have been found to alter the chemical properties of the compounds, particularly in relation to those impacting their therapeutic utility e.g., efficacy, RNF31 inhibition, stability, half-life, bioavailability, solubility. As appropriate and as is common in the art, chemical symbols of elements have been used rather than writing out the full chemical name. For example, C is carbon, N is nitrogen, O is oxygen, H is hydrogen. The term “aromatic” as used herein has its standard definition known in the art to be a conjugated system often made of alternating single and double bonds in a ring, for example a benzene or phenyl (Ph) ring. The term “Hal” as used herein means halogen. Halogens may suitably be Br, Cl or F, preferably Cl or F, more preferably F. The term “CHal1-3” as used herein means a carbon substituted by 1 to 3 halogens, preferably Cl or F, more preferably F. The other valence(s) on the carbon atom are filled with H (and the bond to the rest of the compound). Examples of CHal2may include CHCl2or CHF2and examples of CHal1 may include CH2Cl or CH2F. The term “R(Hal0-4)”, wherein R is a ring selected from (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl or (C6-C10)aryl, as used herein means the ring is optionally substituted by 1 to 4, such as 1 to 2, halogens, preferably Cl or F, more preferably F. Suitably when there are 2 to 4 substitutions, the substitutions may be on one or more of the carbon atoms of the ring. In a particular embodiment, the substitutions are on the same carbon. Examples of (C2- C9)heterocycloalkyl(Hal0-4) include difluoropyrrolidine. Alkyl groups which may be present on the compounds of the present invention include straight- chained and branched (C1-C6)alkyl groups, for example and preferably (C1-C4)alkyl or (C1-C2)alkyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. In one embodiment, alkyl refers to straight chain alkyl. Alkylene is to be construed in the same way as alkyl except that it is a divalent group. Derived expressions such as “(C1-C6)alkoxy”, and “(C1-C6)acyl” are to be construed accordingly. Further, the term “di-(C1-C6)alkyl” as used herein is intended to refer to two alkyl groups comprising 1 to 6 carbon atoms attached to the same carbon. Alkenyl groups may be branched or straight-chained and may contain one or more carbon- carbon double bond(s). (C2-C6)alkenyl groups may for example represent (C2-C4)alkenyl or (C2- C3)alkenyl. Examples of alkenyl groups include allyl, vinyl, ethenyl, propenyl and butenyl. Alkynyl groups may be branched or straight-chained and may contain one or more carbon- carbon triple bond(s). (C2-C6)alkynyl groups may for example represent (C2-C4)alkynyl or (C2- C3)alkynyl. Examples of alkynyl groups include ethynyl, propynyl, propargyl and butynyl. The term “(C3-C10)cycloalkyl” as used herein refers to monovalent groups of 3 to 10 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof. (C3-C10)cycloalkyl groups may for example represent (C3-C8)cycloalkyl or preferably (C3-C6)cycloalkyl, more preferably (C5-C6)cycloalkyl. Suitable (C3-C10)cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl. The term “(C3-C6)cycloalkyl” as used herein refers to monovalent groups of 3 to 6 carbon atoms derived from a saturated monocyclic hydrocarbon, such as including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The term “(C3-C10)cycloalkyl” may also refer to cycloalkenyl groups, and may comprise benzo-fused analogues thereof. In one embodiment, the “(C3-C10)cycloalkyl” are fully saturated. The term “aryl” as used herein has its standard definition known in the art to be a cyclic compound that has a conjugated system often made of alternating single and double bonds in a ring i.e., it is aromatic, for example a benzene ring. The term “(C2-C9)heterocycloalkyl” as used herein refers to saturated monocyclic rings containing 2 to 9 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 5 to 6 carbon atoms, such as 6 carbon atoms, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen, and may comprise benzo- fused analogues thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro- [1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl groups. The term “(C2-C9)heteroaryl” as used herein refers to monovalent aromatic groups containing 2 to 9 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 5 to 6 carbon atoms, such as 6 carbon atoms, derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, diazepanyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]-pyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups. Preferably heterocycloalkyls or heteroaryls contain one to three heteroatoms, preferably one or two, such as one. When there is more than one heteroatom in a heterocycle, the heteroatoms may be the same atom or different atoms. Preferably the heteroatom is selected from sulphur, oxygen or nitrogen, preferably oxygen or nitrogen. The term “alkoxy” as used herein means alkyl which is singularly bonded to an oxygen. Examples of such alkoxy groups include methoxy and ethoxy. The term “hydroxyalkyl” as used herein means alkyl with hydroxyl substituent in any position. Examples of hydroxyalkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl and 4-hydroxy-n-butyl. The term “(C4-C9)spiroheterocycloalkyl” as used herein refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom. Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-heptanyl, 2-azaspiro[3.3]heptanyl, 2- oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]-octanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro-[3.5]nonanyl, 2,4,8-triazaspiro[4.5]decanyl, 1-oxaspiro[2.3]hexanyl, 2-oxaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl and 2-oxaspiro[3.5]nonanyl groups. The term “(C5-C9)bicycloalkyl” as used herein refers to monovalent groups of 5 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl groups. Alternatively or in addition, instead of (C5-C9)bicycloalkyl groups, also (C4-C9)heterobicycloalkyl groups may be present on the compounds of the present invention which (C4-C9)heterobicycloalkyl groups corresponds to the (C5-C9)bicycloalkyl groups wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen. Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1. 1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl and 3,9- diazabicyclo[4.2.1]nonanyl. Derived expressions such as “(C6-C10)aryl(C1-C6)alkyl”, “(C2-C9)heteroaryl(C1-C6)alkyl”, “(C3-C10)cycloalkyl(C1-C6)alkyl” and “(C1-C6)alkoxy(C1-C6)alkyl” are to be construed accordingly. For example, suitable (C6-C10)aryl(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl groups. Suitable (C2-C9)heteroaryl(C1-C6)alkyl groups include pyridylmethyl, pyridazinylmethyl, oxadiazolylmethyl, furanylethyl, oxo-pyridinylethyl and 1H- indazolylmethyl groups. Suitable (C3-C10)cycloalkyl(C1-C6)alkyl groups include cyclopropylmethyl groups. Suitable (C1-C6)alkoxy(C1-C6)alkyl groups include methoxyethyl and methoxypropanyl groups. Derived expressions such as “(C0-C6)alkyl(C3-C6)cycloalkyl”, “(C0-C6)alkyl(C3-C6)aryl” and “(C0- C6)alkyl(C2-C5)heterocycloalkyl” are to be construed accordingly and mean that the (C3- C6)cycloalkyl, (C3-C6)aryl or (C2-C5)heterocycloalkyl group is optionally substituted with a (C1- C6)alkyl. For example, a suitable “(C0-C6)alkyl(C3-C6)aryl” is methylbenzene. A suitable (C0- C6)alkyl(C2-C5)heterocycloalkyl group is methyloxetane. Suitably when present, the (C1-C6)alkyl may be acting as a linker between the cycloalkyl, aryl or heterocycloalkyl groups and the rest of the compound. The term “primary amino” as used herein refers to a nitrogen bonded to two hydrogens and one “R” group. Examples of such primary amines include methylamine and aniline. The term “secondary amino” as used herein refers to a nitrogen bonded to one hydrogen and two “R” groups. Examples of such secondary amines include dimethylamine and diphenylamine. The term “tertiary amino” as used herein refers to a nitrogen bonded to three “R” groups. Examples of such tertiary amines include trimethylamine and pyridine. The term “methylene bridge” as used herein refers to a carbon bonded to two hydrogen atoms and two other distinct atoms in the rest of a molecule via single bonds. For example, a cyclic ring may comprise a methylene group bonded to two independent carbon atoms of the cyclic ring, forming a methylene “bridge” between the two independent carbon atoms of the ring. In one embodiment the two carbon atoms of the ring are not adjacent to each other, to avoid potential unfavourable ring strain. Examples of such rings include bicyclo[2.2.1]heptane, decahydro-1,3-methanonaphthalene and decahydro-1,4-methanonaphthalene. In addition, it is further noted that the optional substituents as defined for the present invention may comprise further substituents as such. For example, in case a specific group is optionally substituted with (C1-C6)alkoxy, the (C1-C6)alkoxy may be further substituted with, for example, Hal, hydroxy, cyano, oxo, primary, secondary or tertiary amino or the like. The present invention includes solvates of the compounds of the present invention. Such solvates may be formed with common organic solvents, e.g., hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates. Compounds with which the invention is concerned, which may exist in one or more stereoisomeric forms because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomers with R or S stereochemistry at each chiral axis. Compounds of the invention include all such enantiomers, diastereoisomers and mixtures thereof. The invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of the present invention may exist as tautomers, for example keto (CH2C=O) <-> enol (CH=CHOH) tautomers, amide (NHC=O) <-> hydroxyimine (N=COH) tautomers or 2-hydroxypyridine <-> 2-pyridone tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. Where an atom is identified herein, whether written or structurally indicated, said atom may be replaced by any known atomic isotopes of said atom, including stable and radioactive isotopes (i.e. variants of said atom differing in neutron number); for example, a deuterium atom may replace a hydrogen atom where a hydrogen atom is indicated. Synthetic methods for incorporating stable- and radio-isotopes are well-known in the art. Preferably, the atom is as identified herein. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a12C,13C or14C atom, preferably12C. Compounds of the invention also include co-crystals of the compounds of the present invention. The term “co-crystal” is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity. Typical examples of co-crystal formers, which may be present in the co-crystal alongside the active pharmaceutical ingredient, include L-ascorbic acid, citric acid, glutaric acid, urea and nicotinamide. Compounds of the invention also extend to all polymorphic forms of the compounds herein defined, including salts thereof. Preferred embodiments of the invention will now be described in further detail. Suitably R2, R3and R4are all H, such compounds of the invention were found to exhibit further improved RNF31 inhibiting properties as well as improved downregulating properties of the NF- κB signalling pathway and / or upregulating properties of TNFα induced cytotoxicity. Suitably, m is 0 or 1, preferably 1. Suitably, R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C0- C6)alkyl(C3-C6)cycloalkyl, (C0-C6)alkyl(C3-C6)aryl, (C0-C6)alkyl(C2-C5)heterocycloalkyl and SR10, wherein the (C1-C6)alkyl, cycloalkyl, aryl and heterocycloalkyl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy. Suitably, when R11 is the (C1-C6)alkyl or (C0-C6)alkyl(C3-C6)cycloalkyl, the optional substitutions are preferably one to three Hal (preferably F) and / or one (C1-C6)alkoxy. Preferably R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C0- C6)alkyl(C3-C6)aryl, and SR10, wherein the (C1-C6)alkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy and most preferably, R11, when present, is H, (C1-C6)alkyl or (C0-C6)alkyl(C3-C6)aryl, wherein the (C1-C6)alkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy. Suitably, A is O or N, preferably N. Suitably, Y is C or N, preferably C. Suitably, R2, R3, and R4are each independently selected from the group consisting of H and (C1- C4)alkyl, preferably, R2, R3, and R4are all H. Suitably, R5is (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C9)heterocycloalkyl(Hal0-4), (C6-C10)aryloxy, CN or secondary amino, preferably R5is phenyl substituted with one to three Hal, (C1-C6)alkyl, (C1-C6)alkoxy, CN or secondary amino. Preferably the (C6-C10)aryl is (C6-C8)aryl, preferably (C6)aryl. Suitably, R5is (C6-C10)aryl substituted with (C2-C9)heterocycloalkyl(Hal0-4). Example of R5is difluoro-phenylpyrrolidine. Alternatively, R5is (C6-C10)aryl substituted with (C6-C10)aryloxy. Example of R5is oxydibenzene. Suitably, R6and R7are each independently selected from the group consisting of H and (C1- C6)alkyl, preferably H and (C1-C4)alkyl and more preferably, H and CH3. Suitably, n is 0 or 1, preferably 0. Suitably, t is 1, 2 or 3, preferably 1 or 2 and most preferably, t is 2. Suitably, R10is CH3 or CHal(1-3), preferably CHal(1-3) and most preferably R10is CHal(1-3), wherein Hal is Cl or F, preferably F. In one embodiment, the present invention relates to a compound of formula (I) as described above and herein wherein: R2, R3and R4are H; and R5is (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy. In one embodiment, the present invention relates to a compound of formula (I) as described above and herein wherein: R2, R3and R4are H; and when Y is C, R6and R7are independently selected from the group consisting of H and (C1-C4)alkyl, R8is selected from the group consisting of H, OH, (C1-C6)alkyl and O(C1-C6)alkyl and at least one of R6, R7or R8is not H; or when Y is N, R7is (C1-C4)alkyl and R8is H. In one embodiment, the present invention relates to a compound having the formula (II): or a pharmaceutically acceptable salt or prodrug thereof, wherein: m is 0 or 1; R11, when present, is H; A is O or N; when A is O, m is 0; and R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy. In one embodiment, the present invention relates to a compound having the formula (III): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R6and R7are independently selected from H and (C1-C3)alkyl; and R8is selected from the group consisting of OH, (C1-C4)alkyl and O(C1-C4)alkyl. In one embodiment, the present invention relates to a compound having the formula (IV): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R11is selected from the group consisting of H, (C1-C6)alkyl, (C0-C6)alkyl(C3- C6)cycloalkyl, (C0-C6)alkyl(C3-C6)aryl, (C0-C6)alkyl(C2-C5)heterocycloalkyl and SR10, wherein the (C1-C6)alkyl, cycloalkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy or CN; R8is H or OH; n is 0 or 1; R9, when present, is CH2bonded to two independent carbon atoms of the cyclic ring, forming a methylene bridge between the two carbon atoms of the cyclic ring; R10is CHal(1-3); and when n is 0, i) R8is not H or ii) A is N and R11is not H. In relation to formula (IV), preferably, R8is OH. In one embodiment, the present invention relates to a compound having the formula (VIII): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R11is selected from the group consisting of H, (C1-C6)alkyl and (C0-C6)alkyl(C3-C6)aryl, wherein the (C1-C6)alkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R5is (C6-C10)aryl, wherein the aryl group is optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C2- C9)heterocycloalkyl(Hal0-4), (C6-C10)aryloxy, CN and secondary amino; and t is 1, 2 or 3. In one embodiment, the present invention relates to a compound having the formula (V): or a pharmaceutically acceptable salt or prodrug thereof, or wherein: wherein: R11is selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)aryl and SR10; X is C or N or wherein R12-X is O; Y is C or N; Z is H, (C1-C6)alkyl or di-(C1-C6)alkyl; R2and R3are each independently selected from the group consisting of H and (C1-C4)alkyl or wherein R2and R3together with the carbon to which they are attached form (C3-C6)cycloalkyl; R4is selected from the group consisting of H, Hal and (C1-C6)alkyl; R5is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, CN, primary, secondary and tertiary amino; R10is CH3or CHal(1-3); when X is C, R12, when present, is R4and R12’, wherein R4is as defined above, and wherein R12’ is selected from the group consisting of H, Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl(C2-C6)alkynyl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl; when X is N, R12is selected from the group consisting of H, (C1-C6)alkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, and (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl or wherein R12is R13M, wherein: M is selected from the group consisting of -C(O)-, -O-C(O)-, -NH-C(O)- and -S(O)2-; and R13is selected from the group consisting of (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl and (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four Hal, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, CN, =O and OH; and p is 1, 2, 3 or 4. Preferred embodiments of formula (V) will now be described in further detail. Suitably R2, R3and R4are all H, such compounds of the invention were found to exhibit further improved RNF31 inhibiting properties as well as improved downregulating properties of the NF- κB signalling pathway and / or upregulating properties of TNFα induced cytotoxicity. Suitably, R5is selected from the group consisting of (C6-C10)aryl and (C2-C9)heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, CN, primary, secondary and tertiary amino. Suitably, when X is C, R12, when present, is R4and R12’, wherein R4is as defined above, and wherein R12’ is selected from the group consisting of H, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl. Suitably, when X is N, R12is selected from the group consisting of R13M, H, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl. Suitably, when X is N and R12is R13M, M is selected from the group consisting of -O-C(O)-, -NH- C(O)- and -S(O)2-, and R13is selected from the group consisting of (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl and (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four Hal, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, CN, =O and OH. Suitably, X is N, and R12is not H. Suitably, p is 1, 2, 3 or 4, preferably 1, 2 or 3. In one embodiment, the present invention relates to a compound having formula (VI): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R5is selected from the group consisting of (C1-C6)alkyl, (C6-C10)aryl and (C2-C9)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, CN, primary, secondary and tertiary amino; R11is selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)aryl and SR10, wherein the aryl group is optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy; R10is CH3 or CHal(1-3); and p is 1, 2 or 3. In relation to formula (VI), preferably the (C6-C10)aryl is phenyl and the (C2-C9)heteroaryl is pyridinyl, wherein the phenyl or pyridinyl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br and methoxy. In one embodiment, the present invention relates to a compound having formula (VII): or a pharmaceutically acceptable salt or prodrug thereof, wherein: R5is selected from the group consisting of (C6-C10)aryl and (C2-C9)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, CN, primary, secondary and tertiary amino; R11is selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)aryl and SR10; R10is CH3 or CHal(1-3); M’ is C or -O-C(O)-; and R13is selected from the group consisting of (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl and (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four Hal, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, CN, =O or OH. In one embodiment, compounds of the present invention, are selected from the group consisting of: N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4- carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-6- methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4- hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4,5- dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4- hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-ethoxy-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1- yl]-2-oxo-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo- 2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4-oxo- 3-azatricyclo[6.2.1.0,2,7]undeca-2(7),5-diene-5-carboxamide; N-[(2E)-3-[(cyclopropylimino)(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1- yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo)(propylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]- 2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo) (phenylimino)-λ⁶-sulfanyl]prop-2-en-1- yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]- 2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(ethylimino)(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2- oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo){[(trifluoromethyl)sulfanyl]amino}-λ⁶- sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4-oxo-3- azatricyclo[6.2.1.0²,⁷]undeca-2(7),5-diene-5-carboxamide; N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4-oxo-3- azatricyclo[6.2.1.0²,⁷]undeca-2(7),5-diene-5-carboxamide; N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo- 2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-{[4-(3,3-difluoropyrrolidin-1-yl)phenyl](imino)oxo-λ⁶-sulfanyl}prop-2-en-1- yl]-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[imino(oxo)(4-phenoxyphenyl)-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo- 2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-{imino[4-(methylamino)phenyl]oxo-λ⁶-sulfanyl}prop-2-en-1-yl]-3-oxo- 2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-{[3-cyano-4-(methylamino)phenyl](imino)oxo-λ⁶-sulfanyl}prop-2-en-1-yl]- 3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-{[3-fluoro-4-(methylamino)phenyl](imino)oxo-λ⁶-sulfanyl}prop-2-en-1-yl]- 3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo- 2H,3H,5H,6H,7H-cyclopenta[c]pyridine-4-carboxamide; N-[(2E)-3-[imino(4-methoxy-2,3-dimethylphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3- oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(2-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo- 2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo- 2H,3H,5H,6H,7H,8H,9H-cyclohepta[c]pyridine-4-carboxamide; N-[(2E)-3-{[3-fluoro-5-(pyrrolidin-1-yl)phenyl](imino)oxo-λ⁶-sulfanyl}prop-2-en-1-yl]- 3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-λ⁶-sulfanyl]prop-2- en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-λ⁶-sulfanyl]prop-2- en-1-yl]-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-λ⁶-sulfanyl]prop-2- en-1-yl]-4-oxo-3-azatricyclo[6.2.1.0²,⁷]undeca-2(7),5-diene-5-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-λ⁶-sulfanyl]prop-2- en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]- 3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(²H₃)methylimino]oxo-λ⁶-sulfanyl]prop-2-en- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]- 2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide; N-[(2E)-3-[(4-cyanophenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo- 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-cyanophenyl)[(2-fluoroethyl)imino]oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2- oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]- 2-oxo-1,2-dihydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)({[(oxetan-3-yl)methyl]imino})oxo-λ⁶- sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(benzylimino)(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2- oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2-en-1- yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2-en-1- yl]-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide; N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2-en-1- yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide; and N-[(2E)-3-[methyl(oxo)(phenylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- hexahydroquinoline-3-carboxamide. The present invention also provides a method of preparing compounds of formula (I). Compounds of formula (I): may be prepared by a process comprising treating a compound of Int. 1: with R1-COOH in the presence of an amide coupling agent and an organic base, suitably in a polar solvent such as DMF or acetonitrile. Suitably, the amide coupling agent may be n-propanephosphonic acid anhydride (T3P) or 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Suitably, the organic base may be triethylamine or diisopropylethylamine. Suitably, the reaction mixture is stirred at room temperature for a period of time between 8h and 72h, preferably between 9h and 30h, preferably 16h. Room temperature refers to 20 to 25°C. Compounds of formula (I), wherein A-R11is N-H, may further be treated with N- bromosuccinimide and a silver salt of a thiol in a solvent, such as acetonitrile, to obtain compounds of formula (I) wherein A is N and R11is SR10. Suitably, the reaction mixture is stirred at room temperature for a period of time between 1h and 24h, preferably 16h. Therapeutic Uses The term “treatment” or “treating” as used herein, refers to therapeutic (curative) treatment including amelioration. Treatment also includes stopping the disease from developing or slowing further progression of the disease. For example, treatment may include preventing symptoms from worsening. The term “prevention” as used herein, refers to prophylaxis treatment i.e., action taken to prevent disease. The terms “patient” and “subject” are used interchangeably and refer to a subject of treatment or prevention with the pharmaceutical composition comprising compounds of the present invention. Preferably, the subject is human. Suitably, the subject has cancer. Suitably the cancer is melanoma, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, breast cancer, bone cancer, lung cancer or haematological malignancies. In one embodiment, there is provided a pharmaceutically acceptable salt of the compound of formula (I). For use in medicine, the salts of the compounds of the present invention will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. As used herein, a “pharmaceutically acceptable salt” is a salt with a pharmaceutically acceptable acid or base. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as ethanesulfonic, maleic, malonic, L-tartaric, fumaric, citric, succinic, acetic, triphenyl acetic, hydrochloric, sulfuric, phosphoric, 1-hydroxy-2-naphthoic, hydrobromic, methanesulfonic, tartaric, palmitic, isethionic, pamoic, formic, cinnamic benzoic, ascorbic, galactaric, lactic, malic, oxalic, para- toluenesulfonic, benzenesulphonic, propionic, furoic, phosphonic and glutaric acid. Furthermore, where the compounds of use in the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts, and meglumine salts. Compounds of the invention include pharmaceutically acceptable prodrugs thereof. The term “pharmaceutically acceptable prodrug” refers to a biologically inactive compound which can be metabolized in the body to produce a drug. Suitably, a compound of the invention is administered in the form of a prodrug which is converted to the active form during absorption into the body. Suitably, the compound prodrug of the present invention is an ester, carbonate, carbamate, amide, phosphate or oxime prodrug. In one embodiment, there is provided a pharmaceutical composition comprising a compound according to the invention optionally in combination with one or more pharmaceutically acceptable diluents or carriers. By “pharmaceutically acceptable diluent or carrier” is meant any diluent or excipient, such as fillers or binders, that is compatible with the other ingredients of the composition, and which is not deleterious to the recipient. The pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices. Diluents and carriers may include those suitable for parenteral, oral, topical including by inhalation via the mouth into the lungs or inhalation via the nose, mucosal and rectal administration, and may be different depending on the route of administration. In a preferred embodiment of the present invention, the use of the compound is combined with radiotherapy, targeted therapy, agents suitable for use in chemotherapy (chemotherapeutic agents), and / or agents suitable for use in immunotherapy (immunotherapeutic agents). In particular, the use of the compound is combined with such therapies and agents that cause increased levels of tumor necrosis factor (TNF), e.g. tumor necrosis factor alpha (TNFα) as the consequence of the treatment with such chemotherapeutic agents, immunotherapeutic agents, targeted therapy and / or radiotherapy. In one embodiment, there is provided a compound according to the invention, or a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of cancer. In one embodiment, there is provided a compound according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, for use as a medicament, optionally in combination with radiotherapy, agents suitable for use in chemotherapy, and / or agents suitable for use in immunotherapy, in particular wherein use of the compound is combined with chemotherapeutic agents, immunotherapeutic agents, targeted therapy and / or radiotherapy that cause increased levels of tumor necrosis factor (TNF). In one embodiment, there is provided a composition comprising a compound according to the invention optionally in combination with one or more pharmaceutically acceptable diluents or carriers. Cancers to be treated by compounds of the invention or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, include melanoma, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, breast cancer, bone cancer, lung cancer or haematological malignancies. It was found that compounds of the present invention exhibit particularly promising results in the treatment of ovarian cancer, lung cancer or haematological malignancies. Patients with dysregulation of Met1-linked ubiquitin, may be more prone to developing particular cancers. In one embodiment, there is provided a method for inhibiting Met1-linked ubiquitination. Such method may relate to an in vitro method. However, in another embodiment, the method may also relate to a method of treating a subject, such as a mammal or human, preferably human. As such, the present invention relates to the compound of the present invention for inhibiting Met1-linked ubiquitination. In one embodiment, there is provided a pharmaceutical composition comprising compounds of the present invention. Such compositions may further comprise at least one pharmaceutically acceptable carrier. In an embodiment of the present invention the pharmaceutical compositions may further comprise tumor necrosis factor (TNF). Examples of radiotherapies that cause increased levels of TNF, e.g. TNFα, are, for example, described in the following publications: Rodemann, H. Peter, and Marcel A. Blaese ("Responses of normal cells to ionizing radiation." Seminars in radiation oncology. Vol. 17. No. 2. WB Saunders, 2007), Di Maggio, Federica Maria, et al. ("Portrait of inflammatory response to ionizing radiation treatment." Journal of inflammation 12.1 (2015): 1-11), and Meng, Guanmin, et al. ("Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy." The FASEB Journal 31.9 (2017): 4064-4077). Examples of targeted therapies that cause increased levels of TNF, e.g. TNFα, are, for example, described in the following publications: Tabolacci et al. ("Melanoma cell resistance to vemurafenib modifies inter-cellular communication signals." Biomedicines 9.1 (2021): 79), Mercogliano et al. ("Tumor necrosis factor α blockade: an opportunity to tackle breast cancer." Frontiers in oncology 10 (2020): 584), and Labrie et al. ("Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer." Nature Reviews Cancer 22.6 (2022): 323-339). Examples of chemotherapeutic and / or immunotherapeutic agents that cause increased levels of TNF, e.g. TNFα, are, for example, described in the following publications: Edwardson et al. ("Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance." PloS one 12.9 (2017): e0183662), Mercogliano et al. ("Tumor necrosis factor α blockade: an opportunity to tackle breast cancer." Frontiers in oncology 10 (2020): 584), Vyas et al. ("Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis." OncoTargets and therapy 7 (2014): 1015), Husain et al. ("Inflammatory markers in autoimmunity induced by checkpoint inhibitors." Journal of Cancer Research and Clinical Oncology 147.6 (2021): 1623-1630), and Vanneman and Dranoff ("Combining immunotherapy and targeted therapies in cancer treatment." Nature reviews cancer 12.4 (2012): 237-251). It is noted that the inhibition of the Met1-linked ubiquitination comprises the inhibition of linear ubiquitin (Ub) chain assembly complex (LUBAC). Inhibition of LUBAC preferably includes the inhibition of RNF31 (HOIP). In one embodiment of the present invention, the present invention relates to a method for inhibiting Met1-linked ubiquitination, wherein the method comprises the administration of the compound according to the present invention, and wherein the inhibition of the Met1-linked ubiquitination comprises the irreversible or reversible inhibition of linear ubiquitin (Ub) chain assembly complex (LUBAC) via a covalent binding of the compound. It was found that the compounds of the present invention covalently inhibit the linear ubiquitin (Ub) chain assembly complex (LUBAC), in particular covalently inhibit RNF31. In one embodiment, there is provided a use of compounds of the invention, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for use in the treatment of cancer, preferably the cancer is selected from melanoma, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, breast cancer, bone cancer, lung cancer or haematological malignancies. This embodiment may have any of the preferred features described above. In one embodiment, there is provided a method of treating cancer comprising administering the patient with composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof. This embodiment of the invention may have any of the preferred features described above. The method of administration may be according to any of the routes described below. In one embodiment, the present invention also relates to formulations suitable for use as a pharmaceutical composition. Such formulations include, but are not limited to tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, patch, or suppositories, including rectal and urethral suppositories. In one embodiment, compositions may be prepared e.g. for parenteral administration e.g., subcutaneous, intramuscular, intravenous, intra-dermal, intra-articular or peri-articular administration, particularly in the form of liquid solutions or suspensions; for oral administration, particularly in the form of tablets, capsules, powder, granules, solid dispersions or in the form of liquid solutions or suspensions including nanosuspensions; for inhalation to the lungs or nose e.g. pulmonary or intranasal administration, particularly in the form of dry powders, solutions, suspensions including nanosuspensions for nebulisation, nasal sprays or drops comprising solutions or suspensions or suspension or solution pressurised or non-pressurised aerosols; for topical or transdermal administration e.g. as creams, sprays, foams, gels, ointments, liquids, patches; for mucosal administration e.g. to buccal, sublingual or vaginal mucosa, and for rectal administration e.g. in the form of a foam or suppository. The composition may also be administered by inhalation. An advantage of inhaled medications is their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed. The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985). The compositions may also conveniently be administered in multiple unit dosage form. The present invention also provides an inhalation device containing compositions comprising compounds of the present invention. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler. The composition comprising compounds of the present invention may also be administered by intranasal administration. The nasal cavity’s highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability. The composition may also be administered by transdermal administration. For topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions or suspensions may be employed. The composition may also be administered by sublingual administration. The composition may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound. Formulations for oral administration may comprise one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulphate. Liquid formulations may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents and surfactants such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Formulations for parenteral administration may contain as excipients sterile water or saline, buffers, tonicity-adjusting agents, preservatives, anti-oxidants, viscosity adjusting agents, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Formulations for nasal administration may be powders and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray. Formulations for nasal administration may also be in the form of aqueous suspensions or pressurised non-aqueous solutions or suspensions. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. In an embodiment of the invention, the compounds or compositions are administered in an effective amount to treat cancer. An effective dose will be apparent to one skilled in the art and is dependent on a number of factors including age, sex, weigh, which the medical practitioner will be capable of determining. For the avoidance of doubt, the present invention also embraces prodrugs which react in vivo to give a compound of the present invention. The following examples illustrate the invention. EXAMPLES Abbreviations Abbreviations as used herein will be known to those skilled in the art. In particular, the following abbreviations may be used herein: aq aqueous eq equivalents CDCl3Deuterated chloroform DCE 1,2-dichloroethane DCM Dichloromethane DMF N,N-dimethylformamide DMSO Dimethylsulfoxide MeOH Methanol HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate THF Tetrahydrofurann-propanephosphonic acid anhydride T3P n-Propanephosphonic acid anhydride NMR Nuclear magnetic resonance UPLC Ultra performance liquid chromatography Route of Synthesis The following reaction Schemes illustrate the preparation of the compounds of the present invention and reaction intermediates thereof. Unless indicated otherwise, R1, R4, R5, R10and R11in the reaction Schemes are as defined above. The compound numbers as used in this examples section are specific to the following examples and do not correspond to the compound numbers as used hereinbefore. Scheme 1: In Reaction 1 of Scheme 1, diethyl (tosyloxy)methylphosphonate is converted to thecorresponding thioether of formula III by treating the tosylate with a thiol in the presence of aninorganic base, such as potassium carbonate in anhydrous N,N-dimethylformamide. The reaction mixture is stirred at room temperature for a period of time ranging from 8h to 72h, preferably 12h.In Reaction 2 of Scheme 1, compound of formula III is oxidized to the corresponding sulfone offormula IV by treating III with oxidizing agent such as Oxone® monopersulfate or sodiumtungstate and hydrogen peroxide in a mixture of water and a polar solvent such as ethyl acetate or alcohol solvent such as methanol. The reaction mixture is stirred at room temperature for a period of time between 8h to 72h, preferably 12h. When R4is not hydrogen, compound offormula IV is treated with an electrophilic agent, e.g., Selectfluor® or iodomethane, in presenceof an organic base, e.g., potassium tert-butoxide in a polar aprotic solvent, e.g., tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of time between 8h to 24h, preferably 16h. In Reaction 3 of Scheme 1, compound of formula IV is converted to compound of formula V byreacting IV with (2-oxoethyl)carbamic acid tert-butyl ester in presence of an organic base such as potassium tert-butoxide in a polar aprotic solvent, e.g., tetrahydrofuran. The reaction mixture is stirred for a period of time between 1h to 24h, preferably 1.5h. In Reaction 4 of Scheme 1, removal of the protecting group from the compound of formula V is carried out by treating V with and an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of time between 10 min to 3h, preferably 1h. In Reaction 5 of Scheme 1, compound of formula III is oxidized to the corresponding sulfoxide of general structure VI by treating III with oxidizing agent such as Oxone®monopersulfate in stochiometric amounts in a mixture of water and alcohol solvent such as methanol. The reaction is stirred for a period of time between 8h to 72h, preferably 12h at room temperature. In Reaction 6 of Scheme 1, compound of formula VI is converted in compound of formula VII by treating sulfoxide with tert-butyl carbamate and iodobenzene diacetate in presence of rhodium (II) acetate dimer and magnesium oxide in a aprotic solvent such as dichloromethane. Reaction mixture is stirred at a temperature between 10oC and 70oC, preferably 40oC for a period of time between 6h to 72h, preferably 12h. In Reaction 7 of Scheme 1, compound of formula VII is converted in compound of formula VIII by reacting VII with (2-oxoethyl)carbamic acid tert-butyl ester in presence of organic base such as potassium tert-butoxide in a polar aprotic solvent such as tetrahydrofuran. The reaction mixture is stirred for a period of time between 1h to 24h, preferably 1.5h. In Reaction 8 of Scheme 1, removal of the protecting group from the compound of formula VIII is carried out by treating VIII with an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of time between 10 min to 3h, preferably 1h.

[0002] Scheme 2: In Reaction 1 of Scheme 2, 1,3-bis(1,1-dimethylethyl) 2-(2-propyn-1-yl) imidodicarbonate isconverted to the corresponding vinyl thioether of formula IX by treating alkyne with a thiol inpresence of rhodium catalyst preferably tris(triphenylphosphine)rhodium(I) chloride in an aprotic solvent preferably DCE. The reaction mixture is stirred at a temperature between -10°C to about 50°C, preferably 0oC for a period of time between 12h to 80h, preferably 24h.In Reaction 2 of Scheme 2, compound of formula IX is oxidized to the corresponding sulfoximineof formula X by treating IX with ammonium carbonate and iodobenzene diacetate in an alcoholsolvent such as methanol. The reaction mixture is stirred at a temperature between -10°C to about 50°C, preferably 0°C for a period of time between 10 min to 3h, preferably 30 min. In Reaction 3 of Scheme 2, removal of the protecting group from the compound of formula X is carried out by treating X with an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of time between 10 min to 3h, preferably 30 min. Scheme 3: In Reaction 1 of Scheme 3, the amine of general structure I and II are converted into thecorresponding amides of general structure XI and XII, respectively, by treatment with ancarboxylic acid in the presence of an amide coupling agent such as T3P or HATU and an organic base such as triethylamine or diisopropylethylamine in a polar solvent such as DMF or acetonitrile. The reaction mixture is stirred at room temperature for a period of time between 8h to 72h, preferably 16h. Scheme 4: In Reaction 1 of Scheme 4, sulfoximine of formula X is functionalized on the nitrogen to the corresponding substituted sulfoximine of formula XIII, where R11is an aryl or (cyclo)alkyl, by treating with a boronic ester or acid in the presence of a transition metal preferably copper or palladium, organic or inorganic base and a phosphine, in a solvent like dioxane or toluene. The reaction mixture is stirred at a temperature between 25°C to about 150°C, preferably 100°C for a period of time between 1h to 60h, preferably 2h. Alternatively, compound of formula X can be treated with a bromo alkyl in the presence of an inorganic base such as potassium carbonate in a polar aprotic solvent preferably DMF. The reaction mixture is stirred at a temperature between 25°C to 150°C, preferably 100°C with microwave irradiation for a period of time between 1h to 60h, preferably 2h.In Reaction 2 of Scheme 4, removal of the protecting group from the compound of formula XI tofurnish XII is carried out by treating XI with an acid such as hydrogen chloride in an aprotic polarsolvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of time between 10 min to 3h, preferably 30 min.In Reaction 3 of Scheme 4, amine of general structure XIV is converted into the correspondingamide of general structure XV by treating with an carboxylic acid in the presence of an amide coupling agent such as T3P or HATU and an organic base such as triethylamine or diisopropylethylamine in a polar solvent such as DMF or acetonitrile. The reaction mixture is stirred at room temperature for a period of time between 8h to 72h, preferably 16h. Scheme 5: In Reaction 1 of Scheme 5, the amide of general formula XV is functionalized to the corresponding sulfoximine of formula XVI, where R11is SR10, by treating XV (wherein R11is H) with N-bromosuccinimide and a silver salt of a thiol in a solvent such acetonitrile. The reaction mixture is stirred at room temperature for a period of time between 1h to 24h, preferably 16h. The following Examples illustrate the preparation of the compounds of the present invention and intermediates thereof, but is not limited to the details thereof. NMR data are reported in parts per million (δ) and are referenced to the deuterium lock signal from the sample solvent (deuterochloroform unless otherwise specified). Commercial reagents were used without furtherpurification. Room temperature refers to 20 to 25°C.Scheme 6: In Reaction 1A of Scheme 6, sulfoximine XVII is converted to the R11-substituted derivative XVII by treatment of XVII with R11-X (X = Cl, Br or I) in the presence of a transition metal like Pd,such as tris(dibenzylideneacetone)dipalladium(0), an organic or inorganic base, such as sodiumtert-butoxide and a phosphine, or in an aprotic solvent such as dioxane. The reaction mixture isstirred at a temperature between 40°C to about 150°C preferably at 100°C for a period of time between 1h to 72h, preferably 4h. In Reaction 1B of Scheme 6, sulfoximine XVII is converted to the R11-substituted derivative XVII by treatment of XVII with R11-X (X = Cl, Br or I) in the presence of an inorganic or organic base, preferably NaH 60% dispersion in mineral oil, in a protic solvent like DMF. The reaction mixture is stirred at a temperature between -10oC to 50oC, preferably at room temperature, for a period of time between 1h to 48h, preferably 16h. In Reaction 1C of Scheme 6, sulfoximine XVII is converted to the R11-substituted derivative XVII by treatment of XVII with R11-X (X = B(OH2) in the presence of a transition metal like copper such as Cu(OAc)2 and a protic polar solvent like methanol. The reaction mixture is stirred at room temperature for a period of time between 2h and 72h, preferably 16h. In Reaction 2 of Scheme 6, sulfoximine of general structure XVIII is converted into the corresponding phosphonate by treatment with diethyl chlorophosphate in the presence of an inorganic base, such as lithiumbis(trimethylsilyl)amide in THF at -78°C. The reaction mixture is stirred at room temperature for a period of time ranging from 30 min to 4h, preferably 1h. In Reaction 3 of Scheme 6, compound of formula XIX is converted to compound of formula XX by reacting XIX with (2-oxoethyl)carbamic acid tert-butyl ester in the presence of an organic base such as potassium tert-butoxide in a polar aprotic solvent, e.g., tetrahydrofuran. The reaction mixture is stirred for a period of time between 1h to 24h, preferably 1.5h. In Reaction 4 of Scheme 6, removal of the protecting group from the compound of formula XX is carried out by treating XX with and an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of time between 10 min to 3h, preferably 1h. Preparation of Intermediate (2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-amine hydrochloride (via Scheme 1) Reaction 1: Diethyl (tosyloxy)methylphosphonate (3.0 g, 9.1 mmol, 1.0 eq) and potassium carbonate anhydrous (3.15 g, 22.8 mmol, 2.5 eq) were suspended in anhydrous DMF (24.0 ml, 8.0 vol) before mixing with 4-bromothiophenol (1.91 g, 9.6 mmol, 1.05 eq) in one go and stirring at room temperature UPLC after stirring 12h indicated full consumption of the starting material to give the desired product. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 mL) and distilled water (30 mL) with saturated NaCl solution (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a light-yellow oil (3.39 g). The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 55%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-bromophenyl)sulfanyl]methyl}phosphonate, as a colorless oil (3.02 g, Y: 97%). UPLC and1H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 2.02, m / z: 341.0 [M+1]; Purity (254 nm): 99%; 1H NMR (300 MHz, Chloroform-d) δ 7.47 – 7.37 (m, 2H), 7.36 – 7.27 (m, 2H), 4.14 (dqd, J = 8.2, 7.0, 1.0 Hz, 4H), 3.17 (s, 1H), 3.13 (s, 1H), 1.31 (td, J = 7.1, 0.5 Hz, 6H). Reaction 2: Diethyl {[(4-bromophenyl)sulfanyl]methyl}phosphonate (0.4 g, 1.18 mmol, 1.0 eq.) was dissolved in anhydrous MeOH (4.0 ml) before addition of Oxone®, monopersulfate compound (0.91 g, 2.95 mmol, 2.5 eq.) solution in distilled water (4.0 ml), immediately turning the pale yellow solution into a bright white mixture. After stirring for 12h, UPLC analysis indicated full conversion to the desired product. The mixture was filtered through Celite, washed through with MeOH and concentrated under reduced pressure to a low volume. The reduced filtrate was partitioned between ethyl acetate (20 mL) and water (25 mL) with saturated NaCl solution (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give the desired product, diethyl [(4- bromobenzenesulfonyl)methyl]phosphonate, as a yellow oil (448 mg, Y: 99%). The product was used in the next step without any further purification. UPLC and1H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.99, m / z: 373.0 [M+1];1H NMR (300 MHz, Chloroform-d) δ 7.92 – 7.80 (m, 2H), 7.77 – 7.66 (m, 2H), 4.17 (dq, J = 8.3, 7.1 Hz, 4H), 3.77 (s, 1H), 3.72 (s, 1H), 1.36 – 1.27 (m, 6H). Reaction 3: Potassium tert-butoxide (0.13 g, 1.18 mmol, 1.0 eq.) was suspended in anhydrous THF (9.0 ml) with cooling to 0oC over 5 min. Diethyl [(4- bromobenzenesulfonyl)methyl]phosphonate (0.45 g, 1.18 mmol, 1.0 eq.) was added dropwise, as a solution in anhydrous THF (2.83 ml), instantly forming a yellow solution, which was stirred at 0oC under argon for 30 min. Tert-butyl N-(2-oxoethyl)carbamate (0.20 g, 1.24 mmol, 1.05 eq.) was added, as a solution in anhydrous THF (2.37 ml, 0.5 M) over 1 min, and the reaction was stirred under argon and, subsequently, allowed to reach room temperature. After 90 min, the reaction was concentrated under reduced pressure to give a yellow oil, which was partitioned between ethyl acetate (10 mL) and saturated aqueous NaHCO3(20 mL). The layers were separated and the organic layer was washed with saturated NaCl solution (20 mL). The combined aqueous layers were extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 36%). Clean product-containing fractions were collected andconcentrated under reduced pressure to give the desired product, tert-butyl N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]carbamate, as a pale yellow oil (211 mg, Y: 47%). UPLC and1H NMR (DMSO-d6, 300 MHz) confirmed structure and purity of the product as the (E)- isomer. UPLC Rt: 1.87, m / z: 376.0 [M+Na]; Purity (254 nm): 99%;1H NMR (300 MHz, DMSO-d6) δ 7.91– 7.83 (m, 2H), 7.83 – 7.73 (m, 2H), 7.18 (t, J = 5.2 Hz, 1H), 6.86 (dt, J = 15.1, 4.4 Hz, 1H),6.68 (d, J = 15.2 Hz, 1H), 3.78 (d, J = 6.0 Hz, 2H), 1.36 (s, 9H). Reaction 4: Refrigerated 4N HCl in dioxane, 3.7-4.3N (1.40 ml, 5.61 mmol, 10.0 eq.) was added to tert-butyl N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]carbamate (0.21 g, 0.56 mmol, 1.0 eq.) and the solution was stirred at room temperature. A white solid began to form within the first 10 min and after stirring for 1 h, the reaction was concentrated under reduced pressure to give the title compound, (2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-amine hydrochloride, as a white solid (161 mg, Y: 92%), which may be taken forward to the next reaction without further purification. UPLC and1H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.41 min, m / z: 276.0 [M+1], Br pattern; Purity (254 nm): 99%;1H NMR (300 MHz,DMSO-d6) δ 8.23 (s, 3H), 7.96 – 7.86 (m, 2H), 7.84 – 7.75 (m, 2H), 7.08 (dt, J = 15.3, 1.6 Hz,1H), 6.90 (dt, J = 15.3, 5.2 Hz, 1H), 3.72 (d, J = 5.7 Hz, 2H). Preparation of Intermediate [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ⁶-sulfanonedihydrochloride (via Scheme 1) Reaction 1: Diethyl (tosyloxy)methylphosphonate (9.86 g, 30 mmol, 1.0 eq.) and potassium carbonate anhydrous (10.4 g, 75 mmol, 2.5 eq.) were suspended in anhydrous DMF (79 ml, 8.0 vol) before mixing with 4-fluorothiophenol (4.04 g, 31.5 mmol, 1.05 eq) and stirring at room temperature. UPLC after stirring overnight indicated full consumption of the starting material with formation of the desired product. The reaction was concentrated under reduced pressure to a low volume and partitioned between ethyl acetate (20 mL) and distilled water (70 mL) with saturated NaCl solution (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 50%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-fluorophenyl)sulfanyl]methyl}phosphonate, as a light yellow oil (8.19 g, Y:98% ). UPLC and1H NMR (CDCl3, 300 MHz) confirmed structure and purity of the product. UPLC Rt: 1.76, m / z: 279.10 [M+1]; Purity (254 nm): 94%;1H NMR (300 MHz, Chloroform-d) δ 7.55 – 7.41 (m, 2H), 7.07 – 6.95 (m, 2H), 4.13 (dqd, J = 8.4, 7.0, 1.3 Hz, 4H), 3.15 (s, 1H), 3.10 (s, 1H), 1.31 (t, J = 7.1 Hz, 6H). Reaction 5: Diethyl {[(4-fluorophenyl)sulfanyl]methyl}phosphonate (8.19 g, 29.4 mmol, 1.0 eq) was dissolved in anhydrous MeOH (82 ml) and cooled to 0oC for 20 min before addition of Oxone®, monopersulfate compound (9.50 g, 31 mmol, 1.05 eq.) solution in distilled water (82 ml), immediately turning the pale yellow solution into a bright white mixture, which was stirred at 0oC for 30 min before being allowed to reach room temperature. After stirring overnight, UPLC suggested complete formation of the desired product with consumption of the starting material. The reaction was filtered through Celite, washed through with MeOH (5 x 20 mL) and concentrated under reduced pressure to a low volume. The concentrated filtrate was partitioned between ethyl acetate (40 mL) and distilled water (80 mL) with NaCl saturated solution (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give the desired product, diethyl [(4-fluorobenzenesulfinyl)methyl]phosphonate, as a yellow oil (8.754 g) suitable pure for the next step. UPLC and1H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.53, m / z: 295.00 [M+1]; Purity (254 nm): 99%;1H NMR (300 MHz, Chloroform-d) δ 7.83 – 7.71 (m, 2H), 7.28 – 7.20 (m, 2H), 4.26 – 4.00 (m, 4H), 3.42 (t, J = 14.7 Hz, 1H), 3.28 (t, J = 14.9 Hz, 1H), 1.31 (dt, J = 10.5, 7.0 Hz, 6H). Reaction 6: Diethyl [(4-fluorobenzenesulfinyl)methyl]phosphonate (1.0 g, 3.4 mmol, 1.0 eq) was added, as a solution in anhydrous DCM (20 ml, 0.17 M), to a vial containing rhodium(II) acetate dimer (0.045 g, 0.10 mmol, 0.03 eq), tert-butyl carbamate (0.80 g, 6.8 mmol, 2.0 eq) and magnesium oxide (0.55 g, 13.6 mmol, 4.0 eq). The mixture was degassed with argon for 20 min before addition of iodobenzene diacetate (1.642 g, 5.097 mmol, 1.5 eq). The vial was sealed before heating and after stirring 12h at 50oC UPLC indicated near-total consumption of the starting material. The reaction mixture was filtered through Celite, washed through with DCM (6 x 10 mL) and concentrated under reduced pressure to give a yellow oil (3.458 g). The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 65%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product, tert-butyl N- {[(diethoxyphosphoryl)methyl](4-fluorophenyl)oxo-λ⁶-sulfanylidene}carbamate, as a yellow oil (825 mg Y: 59%). UPLC and1H NMR (CDCl3, 300 MHz) confirmed the purity and structure of the product. UPLC Rt: 1.78, m / z: 432.3 [M+Na]; Purity (254 nm): 99%;1H NMR (300 MHz, Chloroform-d) δ 8.14 – 8.04 (m, 2H), 7.31 – 7.20 (m, 2H), 4.39 (dd, J = 16.3, 15.4 Hz, 1H), 4.21 – 4.07 (m, 4H), 4.07 – 3.96 (m, 1H), 1.43 (s, 9H), 1.27 (dtd, J = 12.5, 7.1, 0.7 Hz, 6H). Reaction 7: Potassium tert-butoxide (0.14 g, 1.22 mmol, 1.0 eq) was suspended in anhydrous THF (9.0 ml) and the mixture was degassed with argon while cooling at 0oC over 20 min. N- {[(diethoxyphosphoryl)methyl](4-fluorophenyl)oxo-λ⁶-sulfanylidene}carbamate (0.5 g, 1.22 mmol, 1.0 eq) was added, as a solution in anhydrous THF (3.2 ml), causing the mixture to form a yellow solution. This was stirred at 0oC for 30 min before adding tert-butyl N-(2- oxoethyl)carbamate (0.20 g, 1.28 mmol, 1.05 eq), as a solution in anhydrous THF (2.44 ml, 0.5 M), and the reaction was allowed to reach room temperature, stirring under argon. After 90 min, the reaction was concentrated to dryness under reduced pressure before partitioning between ethyl acetate (20 mL) and saturated aqueous NaHCO3solution (20 mL). The layers were separated and the organic layer was washed with saturated NaCl solution (10 mL). The aqueous layers were extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a yellow oil (589 mg). The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with DCM / ethyl acetate (0 to 12%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product, tert-butyl N-{[(1E)-3-{[(tert- butoxy)carbonyl]amino}prop-1-en-1-yl](4-fluorophenyl)oxo-λ⁶-sulfanylidene}carbamate, as a yellow oil (225 mg, Y: 44%). UPLC and1H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the (E)-isomer product. UPLC Rt: 1.87, m / z: 437.1 [M+Na]; Purity (254 nm): 99%; 1H NMR (300 MHz, DMSO-d6) δ 8.00 – 7.86 (m, 2H), 7.57 – 7.44 (m, 2H), 7.21 (t, J = 5.2 Hz, 1H), 6.84 (dt, J = 14.9, 4.2 Hz, 1H), 6.72 (d, J = 15.1 Hz, 1H), 3.80 (s, 2H), 1.36 (s, 9H), 1.25 (s, 9H). Reaction 8: Refrigerated 4N HCl in dioxane, 3.7-4.3N (1.36 ml, 5.4 mmol, 10.0 eq.) was added to tert-butyl N-[(2E)-3-({[(tert-butoxy)carbonyl]imino}(4-fluorophenyl)oxo-λ⁶-sulfanyl)prop- 2-en-1-yl]carbamate (0.23 g, 0.54 mmol, 1.0 eq) and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 1 h, the reaction was concentrated under reduced pressure to give the title product, [(1E)-3-aminoprop-1-en-1-yl](4- fluorophenyl)imino-λ⁶-sulfanone dihydrochloride, as a light brown solid (198 mg), which may be taken forward to the next reaction without further purification.1H NMR (DMSO-d6, 300 MHz) confirmed the structure of the product. UPLC Rt: 0.66, m / z = 215.1 [M+1]; Purity (254 nM): 71% (sum of the 3 peaks);1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 6H), 8.06 – 7.91 (m, 5H), 7.55 – 7.43 (m, 4H), 6.96 (d, J = 15.1 Hz, 1H), 6.78 (dt, J = 15.1, 5.3 Hz, 1H). Preparation of Intermediate (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride (via Scheme 1) F O HCl H 2N Reaction 1: Diethyl (tosyloxy)methylphosphonate (11.2 g, 34.3 mmol, 1.0 eq) and potassium carbonate anhydrous (11.8 g, 85.7 mmol, 2.5 eq) were suspended in N,N-dimethylformamide anhydrous (90 ml) before mixing with 4-chlorothiophenol (5.6 g, 37.7 mmol, 1.1 eq) in one go and stirring at room temperature UPLC after stirring 12h indicated full consumption of the starting material to give the desired product. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (50 mL) and distilled water (750 mL) with saturated NaCl solution (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a light-yellow oil (12.896 g). The oil was dissolved in minimal dichloromethane and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 75%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4- chlorophenyl)sulfanyl]methyl}phosphonate, as a light yellow oil (9.88 g, Y: 97%). UPLC and1H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.84, m / z: 295.1 [M+1] Cl pattern; Purity (254 nm): 99%;1H NMR (300 MHz, Chloroform-d) δ 7.44 – 7.37 (m, 2H), 7.33 – 7.26 (m, 2H), 4.25 – 4.07 (m, 4H), 3.20 (s, 1H), 3.15 (s, 1H), 1.33 (t, J = 7.1 Hz, 6H). Reaction 2: Diethyl {[(4-bromophenyl)sulfanyl]methyl}phosphonate (9.8 g, 33.5 mmol, 1.0 eq) was dissolved in anhydrous methanol (59.3 ml, 6.0 vol) before addition of Oxone®monopersulfate compound (22.6 g, 73.7 mmol, 2.2 eq) solution in distilled water (59.3 ml, 6.0 vol), immediately turning the pale yellow solution into a bright white mixture. After stirring for 12h, UPLC analysis indicated full conversion to the desired product. The mixture was filtered through Celite, washed through with MeOH and concentrated under reduced pressure to a low volume. The reduced filtrate was partitioned between ethyl acetate (30 mL) and water (90 mL) with saturated NaCl solution (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give the desired product, diethyl [(4- chlorobenzenesulfonyl)methyl]phosphonate, as a yellow oil (10.76 g, Y: 98%). The product was used in the next step without any further purification. UPLC and1H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.68, m / z: 325.1 [M-1], Cl pattern; Purity (254 nm): 98%. Potassium tert-butoxide (0.34 g, 3.06 mmol, 1.0 eq) was added to a dried flask and suspended in tetrahydrofuran anhydrous (25.0 ml) with cooling to 0 C over 10 min. diethyl [(4- chlorobenzenesulfonyl)methyl]phosphonate (1.0 g, 3.06 mmol, 1.0 eq) was added dropwise, as a solution in tetrahydrofuran anhydrous (5.6 ml), forming a yellow solution, which was stirred at 0 C under argon for 30 min. Selectfluor®(1.14 g, 3.21 mmol, 1.05 eq) was added dropwise over 1 min, as a solution in anhydrous N,N-dimethylformamide (4.1 ml, 4.1 vol), and the reaction was allowed to reach room temperature and stirred for 16h in argon atmosphere. The reaction was quenched with saturated aq. NH4Cl solution (50 mL) and stirred for 10 min before concentrating to a low volume under reduced pressure and partitioning with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layer was dried with MgSO4, filtered and concentrated under reduced pressure to give a yellow oil (1.27 g). The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0-40%). Product-containing fractions were collected and concentrated under reduced pressure to give diethyl [(4- chlorobenzenesulfonyl)(fluoro)methyl]phosphonate, as a light yellow oil (758 mg, Y:72%). UPLC and1H NMR (CDCl3, 300 MHz) confirmed structure and purity of the product. UPLC Rt: 1.79, m / z: 367.0 [M+Na], Cl pattern; Purity (254 nm): 98%;1H NMR (300 MHz, Chloroform-d) δ 8.02 – 7.89 (m, 2H), 7.63 – 7.51 (m, 2H), 5.37 (dd, J = 45.4, 6.7 Hz, 1H), 4.43 – 4.17 (m, 4H), 1.36 (tdd, J = 7.1, 3.7, 0.7 Hz, 6H). Reaction 3: Potassium tert-butoxide (0.247 g, 2.2 mmol, 1.0 eq) was suspended in anhydrous tetrahydrofuran (17.0 ml) with cooling to 0oC over 5 min. Diethyl [(4- chlorobenzenesulfonyl)(fluoro)methyl]phosphonate (0.758 g, 2.2 mmol, 1.0 eq) was added dropwise, as a solution in anhydrous tetrahydrofuran (4.9 ml), instantly forming a yellow solution, which was stirred at 0oC under argon for 30 min. Tert-butyl N-(2-oxoethyl)carbamate (0.368 g, 2.31 mmol, 1.05 eq) was added, as a solution in anhydrous tetrahydrofuran (4.6 ml, 0.5 M) over 1 min, and the reaction was stirred under argon and, subsequently, allowed to reach room temperature. After 90 min, the reaction was concentrated under reduced pressure to give a yellow oil, which was partitioned between ethyl acetate (10 mL) and saturated aqueous NaHCO3(20 mL). The layers were separated and the organic layer was washed with saturated NaCl solution (20 mL). The combined aqueous layers were extracted with ethyl acetate (4 x 5 mL) and the combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. Next, the oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 15%). Clean product- containing fractions with the E-isomer and the fractions containing Z-isomer were collected separately and concentrated under reduced pressure to give tert-butyl N-[(2E)-3-(4- chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-yl]carbamate, as a white solid (170 mg, Y: 22%). UPLC and1H NMR confirmed structure and purity, coupling constant the geometry of molecule as (E)-isomer. UPLC Rt: 1.91, m / z: 372.0 [M+Na], Cl pattern; Purity (254 nm): 94%; 1H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J = 8.7 Hz, 2H), 7.87 – 7.74 (m, 2H), 7.22 (t, J = 5.2 Hz, 1H), 6.28 (dt, J = 33.7, 6.5 Hz, 1H), 3.75 (s, 2H), 1.37 (s, 9H). Reaction 4: Refrigerated 4N HCl in dioxane, 3.7-4.3N (1.21 ml, 4.86 mmol, 10.0 eq) was added to tert-butyl N-[(2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-yl]carbamate (0.17 g, 0.48 mmol, 1.0 eq) and the solution was stirred at room temperature. A white solid began to form within the first 10 min and after stirring for 1 h, the reaction was concentrated under reduced pressure to give the title product, (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en- 1-amine hydrochloride, as a white solid (138 mg, Y: 99%), which may be taken forward to the next reaction without further purification. UPLC and1H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.41, m / z: 249.9 [M+1], Cl pattern; Purity (254 nm): 99%;1H NMR (300 MHz, DMSO- d6) δ 8.24 (s, 3H), 8.04 – 7.95 (m, 2H), 7.90 – 7.80 (m, 2H), 6.50 (dt, J = 33.0, 6.9 Hz, 1H), 3.70 (s, 2H). Reaction 1: 1,3-Bis(1,1-dimethylethyl) 2-(2-propyn-1-yl)imidodicarbonate (0.3 g, 1.12 mmol, 1.0 eq.), Tris(triphenylphosphine)rhodium(I) chloride (0.03 g, 0.033 mmol, 0.03 eq.) and 1,2- dichloroethane (4.0 ml) were degassed with argon for 30 min while cooling to 0°C. Next, 4- (trifluoromethoxy)thiophenol (0.24 g, 1.23 mmol, 1.1 eq.) was added, as a solution in 1,2- dichloroethane (1.6 ml) dropwise over 10 min, forming a dark brown solution. The reaction was stirred at room temperature under argon overnight and, subsequently, concentrated to a dark brown oil under reduced pressure. UPLC of the crude material was indicative of the desired product formation. The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 90%). Product-containing fractions were collected and concentrated under reduced pressure to give a light-yellow oil (428 mg). UPLC and1H NMR(CDCl3, 300 MHz) confirmed formation of the desired product, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]sulfanyl}prop-2-en-1-yl]carbamate, as an approximately 93:7 mixture with the vicinal alkene side-product, formed by addition of the thiophenol to the other side of the triple bond. The mixture was used without further purification in the next step. UPLC Rt: 2.31, m / z: 472.1 [M+Na]; Purity (NMR): 93%; 1H NMR (300 MHz, Chloroform-d) δ7.38 – 7.31 (m, 2H), 7.15 (dq, J = 7.7, 1.0 Hz, 2H), 6.32 (dt, J = 15.0, 1.2 Hz, 1H), 5.92 (dt, J= 15.0, 6.3 Hz, 1H), 4.23 (dd, J = 6.3, 1.3 Hz, 2H), 1.50 (s, 18H). Reaction 2: Tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]- sulfanyl}prop-2-en-1-yl]-carbamate (0.43 g, 0.89 mmol, 1.0 eq.) was dissolved in MeOH (17.1 ml, 40 vol), and cooled to 0°C over 10 min before addition of ammonium carbamate (0.28 g, 3.5 mmol, 4.0 eq.). The mixture was stirred at 0°C for 30 min before addition of iodobenzene diacetate (0.71 g, 2.2 mmol, 2.5 eq), in three portions, 10 minutes apart. Following addition of the final portion, the mixture was allowed to reach room temperature. After 30 min, UPLC indicated full consumption of the starting material. The reaction mixture was concentrated to a low volume under reduced pressure, before dissolving in minimal MeOH, adsorbing onto celiteand purified by flash chromatography, eluting with hexanes / ethyl acetate (0 to 60%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4- (trifluoromethoxy)phenyl]-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate, as a white solid (336 mg, Y:77%). UPLC and1H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.98, m / z: 481.00 [M+1]; Purity (NMR): 99%;1H NMR (300 MHz, Chloroform-d) δ 8.08 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.01 (dt, J = 15.0, 5.1 Hz, 1H), 6.62 (d, J = 15.0 Hz, 1H), 4.42 (dd, J = 5.2, 1.6 Hz, 2H), 1.41 (s, 18H). Reaction 3: Refrigerated 4N HCl in dioxane (1.7 ml, 6.9 mmol, 10.0 eq) was added to N-[(tert- butoxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ⁶-sulfanyl]prop-2-en-1- yl]carbamate (0.34 g, 0.69 mmol, 1.0 eq.) and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 30 min, the reaction was concentrated under reduced pressure and the resulting solid was triturated with diethyl ether (10 mL) and dried under vacuum to give the title product, [(1E)-3-aminoprop-1-en-1-yl](imino)[4- (trifluoromethoxy)phenyl]-λ⁶-sulfanone dihydrochloride, as a white solid (258 mg, Y: 85%), which may be taken forward to the next reaction without further purification. UPLC and1H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.39, m / z: 281.00 [M+1]; Purity (254): 75%;1H NMR (300 MHz, DMSO-d6) δ 8.43 – 8.22 (m, 5H), 8.11 – 7.96 (m, 3H), 7.69 – 7.59 (m, 3H), 7.04 – 6.93 (m, 1H), 6.82 (dt, J = 15.2, 5.3 Hz, 1H), 3.76 – 3.63 (m, 2H). Preparation of Intermediate [(1E)-3-aminoprop-1-en-1-yl][(3-fluoro-4- methoxyphenyl)imino]methyl-λ⁶-sulfanone hydrochloride (via Scheme 6) Reaction 1A: To a pressure flask containing 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.847 g, 1.46 mmol, 0.3 eq) and sodium tert-butoxide (1.17 g, 12.2 mmol, 2.5 eq) was added 4-bromo-2-fluoroanisole (1.0 g, 4.87 mmol, 1.0 eq) and S,S-dimethyl sulfoximine (0.5 g, 5.36 mmol, 1.1 eq), as a solution in anhydrous dioxane (24.4 ml, 0.2 M). The mixture was degassed with nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (0.45 g, 0.48 mmol, 0.1 eq) was added and the flask was sealed and heated to 100°C, forming a brown mixture. UPLC of the reaction mixture after 8h indicated consumption of the starting material. The reaction mixture was partitioned between water (40 ml) with a saturated solution of NaCl (10 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The red oily residue was purified by flash chromatography, eluting with cyclohexane / ethyl acetate (0-75%). Product-containing fractions were collected and concentrated under reduced pressure to give [(3-fluoro-4-methoxyphenyl)imino]dimethyl-λ⁶- sulfanone, as a light brown solid (395 mg). LCMS and1H NMR confirmed the structure and purity of the product. UPLC Rt: 1.97, m / z 217.80 (M+1); Purity (254nm): 95%;1H NMR (400 MHz, Methanol-d4) δ 6.95 (dd, J = 9.7, 8.3 Hz, 1H), 6.84 – 6.78 (m, 1H), 6.78 (d, J = 2.3 Hz, 1H), 3.82 (s, 3H), 3.17 (d, J = 0.6 Hz, 6H). Reaction 2: [(3-fluoro-4-methoxyphenyl)imino]dimethyl-λ⁶-sulfanone (0.345 g, 1.57 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (15.7 ml, 0.1 M) and the solution was cooled to -78°C. Lithium bis(trimethylsilyl)amide 1M solution in tetrahydrofuran (3.14 ml, 3.14 mmol, 2.0 eq) was added dropwise and the mixture was stirred in an inert atmosphere at -78°C for 30 minutes. Next, diethyl chlorophosphate (0.30 g, 1.73 mmol, 1.1 eq) was added dropwise and the reaction mixture was allowed to stir at -78°C for 1 h. UPLC of the reaction mixture indicated full conversion to the desired product. Then, the reaction was quenched by pouring the mixture into a saturated solution of ammonium chloride (20 mL), and the aqueous phase was extracted with ethyl acetate (4x30 mL). The combined organic layers were washed with a saturated solution of NaCl (20 mL) and dried over Na2SO4. The crude was purified by flash chromatography eluting with cyclohexane / ethyl acetate (30-100%). Product-containing fractions were collected and concentrated under reduced pressure to give diethyl ({[(3-fluoro-4- methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}methyl)phosphonate (0.46 g, Y: 81%) as a dark yellow oil. LCMS and 1H NMR confirmed the structure and purity of the product. UPLC R: 2.09 min, m / z: 353.85 [M+1]; Purity (254nm): 99%;1H NMR (400 MHz, DMSO-d6) δ 7.00 (dd, J = 10.0, 8.6 Hz, 1H), 6.79 – 6.59 (m, 2H), 4.36 – 4.21 (m, 2H), 4.12 – 4.00 (m, 4H), 3.77 (s, 3H), 1.21 (dt, J = 24.3, 7.0 Hz, 6H). Reaction 3: Potassium tert-butoxide (0.137 g, 1.22 mmol, 1.0 eq) was suspended in anhydrous tetrahydrofuran (22.0 ml) under a nitrogen atmosphere and cooled to 0°C. Then, a solution of diethyl ({[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}methyl)phosphonate (0.44 g, 1.22 mmol, 1.0 eq) in anhydrous tetrahydrofuran (1.54 ml) was added dropwise and the mixture was stirred under an inert atmosphere for 30 minutes at 0°C. Next, the reaction was cooled to -78°C and a solution of tert-butyl N-(2-oxoethyl)carbamate (0.216 g, 1.22 mmol, 1.0 eq) in anhydrous tetrahydrofuran (1.54 ml) was added dropwise. The reaction mixture was stirred at -78°C for 1 h and UPLC confirmed formation of the product as a mixture of E and Z isomers. The reaction was quenched by pouring the mixture into a saturated solution of ammonium chloride (20 mL), the aqueous phase was extracted with ethyl acetate (4x20 mL), and the combined organic layers were washed with a saturated solution of NaCl (20 mL) and dried over Na2SO4. The crude material was purified by flash chromatography eluting with cyclohexane / ethyl acetate (0-80%). Product-containing fractions were collected and concentrated under reduced pressure to give tert-butyl N-[(2E)-3-{[(3-fluoro-4- methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2-en-1-yl]carbamate (0.208 g, Y: 45%) as a colorless oil. The Z isomer was a minor product and not isolated. UPLC Rt: 2.24 min, m / z 358.90 [M+1]; Purity (254 nm): 87%;1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J = 6.0 Hz, 1H), 6.94 (dd, J = 10.0, 8.5 Hz, 1H), 6.75 (dt, J = 15.1, 4.6 Hz, 1H), 6.71 – 6.58 (m, 2H), 6.54 (d, J = 15.1 Hz, 1H), 3.77 (s, 2H), 3.74 (s, 3H), 3.16 (s, 4H), 1.37 (s, 9H). Reaction 4: 4M HCl in dioxane (0.33 ml, 1.33 mmol, 10.0 eq) was added to tert-butyl N-[(2E)- 3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2-en-1-yl]carbamate (0.05 g, 0.133 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 15 minutes forming a white precipitate. UPLC of the reaction mixture indicated complete conversion of the starting material. Subsequently, the reaction mixture was concentrated to under vacuum dryness and the resulting solid was triturated with diethyl ether (3x2 mL), filtered and dried under vacuum to give [(1E)-3-aminoprop-1-en-1-yl][(3-fluoro-4-methoxyphenyl)imino]methyl- λ⁶-sulfanone dihydrochloride (0.043 g, Y: 98%) as a white solid that was used in the next step without further purification. UPLC Rt: 1.64 min, m / z: 258.80 [M+1]; Purity ( 254 nm): 99%;1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 6.96 (dd, J = 10.0, 8.6 Hz, 0H), 6.93 – 6.87 (m, 0H), 6.80 (dt, J = 15.3, 5.3 Hz, 0H), 6.74 – 6.64 (m, 1H), 3.75 (s, 1H), 3.72 (d, J = 5.9 Hz, 1H), 3.20 (s, 1H). Preparation of Intermediate [(1E)-3-aminoprop-1-en-1-yl][(3-fluoro-4- methoxyphenyl)imino](2H3)methyl-λ⁶-sulfanone hydrochloride Reaction 1B: (3-fluoro-4-methoxyphenyl)(imino)methyl-λ⁶-sulfanone (0.2 g, 0.89 mmol, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (16.0 ml) and cooled to 0°C, sodium hydride 60% dispersion in mineral oil (0.044 g, 1.11 mmol, 1.25 eq) was added in portions at 0°C and the mixture was stirred at 0°C for 30 minutes. Next, iodomethane-d3 (0.154 g, 1.06 mmol, 1.2 eq) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 3h. UPLC of the reaction mixture indicated full consumption of starting material. The reaction mixture was quenched with isopropanol (1 mL) and distilled water (10 mL). The aqueous phase was extracted with ethyl acetate (4x20 mL), the combined organic layers were washed with a saturated solution of NaCl (20 mL), dried over Na2SO4, and concentrated to dryness to give [(3-Fluoro-4-methoxyphenyl)(methyl)oxo-λ⁶- sulfanylidene]((²H₃)methyl)amine (0.215 g, Y: 99%) as a yellow oil that was used in the next step without further purification. UPLC Rt: 1.86 min; m / z: 220.80 [M+1]; Purity (254 nm): 99%;1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 3.6, 2.1 Hz, 1H), 7.41 (t, J = 8.5 Hz, 1H), 3.94 (s, 3H), 3.11 (s, 3H). Reactions 2 to 4 were performed by methods analogous to that described for the preparation of intermediate [(1E)-3-aminoprop-1-en-1-yl][(3-fluoro-4-methoxyphenyl)imino]methyl-λ⁶- sulfanone hydrochloride. [(1E)-3-aminoprop-1-en-1-yl][(3-fluoro-4- methoxyphenyl)imino](2H3)methyl-λ⁶-sulfanone hydrochloride was obtained as a white solid (Y:100%). UPLC Rt: 1.36 min; m / z: 259.45 [M+1]; Purity (254 nm): 93%; 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 6.96 (dd, J = 10.0, 8.7 Hz, 0H), 6.92 – 6.85 (m, 0H), 6.79 (dt, J = 15.3, 5.3 Hz, 0H), 6.74 – 6.63 (m, 1H), 3.75 (s, 1H), 3.20 (s, 1H). Preparation of Intermediate [(1E)-3-aminoprop-1-en-1-yl][(4-fluorophenyl)imino]methyl-λ⁶- sulfanone hydrochloride Reaction 1C: S,S-dimethyl sulfoximine (0.50 g, 5.4 mmol, 1.0 eq), 4-fluorophenylboronic acid (1.72 g, 12.3 mmol, 2.3 eq) and copper(ii) acetate (0.098 g, 0.54 mmol, 0.1 eq) were placed in a 3-neck flask equipped with a magnetic stirrer and air condenser. Methanol (20 ml,) was added and the reaction mixture was vigorously stirred, bubbling air into the solution for 18 h. UPLC of the reaction mixture indicated formation of the product. The reaction was quenched with saturated NaHCO3solution (20 mL) and extracted with dichloromethane (4x20 mL). The organic layers were combined, dried over Na2SO4and concentrated in vacuo. The crude material was purified by flash chromatography eluting with dichloromethane / methanol (0-5%). Product- containing fractions were collected and concentrated under reduced pressure to give[(4- fluorophenyl)imino]dimethyl-λ⁶-sulfanone (0.265 g, Y; 25%) as a white solid. UPLC Rt: 1.49 min, m / z 188.3 [M+1]; Purity (254 nm): 99%; 1H NMR (400 MHz, DMSO-d6) δ7.04 – 6.97 (m, 2H), 6.94 – 6.88 (m, 2H), 3.17 (s, 6H).Reactions 2 to 4 were performed by methods analogous to that described for the preparation ofintermediate [(1E)-3-aminoprop-1-en-1-yl][(3-fluoro-4-methoxyphenyl)imino]methyl-λ⁶- sulfanone hydrochloride. [(1E)-3-aminoprop-1-en-1-yl][(4-fluorophenyl)imino]methyl-λ⁶-sulfanone hydrochloride was obtained as a white solid (Y: 93.5%). 6-Methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic (0.028 g, 0.183 mmol, 1.0 eq) and 1- propylphosphonic acid anhydride, 50+% w / w solution in acetonitrile, (0.233 g, 0.37 mmol, 2.0 eq) were dissolved in anhydrous DMF (0.6 mL). Next, N,N-diisopropylethylamine (0.127 ml, 0.73 mmol, 4.0 eq) was added and the yellow mixture was stirred for 10 min. (2E)-3- (benzenesulfonyl)prop-2-en-1-amine (0.045 g, 0.183 mmol, 1.0 eq) was added and mixture was stirred at room temperature for 2h. UPLC indicated full consumption of starting material and the reaction mixture was poured into water and extracted with DCM. The organic phase was washed with saturated aq. Na2CO3, water and saturated aq. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC, the product fractions were collected and concentrated under reduce pressure to give N-[(2E)-3- (benzenesulfonyl)prop-2-en-1-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide (0.009 g, 0.026 mmol, Y: 14%) as an off-white solid. LCMS Rt = 2.47 min, m / z= 334.2 [M+1]; Purity (254 nm): 97.6%;1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 9.78 (t, J = 6.0 Hz, 1H), 7.96 (s, 1H), 7.89 – 7.83 (m, 2H), 7.76 – 7.70(m, 1H), 7.68 – 7.61 (m, 2H), 6.94 (dt, J = 15.1, 4.2 Hz, 1H), 6.79 (dt, J = 15.1, 1.9 Hz, 1H),4.21 (ddd, J = 6.1, 4.2, 1.9 Hz, 2H), 2.34 (s, 3H).Example 2: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 6-Methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic (0.016 g, 0.10 mmol, 0.10 eq) and HATU (0.042 g, 0.11 mmol, 1.09 eq) were dissolved in anhydrous DMF (1.02 ml). Then, N,N- diisopropylethylamine (0.07 ml, 0.40 mmol, 3.98 eq) was added and the orange mixture was stirred for 10 min. [(1E)-3-Aminoprop-1-en-1-yl](3-fluoro-4-methoxyphenyl)imino-λ⁶- sulfanone dihydrochloride (0.04 g, 0.10 mmol, 1.0 eq) was added and the mixture was stirred at room temperature for 2 h. UPLC showed consumption of starting material and the reaction mixture was poured into water and extracted with DCM. The organic phase was subsequently washed with saturated aq. Na2CO3, water and saturated aq. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC and product fractions were collected and concentrated under reduced pressure to furnish N- [(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-6-methyl-3-oxo- 2,3-dihydropyridazine-4-carboxamide (0.002 g, 0.005 mmol, Y: 5%) as a white solid. LCMS Rt = 1.52 min, m / z= 381.2 [M+1]; Purity (254 nm): 87.3%;1H NMR (400 MHz, DMSO-d6) δ 9.76 (t, J = 6.1 Hz, 1H), 7.97 (s, 1H), 7.71 – 7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.76(dt, J = 15.0, 4.5 Hz, 1H), 6.63 – 6.55 (m, 1H), 4.59 (s, 1H), 4.16 (t, J = 5.0 Hz, 2H), 3.92 (s,3H), 2.34 (s, 3H).The title compounds of Examples 3-8 were prepared by a method analogous to that describedin Examples 1 and 2.Example 3: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 2.57 min, m / z= 436.2 [M+1]; Purity (254 nm): 93.5%;1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.57 (d, J = 3.0 Hz, 1H), 8.46 (s, 1H), 8.09 (d, J = 2.8 Hz, 1H), 7.72 –7.56 (m, 5H), 7.51 – 7.40 (m, 2H), 7.40 – 7.29 (m, 1H), 6.80 (dt, J = 15.0, 4.6 Hz, 1H), 6.62– 6.49 (m, 1H), 4.61 (s, 1H), 4.21 – 4.14 (m, 2H), 3.92 (s, 3H).Example 4: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]- LCMS Rt = 1.6 min, m / z= 393.85 [M+1]; Purity (254 nm): 88.3%;1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.02 (t, J = 5.4 Hz, 1H), 8.09 (s, 1H), 7.69 – 7.60 (m, 2H), 7.35 (t, J =8.4 Hz, 1H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (dt, J = 14.9, 1.8 Hz, 1H), 4.60 (s, 1H), 4.13 (t, J = 5.1 Hz, 2H), 3.92 (s, 3H), 2.25 (s, 3H), 2.05 (s, 3H).Example 5: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide LCMS Rt = 1.85 min, m / z= 410.2 [M+1]; Purity (254 nm): 98.1%;1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.40 (t, J = 5.8 Hz, 1H), 7.68 – 7.56 (m, 2H), 7.43 (d, J = 7.5 Hz, 1H),7.36 (t, J = 8.5 Hz, 1H), 6.89 – 6.80 (m, 1H), 6.75 (dt, J = 14.9, 3.5 Hz, 1H), 6.21 (d, J = 7.5 Hz, 1H), 4.50 (s, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.95 (d, J = 5.2 Hz, 2H), 3.92 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H).Example 7: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide LCMS Rt = 2.51 min, m / z= 420.22 [M+1]; Purity (254 nm): 91.5%;1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.99 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.70 – 7.59 (m, 2H), 7.35 (t, J = 8.5Hz, 1H), 6.76 (dt, J = 15.0, 4.6 Hz, 1H), 6.53 – 6.44 (m, 1H), 4.60 (s, 1H), 4.13 (t, J = 5.3 Hz,2H), 3.92 (s, 3H), 2.58 (t, J = 5.9 Hz, 2H), 1.79 – 1.59 (m, 4H).Example 8: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-4-oxo-3-azatricyclo[6.2.1.0,2,7]undeca-2(7),5-diene-5-carboxamide LCMS Rt = 2.48 min, m / z= 432.19 [M+1]; Purity (254 nm): 86.4%;1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 10.04 (s, 1H), 8.20 (s, 1H), 7.68 – 7.58 (m, 2H), 7.35 (t, J = 8.6 Hz, 1H),6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.47 (d, J = 15.1 Hz, 1H), 4.58 (s, 1H), 4.23 – 4.03 (m, 2H),3.92 (s, 3H), 3.35 (s, 2H), 2.00 – 1.82 (m, 2H), 1.70 (d, J = 8.7 Hz, 1H), 1.48 (d, J = 8.9 Hz,1H), 1.17 – 1.07 (m, 2H).Example 9: N-[(2E)-3-[(cyclopropylimino)(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2- Reaction 1: Tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3-fluoro-4- methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate (0.2 g, 0.45 mmol, 1.0 eq) and copper(II) acetate (0.123 g, 0.68 mmol, 1.5 eq) were suspended in anhydrous dioxane (4.0 ml), pyridine was added (0.087 ml, 1.1 mmol, 2.4 eq), and the mixture was purged with oxygen for 10 min. Next, cyclopropylboronic acid (0.155 g, 1.8 mmol, 4.0 eq) was added in one go and the reaction was heated to 100°C for 2h. LCMS indicated approximately 60% conversion of the starting material into the desired product. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a green oil. The crude was purified by flash chromatography eluting with hexane / ethyl acetate (30 to 50%). Product- containing fractions were collected and concentrated under reduced pressure to give the desired product, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(cyclopropylimino)(3-fluoro-4- methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate, as a yellow oil (0.07 g, Y: 30%). UPLC and1H NMR confirmed the structure and purity of the product.1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.59 (m, 2H), 7.39 (t, J = 8.6 Hz, 1H), 6.67 (dt, J = 15.1, 4.8 Hz, 1H), 6.49 (dt, J = 15.1, 1.6 Hz, 1H), 4.33 – 4.23 (m, 2H), 3.92 (s, 3H), 2.39 – 2.31 (m, 1H), 1.35 (s, 18H), 0.48 – 0.26 (m, 4H). Reaction 2: Refrigerated 4N HCl in dioxane, 3.7-4.3N (0.34 ml, 1.37 mmol, 10.0 eq), was added to tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(cyclopropylimino)(3-fluoro-4- methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate (0.07 g, 0.137 mmol, 1.0 eq) and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 1 h, the reaction was concentrated under reduced pressure to give the desired product, [(1E)- 3-aminoprop-1-en-1-yl](cyclopropylimino)(3-fluoro-4-methoxyphenyl)-λ⁶-sulfanone dihydrochloride, as a yellow oil (63 mg), which was taken forward to the next reaction without further purification. UPLC Rt: 1.42, m / z: 285.0 [M+1]; Purity (254 nm): 85%. Reaction 3: Preparation of the title compound followed the same procedure as described in Scheme 4, Reaction 1 using T3P 50+% w / w solution in acetonitrile as coupling agent. After work up, the crude product was purified by preparative TLC eluting with dichloromethane / methanol 10% to give N-[(2E)-3-[(cyclopropylimino)(3-fluoro-4- methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3- carboxamide as a yellow solid (0.011 g, Y: 19%). LCMS Rt= 2.73 min, m / z=460.40 [M+1]; Purity (254 nm): 95.1%;1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.68 – 7.58 (m, 2H), 7.42 – 7.33 (m,1H), 6.77 (dt, J = 15.0, 4.6 Hz, 1H), 6.49 (dt, J = 15.0, 1.8 Hz, 1H), 4.11 (dq, J = 10.5, 5.3 Hz,2H), 3.93 (s, 3H), 2.58 (t, J = 6.0 Hz, 2H), 2.34 – 2.26 (m, 1H), 1.76 – 1.61 (m, 4H), 0.47 –0.23 (m, 4H).Example 10: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo)(propylimino)-λ⁶-sulfanyl]prop-2- Reaction 1: Tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3-fluoro-4- methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate (0.200 g, 0.450 mmol, 1.0 eq), 1-bromopropane (0.163 ml, 1.8 mmol, 4.0 eq) and potassium carbonate (0.124 g, 0.9 mmol, 2.0 eq) were mixed in anhydrous DMF (4.5 ml, 0.1 M) and the reaction mixture was stirred at 100°C in a microwave reactor for 2h. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give a green oil. The crude was purified by flash chromatography eluting with hexane / ethyl acetate (40 to 100%). Product- containing fractions were collected and concentrated under reduced pressure to give the desired product tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3-fluoro-4- methoxyphenyl)(oxo)(propylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate as a yellow oil (0.045 g, Y: 20%). UPLC and1H NMR confirmed the structure and purity of the product. LCMS Rt= 2.88 min, m / z=487.45 [M+1]; Purity (254 nm): 88%;1H NMR (300 MHz, DMSO-d6)δ 7.69 – 7.51 (m, 2H), 7.38 (t, J = 8.5 Hz, 1H), 6.65 (dt, J = 15.0, 4.8 Hz, 1H), 6.42 (d, J =15.1 Hz, 1H), 4.34 – 4.22 (m, 2H), 3.92 (s, 3H), 2.92 – 2.73 (m, 2H), 1.56 – 1.37 (m, 4H),1.35 (s, 18H), 0.86 (t, J = 7.3 Hz, 3H). Reaction 2: Refrigerated 4N HCl in dioxane, 3.7-4.3N (0.18 ml, 0.74 mmol, 10.0 eq) was added to tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3-fluoro-4- methoxyphenyl)(oxo)(propylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate (0.045 g, 0.092 mmol, 1.0 eq) and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 1 h, the reaction was concentrated under reduced pressure to give the desired product, {[(1E)-3-aminoprop-1-en-1-yl](3-fluoro-4-methoxyphenyl)oxo-λ⁶- sulfanylidene}(propyl)amine dihydrochloride (0.031 g) as a yellow oil (63 mg), which was taken forward to the next reaction without further purification. Reaction 3: Preparation of the title compound followed the same procedure as described in Scheme 4, Reaction 1 using HATU as a coupling agent. After work up, the crude product was purified twice by preparative TLC eluting with dichloromethane / methanol 10% to give N-[(2E)- 3-[(3-fluoro-4-methoxyphenyl)(oxo)(propylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo- 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide as a yellow solid (3 mg, Y: 11%). LCMS Rt= 2.74 min, m / z=462.20 [M+1]; Purity (254 nm): 96.4% (254 nm);1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.64 – 7.54 (m, 2H), 7.42 – 7.33 (m, 1H), 6.76 (dt, J = 15.0, 4.6 Hz, 1H), 6.46 (dt, J = 15.0, 1.8 Hz, 1H), 4.18 – 4.10 (m, 2H), 3.93 (s, 3H), 2.87 – 2.68 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.76 – 1.64 (m, 4H), 1.52 – 1.38 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). Reaction 1: In a dry vial flushed with argon, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3- fluoro-4-methoxyphenyl)(imino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate (0.1 g, 0.225 mmol, 1.0 eq) and bromobenzene (0.028 ml, 0.27 mmol, 1.2 eq) were dissolved in anhydrous toluene (3.21 ml, 0.07 M). The mixture was degassed for 10 min, then palladium (II) acetate (0.005 g, 0.022 mmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.026 g, 0.045 mmol, 0.2 eq) and cesium carbonate (0.11 g, 0.337 mmol, 1.5 eq) were added. The reaction mixture was heated at 100°C for 16h. UPLC showed consumption of starting material and the mixture was cooled, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was collected and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with hexane / ethyl acetate (30-100%). Product-containing fractions were collected and concentrated under reduced pressure to give the desired product tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo)(phenylimino)-λ⁶- sulfanyl]prop-2-en-1-yl]carbamate (0.064 g, Y: 33%) as a yellow solid. LCMS Rt= 2.88 min, m / z=521.25 [M+1]; Purity (254 nm): 64%. Reaction 2: Refrigerated 4N HCl in dioxane, 3.7-4.3N (0.231 ml, 0.925 mmol, 10.0 eq) was added to tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[(3-fluoro-4- methoxyphenyl)(oxo)(phenylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]carbamate (0.064 g, 0.074 mmol, 1.0 eq) and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 1 h, the reaction was concentrated under reduced pressure to give the desired product, [(1E)-3-aminoprop-1-en-1-yl](3-fluoro-4-methoxyphenyl)(phenylimino)-λ⁶- sulfanone dihydrochloride as a yellow oil (49 mg), which was taken forward to the next reaction without further purification. UPLC Rt: 1.54, m / z: 287.3 [M+1]; Purity (254 nm): 90%. Reaction 3: Preparation of title compound followed the same procedure as described in Scheme 4, Reaction 1 using T3P 50+% w / w solution in acetonitrile as coupling agent. After work up, the crude product was purified by preparative TLC eluting with 10% dichloromethane / methanol to give the title compound, N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo)(phenylimino)-λ⁶- sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide as a yellow solid (0.011 g, Y: 30%). LCMS Rt= 5.81 min, m / z= 496.20 [M+1]; Purity (254 nm): 94.4%;1H NMR (300 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.69 (dd, J = 22.5, 9.7 Hz, 2H), 7.31 – 7.19 (m, 1H), 7.17 – 6.96 (m, 5H),6.88 (t, J = 7.7 Hz, 1H), 6.67 (d, J = 15.0 Hz, 1H), 4.26 (d, J = 4.6 Hz, 2H), 3.94 (s, 3H), 2.74– 2.52 (m, 4H), 1.93 – 1.74 (m, 4H).The title compounds of Examples 12 and 13 were prepared by a method analogous to thatdescribed in Examples 9-11.Example 12: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 2.39 min, m / z= 434.22 [M+1]; Purity (254 nm): 93.3%;1H NMR (400 MHz,DMSO-d6) δ 12.27 (s, 1H), 10.00 (t, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.63 – 7.52 (m, 2H), 7.42– 7.33 (m, 1H), 6.77 (dt, J = 15.1, 4.6 Hz, 1H), 6.45 (dt, J = 14.8, 1.8 Hz, 1H), 4.17 – 4.10(m, 2H), 3.93 (s, 3H), 2.58 (t, J = 5.7 Hz, 2H), 2.54 (s, 3H), 1.74 – 1.61 (m, 4H).Example 13: N-[(2E)-3-[(ethylimino)(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en-1- LCMS Rt = 2.48 min, m / z= 334.21 [M+1], 332.31 [M-1]; Purity (254 nm): 97.6%;1H NMR (400MHz, DMSO-d6) δ 13.46 (s, 1H), 9.78 (t, J = 6.0 Hz, 1H), 7.96 (s, 1H), 7.89 – 7.83 (m, 2H),7.76 – 7.70 (m, 1H), 7.68 – 7.61 (m, 2H), 6.94 (dt, J = 15.1, 4.2 Hz, 1H), 6.79 (dt, J = 15.1,1.9 Hz, 1H), 4.21 (ddd, J = 6.1, 4.2, 1.9 Hz, 2H), 2.34 (s, 3H).Example 14: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo){[(trifluoromethyl) sulfanyl]amino}-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (via Scheme 5) Reaction 1: A solution of N-[(2E)-3-[amino(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2- en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (0.03 g, 0.068 mmol, 1.0 eq) in dry acetonitrile (0.6 mL) was added to a dry Schlenk tube flushed with argon. Next, N- bromosuccinimide 99% (0.012 g, 0.068 mmol, 1.0 eq) was added and the reaction mixture was stirred for 30 min at room temperature after which a solution of silver trifluoromethanethiolate (0.017 g, 0.082 mmol, 1.2 eq) in dry acetonitrile (0.6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was filtered through Celite®, rinsed with acetonitrile and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC, eluting with 5% dichloromethane / methanol to furnish N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo){[(trifluoromethyl)sulfanyl]imino}-λ⁶- sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (0.01 g, Y: 26%) as a colorless solid. LCMS Rt= 2.59 min, m / z= [M+1] 520.11; Purity (254 nm): 94.4%;1H NMR (400 MHz, DMSO- d6) δ 12.27 (s, 1H), 10.04 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.81 – 7.68 (m, 2H), 7.45 (t, J = 8.5 Hz, 1H), 7.01 (dt, J = 15.1, 4.3 Hz, 1H), 6.85 (dt, J = 14.9, 1.8 Hz, 1H), 4.22 (d, J = 5.4 Hz, 2H), 3.96 (s, 3H), 2.58 (t, J = 5.7 Hz, 2H), 1.79 – 1.60 (m, 4H). The title compounds of Examples 15-42 were prepared by a method analogous to that described in Examples 1 and 2. LCMS Rt = 2.56 min, m / z= 412.26 [M+1]; Purity (254 nm): 96.9%;1H NMR (400 MHz, DMSO- d6) δ 12.93 (s, 1H), 10.13 (s, 1H), 8.16 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 7.9, 2.1 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.72 (dt, J = 14.9, 4.6 Hz, 1H), 6.41 (d, J = 14.9 Hz, 1H), 4.42 (s, 1H), 4.14 – 4.05 (m, 2H), 3.29 (s, 2H), 2.28 (s, 6H), 1.98 – 1.81 (m, 2H), 1.69 (d, J = 8.8 Hz, 1H), 1.46 (d, J = 8.9 Hz, 1H), 1.10 (d, J = 7.4 Hz, 2H). LCMS Rt = 2.01 min, m / z= 400.10 [M+1]; Purity (254 nm): 96.1%;1H NMR (400 MHz, DMSO- d6) δ 12.25 (s, 1H), 10.01 (s, 1H), 8.02 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.9, 2.1 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.72 (dt, J = 14.9, 4.6 Hz, 1H), 6.47 – 6.39 (m, 1H), 4.43 (s, 1H), 4.11 (t, J = 5.3 Hz, 2H), 2.57 (t, J = 6.0 Hz, 2H), 2.28 (s, 6H), 1.68 (d, J = 7.6 Hz, 4H). LCMS Rt = 1.96 min, m / z= 477.36 [M+1]; Purity (254 nm): 88.0%;1H NMR (400 MHz, DMSO- d6) δ 12.26 (s, 1H), 9.97 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.65 – 7.61 (m, 2H), 6.68 (d, J = 8.9 Hz, 2H), 6.62 (dt, J = 14.9, 4.6 Hz, 1H), 6.37 (d, J = 15.0 Hz, 1H), 4.20 (s, 1H), 4.09 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 13.2 Hz, 2H), 3.55 (t, J = 7.3 Hz, 2H), 2.56 (d, J = 6.9 Hz, 4H), 1.79 – 1.58 (m, 6H). LCMS Rt = 1.97 min, m / z= 400.83 [M+1]; Purity (254 nm): 97.8%;1H NMR (400 MHz, DMSO- d6) δ 12.14 (s, 1H), 10.10 (s, 2H), 8.01 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.60 – 6.56 (m, 3H), 6.36 (d, J = 14.9 Hz, 1H), 4.08 (t, J = 5.5 Hz, 2H), 4.04 (s, 1H), 3.17 (d, J = 4.0 Hz, 2H), 2.71 (d, J = 4.9 Hz, 3H), 2.56 (t, J = 6.0 Hz, 2H), 1.68 (d, J = 5.3 Hz, 4H). LCMS Rt = 2.53 min, m / z= 426.04 [M+1]; Purity (254 nm): 73.6%;1H NMR (400 MHz, DMSO- d6) δ 12.20 (s, 1H), 9.98 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 9.1, 2.2 Hz, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.80 (d, J = 9.1 Hz, 1H), 6.70 (dt, J = 14.8, 4.6 Hz, 1H), 6.46 – 6.40 (m, 1H), 4.43 (s, 1H), 4.11 (t, J = 5.4 Hz, 2H), 2.82 (d, J = 4.7 Hz, 3H), 2.57 (s, 2H), 1.68 (s, 4H). Example 21: N-[(2E)-3-{[3-fluoro-4-(methylamino)phenyl](imino)oxo-λ⁶-sulfanyl}prop-2-en- LCMS Rt = 2.58 min, m / z= 406.15 [M+1]; Purity (254 nm): 92.9%;1H NMR (400 MHz, DMSO- d6) δ 11.98 (s, 1H), 10.25 (t, J = 5.8 Hz, 1H), 7.68 – 7.59 (m, 2H), 7.47 (d, J = 1.3 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.52 (d, J = 14.9 Hz, 1H), 4.59 (s, 1H), 4.12 – 4.05 (m, 2H), 3.91 (s, 3H), 3.21 (t, J = 7.5 Hz, 2H), 2.66 – 2.59 (m, 2H), 1.92 (p, J = 7.5 Hz, 2H). LCMS Rt = 2.62 min, m / z= 433.98 [M+1]; Purity (254 nm): 92%;1H NMR (400 MHz, DMSO- d6) δ 11.50 (s, 1H), 8.52 (t, J = 5.8 Hz, 1H), 7.69 – 7.62 (m, 1H), 7.60 (dd, J = 10.8, 2.2 Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.15 (s, 1H), 6.98 (d, J = 14.9 Hz, 1H), 6.73 (dt, J = 14.8, 3.9 Hz, 1H), 4.51 (s, 1H), 3.98 (s, 2H), 3.92 (d, J = 10.9 Hz, 3H), 1.67 (s, 3H), 1.50 (s, 4H), 1.43 – 1.21 (m, 3H). Example 26: N-[(2E)-3-{[3-fluoro-5-(pyrrolidin-1-yl)phenyl](imino)oxo-λ⁶-sulfanyl}prop-2- en-1-yl]-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide LCMS Rt = 2.85 min, m / z= 466.00 [M+1]; Purity (254 nm): 97.7%;1H NMR (400 MHz, DMSO- d6) δ 12.26 (s, 1H), 10.01 (d, J = 6.1 Hz, 1H), 8.03 (s, 1H), 7.66 – 7.55 (m, 2H), 7.38 (t, J = 8.6 Hz, 1H), 6.79 (dt, J = 15.0, 4.5 Hz, 1H), 6.49 (dt, J = 15.1, 1.8 Hz, 1H), 4.48 (t, J = 5.4 Hz, 1H), 4.36 (t, J = 5.3 Hz, 1H), 4.16 – 4.11 (m, 2H), 3.92 (s, 3H), 3.18 – 2.97 (m, 2H), 2.57 (d, J = 6.2 Hz, 1H), 1.68 (d, J = 6.6 Hz, 4H). Example 29: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-λ⁶- sulfanyl]prop-2-en-1-yl]-4-oxo-3-azatricyclo[6.2.1.0²,⁷]undeca-2(7),5-diene-5-carboxamide LCMS Rt = 2.39 min, m / z= 434.30 [M+1]; Purity (254 nm): 96.6%;1H NMR (400 MHz, DMSO- d6) δ 12.27 (s, 1H), 10.02 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.65 – 7.49 (m, 2H), 7.37 (t, J = 8.6 Hz, 1H), 6.77 (dt, J = 15.2, 4.6 Hz, 1H), 6.45 (dt, J = 15.1, 1.8 Hz, 1H), 4.13 (q, J = 3.5, 1.8 Hz, 2H), 3.92 (s, 3H), 2.58 (t, J = 5.9 Hz, 2H), 2.54 (s, 3H), 1.76 – 1.63 (m, 4H). LCMS Rt = 2.21 min, m / z= 420.00 [M+1]; Purity (254 nm): 97.6%;1H NMR (400 MHz, DMSO- d6) δ 12.75 (s, 1H), 10.09 (s, 1H), 8.21 (s, 1H), 7.66 – 7.49 (m, 2H), 7.37 (t, J = 8.5 Hz, 1H), 6.77 (dt, J = 15.0, 4.6 Hz, 1H), 6.45 (dt, J = 14.9, 1.8 Hz, 1H), 4.19 – 4.10 (m, 2H), 3.92 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.09 – 2.01 (m, 2H). Example 34: N-[(2E)-3-[(4-cyanophenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en-1-yl]-2- oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 2.29 min, m / z= 410.80 [M+1]; Purity (254 nm): 97.6%;1H NMR (400 MHz, DMSO- d6) δ 12.27 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.16 – 8.04 (m, 2H), 8.03 (s, 1H), 7.99 – 7.90 (m, 2H), 6.88 (dt, J = 15.1, 4.5 Hz, 1H), 6.53 (dt, J = 14.9, 1.9 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H), 2.58 (q, J = 6.0, 4.6 Hz, 2H), 2.55 (s, 3H), 1.76 – 1.63 (m, 4H). Example 35: N-[(2E)-3-[(4-cyanophenyl)[(2-fluoroethyl)imino]oxo-λ⁶-sulfanyl]prop-2-en-1- yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 2.62 min, m / z= 442.98 [M+1]; Purity (254 nm): 97.7%;1H NMR (400 MHz, DMSO- d6) δ 12.25 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.10 – 8.06 (m, 2H), 8.03 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 6.90 (dt, J = 15.0, 4.5 Hz, 1H), 6.62 – 6.48 (m, 1H), 4.47 (t, J = 5.2 Hz, 1H), 4.36 (t, J = 5.2 Hz, 1H), 4.16 (s, 2H), 3.22 – 2.96 (m, 2H), 2.56 (d, J = 6.4 Hz, 1H), 1.68 (d, J = 7.5 Hz, 4H). Example 36: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-λ⁶-sulfanyl]prop-2-en- 1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide LCMS Rt = 2.75 min, m / z= 430.01 [M+1]; Purity (254 nm): 92.3%;1H NMR (400 MHz, DMSO- d6) δ 9.98 (s, 1H), 8.81 (s, 1H), 7.96 – 7.90 (m, 1H), 7.66 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.43 – 7.34 (m, 2H), 7.29 (t, J = 7.5 Hz, 1H), 6.79 (dt, J = 15.1, 4.5 Hz, 1H), 6.55 (d, J = 15.2 Hz, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.91 (s, 3H), 2.53 (s, 3H). Example 37: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)({[(oxetan-3-yl)methyl]imino})oxo-λ⁶- sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 1.71 min, m / z= 490.27 [M+1]; Purity (254 nm): 88.3%;1H NMR (400 MHz, DMSO- d6) δ 12.27 (s, 1H), 10.05 (s, 1H), 8.02 (s, 1H), 7.61 (dt, J = 10.9, 2.6 Hz, 2H), 7.38 (t, J = 8.6 Hz, 1H), 6.78 (dt, J = 15.0, 4.5 Hz, 1H), 6.49 (d, J = 15.1 Hz, 1H), 4.57 (ddd, J = 7.4, 6.0, 1.8 Hz, 2H), 4.24 (dt, J = 8.3, 5.6 Hz, 2H), 4.14 (t, J = 5.1 Hz, 2H), 3.93 (s, 3H), 3.16 – 2.97 (m, 3H), 2.57 (d, J = 6.3 Hz, 2H), 1.75 – 1.57 (m, 4H). Example 38: N-[(2E)-3-[(benzylimino)(3-fluoro-4-methoxyphenyl)oxo-λ⁶-sulfanyl]prop-2-en- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 3.69 min, m / z= 510.17 [M+1]; Purity (254 nm): 96.7%;1H NMR (400 MHz, DMSO- d6) δ 12.26 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.68 – 7.58 (m, 2H), 7.37 (t, J = 8.6 Hz, 1H), 7.34 – 7.30 (m, 2H), 7.27 (dd, J = 8.5, 6.7 Hz, 2H), 7.21 – 7.15 (m, 1H), 6.84 (dt, J = 15.0, 4.5 Hz, 1H), 6.55 (dt, J = 14.9, 1.8 Hz, 1H), 4.20 – 4.12 (m, 2H), 4.08 (d, J = 14.8 Hz, 1H), 3.98 (d, J = 14.9 Hz, 1H), 3.92 (s, 3H), 2.57 (t, J = 5.9 Hz, 2H), 1.73 – 1.49 (m, 4H). Example 39: N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2- en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 3.28 min, m / z= 434.24 [M+1]; Purity (254 nm): 99.3%;1H NMR (400 MHz, DMSO- d6) δ 12.28 (s, 0H), 10.04 (t, J = 6.0 Hz, 0H), 8.05 (s, 0H), 6.93 (t, J = 9.3 Hz, 0H), 6.85 (dt, J = 15.2, 4.6 Hz, 0H), 6.70 – 6.60 (m, 1H), 6.53 (dt, J = 15.1, 1.8 Hz, 0H), 4.17 (q, J = 5.5 Hz, 1H), 3.73 (s, 1H), 3.16 (s, 1H), 2.58 (t, J = 5.8 Hz, 1H). Example 40: N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2- en-1-yl]-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide LCMS Rt = 2.98 min, m / z= 434.3 [M+1]; Purity (254 nm): 98.5%;1H NMR (400 MHz, DMSO- d6) δ 12.28 (s, 1H), 10.04 (t, J = 6.0 Hz, 1H), 8.05 (s, 1H), 6.93 (dd, J = 10.0, 8.5 Hz, 1H), 6.85 (dt, J = 15.1, 4.6 Hz, 1H), 6.70 – 6.61 (m, 2H), 6.53 (dt, J = 15.1, 1.8 Hz, 1H), 4.17 (q, J = 4.7 Hz, 2H), 3.73 (s, 3H), 3.16 (s, 3H), 2.58 (t, J = 5.8 Hz, 2H), 1.69 (d, J = 6.1 Hz, 5H). Example 41: N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-λ⁶-sulfanyl}prop-2- en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide LCMS Rt = 2.78 min, m / z= 420.21 [M+1]; Purity (254 nm): 99.2%;1H NMR (400 MHz, DMSO- d6) δ 12.75 (s, 1H), 10.10 (t, J = 5.7 Hz, 1H), 8.23 (s, 1H), 6.93 (dd, J = 10.0, 8.5 Hz, 1H), 6.86 (dt, J = 15.1, 4.6 Hz, 1H), 6.70 – 6.61 (m, 2H), 6.54 (dt, J = 15.0, 1.8 Hz, 1H), 4.17 (q, J = 6.3, 5.4 Hz, 2H), 3.73 (s, 3H), 3.16 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.10 – 1.99 (m, 2H). Example 42: N-[(2E)-3-[methyl(oxo)(phenylimino)-λ⁶-sulfanyl]prop-2-en-1-yl]-2-oxo- 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 2.92 min, m / z= 385.77 [M+1]; Purity (254 nm): 98.4%;1H NMR (400 MHz, DMSO- d6) δ 12.27 (s, 1H), 10.22 – 9.84 (m, 1H), 8.05 (s, 1H), 7.17 – 7.09 (m, 2H), 6.91 – 6.80 (m, 4H), 6.60 – 6.52 (m, 1H), 4.18 (s, 2H), 3.18 (s, 3H), 2.57 (d, J = 6.5 Hz, 2H), 1.84 – 1.52 (m, 4H). Biological Assays Cell-free HTRF-based HOIP inhibition assay The cell-free homogenous time-resolved fluorescence (HTRF) HOIP inhibition assay was performed to evaluate compound inhibition of HOIP activity similar to assays described in Katsuya et al. (SLAS Discov 2018). This assay was performed in the following steps: a) synthesis of recombinant fragment of human E3 ubiquitin-protein ligase RNF31 (HOIP), expressed with purity >90% in E. coli system (the protein was prepared as 1 mg / mL stock in a standard formulation); b) incubation of the compounds in a typical concentration range: 100-0.005 μM, at a final DMSO conc. 1% with a mixture of HOIP and ubiquitin activating enzyme E1 at 25oC, for 1h at 25oC; c) followed by addition of a ubiquitination solution including E2 and substrates (the reaction proceeds for 2.5h at 25oC); and d) HTRF detection was performed using a PHERAstar FSX (BMG Labtech) plate reader (excitation at 337 nm, dual emissions at 665 and 620 nm). Cell-based dual luciferase NF-ĸB reporter assay Dual-luciferase reporter assay was designed to find inhibitors of HOIP affecting NF-ĸB signaling pathway. The assay was performed in HEK293 cells which were transfected with plasmids coding for Firefly and NanoLuc luciferases. The NanoLuc luciferase plasmid contains NF-ĸB response element which determines its expression. The assay was run following standard dual-luciferase protocols. The assay consists of a few steps: - compounds were dispensed at a concentration range: 100-0.005 μM with a final DMSO concentration of 1% of final volume (25 μL); - cells were stimulated after 30 min with 2.5 ng / mL TNF; and - after 6h Firefly and NanoLuc luciferase activities are determined according to the procedure described by the manufacturer of Nano-Glo Dual-Luciferase Reporter Assay System. TNF-α-induced cytotoxicity assay A viability assay, using bladder carcinoma RT4 cell line, was used for identifying the potential inhibitory effect of tested compounds on HOIP activity. The viability was determined by CellTiter- Glo Luminescent Cell Viability Assay (G7571, Promega) which measures the ability of generating a luminescent signal proportional to the amount of ATP present in living cells. The assay consists of a few steps: a) the cells were routinely sub cultivated twice a week with standard complete growth medium composition; b) cells were preparated for the assay by creating a cell suspension at the density of 0.05 mln cells / mL and dispensed into plates (ViewPlate-384, PerkinElmer) resulting in 1000 cells / well; c) cells were stimulated with 1.25 ng / mL TNFα and with compounds and incubated for 72h at 37°C in the atmosphere with 5% CO2; and d) for detection cytotoxicity was measured with CellTiter-Glo® Luminescent Cell Viability Assay based on the method described by the manufacturer. Biological Assay Results The compounds of the present invention (Examples 1-42) were tested in one or more of the biological assays listed above. The below Table 1 includes all IC50values for biochemical (HTRF) and cellular (TNF, NFkB) activities of the compounds tested. Table 1. IC50values (μM) for biochemical and cellular activities Example HTRF NF-кB TNF-α 1 7.6 ND 39 2 2.9 5.5 6.7 3 0.06 0.58 0.81 4 0.26 2.9 2.0 5 0.17 ND 2.9 6 100 ND 50 7 0.07 ND 0.62 8 0.07 ND 1.21 9 0.04 ND 0.17 10 0.03 ND 0.11 11 0.16 ND 1.7 12 0.03 0.06 0.11 13 0.03 ND 0.12 14 0.08 ND 0.86 15 0.2 ND 1.26 16 0.07 ND 0.26 17 0.12 ND 0.27 18 0.09 ND 0.78 19 0.21 ND 0.7 20 0.06 ND 1.51 21 0.11 ND 0.62 22 1 ND 5.35 23 0.07 ND 0.19 24 0.09 ND 0.71 25 10 ND 50 26 0.03 ND 0.31 27 0.09 ND 0.18 28 0.05 ND 0.15 29 0.07 ND 0.37 30 0.05 ND 0.33 0.03 ND 0.22 0.03 ND 0.15 0.04 ND 0.3 0.02 ND 1.25 0.03 ND 1.27 0.03 ND 0.24 0.05 ND 0.45 0.05 ND 0.24 0.1 ND 0.87 0.06 ND 0.33 0.12 ND 0.88 0.39 ND 1.16 *ND = Not determined

Claims

AMENDED CLAIMS received by the International Bureau on 19 May 2025 (19.05.2025)1. A compound having the formula (I) :or a pharmaceutically acceptable salt or prodrug thereof, wherein R1is: wherein:m is 0 or 1;R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C0- C6)alkyl(C3-C6)cycloalkyl, (C0-C6)alkyl(C3-C6)aryl, (C0-C6)alkyl(C2-C5)heterocycloalkyl and SR10, wherein the (C1-C6)alkyl, cycloalkyl, aryl and heterocycloalkyl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy;A is O or N; when A is O, m is 0;Y is C or N; when Y is N, R6is not present; each t is independently selected from the group consisting of 1, 2 or 3; when t is 1, n is 0;R2and R3are each independently selected from the group consisting of H, (C1-C4)alkyl or wherein R2and R3together with the carbon to which they are attached form (C3- C6)cycloalkyl;R4is selected from the group consisting of H, Hal and (C1-C6)alkyl;R5is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9) heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of oonnee to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl(Halo-4), (C2-C9)heterocycloalkyl(Halo-4), (C3-C6)cycloalkoxy, (C6-C10)aryl(Halo-4), (C6-C10)aryloxy, CN, primary, secondary and tertiary amino;R6and R7are independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C6jcycloalkyl wherein the alkyl or cycloalkyl is optionally substituted with one to four substituents selected from Hal and (C1-C6)alkyl; n is 0 or 1;R8is selected from the group consisting of H, OH, Hal, (C1-C6)alkyl and O(C1- C6)alkyl;R9, when present, is CH2bonded to two independent carbon atoms of the cyclic ring, forming a methylene bridge between the two carbon atoms of the cyclic ring;R10is CHs or CHal(1-3); when n is 0, i) R8is not H or ii) A is N and R11is not H; and when Y is C, at least one of R6, R7or R8is not H.

2. A compound having the formula (I):or a pharmaceutically acceptable salt or prodrug thereof, wherein R1is:wherein: m is 0 or 1;R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C3-C6)aryl and SR10;A is O or N; when A is O, m is 0;Y is C or N; when Y is N, R6is not present; each t is independently selected from the group consisting of 1, 2 or 3; when t is 1, n is 0;R2and R3are each independently selected from the group consisting of H, (C1-C4)alkyl or wherein R2and R3together with the carbon to which they are attached form (C3- C6)cycloalkyl;R4is selected from the group consisting of H, Hal and (C1-C6)alkyl;R5is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cio)cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9) heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6jcycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, CN, primary, secondary and tertiary amino;R6and R7are independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C6)cycloalkyl wherein the alkyl or cycloalkyl is optionally substituted with one to four substituents selected from Hal and (C1-C6)alkyl; n is 0 or 1;R8is selected from the group consisting of H, OH, Hal, (C1-C6)alkyl and O(C1- C6)alkyl;R9, when present, is CH2bonded to two independent carbon atoms of the cyclic ring, forming a methylene bridge between the two carbon atoms of the cyclic ring;R10is CH3or CHal(i-3); when n is 0, i) R8is not H or ii) A is N and R11is not H; and when Y is C, at least one of R6, R7or R8is not H.

3. The compound according to claim 1 or claim 2, wherein m is 1.

4. The compound according to any of the preceding claims, wherein R11, when present, is selected from the group consisting of H, (C1-C6)alkyl, (C0-C6)alkyl(C3-C6)aryl and SR10, wherein the (C1-C6)alkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy, preferably R11, when present, is selected from the group consisting of H, (Co- C6)alkyl(C3-C6)aryl and (C1-C6)alkyl, wherein the (C1-C6)alkyl and aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy.

5. The compound according to any of the preceding claims, wherein A is N.

6. The compound according to any of the preceding claims, wherein Y is C.

7. The compound according to any of the preceding claims, wherein R2, R3and R4are each H.

8. The compound according to any of the preceding claims, wherein R6and R7are independently selected from H and (C1-C6)alkyl, preferably H and (C1-C4)alkyl, more preferably H and CH3.

9. The compound according to any of the preceding claims, wherein n is 0.

10. The compound according to any of the preceding claims, wherein t is 2.

11. The compound according to any of the preceding claims, wherein R10is CHal(i-3), preferably wherein Hal is Cl or F, preferably F.

12. The compound according to claim 1 or claim 2, wherein:R2, R3and R4are H; andR5is (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy.

13. The compound according to any of the preceding claims, wherein:R2, R3and R4are H; and when Y is C, R6and R7are independently selected from the group consisting of H and (C1-C4)alkyl, R8is selected from the group consisting of H, OH, (C1-C6)alkyl and O(C1- C6)alkyl and at least one of R6, R7or R8is not H; or when Y is N, R7is (C1-C4)alkyl and R8is H.

14. A compound having formula (II):or a pharmaceutically acceptable salt or prodrug thereof, wherein: m is 0 or 1;R11, when present, is H;A is O or N; when A is O, m is 0; andR5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy.

15. A compound having formula (III):or a pharmaceutically acceptable salt or prodrug thereof, wherein :R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1-C6)alkoxy;R6and R7are independently selected from H and (Ci-C3)alkyl; andR8is selected from the group consisting of OH, (C1-C4)alkyl or 0(C1-C4)alkyl.

16. A compound having formula (IV) :or a pharmaceutically acceptable salt or prodrug thereof, wherein :R11is selected from the group consisting of H, (C1-C6)alkyl, (C0-C6)alkyl(C3-C6- )cycloalkyl, (C0-C6)alkyl(C3-C6)aryl, (C0-C6)alkyl(C2-C5)heterocycloalkyl and SR10, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl and (C3-C6)aryl groups are optionally substituted with one or more groups selected from the group consisting of one to four Hal and (C1- C6) alkoxy;R5is a (C6-C10)aryl optionally substituted with one or more groups selected from the group consisting of one to four Hal, (C1-C6)alkyl, (C1-C6)alkoxy or CN;R8is H or OH; n is 0 or 1; andR9, when present, is CH2bonded to two independent carbons of the cyclic ring, forming a methylene bridge between the two carbons of the cyclic ring;R10is CHal(i-3); and when n is 0, i) R8is not H or ii) A is N and R11is not H.

17. The compound according to claim 16, wherein R8is OH.

18. The compound according to any of claims 14-16, wherein R5is phenyl optionally substituted with one or more groups selected from the group consisting of one to three Hal and (C1-C6)alkoxy.

19. The compound according to any of the preceding claims, wherein the compound is selected from the group consisting of:N-[(2E)-3-(benzenesulfonyl)prop-2-en-l-yl]-6-methyl-3-oxo-2,3- dihydropyridazine-4-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-l-yl]-6- methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-l-yl]-4- hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-l-yl]- 4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-l-yl]-4- hydroxy-5, 6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide;4-ethoxy-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-A6-sulfanyl]prop-2- en-l-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-l-yl]-4- oxo-3-azatricyclo[6.2.1.0,2'7]undeca-2(7),5-diene-5-carboxamide;N-[(2E)-3-[(cyclopropylimino)(3-fluoro-4-methoxyphenyl)oxo-A6-sulfanyl]prop-2- en-l-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo)(propylimino)-A6-sulfanyl]prop-2-en- l-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo)(phenylimino)-A6-sulfanyl]prop-2- en-l-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-A6-sulfanyl]prop-2-en- l-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(ethylimino)(3-fluoro-4-methoxyphenyl)oxo-A6-sulfanyl]prop-2-en-l- yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(oxo){[(trifluoromethyl)sulfanyl]amino}- A6-sulfanyl]prop-2-en-1-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-1-yl]-4-oxo-3- azatricyclo[6.2.1.02'7]undeca-2(7),5-diene-5-carboxamide;N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxo-A6-sulfanyl]prop-2-en-l-yl]-4-oxo-3- azatricyclo[6.2.1.02'7]undeca-2(7),5-diene-5-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-A6- sulfanyl]prop-2-en-1-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-A6- sulfanyl]prop-2-en-1-yl]-4-oxo-3-azatricyclo[6.2.1.02'7]undeca-2(7),5-diene-5- carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2-fluoroethyl)imino]oxo-A6- sulfanyl]prop-2-en-1-yl]-2-oxo-l,2-dihydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)[(2H3)methylimino]oxo-A6-sulfanyl]prop- 2-en-l-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-A6-sulfanyl]prop-2-en- l-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;N-[(2E)-3-[(4-cyanophenyl)(methylimino)oxo-A6-sulfanyl]prop-2-en-1-yl]-2-oxo-1.2.5.6.7.8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(4-cyanophenyl)[(2-fluoroethyl)imino]oxo-A6-sulfanyl]prop-2-en-1- yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(methylimino)oxo-A6-sulfanyl]prop-2-en- 1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)({[(oxetan-3-yl)methyl]imino})oxo-A6- sulfanyl]prop-2-en-1-yl]-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-[(benzylimino)(3-fluoro-4-methoxyphenyl)oxo-A6-sulfanyl]prop-2-en- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-A6-sulfanyl}prop-2- en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;N-[(2E)-3-{[(3-fluoro-4-methoxyphenyl)imino](methyl)oxo-A6-sulfanyl}prop-2- en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide; andN-[(2E)-3-[methyl(oxo)(phenylimino)-A6-sulfanyl]prop-2-en-1-yl]-2-oxo-1.2.5.6.7.8-hexahydroquinoline-3-carboxamide.

20. The compound according to any of the preceding claims, or a pharmaceutically acceptable salt or prodrug thereof, for use as a medicament.

21. The compound for use as a medicament according to claim 21, wherein use of the compound is combined with radiotherapy, agents suitable for use in chemotherapy, and / or agents suitable for use in immunotherapy, in particular wherein use of the compound is combined with chemotherapeutic agents, immunotherapeutic agents, targeted therapyy and / or radiotherapy that cause increased levels of tumor necrosis factor (TNF).

22. A pharmaceutical composition comprising the compounds according to any of claims 1-19, or a pharmaceutically acceptable salt or prodrug thereof, preferably the composition further comprises at least one pharmaceutically acceptable carrier.

23. The compound or composition according to any of the preceding claims, for use in the treatment of cancer, preferably the cancer is one of melanoma, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, breast cancer, bone cancer, lung cancer or haematological malignancies, preferably ovarian cancer, lung cancer or haematological malignancies.

24. A method for inhibiting Metl-linked ubiquitination, wherein the method comprises the administration of any one of the compounds or compositions according to any of claims 1-23.

25. The method according to claim 24, wherein the inhibition of the Metl-linked ubiquitination comprises the inhibition of linear ubiquitin (Ub) chain assembly complex (LUBAC), preferably the inhibition of RNF31 (HOIP).

26. The method according to claim 24 or 25, wherein the inhibition of the Metl-linked ubiquitination comprises the irreversible or reversible inhibition of linear ubiquitin (Ub) chain assembly complex (LUBAC) via a covalent binding of the compound, preferably the irreversible inhibition of R.NF31 (HOIP).

27. The compound, pharmaceutical composition or method according to any one of claims 1 to 18, 20-26, wherein when R11is the (C1-C6)alkyl or (C0-C6)alkyl(C3-C6)cycloalkyl, the optional substitutions are one to three Hal (preferably F) and / or one (C1-C6)alkoxy.