Novel compounds

Abstract

Provided herein are compounds of formula (I) and formula (II) which are activators of Nuclear Factor Erythroid 2 Related Factor (Nrf2), pharmaceutical compositions comprising the compounds, and methods and uses of the compounds for treating conditions in which activation of Nrf2 is beneficial, such as inflammatory disorders and degenerative diseases.

Description

[0001] NOVEL COMPOUNDS

[0002] Cross-Reference to Related Application

[0003] The present patent application claims priority to Australian provisional application no.

[0004] 2024904179 filed on 17 December 2024, the entire contents of which is incorporated herein by this cross-reference.

[0005] Field

[0006] The present invention relates to compounds which are activators of Nuclear Factor Erythroid 2 Related Factor (Nrf2), pharmaceutical compositions comprising the compounds, and methods and uses of the compounds for treating conditions in which activation of Nrf2 is beneficial, such as inflammatory disorders and degenerative diseases.

[0007] Background

[0008] Nrf2 is a key transcription factor in most cells of all vertebrates. It is normally located in the cytoplasm in an inactive form, bound to a Kelch-like associated protein (Keapl). Keapl plays a key role not only as a negative regulator of Nrf2 by binding it intracellularly but also as a sensor of oxidative and electrophilic stressors. In response to oxidative stress, Nrf2 dissociates from Keapl and translocates to the nucleus where it binds to an antioxidant response element (ARE) in the enhancer regions of its target genes. This initiates the transcription of cytoprotective genes such as those for antioxidant enzymes (such as glutathione synthase that synthesise glutathione, a free radical scavenger) as well as for other protective proteins such as brain derived neurotropic factor. In addition to elevating intracellular levels of glutathione to quench free radicals, activation of Nrf2 provides substrates for mitochondria thus increasing ATP production, which is also protective of cells as well as supporting mitochondrial integrity by promoting mitophagy of damaged mitochondria and conferring resistance to oxidative stress-mediated permeability transition opening, which induces cell death. Nrf2 plays an important role in the regulation of genes that control the expression of proteins critical in the detoxification and elimination of reactive oxygen species (ROS) and electrophiles (Dodson et al. 2019).

[0009] Oxidative stress and chronic inflammation are common features in many diseases. Activation of Nrf2 is proposed to be useful in the treatment of many medical conditions involving oxidative stress and chronic inflammation, including chronic diseases of the lung, heart and liver, autoimmune, degenerative, and metabolic disorders, and cancer initiation. However, to date the only Nrf2 activators that have been approved for clinical use are dimethyl-fumarate for treating relapsing multiple sclerosis, and omaveloxolone for treating Friedreich's ataxia (Dinkova-Kostova et al. 2023).

[0010] It would therefore be desirable to provide further Nrf2 activators having good efficacy, thereby providing a suitable therapy for conditions in which Nrf2 activation is beneficial.

[0011] One issue with therapies based on Nrf2 activation is that overactivation of Nrf2 has been shown to promote cancer cell growth and proliferation, block cell apoptosis and enhance the chemoresistance and radioresistance of cancer cells. In addition, prolonged activation of Nrf2 has been shown to cause tissue damage (Rojo de la Vega et al. 2016). It would thus further be desirable to provide Nrf2 activators with specificity combined with good pharmacokinetic and toxicity profiles.

[0012] Summary

[0013] In one aspect, there is provided a compound of formula (I),

[0014]

[0015] wherein:

[0016] X is S=O;

[0017] R4R4

[0018] R31 R5R31 R5

[0019] R1is hydrogen

[0020]

[0021] orRand R2is hydrogen orR, wherein one of R1and R4

[0022] R31 R5

[0023] R2is hydrogen and the other o

[0024]

[0025] f R1and R2isr7

[0026] R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl; R4is selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0027] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0028] or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, X is S=O;

[0030] R4R4

[0031] R3J. R5R3J.r5

[0032] Y^Y^R6

[0033] R1is hydrogen o

[0034]

[0035] rr7and R2is hydrogen orr7, wherein one of R1and R4

[0036] R31 R5

[0037] R2is hydrogen and the other o

[0038]

[0039] f R1and R2isR

[0040] R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0041] R4is selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0042] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl.

[0043] In some embodiments,

[0044]

[0045] R1is and R2is hydrogen.

[0046] In some embodiments, R5is OCi-6-alkyl, optionally wherein R5is methoxy or ethoxy. In some embodiments, R3and R7are each hydrogen.

[0047] In some embodiments, R4and R6are each Ci-ealkyl, optionally methyl, ethyl, z-propyl or / -butyl.

[0048] In some embodiments, R4and R6are the same.

[0049] In some embodiments, R4is hydrogen and R6is Ci-ealkyl, OH or (CH2)I-4OH, optionally R6is methyl, OH or CH2OH.

[0050] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0051]

[0052] In another aspect, there is provided a compound of formula (II),

[0053]

[0054] wherein

[0055] X is S or S=O;

[0056] R1is hydrogen o

[0057]

[0058] r and R2is hydrogen

[0059]

[0060] or wherein one of R1and

[0061] R2is hydrogen and the other o

[0062]

[0063] f R1and R2is

[0064] R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl; R4is hydrogen;

[0065] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0066] or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, X is S or S=O;

[0068]

[0069] and R2is hydrogen or, wherein one of R1and R4

[0070] R2is hydrogen and the other o

[0071]

[0072] f R1and R2is

[0073] R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl;

[0074] R4is hydrogen;

[0075] R5is selected from the group consisting of halogen, OC1-6-alkyl and OC1-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl.

[0076] In some embodiments,

[0077]

[0078] R1is and R2is hydrogen.

[0079] In some embodiments, X is S.

[0080] In some embodiments, R5is OCi-6-alkyl, optionally wherein R5is methoxy or ethoxy. In some embodiments, R3and R7are each hydrogen.

[0081] In some embodiments, R6is Ci-ealkyl, OH or (CH2)I-4OH, optionally wherein R6is methyl, OH or CH2OH.

[0082] In some embodiments, the compound of formula (II) is selected from the group consisting of

[0083]

[0084] In another aspect, there is provided a pharmaceutical composition comprising the compound or salt as defined herein, and one or more pharmaceutically acceptable excipients.

[0085] In another aspect, there is provided a method of treating or preventing a condition associated with Nuclear Factor Erythroid 2 Related Factor (Nrf2), a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione, in a subject, comprising administering an effective amount of a compound, salt or pharmaceutical composition as defined herein, to the subject.

[0086] In another aspect, there is provided a use of a compound, salt or pharmaceutical composition as defined herein, for the manufacture of a medicament, for treating or preventing a condition associated with Nrf2, a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

[0087] In another aspect, there is provided a compound, salt or pharmaceutical composition as defined herein, for use in treating or preventing a condition associated with Nrf2, a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

[0088] In some embodiments, the condition is a chronic inflammatory condition selected from the group consisting of a chronic respiratory disorder, a heart disorder, cancer, obesity, and type 2 diabetes, a chronic neurological disorder selected from epilepsy, stroke and Friedreich's Ataxia, a chronic liver disease, a chronic kidney disease and a chronic inflammatory disease of the intestinal mucosa.

[0089] In some embodiments, the chronic neurological disorder is epilepsy, optionally wherein administration of the compound, salt or pharmaceutical composition reduces seizure severity, duration and / or frequency. In some embodiments, the chronic inflammatory condition is a chronic respiratory disorder selected from the group consisting of acute lung injury, bronchopulmonary dysplasia (BPD), respiratory infection, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer.

[0090] In some embodiments, the chronic inflammatory condition is:

[0091] a heart disorder selected from the group consisting of pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, cardiac arrhythmias and diabetic cardiomyopathy;

[0092] a chronic liver disease selected from the group consisting of cirrhosis, toxin-induced liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis; or a chronic inflammatory disease of the intestinal mucosa selected from the group consisting of inflammatory bowel disease, colitis and Crohn’s disease; or

[0093] skin inflammation caused by UV radiation or exposure to chlorine or HC1 gases, or an autoimmune disease, optionally psoriasis.

[0094] In some embodiments, the chronic inflammatory condition is:

[0095] a heart disorder selected from the group consisting of pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, cardiac arrhythmias and diabetic cardiomyopathy;

[0096] a chronic liver disease selected from the group consisting of cirrhosis, toxin-induced liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis; or a chronic inflammatory disease of the intestinal mucosa selected from the group consisting of inflammatory bowel disease, colitis and Crohn’s disease; or

[0097] skin inflammation caused by UV radiation, or an autoimmune disease, optionally psoriasis.

[0098] In another aspect, there is provided a method of activating Nrf2, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione in a subject, comprising administering an effective amount of a compound, salt or pharmaceutical composition as defined herein, to the subject.

[0099] In another aspect, there is provided a use of a compound, salt or pharmaceutical composition as defined herein, for the manufacture of a medicament for activating Nrf2, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione.

[0100] In another aspect, there is provided a compound, salt or pharmaceutical composition as defined herein for use in activating Nrf2, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione.

[0101] Brief Description of the Drawings

[0102] Embodiments of the invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0103] Figure 1 shows a1H NMR spectrum of compound 24.

[0104] Figure 2 shows concentration-response relationships of glutathione stimulation in mouse astrocytes after incubation with compounds 15, 19, 22, 23 and sulforaphane (a known Nrf2 activator).

[0105] Figure 3 shows the results of compounds 15, 19, 22, 23 and sulforaphane in an MTT Assay, which is a Method for Error Minimization and Interpretation in Measuring Cytotoxicity and Estimating Cell Viability.

[0106] Figure 4 shows a graph of plasma concentrations of compound 23 in male Swiss outbred mice (n=3 mice per time point) following IV, IP and oral administration.

[0107] Detailed Description

[0108] Definitions

[0109] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art.

[0110] The present disclosure may refer to the contents of certain documents being incorporated herein by reference. In the event of any inconsistent teaching between the teaching of the present disclosure and the contents of those documents, the teaching of the present disclosure takes precedence.

[0111] It is to be understood that if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0112] As used herein, the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0113] As used herein, the term “and / or”, e.g., “X and / or Y” shall be understood to mean either " X and Y" or " X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

[0114] As used herein, the term about, unless stated to the contrary, refers to + / - 10%, of the designated value.

[0115] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.

[0116] Unless otherwise indicated, terms such as "first," "second," etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and / or a higher-numbered item (e.g., a “third” item).

[0117] As used herein, the phrase “at least one of’, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of’ means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination.

[0118] Each embodiment of the present disclosure described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise or required otherwise by context.

[0119] As used herein, “Cato Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl”, or “Ci-4-alkyl” group includes alkyl groups having from 1 to 4 carbons, e.g. CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0120] Terms written as " group AgroupB" are intended to refer to a groupA when linked by a divalent form of groupB. For example, "haloalkyl" is a halogen group when linked by an alkylene group, "alkoxyalkyl" is an alkoxy group when linked by an alkylene group, etc. Similarly, "alkoxy" denotes alkyl, as herein defined, when linked by an oxygen atom, "aryloxy" denotes aryl, as herein defined, when linked by an oxygen atom, etc.

[0121] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may for example have from 1 to 12 carbon atoms (whenever it appears herein, a numerical range such as “1 to 12” refers to each integer in the given range; e.g., “1 to 12 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 12 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as “C1-4-alkyl” or similar designations. By way of example only, “Ci-4-alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, Ao-propyl, / / -butyl, Ao-butyl,.scc-butyl, and / -butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. Where specified, an alkyl group may be optionally substituted by one or more optional substituents as herein defined.

[0122] As used herein, the term “haloalkyl” means an alkyl group as defined above where one or more hydrogen atoms have been replaced with a halogen atom and includes perhalogenated alkyl groups. Examples of suitable haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, difluorochloromethyl, dichlorofluoromethyl, bromomethyl, iodomethyl, 1 -fluoroethyl, 2-fluoroethyl, 1 -chloroethyl, 2-chloroethyl, 1 -bromoethyl, 2-bromoethyl, 1 -iodoethyl, 2-iodoethyl, 1 -fluoropropyl, 2-fluoropropyl, 3 -fluoropropyl, 1-chloropropyl, 2-chloropropyl, 3 -chloropropyl, and the like.

[0123] As used herein, the term “alkenyl” means an aliphatic hydrocarbon group containing a carbon — carbon double bond and which may be straight or branched. For example, an alkenyl group may have from about 2 to about 12 carbon atoms, or having from about 2 to about 6 carbon atoms in the chain. Certain alkenyl groups have from 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. A C2-Ce-alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms. Where specified, an alkenyl group may be optionally substituted by one or more optional substituents as herein defined.

[0124] As used herein, the term "alkynyl" denotes groups formed from straight chain or branched hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C2-12 alkynyl (e.g. C2-10 or C2-6). Examples include ethynyl, 1-propynyl, 2-propynyl, andbutynyl isomers, and pentynyl isomers. Where specified, an alkynyl group may be optionally substituted by one or more optional substituents as herein defined.

[0125] As used herein, the term “alkylene” means a linear or branched saturated divalent hydrocarbon radical. For example, a Ci-6-alkylene includes methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0126] As used herein, the terms “halo” or “halogen,” mean, in the context of the compounds defined herein, a fluorine, chlorine, bromine, or iodine atom, unless otherwise dictated by context. Additionally, terms such as “haloalkyl” may include monohaloalkyl and polyhaloalkyl. For example, the term “halo-Ci-C4-alkyl” may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, l-fluoro-2 -bromoethyl, and the like.

[0127] As used herein, the term “hydroxyl,” means -OH. Each group mentioned above, whether an individual entity or as part of a larger entity may be optionally substituted with one or more optional substituents selected from the group consisting of Ci-ealkyl, C2-ealkenyl, C3-6cycloalkyl, oxo (=0), -OH, -SH, Ci-ealkylO-, C2-ealkenylO-, C3-6cycloalkylO-, Ci-ealkylS-, C2-ealkenylS-, C3-6cycloalkylS-, -CO2H, -C02Ci-ealkyl, -NH2, -NH(Ci-ealkyl), -N(Ci-ealkyl)2, -NH(phenyl), -N(phenyl)2, -CN, -NO2, -halogen, -CF3, -OCF3, -SCF3, -CHF2, -OCHF2, -SCHF2, -phenyl, -heterocyclyl, -heteroaryl, -Oheteroaryl, -Oheterocyclyl, -Ophenyl, -C(=O)phenyl, -C(=0)Ci-6alkyl. Examples of suitable substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, ec-butyl, / e / 7-butyl, vinyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy, oxo, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fluoro, chloro, bromo, iodo, cyano, nitro, -CO2H, -CO2CH3, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy, difluoromethylthio, morpholino, amino, methylamino, dimethylamino, ethylamino, diethylamino, phenyl, phenoxy, phenylcarbonyl, benzyl and acetyl.

[0128] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene”.

[0129] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Other forms of isomerism include double bond isomerism in which compounds containing a carbon-carbon double bond may exist as Z or E isomers, conformational isomerism, and atropisomerism. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds which are used herein. Separation of individual isomers or selective synthesis of individual isomers is accomplished by application of various methods which are known to practitioners in the art.

[0130] The skilled artisan will also recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures. For example, the term “tautomers” may refer to a set of compounds that have the same number and type of atoms, but differ in bond connectivity and are in equilibrium with one another. A “tautomer” is a single member of this set of compounds. Typically, a single tautomer is drawn but it may be understood that this single structure may represent all possible tautomers that might exist. Examples may include enol-ketone tautomerism. When a ketone is drawn it may be understood that both the enol and ketone forms are part of the disclosure. The present disclosure encompasses the use of resonance forms and tautomers of compounds.

[0131] An isotope of an element other than the most commonly occurring isotope may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. Such isotopically labeled compounds may for example be useful as research or diagnostic tools in, for example, metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),10B,11C,13C,14C,15N,18F,31P,32P,35S,36C1 and125I. Various isotopically labelled compounds of the present disclosure, for example those into which radioactive isotopes such as3H,13C and14C are incorporated. In addition to use as pharmaceutical treatments, such isotopically labelled compounds may be useful.

[0132] Those skilled in the art will appreciate that many organic compounds can form complexes in solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates, such as hydrates, exist when the compound incorporates solvent. It will be understood that the present disclosure encompasses use of solvated forms of the compounds of the present disclosure, as well as salts thereof. Solvates of the compounds which are suitable may for example be those where the associated solvent is pharmaceutically acceptable. Suitable solvates include hydrates. It will be understood that the present disclosure encompasses the use of unsolvated forms of the compounds, as well as solvated forms, such as hydrates.

[0133] Compounds and salts disclosed herein may exist in one or more crystalline or amorphous forms. It will be understood that the present disclosure encompasses the use of all such forms of the compounds and salts.

[0134] Compounds of Formula (I) and Formula (II)

[0135] The compounds of formula (I) and formula (II) are structurally related to 1,2-dithiole-3-thione (DTE). This simple low molecular weight chemical has been shown to activate Nrf2 in cultured primary neurones, glia and neuroblastoma cells and increases the expression of the antioxidant response genes for these enzymes. DTE has been described as a chemopreventive agent acting through the Keapl-Nrf2 transcription factors in cells, but it is poorly soluble and is thus not suitable as a therapeutic.

[0136] Anethol trithione (5-(4-methoxyphenyl)-3H-l,2-dithiole-3-thione - ADT) is a well-known DTE analogue, marketed as Sialor™ or Sulfarlem™, for increasing salivary secretion in patients with dry mouth. It has been proposed for the treatment of free-oxygen radical related disease as it can inhibit the production of reactive oxygen species (ROS) in vitro. Anethol trithione (ADT) possesses a high lipophilicity (log P = 3.8) and an extremely low water solubility (0.38 ug / mL), which limits its dissolution, absorption and therapeutic utility. Furthermore, ADT is quickly metabolized into 5-(4-hydroxyphenyl)-3H-l,2-dithiole-3-thione via O-dem ethylation (AOX), which has a similar pharmacological activity and low aqueous solubility compared to ADT. As a consequence, the plasma concentration of ADT / AOX is usually fairly low, and the compound has limited oral bioavailability as well. Given this pharmacodynamic profile, there is continued interest and study in the development of variants of ADT and AOX to achieve therapeutic activity in vivo. To date, this work has focussed on providing means to make ADT or AOX more soluble, for example by mixing with them with a beta cyclodextrin.

[0137] The inventor previously identified DTE derivatives that are cyclooxygenase inhibitors (COX-inhibitors). This work is described in WO2008 / 0522889 (Jarrott et al. 2008).

[0138] The two principal forms of cyclooxygenase (COX) that have been studied are the constitutive isoform (COX-1) and an inducible isoform (COX-2). Expression of these enzymes is upregulated at sites of inflammation. COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The use of conventional COX-1 inhibitors is limited due to side effects such as ulceration and liver and renal toxicity. Compounds that selectively inhibit COX-2 exert antiinflammatory effects without the adverse side effects associated with COX-1 inhibition.

[0139] COX inhibition refers to inhibition of at least one form of cyclooxygenase, and therefore encompasses inhibition of one or both of COX-1 and COX-2 to a degree considered to be statistically significant to a person skilled in the art.

[0140] The term "selective COX-2 inhibitor" refers to a compound able to inhibit COX-2 without significant inhibition of COX-1, e.g., the degree of inhibition of COX-2 compared to COX-1 inhibition that would be considered statistically significant by people of ordinary skill in this art. Preferably, this includes compounds which have a COX-2 IC50 of less than about 25 pM, and also have a selectivity ratio of COX-1 inhibition over COX-2 inhibition of at least about 5, and more preferably of at least about 25.

[0141] The synthesis and COX inhibitory activity of the following DTE derivatives are described in W02008 / 052288:

[0142] 5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (1);

[0143] 5-(3,5-Di-tert-butyl-4-methoxyphenyl)-3H-1,2-dithiole-3-thione (2);

[0144] 5-(3,5-Di-tert-butyl-4-ethoxyphenyl)-3H-1,2-dithiole-3-thione (3);

[0145] 5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3H-1,2-dithiol-3-one (4);

[0146] 5-(3,5-Di-tert-butyl-4-methoxyphenyl)-3H-1,2-dithiol-3-one (5);

[0147] 5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4-methyl-3H-1,2-dithiole-3-thione (6);

[0148] 5-(3,5-Di-tert-butyl-4-methoxyphenyl)-4-(methyl)-3H-1,2-dithiole-3-thione (7); 5-(3,5-Di-tert-butyl-4-ethoxyphenyl)-4-(methyl)-3H-1,2-dithiole-3-thione (8);

[0149] 5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4-(methyl)-3H-1,2-dithiole-3-one (9);

[0150] 5-(3,5-Di-tert-butyl-4-methoxyphenyl)-4-(methyl)-3H-1,2-dithiole-3-one (10);

[0151] 5-(3,5-Diisopropyl-4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (11);

[0152] 5-(3,5-Diisopropyl-4-methoxyphenyl)-3H-1,2-dithiole-3-thione (12);

[0153] 5-(3,5-Diisopropyl-4-ethoxyphenyl)-3H-1,2-dithiole-3-thione (13);

[0154] 5-(3,5-Dimethyl-4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14); 5-(3,5-Dimethyl-4-methoxyphenyl)-3H-1,2-dithiole-3-thione (15);

[0155] 5-(3,5-Dimethyl-4-ethoxyphenyl)-3H-1,2-dithiole-3-thione (16);

[0156] 5-(3,5-Dimethyl-4-methoxyphenyl)-3H-1,2-dithiole-3-one (17);

[0157] 5-(3,5-Dimethyl-4-benzyloxyphenyl)-3H-1,2-dithiole-3-thione (18).

[0158] W02008 / 052288 demonstrates that DTE does not significantly inhibit either COX-1 or COX-2 at 10 pM concentrations, with a percentage inhibition of 9% and 35%, respectively. However, compound 2 was shown to have selective COX-2 activity of at least 100 and compound 1 to have significant COX-1 activity and COX-2 selectivity of approximately 10.

[0159] In W02008 / 052288, compounds 1, 2, 4, 5, 6, 7, 10, 11, 12, 17 and 18 were further subjected to testing in vitro at 1 pM concentrations for % COX-1 inhibition and % COX-2 inhibition and selectivity, with the results as follows:

[0160] Table 1: Compounds disclosed in W02008 / 052288 and COX-1 / 2 activities thereof Comp ID # Chemical Structure MW % COX-1 % COX-2

[0161] 1 pM 1 pM

[0162] Compound 1 338.55 44 98

[0163]

[0164] Compound 2 352.58 7 69

[0165]

[0166] Compound 3 366.6

[0167]

[0168] Compound 4 323 12 53

[0169] Compound 5 337 22 51

[0170]

[0171] Compound 6 352.58 34 73

[0172]

[0173] Compound 7 366.6 31 29

[0174]

[0175] Compound 8 380.63

[0176]

[0177] Compound 9 336.51

[0178]

[0179] Compound 10 350.54 11 43

[0180]

[0181] Compound 11 310.5 10 65

[0182]

[0183] Compound 12 324.52 0 35

[0184]

[0185] Compound 13 338.55

[0186]

[0187] Compound 14 254.39

[0188]

[0189] Compound 15 268.42

[0190]

[0191] Compound 16 282.44

[0192]

[0193] Compound 17 252.35 0 41

[0194]

[0195] Compound 18 344.51 3 30

[0196]

[0197] Further work described in Zanatta, S. D. et al., (2010) reported the COX-1 and COX-2 enzyme inhibiting capabilities of several DTE derivatives, finding compound 1 and compound 2 (of W02008 / 052288) to be the most active.

[0198] Subsequent work described in Jarrott, B. & Williams, S. J. (2016) investigated the neurochemical basis for drugs to reduce chronic brain inflammation. The authors investigated whether COX inhibition and the subsequent effect on inflammation could be effective in reducing chronic brain inflammation and reported that compound 1 (of W02008 / 052288) was a reasonably potent inhibitor of both COX-1 and COX-2 and an equipotent inhibitor of 5-lipoxygenase. They also found that the methyl ether analogue (compound 2 of W02008 / 052288) was a potent and selective COX-2 inhibitor, not causing significant inhibition of COX-1 and was not a 5-lipoxygenase inhibitor (Zanatta et al. 2009). The 4-methoxy group was found to be essential for COX-2 selectivity. They also reported that compound 1 and compound 2 (of W02008 / 052288) both had a central nervous system multi parameter optimisation (CNS MPO) score indicative of high probability of CNS action.

[0199] The inventor postulated that DTE derivatives that were selective COX-2 inhibitors would be Nrf2 activators. To test this theory, Nrf2 activation for compounds 2, 14, 15 and 16 (of W02008 / 052288) was measured by assaying cultured mouse brain cells for increased intracellular glutathione after administration, as evidence of the ability of the compound to activate glutathione synthase, which is linked to Nrf2 activation. They were expecting compound 2 to be an Nrf2 activator based on their earlier work, for compound 14 also be an Nrf2 activator as phenolic compounds are one of the known classes of Nrf2 activators and compound 15 to be inactive as an Nrf2 activator, as often compounds bearing a phenol are O-methylated in the liver as a metabolic step. Surprisingly, the opposite happened, in that compound 15 was found to be potent Nrf2 activator up to 100 pM whereas compound 14 was toxic to cells when exposed at concentrations of 20, 50 and 100 pM, and displayed no activity at 10 pM. Furthermore, compound 2 had only half the Nrf2 activation activity of compound 15. Compound 16 also activated Nrf2 in the cultured brain cell assay, with similar activity to compound 15, thus demonstrating the 4-methoxy and 4-ethoxy group to be a determinant of Nrf2 activation. Based on the prior art, there was no expectation that compound 15 or compound 16 would activate Nrf2 in a cultured brain cell assay and no suggestion that it would have twice the activity of compound 2 in this regard. Without wishing to be bound by theory, one possible explanation for these surprising results is that the phenolic OH of compound 14 ionises to a phenoxide anion at physiological pH of the culture medium, and is toxic to cells, whereas the methoxy group of compound 15 or the ethoxy group of compound 16 does not ionise at that pH, enters the cells and activates Nrf2. Based on this, compound bearing a phenolic group, such as AOX, would also be expected to be toxic to cells. Furthermore, the inventor shows that AOX does not activate the Nrf2 transcription factor in contrast to ADT.

[0200] A second possible explanation is that the 3- and 5-tert butyl-substituted phenyl ring of compound 2 sterically hinders the compounds entrance to the cells, and also results in the compound being not of ideal lipophilicity, so it is retained in the plasma membrane and less is able to reach the Nrf2-KEAP complex. However, without any phenyl substitution as in ADT and AOX, the compound is not sufficiently soluble to be useful without a delivery vehicle.

[0201] The inventor has now also identified further novel compounds which are effective as Nrf2 activators, and which find utility in the therapy of conditions associated with Nrf2.

[0202] Accordingly, provided herein are compounds of formula (I),

[0203] R1

[0204]

[0205] wherein:

[0206] X is S=O;

[0207] R1is hydrogen o

[0208]

[0209] r and R2is hydrogen or wherein one of R1and R4

[0210] R2is hydrogen and the other o

[0211]

[0212] f R1and R2is R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl; R4is selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0213] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0214] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, X is S=O;

[0216] R4R4

[0217] R31 R5R31 R5

[0218] R1is hydrogen

[0219]

[0220] orr7and R2is hydrogen orr7, wherein one of R1and R4

[0221] R^Jl R5

[0222] Yy^6

[0223] R2is hydrogen and the other o

[0224]

[0225] f R1and R2isr7

[0226] R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0227] R4is selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0228] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl.

[0229] R4

[0230] R3^ ^5

[0231] Y Y^R6

[0232] In some embodiments,

[0233]

[0234] R1isr7and R2is hydrogen.

[0235] R4

[0236] R3JL R5

[0237] In some other embodiments, R

[0238]

[0239] 2isRand R1is hydrogen. R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl. In some embodiments, R5is OCi-6-alkyl. In some embodiments, R5is methoxy. In some embodiments, R5is ethoxy. In some embodiments, R5is OCi-6-haloalkyl. In some embodiments, R5is OCF3. In some embodiments, R5is halogen. In some embodiments, R5is fluorine. In some embodiments, R5is chloro. In some embodiments, R5is bromo.

[0240] R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OC1-6-alkyl.

[0241] In some embodiments, R3and R7are selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH and Ci-6-alkyl. In some embodiments, R3is hydrogen. In some embodiments R7is hydrogen. In some embodiments, R3and R7are each hydrogen.

[0242] R4is selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl. In some embodiments, R4is Ci-6-alkyl. In some embodiments, R4is methyl, ethyl, z-propyl or / -butyl. In some embodiments, R4is hydrogen. In some embodiments, R4is OH. In some embodiments, R4is (CH2)I-4OH. In some embodiments, R4is CH2OH.

[0243] R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl. In some embodiments, R6is Ci-6-alkyl. In some embodiments, R4is methyl, ethyl, z-propyl or / -butyl. In some embodiments, R6is hydrogen. In some embodiments, R6is OH. In some embodiments, R6is (CH2)I-4OH. In some embodiments, R6is CH2OH.

[0244] In some embodiments, R3is C1-6 alkyl. In some embodiments, R4is C1-6 alkyl. In some embodiments, R6is C1-6 alkyl. In some embodiments, R7is C1-6 alkyl. In some embodiments, R4and R6are both C1-6 alkyl. Preferred C1-6 alkyl substituents are methyl, ethyl, propyl, or t-butyl. In some embodiments, R4is hydrogen and R6is Ci-ealkyl, optionally R6is methyl. In some embodiments, R4and R6are the same. In some embodiments, R4and R6are each Ci-ealkyl, optionally methyl, ethyl, z-propyl or / -butyl.

[0245] In some embodiments, R3is OH. In some embodiments, R4is OH. In some embodiments, R6is OH. In some embodiments, R7is OH.

[0246] In some embodiments, R3is (CH2)I-4OH. In some embodiments, R4is (CH2)I-4OH. In some embodiments, R6is (CH2)I-4OH. In some embodiments, R7is (CH2)I-4OH. In some embodiments, R4and R6are both (CH2)I-4OH. A preferred (CH2)I-4OH substituent is CH2OH. In some embodiments, R4is hydrogen and R6is (CH2)I-4OH, optionally R6is CH2OH. In some embodiments, R4and R6are each (CH2)I-4OH, optionally CH2OH.

[0247] In some embodiments, R3is halogen. In some embodiments, R4is halogen. In some embodiments, R6is halogen. In some embodiments, R7is halogen. In some embodiments, R4and R6are both halogen.

[0248] In some embodiments, R3and R7are each hydrogen. In some embodiments, R3and R7are hydrogen and R4and R6are selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl. In some embodiments, R3and R7are hydrogen, and R4and R6are halogen, Ci-6-alkyl, OH or (CH2)I-4OH. In some embodiments, R3and R7are each hydrogen and R4and R6is halogen, OH, (CH2)I-4OH or Ci-6-alkyl. In some embodiments, R3and R7are hydrogen and R4and R6are halogen. In some embodiments, R3and R7are hydrogen and R4and R6are Ci-6-alkyl. In some other embodiments, R3and R7are hydrogen and R4and R6are (CH2)I-4OH. In some embodiments, R3and R7are hydrogen, R4is Ci-6-alkyl and R6is (CH2)I-4OH. In some embodiments, R3and R7are hydrogen, R4is Ci-6-alkyl and R6is halogen. In some other embodiments, R3and R7are hydrogen, R4is (CH2)I-4OH and R6is Ci-6-alkyl. In some other embodiments, R3and R7are hydrogen, R4is (CH2)I-4OH and R6is halogen. Preferred C1-6-alkyl groups are methyl, ethyl, i-propyl, and t-butyl. A preferred (CH2)I-4OH group is CH2OH. Preferred halogen groups are fluoro or chloro. In some other embodiments, R3and R7are hydrogen, R4is OH and R6is halogen

[0249] In some embodiments, R3, R4and R7are hydrogen and R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl. In some embodiments, R3, R4and R7are each hydrogen. In some embodiments, R3, R4and R7are hydrogen, and R6is halogen, OH, (CH2)I-4OH or Ci-6-alkyl. In some embodiments, R3, R4and R7are hydrogen, and R6is halogen. In some embodiments, R3, R4and R7are hydrogen, and R6is Ci-6-alkyl. In some embodiments, R3, R4and R7are hydrogen, and R6is OH. In some embodiments, R3, R4and R7are hydrogen, and R6is (CH2)I-4OH. Preferred Ci-6-alkyl groups are methyl, ethyl, i-propyl, and t-butyl. A preferred (CH2)I-4OH group is CH2OH. Preferred halogen groups are fluoro or chloro. In some embodiments, R3, R4and R7are hydrogen, and R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl. In some embodiments, R3, R4and R7are hydrogen, and R5is OC1-6 alkyl. In some embodiments, R3, R4and R7are hydrogen, and R5 is O-methyl. In some embodiments, R3, R4and R7are hydrogen, and R5is O-ethyl. In some embodiments, R3, R4and R7are hydrogen, and R5is OCi-6-haloalkyl. In some embodiments, R3, R4and R7are hydrogen, and R5is OCF3. In some embodiments, R3, R4and R7are hydrogen, and R5is halogen. In some embodiments, R3, R4, R6and R7are hydrogen, and R5is fluoro. In some embodiments, R3, R4and R7are hydrogen, and R5is chloro. In some embodiments, R3, R4and R7are hydrogen, and R5is bromo.

[0250] In some embodiments, R3, R4and R7are selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl, and R5is halogen. In some embodiments, R3is hydrogen and R5is halogen. In some embodiments, R4is hydrogen and R5is halogen. In some embodiments, R7is hydrogen and R5is halogen. In some embodiments, R3and R4is hydrogen and R5is halogen. In some embodiments, R3is hydrogen, R5is halogen and R6is halogen. In some embodiments, R3and R7is hydrogen and R5is halogen. In some embodiments, R3, R4and R7are hydrogen, R5is halogen, and R6is C1-6 alkyl. In some embodiments, R3and R7are hydrogen, R5is halogen, and R4and R6is C1-6 alkyl.

[0251] In some embodiments, R3is hydrogen and R5is OC1-6 alkyl. In some embodiments, R4is hydrogen and R5is OC1-6 alkyl. In some embodiments R6is C1-6 alkyl and R5is OC1-6 alkyl. In some embodiments, R7is hydrogen and R5is OC1-6 alkyl. In some embodiments, R3and R4is hydrogen and R5is OC1-6 alkyl. In some embodiments, R3and R6is hydrogen and R5is OC1-6 alkyl. In some embodiments, R3and R7is hydrogen and R5is OC1-6 alkyl. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl, and R6is C1-6 alkyl. In some embodiments, R3and R7are hydrogen, R5is OC1-6 alkyl, and R4and R6is C1-6 alkyl.

[0252] In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is C1-6-alkyl. In some embodiments, R3and R7are hydrogen, R4is Ci-6-alkyl, R5is OC1-6 alkyl and R6is Ci-6-alkyl. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is OH. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is (CH2)I-4OH. R4

[0253] In some embodiments, R

[0254]

[0255] 1is; R2is hydrogen; R3and R7are each hydrogen; R4is hydrogen, Ci-ealkyl, OH or (CH2)I-4-OH; R5is OCi-ealkyl; and R6is Ci-ealkyl, OH or (CH2)I-4-OH.

[0256] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0257]

[0258] Also provided herein are compounds of formula (II),

[0259]

[0260] wherein:

[0261] X is S or S=O;

[0262] R1is hydrogen o

[0263]

[0264] r and R2is hydrogen

[0265]

[0266] or wherein one of R1and R4

[0267] R3R5

[0268] vX- R2is hydrogen and the other of R1and R2isR

[0269] R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl; R4is hydrogen;

[0270] R5is selected from the group consisting of halogen, OC1-6-alkyl and OC1-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)1-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0271] or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, X is S or S=O;

[0273] R4R4

[0274] R31 R5R31 R5

[0275] R1is hydrogen

[0276]

[0277] orRand R2is hydrogen orR, wherein one of R1and R4

[0278] R31 R5

[0279] y^X

[0280] R2is hydrogen and the other o

[0281]

[0282] f R1and R2isr7

[0283] R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0284] R4is hydrogen;

[0285] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl.

[0286] R4

[0287] R31 R5

[0288] In some embodiments,

[0289]

[0290] R1isRand R2is hydrogen. R4

[0291] R3JL R5

[0292] Y ^Y^R6

[0293] In some other embodiments,

[0294]

[0295] R2isr7and R1is hydrogen.

[0296] In some embodiments, X is S. In some other embodiments, X is S=O.

[0297] R4

[0298] > Y Y> XR6

[0299] In some embodiments, R

[0300]

[0301] 1isr7, R2is hydrogen, and X is S. In some R4

[0302] R31 R5

[0303] embodiments, R1is hydrogen, R

[0304]

[0305] 2isR, and X is S. In some embodiments, R1is R4

[0306] R3!. R5

[0307] Y y^R6

[0308]

[0309] r7, R2is hydrogen, and S=O. In some embodiments, R1is hydrogen, R2is R4R4

[0310] R31 R5R31 R5

[0311]

[0312] R, and S=O. Preferably R1isR, R2is hydrogen, and X is S or S=O.

[0313] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl. In some embodiments, R5is OCi-6-alkyl or halogen. In some embodiments, R5is OCi-6-alkyl. In some embodiments, R5is methoxy. In some embodiments, R5is ethoxy. In some embodiments, R5is OCi-6-haloalkyl. In some embodiments, R5is OCF3. In some embodiments, R5is halogen. In some embodiments, R5is fluorine. In some embodiments, R5is chloro. In some embodiments, R5is bromo.

[0314] In some embodiments, R3is C1-6 alkyl. In some embodiments, R6is C1-6 alkyl. In some embodiments, R7is C1-6 alkyl. In some embodiments, R3is C1-6 alkyl and R6is C1-6 alkyl. In some embodiments, R3is C1-6 alkyl and R7is C1-6 alkyl. In some embodiments, R6is C1-6 alkyl and R7is C1-6 alkyl. In some embodiments, R3is OH. In some embodiments, R6is OH. In some embodiments, R7is OH. In some embodiments, R3is (CH2)I-4OH. In some embodiments, R6is (CH2)I-4OH. In some embodiments, R7is (CH2)I-4OH. In some embodiments, R3is (CH2)I-4OH and R6is (CH2)I-4OH. In some embodiments, R3is (CH2)I-4OH and R7is (CH2)I-4OH. In some embodiments, R6is (CH2)I-4OH and R7is (CH2)I-4OH. In some embodiments, R3is halogen. In some embodiments, R6is halogen. In some embodiments, R7is halogen. In some embodiments, R3is halogen and R6is halogen. In some embodiments, R3is halogen and R7is halogen. In some embodiments, R6is halogen and R7is halogen.

[0315] In some embodiments, R3is hydrogen and R5is OC1-6 alkyl. In some embodiments, R7is hydrogen and R6is OC1-6 alkyl. In some embodiments, R7is hydrogen and R5is OCi-6 alkyl. In some embodiments, R3and R4is hydrogen and R5is OC1-6 alkyl. In some embodiments, R3, R4and R7is hydrogen and R5is OC1-6 alkyl. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is Ci-6-alkyl. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is OH. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is (CH2)I-4OH. In some embodiments, R3, R4and R7are hydrogen, R5is OC1-6 alkyl and R6is halogen.

[0316] R4

[0317] In some embodiments, R

[0318]

[0319] 1isR; R2is hydrogen; R3and R7are each hydrogen; R5is OCi-ealkyl; and R6is Ci-ealkyl, OH or (CH2)I-4-OH.

[0320] In some embodiments, the compound of formula (II) is selected from the group consisting of

[0321]

[0322] In some embodiments, the compound of formula (I), formula (II) as defined herein is any one of the example compounds, or a salt thereof.

[0323] In some embodiments, the compound of formula (I) or formula (II) is not a salt. In other embodiments, the compound of formula (I) or formula (II) is provided in the form of a salt. Suitable salts include those formed with organic or inorganic acids or bases. As used herein, the term “pharmaceutically acceptable salt” means a pharmaceutically acceptable organic or inorganic salt and includes both acid addition salts and base addition salts unless dictated otherwise by context. Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl -propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport.

[0324] Water Solubility

[0325] Example compounds of the present disclosure demonstrated improved solubility properties compared with comparator compounds, i.e., they are water soluble. As used herein, the term ‘water soluble’ refers to a compound or salt having a solubility in water [at 25°C and atmospheric pressure] of at least 1 pM, or at least 5 pM, or at least 10 pM, or at least 20 pM, or at least 30 pM, or at least 40 pM, or at least 50 pM, or at least 75 pM, or at least 100 pM, or at least 250 pM, or at least 500 pM, or at least 1 mM, or at least 5 mM, or at least 10 mM.

[0326] Accordingly, there is also provided a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or salt,

[0327]

[0328] wherein:

[0329] X is S=O;

[0330] R4R4

[0331] R31 R5R31 R5

[0332] R1is hydrogen

[0333]

[0334] orRand R2is hydrogen orR, wherein one of R1and R4

[0335] R31 R5

[0336] R2is hydrogen and the other o

[0337]

[0338] f R1and R2isr7

[0339] R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl; R4is selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0340] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0341] and wherein the compound of formula (I) or salt thereof is water soluble.

[0342] In some embodiments, X is S=O;

[0343] R1is hydrogen o

[0344]

[0345] r and R2is hydrogen or wherein one of R1and R2is hydrogen and the other o

[0346]

[0347] f R1and R2isR

[0348] R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0349] R4is selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0350] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl.

[0351]

[0352] In some embodiments, R5is OCi-6-alkyl, optionally wherein R5is methoxy or ethoxy. In some embodiments, R3and R7are each hydrogen.

[0353] In some embodiments, R4and R6are each Ci-ealkyl, optionally methyl, ethyl, z-propyl or / -butyl.

[0354] In some embodiments, R4and R6are the same.

[0355] In some embodiments, R4is hydrogen and R6is Ci-ealkyl, OH or (CH2)I-4OH, optionally R6is methyl, OH or CH2OH.

[0356] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0357] OEt OEt

[0358]

[0359]

[0360] There is also provided a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or salt,

[0361]

[0362] wherein:

[0363] X is S or S=O;

[0364] R4R4

[0365] R3J. R5R3J. R5

[0366] Y^Y^R

[0367]

[0368] 6^^y^R6

[0369] R1is hydrogen orr7and R2is hydrogen orr7, wherein one of R1and R4

[0370] R31 R5

[0371] R2is hydrogen and the other o

[0372]

[0373] f R1and R2isR

[0374] R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl; R4is hydrogen;

[0375] R5is selected from the group consisting of halogen, OC1-6-alkyl and OC1-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)1-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0376] and wherein the compound of formula (II) or salt thereof is water soluble.

[0377] In some embodiments, X is S or S=O; R4

[0378] R1is hydrogen

[0379]

[0380] or and R2is hydrogen

[0381]

[0382] or wherein one of R1and R4

[0383] R31 R5

[0384] R2is hydrogen and the other o

[0385]

[0386] f R1and R2isR

[0387] R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;

[0388] R4is hydrogen;

[0389] R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci- R4

[0390] 6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl. In some embodiments, R

[0391]

[0392] 1isr7and R2is hydrogen.

[0393] In some embodiments, X is S.

[0394] In some embodiments, R5is OCi-6-alkyl, optionally wherein R5is methoxy or ethoxy. In some embodiments, R3and R7are each hydrogen.

[0395] In some embodiments, R6is Ci-ealkyl, OH or (CH2)I-4OH, optionally wherein R6is methyl, OH or CH2OH.

[0396] In some embodiments, the compound of formula (II) is selected from the group consisting of

[0397]

[0398] Methods and Uses

[0399] The compounds of formula (I) and formula (II), salts thereof, and pharmaceutical compositions comprising the compound or salt, are useful as pharmaceuticals for treating or preventing a condition associated with Nuclear Factor Erythroid 2 Related Factor (Nrf2), a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

[0400] The compounds of formula (I) and formula (II), salts thereof and pharmaceutical compositions comprising the compound or salt, also find use in activating Nrf2, reducing production of reactive oxygen species, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione.

[0401] Accordingly, in one aspect there is provided a method of treating or preventing a condition associated with Nuclear Factor Erythroid 2 Related Factor (Nrf2), a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione, in a subject, comprising administering an effective amount of a compound, salt or pharmaceutical composition as defined herein, to the subject.

[0402] In another aspect, there is provided a use of a compound, salt or pharmaceutical composition as defined herein, for the manufacture of a medicament, for treating or preventing a condition associated with Nrf2, a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

[0403] In another aspect, there is provided a compound, salt or pharmaceutical composition as defined herein, for use in treating or preventing a condition associated with Nrf2, a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

[0404] As used herein, the term ‘condition’ encompasses diseases and disorders.

[0405] In some embodiments, the condition is a condition associated with Nuclear Factor Erythroid 2 Related Factor (Nrf2). As used herein, the term ‘condition associated with Nuclear Factor Erythroid 2 Related Factor’ refers to a condition in which activation of Nrf2 is associated with a beneficial therapeutic response.

[0406] In some embodiments, the condition is a condition associated with oxidative stress. In some embodiments, the condition is a condition which is responsive to activation of glutathione synthase.

[0407] In some embodiments, the condition is a condition which is responsive to increased intracellular glutathione.

[0408] In some embodiments, the condition is a chronic inflammatory condition selected from a chronic respiratory disorder, a heart disorder, cancer, obesity, and type 2 diabetes, a chronic neurological disorder selected from epilepsy, stroke and Friedreich's Ataxia, a chronic liver disease, a chronic kidney disease, a chronic inflammatory disease of the intestinal mucosa, skin inflammation caused by UV radiation, or an autoimmune disease, optionally psoriasis.

[0409] In some embodiments, the condition is a chronic inflammatory condition selected from a chronic respiratory disorder, a heart disorder, cancer, obesity, and type 2 diabetes, a chronic neurological disorder selected from epilepsy, stroke and Friedreich's Ataxia, a chronic liver disease, a chronic kidney disease, a chronic inflammatory disease of the intestinal mucosa, skin inflammation caused by UV radiation or exposure to chlorine or HC1 gases, or an autoimmune disease, optionally psoriasis.

[0410] In some embodiments, the condition is epilepsy. If the condition is epilepsy, administration of a compound of formula (I) may for example reduce seizure severity, duration and / or frequency of epilepsy seizures.

[0411] In some embodiments, the condition is a chronic respiratory disorder selected from the group consisting of acute lung injury, bronchopulmonary dysplasia (BPD), respiratory infection, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer. Particularly the condition may be ARDS caused by or associated with coronavirus infection, particularly when the coronavirus infection is COVID-19 infection.

[0412] In some embodiments, the condition is a heart disorder selected from the group consisting of pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, cardiac arrhythmias and diabetic cardiomyopathy.

[0413] In some embodiments, the condition is a chronic liver disease selected from the group consisting of cirrhosis, toxin-induced liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In some embodiments, the condition is a chronic inflammatory disease of the intestinal mucosa selected from the group consisting of inflammatory bowel disease, colitis and Crohn’s disease.

[0414] In some embodiments, the condition is skin inflammation caused by UV radiation, or an autoimmune disease, optionally psoriasis.

[0415] In some embodiments, the condition is skin inflammation caused by UV radiation or exposure to chlorine or HC1 gases, or an autoimmune disease, optionally psoriasis.

[0416] The term "subject" as used herein refers to any animal, including a human. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is at least 50 years old, at least 60 years old, or at least 70 years old. In some embodiments, the subject is male. In some embodiments the subject is female.

[0417] The term “therapeutically effective amount” refers to an amount of a compound, salt or pharmaceutical composition, of the present invention effective to yield a desired therapeutic response, for example, to treat, ameliorate or prevent a disease and / or condition. The term "therapeutically effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the subject, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compound.

[0418] As used herein, the terms “treatment” or “treating” include curing a condition, as well as alleviation of or reduction of symptoms associated with a condition. The term treating also includes slowing the progression of a condition. The terms “treating”, “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacologic and / or physiologic effect. It may include one or more of a) inhibiting the condition, i.e., arresting its development, or (b) relieving or ameliorating the effects of the condition, i.e., cause regression of the effects of the condition.

[0419] As used herein, the terms “prevention” or “preventing” include prophylaxis, and include reducing the likelihood of having a condition or a symptom thereof. The effect may be prophylactic in terms of completely or partially preventing a condition or sign or symptom thereof.

[0420] The compound, salt or pharmaceutical composition as defined herein may be administered by any suitable route. For example, it may be administered enterally (e.g. orally), parenterally (e.g. intravenously, intramuscularly, subcutaneously, intraarterially), or topically (including transdermally).

[0421] The compound or sad may additionally be combined with other medicaments to provide an operative combination. It is intended to include any chemically compatible combination of pharmaceutically active agents, as long as the combination does not eliminate the activity of the compound of formula (I) or formula (II). Accordingly, in some embodiments, the compound of formula (I) or formula (II) or salt thereof, is administered in combination with a further therapeutic agent. It will be appreciated that the compound of formula (I) or formula (II) or salt thereof and the other medicament, may be administered according to any appropriate dosing regimen, including by administration separately, sequentially or simultaneously.

[0422] Pharmaceutical Compositions

[0423] The compound of formula (I) and formula (II) or pharmaceutically acceptable salt thereof can be provided in the form of a pharmaceutical composition, e.g. for use in treatment of a disease or disorder as defined herein.

[0424] Accordingly, there is also provided a pharmaceutical composition comprising a compound of formula (I) or formula (II) or pharmaceutically acceptable salt as defined herein, and one or more pharmaceutically acceptable excipients.

[0425] The excipient(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.

[0426] The pharmaceutical compositions useful as described above may be provided in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The nature of the pharmaceutical composition and the formulation excipients employed may depend upon the particular route of administration desired.

[0427] The pharmaceutical composition may, for example, be in in solid, semi-solid or liquid dosage form, e.g. in the form of an oral formulation such as a pill, tablet, capsule, caplet, sachet, powder, syrup, liquid, or oral suspension. Where intended for administration intravenously, for example, the pharmaceutical composition may be in the form of a solution (e.g. an aqueous solution) or as a powder for reconstitution.

[0428] The pharmaceutical compositions described herein may be provided in unit dosage form. As used herein, a "unit dosage form" means a composition in a form containing an amount of a compound or salt sufficient to provides a single dose or part-single dose of that compound or salt. Examples of unit dosage forms include pills, capsules, caplets, tablets, sachets, and the like.

[0429] Compositions can be prepared according to conventional dissolution, suspension, mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume, with the balance being one or more suitable pharmaceutical excipients.

[0430] In some embodiments, the pharmaceutical composition is a solid composition.

[0431] Such solid compositions may for example include one or more fillers, binders, humectants, disintegrants, lubricants, preservatives, antioxidants, antimicrobial agents, sweeteners, and the like.

[0432] Examples of fillers include celluloses, calcium carbonate, mannitol, lactose and silicon dioxide. Examples of binders include magnesium aluminium silicate, starches, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate and polyvinylpyrrolidone. Examples of disintegrants include for example starches, alginic acid, cellulose and derivatives thereof such as microcrystalline cellulose and sodium carboxymethylcellulose, and polyvinylpyrrolidone.

[0433] Examples of lubricants include stearic acid and its salts such as magnesium or calcium salts. Examples of emulsifiers include Tween 80, Labrasol, Capmul MCM and Capmul PG-12.

[0434] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.

[0435] Solid compositions may if desired include other excipients, such as an agent that enhances absorption of the compound e.g. a cyclodextrin or PEG; and / or a sugar, such as lactose, dextrose, sucrose, mannitol, sorbitol or glucose; an amino acid, such as glycine; and / or a gum. Glidants such as silicon dioxide can be used to improve flow characteristics of a powder mixture. Coloring agents, such as the FD& C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful additives.

[0436] Solid dosage forms such as tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings. They may optionally be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a pH or time-dependent manner.

[0437] In some embodiments, the pharmaceutical composition is a liquid composition, for example a solution for iv administration.

[0438] Liquid dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules,

[0439] Liquid compositions typically contain a solvent and / or diluent (e.g. water and / or an organic solvent and / or an oil) and may if desired contain additional components such as a solubilizing agent, surfactant, emulsifier, preservative, antioxidant, pH adjusting agent, buffer, tonicity modifier, one or more salts, sweeteners, coloring agents and / or flavoring agents.

[0440] Examples of solvents / diluents include water, and oils such as vegetable oils, e.g. cottonseed, groundnut, corn, germ, olive, castor, sesame oils and oil-in-water emulsions such as milk.

[0441] Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.

[0442] Examples of emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate and propylene glycol

[0443] For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate.

[0444] Typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.

[0445] Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants.

[0446] For intravenous administration, the compounds and pharmaceutical compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.

[0447] Compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration.

[0448] Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modem Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004). Pharmaceutical formulation techniques may also be used such as, for example, those disclosed in Remington's The Science and Practice of Pharmacy, 23rdEd., Elsevier (2020), or Remington's Pharmaceutical Sciences, 21stEdition, Mack Publishing, 2005. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332. The contents of each of the aforementioned documents are incorporated herein by reference in their entirety.

[0449] Compounds, salts and compositions described herein may be provided in an appropriate container and labelled for treatment of an indicated condition.

[0450] The compounds of formula (I), formula (II) or salts may be administered in combination with a further active agent. In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or formula (II) or salt thereof, also contains a further therapeutic agent.

[0451] Methods of preparation The compounds of formula (I), formula (II) or salts thereof, can be prepared by any suitable method. For example, the compounds may be synthesized by methods described below, or by modification of these methods. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0452] Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety.

[0453] Starting materials are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Suppiementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0454] In some cases, it may be necessary and / or desirable to protect sensitive or reactive groups on intermediate compounds during synthesis of compounds of formula (I). This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. Examples of such groups include: OH (including diols), NH2, CO2H, SH and C=O. As used herein, the term "protecting group", means an introduced functionality which temporarily renders a particular functional group inactive under certain conditions. The protecting group may be removed at a convenient subsequent stage using methods known from the art. Exemplary forms of protected groups include: for amino (NH2) - carbamates (such as Cbz, Boc, Fmoc), benzylamines, acetamides (e.g. acetamide, trifluoroacetamide); for carbonyl -acetals, ketals, dioxanes, dithianes, and hydrazones; for hydroxy - ethers (e.g. alkyl ethers, alkoxylalkyl ethers, allyl ethers, silyl ethers, benzyl ethers, tetrahydropyranyl ethers), carboxylic acid esters, acetals (e.g. acetonide and benzylidene acetal); for thio (SH) -ethers (e.g. alkyl ethers, benzyl ethers), esters; and for CO2H - esters (e.g. alkyl esters, benzyl esters).

[0455] Compounds of the present disclosure may be separated from a reaction mixture and further purified, if desired, by any suitable method, such as column chromatography, high pressure liquid chromatography, or recrystallization.

[0456] Where the compounds of the present disclosure contain one or more chiral centers, as discussed above such compounds can be prepared or isolated as pure stereoisomers, e.g. as individual enantiomers, or stereoisomer-enriched mixtures, or racemic mixtures. All such stereoisomers (and enriched and racemic mixtures) are included within the scope of the present technology. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

[0457] A compound of formula (I) or formula (II) which is a free acid or free base may if desired be converted into a salt of the compound. Any suitable method of production of a salt form of the compound may be employed. For example, where the compound is a free base, it may be contacted with an acid (such as HC1 in the case of forming a hydrochloride salt) to form the salt. Where the compound is a free acid, it may for example be contacted with a base (e.g. NaOH, in the case of forming a sodium salt). Such a salt formation step may for example be carried out in the presence of a diluent or solvent. Salt forms of organic compounds often have lower solubility in some organic solvents than the parent compounds, particularly in less polar organic solvents. Thus, in some embodiments, a compound of formula (I) which is a free acid or free base may be dissolved in a suitable solvent, and contacted with a base or acid as appropriate, with the resulting salt precipitating from solution, which can if desired by obtained by filtration or decanting. Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications.

[0458] Examples

[0459] The invention will now be described in detail by way of reference only to the following non-limiting examples.

[0460] General Synthetic Methods for Preparation of Compounds

[0461] The compounds of formula (I) and formula (II) described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. Methods for the synthesis of thione compounds of formula (I) and formula (II) are described generally herein and can be determined from the information in W02008 / 052288 or adapted from methods described in GB patent no. 1,200,886 or Knezevic A, Novak J et al. (2020). An exemplary synthesis of 5-(4-methoxy-3-methylphenyl)-3H-l,2-dithiole-3-thione (compound 23) is detailed below.

[0462] Example 1 - Synthesis of 5-(4-Methoxy-3-methylphenyl)-3Z / -E2-dithiole-3-thione (23) OMe

[0463]

[0464] (i)(■■) (23) On a 2.5 g scale, tetrahydrofuran was added dropwise over 2 hours to a refluxing solution of hexane-washed sodium hydride in mineral oil and dimethyl carbonate in tetrahydrofuran. The reaction was heated for a further 30 min and then cooled to room temperature. Water was then added and then followed with 5 volumes of ether. The ether extract was then washed 3 times with water, once with saturated sodium bicarbonate, once with brine and dried over disodium sulfate. This yielded the desired keto-ester (ii) as a cloudy brown oil (3.3 g, 97%) that did not require chromatography or further purification. Characterization by1H NMR showed that (ii) existed as a 94:6 mixture of keto-enol tautomers. To a solution of keto-ester in xylene was added P2S5, sulfur and hexamethyldisiloxane in xylene and, the solution heated under reflux for 1 hour to give a dark deep-red solution before thin layer chromatography indicated the reaction was complete. Work-up afforded the crude product as a brown solid (2.9 g) which was then subjected to flash chromatography on a silica gel cartridge to give pure 5 -(4-m ethoxy-3 -methylphenyl)-3H-l,2-dithi ole-3 -thi one (23) (1.07 g) as a dark-orange powder (melting point 149-151°C (corrected). The yield over the two steps was 27%. The desired structure was confirmed by1H NMR analysis which showed the loss of the methylene singlet at 3.97 ppm and a new singlet (integrationTH) for the characteristic H4 proton at 7.41 ppm. Vmax(ATR) 1605(m), 1480(s), 1465(s), 1400(s), 1260(s), 1205(s), 1135(m), 1020(s), 950(s), 835(s), 815(s), 670(s) cm'1.

[0465] Further example thione compounds of formula (I) and formula (II) were prepared. The1H NMR spectrum of 5-[3-(hydroxymethyl)-4-methoxyphenyl]-3H-1,2-dithiole-3-thione (24) is depicted in Figure 1.

[0466] Synthesis of S-oxide analogues

[0467] To prepare S-oxide forms of compounds of formula (I) or formula (II), the corresponding 1,2-dithi ole-3 -thi one is prepared (for example using methods described in W02008 / 052288) and subjected to oxidation to yield the S-oxide using methods known in the art. One suitable method is that described in Perez et al. 1981.

[0468] Table 2: Compounds of formula (I) and formula (II)

[0469] DD < <

[0470] LU

[0471] Compound Number Structure o

[0472] 1111O O

[0473] 2a ^)oo c c)^o c^^'7''

[0474] OA—o k c— / / \ \

[0475] o C c —

[0476] oo c co c

[0477] t) t)

[0478] 3a

[0479] 12a

[0480] 13a #0Et

[0481] S

[0482] 19 1"S\

[0483] ( - £ / =\

[0484] ADT)* )>— OMe

[0485] S^S\ / ==^

[0486] 20a i zHOMe

[0487] 0* ' — ( \

[0488] 21a

[0489] 22SJ"S\

[0490] (AOX)* - C V-OH

[0491] S<?5U'^ \= /

[0492]

[0493] S^S\ / =^\

[0494] 23 ■ OMe

[0495] S^S\ / =^

[0496] 23a 1 )> — / )— °Me

[0497] O'

[0498] S"S\ / =\

[0499] 7 — <£ X- OMe

[0500] 24

[0501] HO

[0502] S"S\ / =\

[0503] 7 )> — £ X— OMe

[0504] 24a ' - \

[0505] ° w /

[0506] t yn— HO

[0507] / \

[0508] 25a

[0509] Ok u

[0510] 1 o

[0511] q y-— — D C

[0512] 1 )) $ — OMe

[0513] 26

[0514] OH

[0515] g^-S

[0516] 26a

[0517] (

[0518] 0 OH

[0519]

[0520] *Outside the scope of the claimed invention.

[0521] Biology

[0522] Example 2 - Assessment of the ability of selected compounds of formula (I) and formula (II) to increase glutathione levels in mouse brain

[0523] Selected compounds of formula (I) or formula (II) were tested in mouse brain cells for their ability to increase glutathione and compared to known compound 19 (ADT). The results are expressed as percentages of untreated brain cells and are detailed in Table 3. Table 3: Ability of selected compounds to increase glutathione levels in mouse brain cells (expressed as percentages of untreated brain cells)

[0524] Compound Tube 1 Tube 2 Tube 3 Tube 4

[0525] number Mean Std dev Std error 40 pM

[0526] 19 (ADT)* Insoluble

[0527] 20a (S-oxide) 148.65 142.35 131.29 151.24 143 8.9 4.4 21a (S-oxide) 146.33 133.79 123.19 139.55 136 9.8 4.9

[0528]

[0529] *Outside the scope of the claimed invention.

[0530] An interesting finding was the poor solubility of anethole trithione (19, ADT), which precipitated from the assay medium when tested at 40 pM. On the other hand, the sulfoxide compounds 20a and 21a were all found to have good solubility at 40 pM.

[0531] Further experiments were conducted on known compounds 15, 19 (ADT), 22 (AOX), and the recognised Nrf2 activator Sulforaphane (tested at a single concentration (2 pM) as control), in addition to compound 23, by measuring their ability to elevate cellular glutathione levels (Figure 2). The same compounds were also assessed for toxicity in an MTT Assay (Method for Error Minimization and Interpretation in Measuring Cytotoxicity and Estimating Cell Viability) (Figure 3).

[0532] Referring to Figure 2, it can be seen that known compound 22 (having a 4-hydroxy substituent) gave very little Nrf2 activation at concentrations up to 40 pM but also showed no cell toxicity up to 40 pM and slight toxicity (20%) at 80 pM (Figure 3). In contrast, known compound 19 (having a 4-methoxy substituent) gave Nrf2 activation at 10 pM and 40 pM and showed no toxicity up to 80 pM, however it was only sparingly soluble at this concentration. Surprisingly, compound 23 gave better stimulation at 10 to 40 pM than compound 19 and was soluble at 80 pM. These data show that the nature of the phenyl ring is important together with the sulfur-containing ring for Nrf2 activation and solubility in aqueous medium.

[0533] Table 4. In silico calculated Solubility; Log Po / w; and Polar Surface Area of selected compounds of formula (I) and formula (II) - Calculated using www.swissadme.ch Compound Mol Formula Solubility-Log Log TPSA GI absorption Weight S (ESOL) Po / w (A2)

[0534] 2a 368.58 C18H24O2S3 -5.7 Mod Sol 5.49 114.87 Low

[0535] 19 (ADT)* 240.36

[0536]

[0537] C10H8OS3-4.19 Mod Sol 3.82 97.8 High 20a 284.42

[0538] C12H12O2S3-3.70 Sol 2.88 114.87 High

[0539] 21a 298.44 C13H14O2S3 -3.99 Sol 3.24 114.87 Low

[0540] 22 (AOX)* 226.34 C9H6OS3-4.0 Mod Sol 3.49 108.8 High

[0541] 23 254.39 C11H10OS3 -4.46 Mod Sol 4.18 97.8 High 23a 270.39 C11H10O2S3 -3.47 Sol 2.51 114.87 High

[0542] 24 270.39 C11H10O2S3 -3.67 Sol 2.93 118.03 High 286.39 -2.69 Sol 1.26 135.1

[0543]

[0544] 24a C11H10O3S3 Low *Outside the scope of the claimed invention

[0545] Example 3 - Pharmacokinetic studies of compound 23

[0546] Plasma pharmacokinetic parameters (CL, Vss, ti / 2 and bioavailability) for compound 23 were determined following IV (1 mg / kg), IP (10 mg / kg) and oral (10 mg / kg) administration to male Swiss outbred mice. Compound exposure in brain and lung was also assessed following IP administration. All rodent studies were carried out according to established procedures defined in the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. The detailed method of pharmacokinetic analysis has been published previously by the inventor and colleagues (Nicolazzo, J. A. et al. 2008). The key experimental procedures are summarised in the below tables.

[0547] Table 5: Summary of experimental procedures used for analysis of compound 23

[0548] S^S\ / =^

[0549] 1 )> — <( OMe

[0550] Compound ID \ — /

[0551] Compound 23

[0552] Batch CES-289-031-A

[0553] Molecular Weight 254.38 g / mol

[0554] Salt Unionised

[0555] Species Male Swiss outbred mice

[0556] Dose route IV IP PO Target dose 1 mg / kga10 mg / kg 10 mg / kg Oral gavage at a Tail vein bolus injection IP injection at a

[0557] Dosing details volume of 3 at a volume of 2 mL / kg volume of 3 mL / kg

[0558] mL / kg

[0559]

[0560] Post-dose plasma 1, 2, 5, 15 and 30 mm; 1,

[0561] 1, 2, 5, 15 and 30 min; 1, 2, 4, 7.5 and 24 h collection 2, 4, 7.5 and 24 h

[0562] Brain and lung were

[0563] Post-dose tissue collected at four time

[0564] Not required Not required collection points over 24 h (5

[0565] min, 1, 4 & 24 h)

[0566] 5% (v / v) DMSO and 20%

[0567] (v / v) PEG400 in 0.9% 10% (v / v) PEG400 in 0.9% (w / v) saline Vehicle

[0568] (w / v) saline containing containing 10% (v / v) Solutol HS-15 10% (v / v) Solutol HS-153

[0569] Orange solution Uniform pearlescent orange suspension Appearance

[0570] (pH 3.1) (pH 3.4)

[0571] Target

[0572] 0.50 mg / mL 3.33 mg / mL

[0573] concentration

[0574]

[0575] aDue to the poor solubility of the compound in the planned IV formulation vehicle, 5% DMSO was added to the vehicle and the PEG400 concentration was increased to 20%. The dose was reduced from 2 mg / kg to Img / kg.

[0576] bPlasma samples were also taken from 2 mice that were not administered test compound for use as analytical blanks.

[0577] Results and Discussion

[0578] The apparent whole blood-to-plasma (B / P) ratio in mouse blood was 0.61, suggesting that the compound is predominantly resident within the plasma fraction of whole blood.

[0579] The plasma concentration versus time profile for each dosing route is presented in Figure 4. Pharmacokinetic parameters for plasma are summarised in Table 6, while exposure parameters for brain and lung along with the time-averaged tissue-to- plasma partitioning ratios after IP administration are summarised in Table 7.

[0580] There were no adverse reactions or compound-related side effects observed in any mice during the 24 h sampling period after IV, IP or oral administration. Plasma concentration versus time profiles exhibited an apparent terminal half-life of ~1 h after IV dosing and ~6 h after IP dosing (Figure 4). A clear terminal phase was not defined after oral administration (precluding the determination of half-life); however, the oral profile was following a similar trend to the IP profile. Differences in apparent half-life between dosing routes may simply reflect differences in the extent to which the terminal phase was defined by the available data (noting that the plasma concentrations were measurable only up to 4 h after IV dosing). Alternatively, the longer half-life after IP administration (relative to IV) could possibly be due to slow dissolution and absorption after dosing a suspension into the peritoneal space.

[0581] The apparent blood volume of distribution and the blood clearance were both high. The apparent blood clearance was slightly higher than the nominal hepatic blood flow in the mouse (120 ml / min / kg), suggesting that extra-hepatic clearance pathways may contribute to the in vivo elimination of compound 23.

[0582] Following oral administration, the maximum plasma concentration was observed at 0.5 h post-dose, suggesting that absorption was rapid, and the estimated oral bioavailability was -16%. Assuming that hepatic elimination is a substantial contribution to the high blood clearance observed after IV administration, first pass elimination would likely be a significant determinant of the oral bioavailability. Absorption was similarly rapid after IP administration, with maximum plasma concentrations observed at 15 min post-dose, and IP bioavailability (-19%) was comparable to oral bioavailability.

[0583] Compound 23 was detected in brain and lung for the duration of the 24-hour sampling period, and the time-averaged tissue4o-plasma partitioning ratio (based on AUC0-24h) was higher in lung than in brain.

[0584] Table 6: Plasma pharmacokinetic parameters for compound 23 in male Swiss outbred mice following IV, IP and oral administration

[0585] Parameter IV (1 mg / kg) IP (10 mg / kg) Oral (10 mg / kg) Apparent ti / 2 (h) 1.0a5.5 c.n.c.bPlasma Cmax (pM) — 0.726 0.202

[0586] Tmax (h) — 0.25 0.50 Plasma AUCo-inf (h*pM) 0.718a1.35 1.12c dPlasma CL (mL / min / kg 91a— — Plasma Vss (L / kg) 2.47a— —

[0587] B / P ratio 0.61a— — Blood CL (mL / min / kg 150a— —

[0588]

[0589] Blood Vss (L / kg) 4.05a— — Estimated BA (%) — 18.9 15.6d

[0590]

[0591] aValue was an approximation only as concentrations fell below LLQ before the terminal phase was completely defined.

[0592] bCould not calculate due to insufficient definition of an apparent terminal elimination phase.

[0593] cThe terminal phase was not clearly defined. AUC°'infwas estimated based on extrapolation with terminal slope defined in IP mice.

[0594] DValue was an approximation only as the extrapolated portion contributed significantly to AUC0-inf.

[0595] Table 7: Exposure parameters and tissue-to-plasma partitioning ratios for compound 23 in male Swiss outbred mice following IP administration at 10 mg / kg

[0596] Tissue Cmax (pM) AUCo-24h (h*pM) Tissue: Plasma Ratio Plasma 0.726 1.31 — Brain 0.473 2.44 1.9 Lung 0.846 4.08 3.1

[0597]

[0598] Example 4 - Animal studies

[0599] Based on the finding that compounds of formula (I) and formula (II) increase glutathione levels in cultured astrocytes as shown in Example 2, the inventor proposes that these compounds are activators of Nrf2 and accordingly will be useful in preventing or treating conditions associated with Nrf2, conditions associated with oxidative stress, and conditions which are responsive to activation of glutathione synthase and / or increased intracellular glutathione. Such conditions include chronic respiratory disorders including acute lung injury, bronchopulmonary dysplasia (BPD), respiratory infection, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer, heart disorders, cancer, obesity, and type 2 diabetes, chronic neurological disorders selected from epilepsy, stroke and Friedreich's Ataxia, chronic liver disease, chronic kidney disease, chronic inflammatory diseases of the intestinal mucosa, acute skin inflammation caused by UV radiation or exposure to chlorine or HC1 gases, and chronic skin inflammation from auto-immune disorders such as psoriasis.

[0600] The inventor proposes to test the effect of compounds of formula (I) and formula (II) in an acute respiratory distress syndrome (ARDS) mouse model in which mice are given an insufflation of a known dose of bacterial lipopolysaccharide (1 pg) that induces an inflammatory response in the lungs as judged by biochemical and histological methods (Wei et al. 2018). On the following day post-insufflation, 3 groups of mice are injected with either 10 or 30 or 100 mg / kg of a compound of formula (I) or formula (II) twice daily for 3 days. The mice are then anaesthetised, the lungs removed, fixed with formalin and the extent of inflammatory exudate in each lung measured by biochemical and histological methods (Wei et al 2018). Of particular note, Wei et al (2018) proposed that Nrf2 activation may shift local macrophages from a Ml phenotype producing pro-inflammatory cytokines (IL-6; IL-12; tumor necrosis factor-α) to a M2 phenotype producing anti-inflammatory cytokines (IL- 10; TGF-β). This switch from a pro-inflammatory state to an anti-inflammatory state could be the basis for prevention or progression of ARDS. The dose of a compound of formula (I) or formula (II) that significantly reduces inflammation is calculated. The inventors envisage that compounds of formula (I) or formula (II) will significantly reduce inflammation at a dose of 10, 30 and 100 mg / kg and increase the lung concentration of anti-inflammatory cytokines.

[0601] The inventor also proposes to test the effect of compounds of formula (I) and formula (II) in an established model of refractory epilepsy in rats whose spontaneous seizures are not reduced by conventional clinical anti-seizure drugs such as phenytoin and carbamazepine. Rats are initially injected with kainic acid (5 mg / kg, intraperitoneally (IP)) every hour (maximum of 9 doses) until severe seizures (graded 5 on the Racine classification) lasting for 2 hours as measured by an electroencephalographic (EEG) instrument (Shekh- Ahmad et al. 2018). At this time, an injection of diazepam (5 mg / kg, IP) is given to terminate the actions of kainic acid. Rats are housed individually in a Faraday cage and EEG recordings are made daily to establish that the rat shows consistent and reproducible EEG waves during behavioural seizures that last for several weeks. At this stage, rats are divided into two groups and one group is given a daily injection of a compound of formula (I) or formula (II) at a dose of 25 mg / kg IP and the second group are given an IP injection (5 mL / kg) of 10% dimethylsulfoxide in saline as a vehicle control. The frequency of seizures is recorded daily over the next 6 weeks in the drug-treated and vehicle-treated rats. As it is known that a Nrf2 activator drug (RTA408) will abolish seizures after this dosage treatment (Shekh-Ahmad et al 2018), we envisage that compounds of formula (I) or formula (II) will significantly reduce seizures at a dose of 25 or 50 mg / kg. When this is established, the experiment will be repeated after administering compounds of formula (I) or formula (II) orally daily for 3 days to show that the compound is orally bioavailable.

[0602] The inventor also proposes to test the effect of compounds of formula (I) or formula (II) in an established mouse model of focal stroke in the forebrain whereby transient middle cerebral artery occlusion occurs after insertion of an intraluminal suture thread for 2 hours in an anesthetised mouse (isoflurane gas) (Takagi et al. 2014). After removal of the thread and the anaesthetic gas, reperfusion in the middle cerebral artery occurs and a reperfusion injury occurs resulting in free radical damage to neurons and glial in the perfused forebrain territory leading to excitotoxicity and mitochondrial dysfunction. Neurological damage is evaluated by applying 6 motor tests (Garcia et al. 1995) as well as a grid ladder test to count stepping errors on the affected forelimb when it slips off a rung as recorded using a videocamera. A known Nrf2 activator (bardoxolone 2 mg / kg, intravenous injection just before removal of the intraluminal suture thread) in these mice is known to significantly improve their Garcia score signifying less neurological damage and give fewer errors on the ladder test compared to mice given an injection of vehicle. It is proposed to inject compounds of formula (I) or formula (II) (10 mg / kg intravenously just before the removal of the intraluminal suture thread) to demonstrate reduced unilateral neurological damage in the mice after transient occlusion of the middle cerebral artery.

[0603] The inventor also proposes to test the effects of compounds of formula (I) or formula (II) in inducing mitochondrial autophagy (that is, mitophagy) in cells after activation of Nrf2 (East et al. 2014). Mitophagy is a highly selective process for elimination of dysfunctional mitochondria which occur in neurodegenerative disorders such as Parkinson’s and Huntington’s diseases thus promoting mitochondrial turnover and improved mitochondrial respiration (East & Campanella 2016). Nrf2 activation of the gene for the protein p62, an autophagy adaptor, is necessary to induce mitophagy. East et al. (2014) have shown that Nrf2 activators promote the targeted autophagic degradation of damaged mitochondria without affecting general autophagy thus improving mitochondrial health and function. This recycling of aged and damaged mitochondria renews the pool of healthy mitochondria to maintain efficient respiratory activity. East et al. (2014) show, using high-resolution confocal microscopy, how mouse embryonic fibroblasts and HeLa cells can be used to study Nrf2 activators for activating mitophagy without collapsing the mitochondrial membrane potential and for promoting mitochondrial accumulation. It is proposed to incubate compounds of formula (I) or formula (II) with cultured mouse embryonic fibroblasts and HeLa cells and study, using the fluorescence microscopy imaging techniques of East et al. (2014), that compounds of formula (I) or formula (II) at a concentration of 1–10 μM will induce mitophagy, maintain mitochondrial membrane potential and increase the size of the mitochondrial network.

[0604] The inventor also proposes to test the effects of compounds of formula (I) and formula (II) to block the neuronal toxicity of amyloid-β42-oligomer in cultured neuronal SH-SY5Y cells and also in cultured primary mouse neurons in 96-well plates following the method of Kerr et al. (2017). Oxidative damage and neurodegeneration are a prominent feature in postmortem brains of patients with a diagnosis of Alzheimer’s dementia. Amyloid-1342 peptides are regarded as the trigger for neuronal degeneration particularly when aggregated as oligomers. Both cells will be first cultured with compounds of formula (I) or formula (II) for 16 hours at 37°C to activate Nrf2 and then cultured with amyloid-β42-oligomer (1 μM) for a further 24 hours. Resazurin will be added to give a final concentration of 20 μM in each well and plates will be incubated for 4 hours at 37°C in a 5% CO₂ gas mixture. The resulting fluorescence intensity will be measured at 590 nm and a decrease is a measure of cell death. The inventor envisages that compounds of formula (I) or formula (II) will significantly reduce cell death at concentrations of 1-10 μM.

[0605] The inventor also proposes to test the effects of compounds of formula (I) and (II) on endothelium-dependent vasodilation in coronary arteries from aged (20 months) male rats since endothelial dysfunction causes oxidative stress that is a key trigger in the development of cardiovascular diseases such as hypertension and angina (Incalza et al. 2018). An imbalance between generation of reactive oxygen species and antioxidant defense macromolecules in cells leads to vascular damage in both metabolic and atherosclerotic diseases. Endothelial cells lining the lumen of blood vessels develop an abnormal pro-inflammatory and pro-thrombotic phenotype. A known Nrf2 activator, sulforaphane has been reported to attenuate age-related impairment of endothelial-dependent vasodilation in coronary vascular arteries and decrease oxidative stress which should therefore relieve angina in humans (Angulo et al. 2019). However, sulforaphane is an electrophilic chemical which can act on a range of thiol containing proteins in addition to the Keapl-Nrf2 complex. Thus, the inventor proposes to test the effect of the non-electrophilic Nrf2 activators (compounds of formula (I) and (II)) to attenuate age-related impairment of endothelial- dependent vasodilation in coronary arteries from aged-rats (20 months). Segments of coronary arteries (~ 2mm long) will be dissected from excised hearts of 20 month-old male rats, immersed in Krebs balanced salt solution bubbled with 95% O₂ / 5% CO₂ and set up in wire myographs for recording isometric tension. After 30 min to equilibrate at 37°C, the artery is contracted with serotonin (3 μM) and a cumulative addition of acetylcholine (1 nM to 10 μM) added to relax the artery with the concentration-response relationship recorded digitally. After washout of the acetylcholine, the artery is then contracted again with serotonin (3 μM) with the addition of compound 15 (10 μM) and the cumulative addition of acetylcholine (1 nM to 10 μM) added to relax the contracted artery. The inventor envisages that compounds of formula (I) or formula (II) will significantly potentiate the relaxant concentration-response curve of acetylcholine by a factor of 10 at a concentration of 10 to 30 μM.

[0606] The inventor also proposes to test the effects of compounds of formula (I) and (II) in alleviating acute kidney injury in mice and show that tubular damage causing chronic kidney disease is prevented (Nezu et al. 2017). Acute kidney injury causes high morbidity when it transitions to chronic kidney disease in humans. It can be experimentally caused in anesthetised mice by inducing ischemia-reperfusion injury by temporary clamping the blood supply to the left kidney for 45 minutes followed by reperfusion and studying renal function over the next 14 days. On the day following surgery, 2 groups of mice are administered orally with a compound of formula (I), formula (II) or vehicle and then administered every 2 days for 14 days. Blood will be collected from a tail vein each day and assayed for blood urea nitrogen (BUN) and creatinine as an index of renal function. We envisage that compounds of formula (I) and formula (II) will significantly reduce BUN levels in the drug-treated group compared to at least a doubling of BUN levels in vehicle-treated group. After 14 days, mice are anesthetised and the kidneys removed, fixed and sectioned for histological examination. Serial sections of the ischemic kidney will be stained by Elastica-Masson stain or hematoxylin-eosin stain to evaluate tubular damage and infiltration of immune cells respectively as described by Nezu et al. (2017). We anticipate that compounds of formula (I) and (formula (II) will preserve tubular areas in the occluded kidney renal cortex of treated mice, but tubular structures will be severely damaged in the occluded kidney renal cortex of vehicle-treated mice. The inventors anticipate that compounds of formula (I) or formula (II) show significant renal protection at a dose of 10 or 30 or 100 mg / kg. The inventor also proposes to test the effects of compounds of formula (I) and (formula (II) in alleviating chemically induced inflammatory colitis in mice as a model of ulcerative colitis which is a prominent cause of inflammatory bowel disease in humans and chronic inflammation can lead to colitis-associated cancer (Francescone et al. 2015). The pathogenesis of ulcerative colitis involves oxidative stress and elevated mucosal immune response involving pro-inflammatory cytokines that damage the epithelial layer of the colon. The addition of dextran sodium sulfate polymer (DSS) (molecular weight: 36,000-50,000 Da) to drinking water to give a 2 % (w / v) solution is a widely used method for inducing acute colitis after one week of ingestion (Wirtz et al. 2007). DSS is toxic to gut epithelial cells of the basal crypts and granulocytes infiltrate the mucosal layer. Two groups of mice will be given a compound of formula (I) or formula (II) orally by gavage twice a day for 10 days and then one group will be given DSS in their drinking water from days 3 to 10 while the second group continue with drinking water for 10 days. On day 10, mice will be euthanised and macroscopic appearance of their colons photographed, colons weighed, and length measured. Colons will then be fixed with 10% formalin and serial sections stained with hematoxylin and eosin (as described by Wirtz et al. 2007) to determine that compounds of formula (I) protect the epithelial cells from degeneration and inhibited inflammatory cell infiltration using the scoring system of Wirtz et al. (2007). The inventors envisage that compounds of formula (I) and formula (II) at a dose of 30 mg / kg per day will significantly prevent shortening of the colon, reduce weight loss and reduce inflammatory damage in the mucosal and epithelial layers.

[0607] The inventor also proposes to test the effects of compounds of formula (I) and formula (II) in reducing inflammation in liver (Kermanizadeh et al. 2019). Inflammation in liver is triggered by overproduction of reactive oxygen / nitrogen species, causing oxidative stress that triggers further inflammation. Initially, liver inflammation causes Non-Alcoholic Fatty Liver Disease (NAFLD), and this is the most common liver disorder in 30-40% of adults in Western nations. NAFLD can progress to Non-Alcoholic Steato-Hepatitis (NASH), which is highly prevalent in 70% of patients with type 2-diabetes and obesity. It has a compound annual growth-rate of -45%. There is no drug approved for treating these liver disorders and liver transplantation is the only option. The inventors propose that administering compounds of formula (I) or formula (II) will treat patients by elevating endogenous levels of glutathione in liver cells through activation of the key transcription-factor Nrf2. It is now recognised that rodent models of NASH are difficult to recapitulate in the laboratory. A more reliable model is to study human liver cells in 3-dimensional (3D) Akura™ 96 well plates using spheroids containing parenchymal hepatocytes with non-parenchymal Kupfler cells, stellate cells and non-parenchymal endothelial cells since these 4 cell types play key roles in mimicking NAFLD and NASH (Kermanizadeh et al. 2019). Drug candidates can be screened in these 3D human liver organoids in order to identify the drug to advance to clinical trials. The concentration of compounds of formula (I) and formula (II) that significantly elevate GSH levels after Nrf2 activation as well as changes in release into the medium of cytokines such as tumour necrosis factor will be quantitated. The inventors envisage that compounds of formula (I) and formula (II) will alter these biomarkers at concentrations of 3 to 25 μM.

[0608] The inventor also proposes to test the effects of compounds of formula (I) and formula (II) in reducing acute inflammation of the skin caused by UV radiation (Law et al. 2014, Tao et al. 2015) or exposure to chlorine or HC1 gases and also chronic inflammation of the skin due to auto-immune disorders such as psoriasis (Chujun et al. 2023). References

[0609] Angulo J, El Assar M et al (2019) Redox Biology 26:101271.

[0610] Bathish B, Robertson H et al (2022) Free Radical Biology and Medicine 188: 221-261. Chujun M. et al., Cell Death & Disease, volume 14, Article number: 768 (2023).

[0611] Daina A, Michielin O et al. (2017) Scientific Reports 7:42717.

[0612] Dinkova-Kostova AT & Coppie IM (2023) Trends in Pharmacological Sciences 44:137-149.

[0613] Dodson M, de la Vega MR et al (2019) Annual Review of Pharmacology & Toxicology 59:555-575.

[0614] Dringen R, & HamprechtB (1996) Journal of Neurochemistry 67:1375-1382.

[0615] East DA, Fagiani F et al (2014) Chemical Biology 21: 1585-1596.

[0616] East DA & Campanella M (2016) International Journal of Biochemistry & Cell Biology 79:382-387.

[0617] Francescone R, Hou V et al (2015) Inflammatory Bowel Disease 21:409-418.

[0618] Garcia JH, Wagner S et al (1995) Stroke 26:627-634.

[0619] Incalza MA, D’Oria R et al (2018) Vascular Pharmacology 100: 1-19.

[0620] JarrottB & Williams SJ (2016) Neurochemistry Research 41: 523-533.

[0621] JarrottB, Williams SJ, & Zanatta SD (2008) Australian Patent 2007314085:1-61.

[0622] Jia Z, Zhu H et al (2008) Brain Research 1197:159-169.

[0623] Kerr JS, Adriaanse BA et al (2017) Trends in Neuroscience 40:151-166.

[0624] Kermanizadeh A, Brown DM et al (2019) Scientific Reports 9:7295.

[0625] Koo JH, Lee WH et al (2012) Molecular Pharmacology 82:27-36.

[0626] Knezevic A, Novak J et al. (2020) Organic & Biomolecular Chemistry 18:9675-9688. Kraft AD, Johnson DA et al (2004) Journal of Neuroscience 24: 1101-1112.

[0627] Law C. et al., Cell & Bioscience, volume 4, Article number: 39 (2014).

[0628] Liddell JR, Lehtonen S et al (2016) Journal of Neuroinflammation 13:49.

[0629] Nezu M, Suzuki N et al (2017) American Journal of Nephrology 45:473-483.

[0630] Nicolazzo JA, Nguyen TT et al (2008) Journal of Pharmacy & Pharmacology 60:171-178. Perez et al. 1981, “3H-l,2-Dithiol-3-Thion-S-Oxide”, Liebigs Ann. Chem. 1981, pp. 1510-1512.

[0631] Rojo de le Vega M et al (2016) Current Opinion in Toxicology 1:62-70. Shekh- Ahmad T, Eckel R et al (2018) Brain 141:1390-1403.

[0632] Takagi T, Kitashoji A et al (2014) Free Radical Biology and Medicine 72: 124-133.

[0633] Tao S, Park SL et al (2015) Free Radical Biology and Medicine 89:690-700.

[0634] Wei J, Chen G et al (2018) Biochemical and Biophysical Research Communications 500: 790-796.

[0635] Wirtz S Neufert C et al (2007) Nature Protocols 2:541-546.

[0636] W02006052288 -JarrottB, Zanatta SD, Williams SJ. PCT Int Appl filed 8.5.2008.

[0637] Zanatta SD, ManallackDT et al (2009) Bioorganic Medicinal Chemistry Letters 19:459-461.

[0638] Zanatta SD, Jarrott B et al (2010) Australian Journal of Chemistry 63:946-957.

Claims

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A compound of formula (I),4. 6.wherein:7.X is S=O;8.R1is hydrogen o9.

10. r and R2is hydrogen or, wherein one of R1and R411.R2is hydrogen and the other o12.

13. f R1and R2isR14.R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl; R4is selected from the group consisting of hydrogen, halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;15.R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;16.or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1, wherein:18.X is S=O;19.R1is hydrogen20.

21. or and R2is hydrogen or, wherein one of R1and R422.R^ ^ R523.Y^ Y^R624.R2is hydrogen and the other o25.

26. f R1and R2isr727.R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;28.R4is selected from the group consisting of hydrogen, halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;29.R5is selected from the group consisting of halogen, OCi-6-alkyl and OCi-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)I-4OH, Ci-6-alkyl, C2-6-alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl.30.R4R3JL R53. The compound as claimed in claim 1 or 2, wherein32.

33. R1isRand R2is hydrogen.

4. The compound as claimed in any one of claims 1 to 3, wherein R5is OCi-6-alkyl, optionally wherein R5is methoxy or ethoxy.

5. The compound as claimed in any one of claims 1 to 4, wherein R3and R7are each hydrogen.

6. The compound as claimed in any one of claims 1 to 5, wherein R4and R6are each Ci-ealkyl, optionally methyl, ethyl, z-propyl or / -butyl.

7. The compound as claimed in claim 6, wherein R4and R6are the same.

8. The compound as claimed in any one of claims 1 to 5, wherein R4is hydrogen and R6is Ci-ealkyl, OH or (CH2)I-4OH, optionally R6is methyl, OH or CH2OH.

9. The compound as claimed in any one of claims 1 to 8, wherein the compound is selected from the group consisting of40.

41.

10. A compound of formula (II),43. 45.wherein46.X is S or S=O;47.R1is hydrogen o48.

49. r and R2is hydrogen50.

51. or wherein one of R1and R452.R31 R553.R2is hydrogen and the other o54.

55. f R1and R2isR56.R3and R7are each independently selected from the group consisting of hydrogen, halogen, OH, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl; R4is hydrogen;57.R5is selected from the group consisting of halogen, OC1-6-alkyl and OC1-6-haloalkyl; and R6is selected from the group consisting of halogen, OH, (CH2)1-4OH, Ci-6-alkyl, C2-6- alkenyl, Ci-6-alkynyl, Ci-6-haloalkyl and OCi-6-alkyl;58.or a pharmaceutically acceptable salt thereof.

11. The compound as claimed in claim 10, wherein:60.X is S or S=O;61.R4R462.R31 R5R31 R563.R1is hydrogen64.

65. orRand R2is hydrogen orR, wherein one of R1and R466.R31 R567.R2is hydrogen and the other o68.

69. f R1and R2isr770.R3and R7are each independently selected from the group consisting of hydrogen, halogen, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl;71.R4is hydrogen;72.R5is selected from the group consisting of halogen, OC1-6-alkyl and OC1-6-haloalkyl; and R6is selected from the group consisting of halogen, (CH2)1-4OH, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-haloalkyl and OC1-6-alkyl.73.R4R31 R512. The compound as claimed in claim 10 or 11, wherein75.

76. R1isRand R2is hydrogen.

13. The compound as claimed in any one of claims 10 to 12, wherein X is S.

14. The compound as claimed in any one of claims 10 to 13, wherein R5is OCi-6-alkyl, optionally wherein R5is methoxy or ethoxy.

15. The compound as claimed in any one of claims 10 to 14, wherein R3and R7are each hydrogen.

16. The compound as claimed in any one of claims 10 to 15, wherein R6is C1-6alkyl, OH or (CH2)1-4OH, optionally wherein R6is methyl, OH or CH2OH.

17. The compound as claimed in any one of claims 10 to 16, wherein the compound is selected from the group consisting of82.

18. A pharmaceutical composition comprising the compound or salt as claimed in any of claims 1 to 17, and one or more pharmaceutically acceptable excipients.

19. A method of treating or preventing a condition associated with Nuclear Factor Erythroid 2 Related Factor (Nrf2), a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione, in a subject, comprising administering an effective amount of a compound, salt or pharmaceutical composition as claimed in any of claims 1 to 18, to the subject.

20. Use of a compound, salt or pharmaceutical composition as claimed in any of claims 1 to 18, for the manufacture of a medicament, for treating or preventing a condition associated with Nrf2, a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

21. A compound or salt as claimed in any of claims 1 to 17, or a pharmaceutical composition as claimed in claim 18, for use in treating or preventing a condition associated with Nrf2, a condition associated with oxidative stress, and / or a condition which is responsive to activation of glutathione synthase and / or increased intracellular glutathione.

22. A method as claimed in claim 19, use as claimed in claim 20, or compound, salt or pharmaceutical composition for use as claimed in claim 21, wherein the condition is a chronic inflammatory condition selected from the group consisting of a chronic respiratory disorder, a heart disorder, cancer, obesity, and type 2 diabetes, a chronic neurological disorder selected from epilepsy, stroke and Friedreich's Ataxia, a chronic liver disease, a chronic kidney disease and a chronic inflammatory disease of the intestinal mucosa.

23. A method, use or compound, salt or pharmaceutical composition for use, as claimed in claim 22, wherein the chronic neurological disorder is epilepsy, optionally wherein administration of the compound, salt or pharmaceutical composition reduces seizure severity, duration and / or frequency.

24. A method, use, or compound, salt or pharmaceutical composition for use, as claimed in claim 22, wherein the chronic inflammatory condition is a chronic respiratory disorder selected from the group consisting of acute lung injury, bronchopulmonary dysplasia (BPD), respiratory infection, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer.

25. A method, use, or compound, salt or pharmaceutical composition for use, as claimed in claim 22, wherein the chronic inflammatory condition is:91.a heart disorder selected from the group consisting of pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, cardiac arrhythmias and diabetic cardiomyopathy;92.a chronic liver disease selected from the group consisting of cirrhosis, toxin-induced liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis; or93.a chronic inflammatory disease of the intestinal mucosa selected from the group consisting of inflammatory bowel disease, colitis and Crohn’s disease; or94.skin inflammation caused by UV radiation or exposure to chlorine or HC1 gases, or an autoimmune disease, optionally psoriasis.

26. The method, use, or compound, salt or pharmaceutical composition for use, as claimed in claim 22, wherein the chronic inflammatory condition is:95.a heart disorder selected from the group consisting of pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, cardiac arrhythmias and diabetic cardiomyopathy;96.a chronic liver disease selected from the group consisting of cirrhosis, toxin-induced liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis; or97.a chronic inflammatory disease of the intestinal mucosa selected from the group consisting of inflammatory bowel disease, colitis and Crohn’s disease; or98.skin inflammation caused by UV radiation or an autoimmune disease, optionally psoriasis.

27. A method of activating Nrf2, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione in a subject, comprising administering an effective amount of a compound, salt or pharmaceutical composition as claimed in any of claims 1 to 18, to the subject.

28. Use of a compound, salt or pharmaceutical composition as claimed in any of claims 1 to 18, for the manufacture of a medicament for activating Nrf2, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione.

29. A compound or salt as claimed in any of claims 1 to 17, or a pharmaceutical composition as claimed in claim 18, for use in activating Nrf2, reducing oxidative stress, activating glutathione synthase activity, and / or increasing intracellular glutathione.

Images