Inhibitors of ACSL4 and their use as medicines

Abstract

The present invention relates to inhibitors of ACSL4 and their use as medicines. So far, no potent and selective well-validated ACSL4 inhibitor has been described. The inventors have designed and studied compounds of formula (I) that inhibit selectively ACSL4 activity at sub-micromolar concentrations and have interesting anti-ferroptotic properties. The biological results obtained by the inventors on this series of compounds demonstrate the interest of using these ACSL4 inhibitors for therapeutic applications in diseases such as cancers, neurodegenerative diseases and infectious diseases. In particular, the present invention relates to compounds of formula (I) and their use in a method of therapeutic treatment of a subject.

Description

Inhibitors of ACSL4 and their use as medicinesTechnical Field

[0001] This disclosure pertains to inhibitors of ACSL4 and their use as medicines.Background Art

[0002] Lipid metabolism encompasses a series of dynamic and interdependent processes that regulate the synthesis, storage, and use of lipids in living organisms. Within this complex set of biochemical processes, the acyl-coenzyme A (Acyl-CoA) synthetase long-chain family of enzymes (ACSLs) plays a pivotal role in the activation of long-chain fatty acids into corresponding fatty acyl- CoA esters. Once activated, fatty acids (FAs) participate in various cellular pathways including the synthesis of phospholipids, triacylglycerol and cholesterol esters, p-oxidation and protein acylation.1In mammals, the ACSL family comprises five members, ACSL1 and ACSL3-6, which have different tissue and subcellular distributions, and substrate preferences.2-4They have all been identified as potential therapeutic targets in various diseases.56More specifically, ACSL4 recently emerged as an attractive target in some cancers including hepatocellular carcinoma,7estrogen receptor-negative breast cancer,89colorectal cancer, and prostate cancer.10In addition, because of its marked preference for polyunsaturated fatty acids (PUFAs) activation, ACSL4 has been identified as a pivotal contributor to ferroptosis,11-13an iron-dependent regulated cell death marked by extensive membrane lipid peroxidation.14 15Notably, ACSL4 plays a role in enriching membrane phospholipids (PLs) with PUFAs, which are highly prone to peroxidation.16Moreover, its phosphorylation by PKCpII (at T328) was shown to promote its dimerization leading to the amplification of lipid peroxidation and subsequent ferroptosis. Interestingly, genetic depletion or pharmacological inhibition of ACSL4 confers a strong protection against ferroptosis.13Therefore inhibiting ACSL4 can have a positive impact on diseases or conditions in which ferroptosis is involved and in some cancers.

[0003] So far, no potent and selective well-validated ACSL4 inhibitor has been described. The most widely used ACSL4 inhibitor is rosiglitazone (ROSI) which selectively inhibits ACSL4 (over other ACSLs) in the micromolar range.17However, its potent activity on peroxisome proliferator-activated receptor-gamma gamma (PPAR-y), a nuclear receptor strongly involved in lipid metabolism constitutes an important limitation.

[0004] Therefore, there is a need to provide inhibitors of ACSL4 with improved properties, and particularly with good anti-ferroptotic properties.Summary

[0005] In this context, the inventors have designed and studied compounds that inhibit selectively ACSL4 activity at sub-micromolar concentrations.

[0006] The biological results obtained by the inventors on this series of compounds demonstrate the interest of using these novel ACSL4 inhibitors for therapeutic applications in diseases such as cancers, neurodegenerative diseases and infectious diseases. In particular, the inventors have demonstrated that the compounds of the present disclosure present interesting anti-ferroptoticproperties which makes them potential candidates for the treatment of diseases or conditions in which ferroptosis is involved.

[0007] The first object of the invention is thus a compound of formula (I)a pharmaceutically acceptable salt or a solvate thereof, wherein each R1 is independently selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; m is an integer between 0 and 5, preferably m is 0 or 1 ;R2 is H or C1-6 alkyl;R3 is selected from C1-6 alkyl and optionally substituted cycloalkyl;R4 is selected from H, Cl, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)P-X-R’, -(CH=CH)-X-R’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R5 is selected from H, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; preferably R5 is H, p is 0 to 6,X is selected from the group consisting of -O-, -NR’-, -O-(CO)-, -(CO)-O-, -NR’-(CO)-, -(CO)-NR’-, - SO2-, -O-(SO2)-, -(SO2)-O-, -NR’-(SO2)-, -(SO2)-NR’-, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; provided that- at least one of R4 and R5 is different from H;- when R4 is Cl or Br, m is an integer from 1 to 5,- when m is 0, R2 is H, R3 is methyl, R5 is H, and R4 is -(CH=CH)-(CO)-O-R’, R’ represents H, Me or a C3-6 alkyl.

[0008] Another object of the invention is a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or a solvate thereof and at least one other ingredient selected from a pharmaceutically acceptable excipient, diluent or carrier.

[0009] Another object of the invention is a compound of the invention or a pharmaceutical composition of the invention for use in a method of therapeutic treatment of a subject.Brief description of the drawings

[0010] Figure 1 A shows the viability of the LUHMES cells after treatment with arachidonic acid, FeC -NTA and the combination of both, Figure 1 B shows the viability of the LUHMES cells after treatment with compounds 2 and 6, and the viability of the LUHMES cells after inducing cell death with arachidonic acid, FeCh-NTA, and treatment with either compound 2 or 6 at 2.5 pM concentration.Detailed Description

[0011] A first object of the invention is a compound of formula (I)a pharmaceutically acceptable salt or a solvate thereof, wherein each R1 is independently selected from the group consisting of 0-6 alkyl, -0-0-6 alkyl, halogen, and C1-6 haloalkyl; m is an integer between 0 and 5, preferably m is 0 or 1 ;R2 is H or C1-6 alkyl;R3 is selected from C1-6 alkyl and optionally substituted cycloalkyl;R4 is selected from H, Cl, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)p-X-R’, -(CH=CH)-X-R’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R5 is selected from H, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; preferably R5 is H, p is 0 to 6,X is selected from the group consisting of -O-, -NR’-, -O-(CO)-, -(CO)-O-, -NR’-(CO)-, -(CO)-NR’-, - SO2-, -O-(SO2)-, -(SO2)-O-, -NR’-(SO2)-, -(SO2)-NR’-, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; provided that- at least one of R4 and R5 is different from H- when R4 is Cl or Br, m is an integer from 1 to 5, and- when m is 0, R2 is H, R3 is methyl, R5 is H and R4 is -(CH=CH)-(CO)-O-R’, R’ represents H, Me or a C3-6 alkyl.

[0012] The inventors demonstrated that compounds of formula (I) have a significative inhibitory activity on ACSL4 with IC50 at sub micromolar concentrations. These compounds are thus of great interest for therapeutic applications in diseases such as cancers, neurodegenerative diseases andinfectious diseases. These compounds have also been validated in a human neuronal cell model (LUHMES cells) for their ability to prevent ferroptosis.

[0013] In the context of the invention, the term “C1-6 alkyl” refers to C1-6 linear (i.e., "straight-chain"), branched, or cyclic, saturated hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl groups. The term “cycloalkyl” refers to a cyclic saturated hydrocarbon chain, preferably having from 3 to 8 ring atoms, including for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups.

[0014] In the context of the invention, the term “aryl” refers to a cyclic group derived from a monocyclic or polycyclic aromatic hydrocarbon by removal of a hydrogen atom from said monocyclic or polycyclic aromatic hydrocarbon. The aryl can have 6 to 10 ring atoms The aryl can be unsubstituted or substituted with at least one suitable substituent, for example with an optionally substituted Ci-Ce alkyl, or -O-C1-6 alkyl, -NO2, -CN, halogen, or an amino group.

[0015] In the context of the invention, the term “heterocycle” refers to a cyclic compound that has atoms of at least two different elements as members of its ring(s), it can comprise 5 to 10 ring atoms. Preferably, the heterocycle is a five- or six-membered ring. Preferably, the heterocycle has from 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycle may be an “heterocycloalkyl”, i.e., a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, or may be an “heteroaromatic” or “heteroaryl”, i.e., an aromatic ring containing at least one heteroatom as part of the aromatic ring. Examples of heterocycloalkyl groups include but without being limited to aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. Examples of heteroaromatic groups include but without being limited to pyridine, furan, thiophene, cytosine, diazole, oxazole, triazole, oxadiazole, tetrazole, and indole. The heterocycle can be unsubstituted or substituted with one or two suitable substituents, for example with an optionally substituted Ci-Ce alkyl.

[0016] In the context of the invention, the term “halogen” refers to fluorine, chlorine, bromine, iodine.

[0017] As used herein, the terms “optionally substituted” can refer to groups that can be substituted with one or more of the substituents independently selected from: -X, -R”, -O', -OR”, =0, -SR”, -S', -NR”2, -NR”3, =NR”, -CX3, -CN, -OCN, -SCN, -NCS, -NO, -NO2, =N2, -NRC(=O)R”, -C(=O)R”, - C(=O)NR”2, -SO3-, -SO3H, -S(=O)2R”, -OS(=O)2OR”, -S(=O)2NR”, -S(=O)R”, -C(=O)R”, -C(=S)R”, - CO2R”, -CO2, -C(=S)OR”, C(=O)SR”, C(=S)SR”, C(=O)NR”2, C(=S)NR”2, and C(=NR”)NR”2, where each X is independently a halogen: -F, -Cl, -Br, or -I; and each R” is independently -H, -Ci-Ce alkyl, -C6-C10 aryl, or -C5-C10 heterocycle. Preferably, the terms “optionally substituted” refer to groups that can be substituted with one or more of the substituents independently selected from: -X, -R”, -O', - OR”, =0, -NR”2, -NR”3, =NR”, -CX3, -CN, -NO2, -NRC(=O)R”, -C(=O)R”, -C(=O)NR”2, -SO3-, -SO3H, -C(=O)R”, and -CO2R”, , where each X is independently a halogen: -F, -Cl, -Br, or -I; and each R” is independently -H, -Ci-Ce alkyl, -Ce-C aryl, or -C5-C10 heterocycle.

[0018] According to an embodiment, m is 1 and R1 is a halogen.

[0019] According to an embodiment X is selected from the group consisting of -O-, -NR’-, -O-(CO)-, -(CO)-O-, -NR’-(CO)-, and -(CO)-NR’-.

[0020] According to an embodiment, R4 is selected from H, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)p-X-R’, -(CH=CH)-X-R’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle.

[0021] According to an embodiment, each R1 is independently selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; m is 0 or 1 ;R2 is H or C1-6 alkyl;R3 is selected from C1-6 alkyl;R4 is selected from H, Cl, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)p-X-R’, -(CH=CH)-X-R’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R5 is H, p is 0 to 6,X is selected from the group consisting of -O-, -NR’-, -O-(CO)-, -(CO)-O-, -NR’-(CO)-, and -(CO)- NR’-,R' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle

[0022] According to an embodiment, the compound can have the formula (II) below:wherein L is a linker selected from C1-6 alkyl, C2-6 alkenyl, cycloalkyl and any combinations thereof;R7 is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, preferably R7 is H or C1-6 alkyl , provided that when m is 0, R2 is H, R3 is methyl and L is C2 alkenyl, R7 represents H, Me or a C3-6 alkyl.

[0023] According to an embodiment, the compound can have the formula (III) below:Wherein= represents a single bond or a double bond, provided that when m is 0, R2 is H, R3 is methyl and L is C2 alkenyl, R7 represents H, Me or a C3-6 alkyl.

[0024] Preferably R7 is a C1-6 alkyl.

[0025] According to an embodiment, the compound can have the formula (IV) below:whereinA represents a cycloalkyl, an aryl, or a heterocycle;R6 is selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl. n is an integer between 0 and 5, preferably n is 0 or 1 .

[0026] According to an embodiment, ring A is selected from aryl having 6 to 10 ring atoms and heterocycle having 5 to 10 ring atoms.

[0027] The compound can be selected from the group consisting of:

[0029] The examples below show that the compounds of the present disclosure have interesting anti-ferroptotic properties, which make them suitable as therapeutic agents.Compound of formula (la)

[0030] The present disclosure also relates to a compound of formula (la) for use in a method of therapeutic treatment of a disease selected from cancers, neurodegenerative diseases and infectious diseases:a pharmaceutically acceptable salt or a solvate thereof, whereineach R1 a is independently selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; m’ is an integer between 0 and 5, preferably m’ is 0 or 1 ;R2a is H or C1-6 alkyl;R3a is selected from C1-6 alkyl and optionally substituted cycloalkyl;R4a is selected from H, Cl, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)rXa-Ra’, -(CH=CH)Xa-Ra’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycleR5a is selected from H, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; preferably R5a is H, r is 0 to 6,Xa is selected from the group consisting of -O-, -NRa’-, -O-(CO)-, -(CO)-O-, -NRa’-(CO)-, -(CO)- NRa’-, -SO2-, -O-(SO2)-, -(SO2)-O-, -NRa’-(SO2)-, -(SO2)-NRa’-, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle,Ra' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle.

[0031] According to an embodiment Xa is selected from the group consisting of -O-, -NRa’-, -O- (CO)-, -(CO)-O-, -NRa’-(CO)-, and -(CO)-NRa’-.

[0032] According to an embodiment, each R1 a is independently selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; m’ is 0 or 1 ;R2a is H or C1-6 alkyl;R3a is selected from C1-6 alkyl;R4a is selected from H, Cl, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)p-X-R’, -(CH=CH)-X-R’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycleR5a is H, p’ is 0 to 6,Xa is selected from the group consisting of -O-, -NRa’-, -O-(CO)-, -(CO)-O-, -NRa’-(CO)-, and - (CO)-NRa’-,Ra' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle

[0033] According to an embodiment, the compound can have the formula (Ila) below:wherein L’ is a linker selected from C1-6 alkyl, C2-6 alkenyl, cycloalkyl and any combinations thereof; R7a is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, preferably R7a is H or C1-6 alkyl.

[0034] According to an embodiment, the compound can have the formula (Illa) below:Wherein= represents a single bond or a double bond.

[0035] Preferably R7a is a C1-6 alkyl.

[0036] According to an embodiment, the compound can have the formula (IVa) below:whereinB represents a cycloalkyl, an aryl, or a heterocycle;R6a is selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl. n’ is an integer between 0 and 5, preferably n’ is 0 or 1 .

[0037] The compound can be selected from the group consisting ofSynthesis of the compounds

[0038] The compounds of the present disclosure can be synthesized according to techniques known by the person skilled in the art. The compounds of the present disclosure may be prepared by known methods, such as nucleophilic substitutions, alkylation, Suzuki reactions, Heck reactions, cyclization reactions, condensations, reduction reactions, from commercial products.

[0039] For example, the compounds of the present disclosure can be synthesized as shown in scheme 1 below.Scheme 1 : Reagents and conditions: (a) NH2OH.HCI, K2CO3, EtOH, reflux; (b) / . (CHsCO^O, reflux, / ' / . NaOH, H2O, 60°C, Hi. HCI 1 N; (c) K2CO3, DMF, 80°C; (d) corresponding acyl chloride, pyridine, DCM, reflux, (e) alkylation, NaH, alkylhalide, DMF

[0040] Depending on the substituents, the synthetic route can vary. For example, depending on the nature of substituent R4, the compounds can also be synthesized using Suzuki coupling or Heck reaction as shown in Scheme 2 below.Scheme 2: Reagents and conditions: (a) corresponding boronic acid, CS2CO3, TBAB, Pd(PPh3)4F / dioxane (2 / 8, v / v), reflux; (b) corresponding alkene, EtsN, Pd(OAc)2, P(o-tolyl)s ACN, 80°C;

[0041] When the compound is of formula (III) with a single bond, another synthetic route, as shown in scheme 3 below can be used.Scheme 3: (a) corresponding alkene, EtsN, Pd(OAc)2, P(o-tolyl)s ACN, 80°C; (b) 10% Pd / C, H2 , THF, rt; (c) / . NaHCOs, MeOH / F (50 / 50, v / v), rt., / ' / . 1 N HCI; (d) corresponding acetophenone, K2CO3, DMF, 80°C; (e) corresponding acyl chloride, pyridine, DCM, reflux, (f): alkylation, NaH, alkylhalide, DMF

[0042] The compounds of the present disclosure may exist in solvated and anhydrous forms. The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term “hydrate” is employed when said solvent is water. Hydrates of any of the formulas described herein may exist as a monohydrate or in the form of a polyhydrate.

[0043] The compounds of the present disclosure may also be used in the form of a pharmaceutically acceptable salt thereof. In the context of the invention, the terms “pharmaceutically acceptable” refer to ingredients of a pharmaceutical composition which are compatible with each other and not deleterious to the subject thereof.

[0044] Particularly, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, acid addition salts may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic mono- and di-carboxylates, phenylsubstituted alkanoates, hydroxy alkanoates, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids; and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. The types of such pharmaceutically acceptable salts may include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 ,4-dioate, hexane-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, p- hydroxyburyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 - sulfonate, naphthalene-2-sulfonate, and mandelate. The acid addition salt may be prepared by a conventional method, for example, by dissolving a derivative of Formula (I) or (la) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, or acetonitrile, adding an organic acid or inorganic acid, and filtering and drying the resulting precipitate, or prepared by distilling the solvent and excess acid under reduced pressure, dehydrating the resulting product and crystallizing the dehydrated product in an organic solvent. In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained using a base. As an example of the metal salt, an alkali metal or alkaline earth metal salt may be obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering an undissolved compound salt, and evaporating and dehydrating the filtrate. As an alkali metal salt, a sodium, potassium, or calcium salt may be pharmaceutically acceptable. In addition, corresponding salts may be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0045] The compounds of the present disclosure and their pharmaceutically acceptable salts or solvates thereof may contain one or more asymmetric centers, chiral axes and chiral planes and maythus give rise to enantiomers, diastereomers, and other stereoisomeric forms and may be defined in terms of absolute stereochemistry, such as (R)- or (S)-. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms.Pharmaceutical composition

[0046] Another object of the invention is a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or a solvate thereof and at least one other ingredient selected from a pharmaceutically acceptable excipient.

[0047] The term “excipient” as used herein means a substance formulated alongside the active agent or active ingredient in a pharmaceutical composition or medicament. Acceptable excipients for therapeutic use are well known in the pharmaceutical art. The choice of excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof. The at least one pharmaceutically acceptable excipient may be for example, a binder, a diluent, a carrier, a lubricant, a disintegrator, a wetting agent, a dispersing agent, a suspending agent, and the like.

[0048] Another object of the invention is a compound of the invention or a pharmaceutical composition of the invention for use in a method of therapeutic treatment, said method comprising administering to a subject in need thereof an effective amount of compound of the disclosure or of a pharmaceutically acceptable salt thereof.

[0049] As used herein, the term “treatment” or “therapy” refers to any action which makes it possible to reduce or suppress the symptoms associated with a pathological condition. It comprises both a curative treatment and a prophylactic treatment for a disease.

[0050] A curative treatment is defined by a treatment resulting in a cure or a treatment which relieves, improves and / or eliminates, reduces and / or stabilizes the symptoms of a disease or the suffering that it causes. The term “curative treatment" may refer to one or more of (1 ) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease or reducing or alleviating one or more symptoms of the disease.

[0051] A prophylactic treatment comprises both a treatment resulting in the prevention of a disease and a treatment which reduces and / or delays the incidence of a disease or the risk of it occurring. The terms “improve” and “reduce” include, but do not require complete recovery or complete prevention. The term “prophylactic treatment" may refer to one or more of preventing the disease; for example, preventing a disease, condition or disorder in an individual who is at risk of experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., preventing the development of the pathology and / or symptomatology); and (2) reducing and / or delaying theincidence of a disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease or reducing or alleviating one or more symptoms of the disease.

[0052] In the context of the invention, the term “administration”, or a variant thereof (e.g., “administering”, “administered”) refers to the provision of an active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the subject or patient in whom / which the condition, symptom, or disease is to be treated, attenuated, visualised or diagnosed.

[0053] In the context of the invention, the terms “subject” or “patient” refers to a warm-blooded animal, more preferably a human, who / which is awaiting or receiving medical care or is or will be the object of a medical procedure.

[0054] The term “human” here refers to subjects of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.

[0055] According to a particular embodiment, the compound of the invention or a pharmaceutical composition of the invention can be used in a method of therapeutic treatment of a disease selected from cancers, neurodegenerative diseases, ischemia / reperfusion injuries, acute kidney injury, traumatic brain Injury, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, stroke, sepsis, myocardial Infarction, infectious diseases, inflammatory bowel disease, psoriasis, atopic dermatitis, multiple sclerosis, rheumatoid arthritis, adrenoleukodystrophy.

[0056] The term “cancer” herein refers to the physiological condition in subjects that is characterized by unregulated or dysregulated cell growth or death. The term "cancer" includes solid tumors and blood born tumors.

[0057] Typically, the compounds or compositions for use according to the present invention applies to various organs of cancer origin (such as breast, colon, gastric, rectum, pancreatic, lung, skin, head and neck, bladder, ovary, prostate, liver), and also to various cancer cell types (adenocarcinoma, squamous cell carcinoma, large cell cancer, melanoma, etc).

[0058] In a particular embodiment, the patient suffers from a solid cancer selected from the group consisting of skin cancer (e.g. melanoma, nonmelanoma skin cancer), colorectal cancer, adrenal cortical cancer, anal cancer, bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g. osteoblastoma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma), sarcomas such as liposarcoma and soft-tissue sarcoma, brain and central nervous system cancer (e.g. meningioma, astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, germinoma, craniopharyngioma), breast cancer (e.g. ductal carcinoma in situ, infiltrating ductal carcinoma, infiltrating lobular carcinoma, lobular carcinoma in situ), cervical cancer, endometrial cancer (e.g. endometrial adenocarcinoma, adenocanthoma, papillary serous adnocarcinoma), esophagus cancer, gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoidtumors (e.g. choriocarcinoma, chorioadenoma destruens), kidney cancer (e.g. renal cell cancer), laryngeal and hypopharyngeal cancer, liver cancer (e.g. hepatic adenoma, hepatocellular carcinoma), lung cancer (e.g. small cell lung cancer, non-small cell lung cancer), mesothelioma, nasal cavity and paranasal sinus cancer (e.g. esthesioneuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g. embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, stomach cancer, testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma).

[0059] The term “neurodegenerative diseases” herein refers to diseases caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include but are not limited to amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases.

[0060] The term “infectious diseases” herein refers to an illness resulting from an infection, said infection being the invasion of tissues by pathogens, or their toxic products, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. Infections can be caused by a wide range of pathogens, most prominently bacteria and viruses, transmitted from an infected person, an infected animal, or a contaminated inanimate object. Infectious diseases include but are not limited to tuberculosis, SARS-COV-2 infection and other viral infections.

[0061] According to a particular embodiment, the disease is amyotrophic lateral sclerosis or Parkinson's disease.

[0062] According to a particular embodiment, the compound or composition for use in a method of therapeutic treatment according to the invention can be administered orally, enteral ly, intravenously, or intramuscularly.

[0063] The present disclosure also relates to the use of a compound of the present disclosure for the manufacture of a medicament for the treatment of a disease, preferably selected from cancers, neurodegenerative diseases, ischemia / reperfusion injuries, acute kidney injury, traumatic brain Injury, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, stroke, sepsis, myocardial Infarction, infectious diseases, inflammatory bowel disease, psoriasis, atopic dermatitis, multiple sclerosis, rheumatoid arthritis, and adrenoleukodystrophy.Examples

[0064] Material and Methods

[0065] Chemical synthesis Starting materials, reagents, and solvents were purchased from commercial vendors and used without further purification. Purification by flash chromatography (FC) was carried out on normal phase using a Reveleris X2 Grade. NMR spectra were recorded on BrukerNEO 300 MHz equipped with a BBFO probe, or on a Bruker NEO 500 MHz spectrometer, equipped with TXI, BBO, or QNP probes, using standard sequences. The data are reported as follows: chemical shifts (<5) are reported in parts per million (ppm) relative to a deuterated solvent as the internal standard, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. Analytical liquid chromatography-mass spectrometry (UPLC / MS) was conducted using a Waters AcQuity UPLC l-Class with UV detection (PDA) and an electrospray mode (ESI). UPLC-MS Waters system was equipped with a UPLC I SMP MGR-FTN sample manager, an ACQUITY UPLC l-Class eK photodiode array detector (210-400 nm) and an ACQUITY QDa (Performance) detector (scan 50-1250). Acquity BEH C18 column (50 mm x 2.1 mm, 1 .7 pm, Waters) was used. The injection volume was 0.5 pL. A mixture of water and acetonitrile was used as mobile phase in gradient-elution. The pH of the mobile phase was adjusted with HCOOH and NH4OH to form a buffer solution at pH 3.8. The analysis time was 5 min (at a flow rate at 600 pL / min), 10 min (at a flow rate at 600 pL / min) or 30 min (at a flow rate at 600 pL / min). Unless otherwise specified, the purity of evaluated compounds was judged to be > 98% as determined by UPLC.

[0066] ACSL4 activity assay: Inorganic pyrophosphate (PPi) production was monitored with a Varioskan Flash spectrophotometer (Thermo Scientific) using the EnzChek® pyrophosphate assay kit (E-6645). Each condition was measured in triplicate at 25°C. The total reaction volume was 100 pL and activity was assayed in buffer containing 50 mM Tris pH 7.5, 200 mM NaCI, 1 mM MgCI2, 200 pM MESG, 50 pM ATP, 100 pM CoA, 1 mM DTT, 10% DMSO (or tested compound), 1 U / mL PNP, 0.03 U / mL pyrophosphatase, and 50 nM purified ACSL4. Reactions were initiated by the addition of a palmitate solution, typically to a final concentration of 100 pM (0.06% triton, 1 % EtOH). A control experiment was performed in which a control solution (0.06% triton, 1 % EtOH) was added instead of palmitate solution. The plate was mixed manually, and the absorption change was recorded every 30 s for 30 min at 360 nm. For data analysis, initial rates were calculated during the linear portion. The slope of the control experiment was subtracted from each slope and the corrected slope was converted to the rate of pyrophosphate (PPi) production by use of PPi standard curve. Results were analyzed using Graph Pad Prism®.

[0067] Anti-ferroptotic evaluation of compounds

[0068] The antiferroptotic potential of compounds 2 and 6, representative of this series, was evaluated in Lund human mesencephalic cells (LUHMES), a human embryonic neuronal precursor cell line which is highly sensitive to ferroptosis I18-20!.

[0069] Cell line and culture conditions: LUHMES cells were a generous gift from Pr. Marcel Leist (In vitro Toxicology and Biomedicine, University of Konstanz, Germany). LUHMES cells are conditionally-immortalized neuronal precursor cells that are differentiated into post-mitotic dopaminergic neurons by shutting-down the myc transgene. All procedures with LUHMES cells were carried out in flasks or well-plates (Nunclon™) pre-coated with 50 pg / ml poly-L-ornithine and 1 pg / ml fibronectin in distilled water overnight before washing twice. Proliferating LUHMES were maintained in proliferative media (Advanced Dulbecco modified Eagle’s Medium / F12 supplemented; 1 X N-2supplement; 2 mM L-glutamine; 40 ng / ml recombinant basic fibroblast growth factor - bFGF) at 37 °C and 5% CO2. Cell differentiation was performed following the published protocol

[0073] . Briefly, cells seeded at 2 x 106 in a T75 flask for 2 days had pro liferative media replaced with differentiation media (Advanced DMEM / F12; 1 x N2 supplement; 2 mM L-glutamine; 1 mM dibutyryl cAMP; 1 pg / ml tetracycline; 2 ng / ml recombinant human GDNF) and termed day 0 (dO). After 2 days of predifferentiation (d2), cells were harvested with Trypsin-EDTA 0.05%, centrifuged (5 min at 300 g) and seeded again with differentiation media at a density appropriate for the receptacle and the use in the subsequent experiment. Cells were left for a further 3 days for full differentiation (d5).

[0070] Co-supplementation of arachidonic acid with iron: Arachidonic acid (AA) was dissolved in ethanol 99% to obtain a stock concentration of 100 mM and stored at 20 °C in the dark for up to 2 weeks before addition to culture media. Iron was prepared on the day of treatment by mixing (V / V) ferric chloride (FeCIs - 20 mM) with nitrilotriacetate acid trisodium salt solution (NTA - 40 mM) in PBS (pH 7,4) to provide a solution of FeCIs-NTA (NTA, 1 :2, mokmol) that maintains stability and solubility of the metal when added to media and facilitates the iron incorporation into cells. For supplementation studies, d5 LUHMES were treated with AA (0-20 pM) for 2 h before addition of FeCIs-NTA (20 pM Fe3+) (i.e AA + Fe). Cell viability was evaluated 48 h after the AA + Fe treatment.

[0071] Treatment with ACSL4 inhibitors: Inhibitors were dissolved in DMSO to obtain a stock concentration of 10 mM and stored at -20 °C. Cells were incubated with inhibitors (2.5 pM) for 4 hours prior to the supplementation of AA.

[0072] Viability assays: LUHMES at d2 were seeded in 24 well-plates at a density of 250 000 cells per well and left to fully differentiate (d5) before treatment with each experimental modulator of ferroptosis. Viability is measured by LIVE / DEAD VIOLET probes. LUHMES were harvested by trypsinization and pelleted (5 min, 300 g, 4 °C) before resuspending in 200 pl PBS containing LIVE / DEAD VIOLET (0,5pL) for 15 min at 37°C. A total of 15 000 cells was acquired using cytoFLEX (Beckman Coulter, California, USA) and quantification was performed with Kaluza Analysis software (Beckman).

[0073] General procedu esGeneral Procedure ATo a solution of appropriate amine (1 equiv) in DCM (20 mL), corresponding acyl chloride (3 equiv) and pyridine (1 .5 equiv) was added. The reaction medium was stirred and heated to reflux for 2 h. The resulting mixture was cooled to rt and hydrolyzed with water and acidified with a 1 N HCI solution. The aqueous layer was extracted three times with DCM, discolored with charcoal and dried over MgSO4. The solution was filtered and evaporated under reduced pressure. The product was further washed with Et20 and filtered.General Procedure B

[0074] In a sealed tube, appropriate bromine derivative (1 equiv) and triethylamine (1 .5 equiv) were solubilized in acetonitrile (10 mL). The solution was stirred and degassed for five minutes with nitrogen and then methyl acrylate (1 .5 equiv) or ethyl acrylate (1 .5 equiv), tri(o-tolyl)phosphine (0.2equiv), palladium diacetate (0.1 equiv) were added. The solution was stirred and heated at reflux for 16 h. The mixture was hot-filtered and the corresponding filtrate was cooled to rt. The precipitate formed was filtered, washed with PE and crystalized from ACN.

[0075] Synthesized compounds

[0076] A / -{2-[3-(Trifluoromethyl)benzoyl]-1-benzofuran-3-yl}acetamide (1 Compound 1 was prepared according to general procedure A starting from 2-[3-(trifluoromethyl)benzoyl]-1 - benzofuran-3-amine (100 mg, 0.33 mmol) and acetyl chloride (70 pL, 0.98 mmol) and obtained as a yellow powder (20 mg, 18%).1H NMR (300 MHz, CDCI3) <52.40 (s, 3H), 7.37 (m, 1 H), 7.56 (m, 2H), 7.74 (m, 1 H), 7.91 (d, J = 6.0 Hz, 1 H), 8.46 (d, J = 7.9 Hz, 1 H), 8.51 (s, 1 H), 8.61 (d, J = 7.9, 1 H), 10.71 (br s, 1 H).13C NMR (75 MHz, CDCI3) <5 24.6, 1 12.2, 120.8, 123.6, 123.8 (q, J = 272.9 Hz), 126.6 (q, J= 3.7 Hz), 128.1 , 129.1 , 129.3 (q, J= 3.7 Hz), 130.4, 131 .2 (q, J= 32.8 Hz), 132.9, 134.5, 137.3, 137.7, 155.0, 168.6, 183.9. LC-MS (ESI) m / z [M+H]+=346.0.

[0077] A / -(2-Benzoyl-5-methylbenzofuran-3-yl)acetamide (2). Compound 2 was prepared according to general procedure A starting from 2-benzoyl-5-methyl-1 -benzofuran-3-amine (600 mg, 2.39 mmol) and acetyl chloride (0.51 mL, 7.16 mmol), and obtained as yellow powder (285 mg, 41 %).1H NMR (300 MHz, CDCI3) <5 2.39 (s, 3H), 2.50 (s, 3H), 7.39 (m, 2H), 7.55-7.65 (m, 3H), 8.24 (m, 2H), 8.32 (m, 1 H), 10.70 (br s, 1 H).13C NMR (75 MHz, CDCI3) <5 21 .5, 24.5, 1 1 1 .7, 121 .0, 126.9, 128.5 (2C), 129.7 (2C), 131 .6, 132.9, 133.0, 133.2, 136.8, 138.4, 153.4, 168.6, 185.7. LC-MS (ESI) m / z [M+H]+= 294.2.

[0078] A / -[2-Benzoyl-5-(furan-2-yl)-1-benzofuran-3-yl]acetamide (3). To a sealed tube were added 2-benzoyl-5-bromo-1 -benzofuran-3-amine (1 .0 g, 2.79 mmol), and tributyl(furan-2- yl)stannane (1 .1 g, 3.07 mmol) in dioxane (10 mL). The solution was degassed with nitrogen during 5 minutes and tetrakis(triphenylphosphine)paliadium(0) (129 mg, 0.1 1 mmol) was added. The solution was stirred and heated in an oil bath at 100°C overnight. The mixture was cooled to rt, hydrolyzed with water and acidified with a 6N HCI solution. Aqueous layer was extracted three times with EtOAc. Combined organic layers were dried over MgSCT, discolored with charcoal, filtered and concentrated in vacuo. Solid was taken up in PE and filtered to afford 3 (376 mg, 39%).1H NMR (500 MHz, CDCI3) <5 2.41 (s, 3H), 6.51 (dd, J = 3.3, 1 .8 Hz,1 H), 6.74 (dd, J = 3.4, 0.7 Hz, 1 H), 7.60 (m, 5H), 7.90 (dd, J= 8.9, 1 .8 Hz, 1 H), 8.25 (m, 2H), 8.88 (d, J= 1 .7 Hz, 1 H), 10.74 (s, 1 H). LC-MS (ESI) m / z [M+H]+= 346.2.

[0079] A / -[2-Benzoyl-5-(furan-3-yl)-1-benzofuran-3-yl]acetamide (4). To a sealed tube were added Compound 14 (1 .0 g, 2.79 mmol), phenylboronic acid (766 mg, 6.28 mmol), CS2CO3 (4.1 g, 12.56 mmol), TBAB (90 mg, 0.28 mmol) in dioxane (20 mL) and water (5 mL). The solution was degassed with nitrogen during 5 minutes and tetrakis(triphenyiphosphine)palladium(0) (130 mg, 0.1 1 mmol) was added. The solution was stirred and heated in an oil bath at 100°C overnight. The mixture was cooled to rt., hydrolyzed with water and acidified with a 6M HCI solution up to acid pH. Aqueous layer was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, discolored with charcoal, filtered and concentrated in vacuo. Solid was taken up in PE and filtered to afford 19 (530 mg, 55%).1H NMR (300 MHz, CDCI3) <52.39 (s, 3H), 6.81 (m, 1 H), 7.50 (m, 2H), 7.58(m, 2H), 7.67 (m, 2H), 7.81 (m, 1 H), 8.24 (m, 2H), 8.68 (d, J= 1 .8 Hz, 1 H), 10.75 (br s, 1 H).13C NMR (75 MHz, CDCI3) <5 24.5, 109.2, 1 12.4, 121 .4, 124.4, 126.2, 128.0, 128.4, 128.5 (2C), 128.6, 129.7 (2C), 133.1 , 133.4, 136.7, 138.6, 143.7, 154.0, 168.7, 185.7. LC-MS (ESI) m / z [M+H]+= 346.1 .

[0080] A / -(2-Benzoyl-5-phenyl-1-benzofuran-3-yl)acetamide (5). To a sealed tube were added Intermediate 1 (1 .0 g, 2.79 mmol), phenylboronic acid (766 mg, 6.28 mmol), CS2CO3 (4.1 g, 12.56 mmol), TBAB (90 mg, 0.28 mmol) in dioxane (20 mL) and water (5 mL). The solution was degassed with nitrogen during 5 minutes and tetrakis(triphenyiphosphine)pailadium(0) (130 mg, 0.1 1 mmol) was added. The solution was stirred and heated in an oil bath at 100°C overnight. The mixture was cooled to rt., hydrolyzed with water and acidified with a 6N HCI solution up to acidic pH. Aqueous layer was extracted three times with EtOAc. Combined organic layers were dried over MgSCk, discolored with charcoal, filtered and concentrated in vacuo. Solid was taken up in PE and filtered to afford 20 (645 mg, 65%).1H NMR (500 MHz, CDCI3) <52.40 (s, 3H), 7.39 (t, J= 7.3 Hz, 1 H), 7.48 (m, 1 H), 7.59 (m, 3H), 7.67 (m, 1 H), 7.70 (m, 2H), 7.81 (dd, J = 8.7, 1 .9 Hz), 8.27 (m, 2H), 8.81 (d, J =1 .6 Hz), 10.76 (br s, 1 H).13C NMR (125 MHz, CDCI3) <524.5, 1 12.3, 121 .5, 126.0, 127.3, 127.5 (2C),128.6 (2C), 128.8 (2C), 129.6, 129.8 (2C), 133.1 , 133.6, 136.7, 136.8, 138.7, 140.8, 154.3, 168.7, 185.7. LC-MS (ESI) m / z [M+H]+= 355.9.

[0081] Methyl (2E)-3-(2-benzoyl-3-acetamido-1-benzofuran-5-yl)prop-2-enoate (6). Compound 6 was prepared according to general procedure B starting from methyl acrylate (78 pL, 0.87 mmol) and A / -(2-benzoyl-5-bromo-1 -benzofuran-3-yl)acetamide (200 mg, 0.56 mmol), and obtained as a pale green solid (838 mg, 83%).1H NMR (300 MHz, DMSO-d6) <52.10 (s, 3H), 3.75 (s, 3H), 6.67 (d, J= 15.8 Hz, 1 H), 7.59 (m, 2H), 7.68-7.82 (m, 3H), 7.98 (m, 3H), 8.26 (s, 1 H), 10.37 (s, 1 H).13C NMR (75 MHz, DMSO-ok) <523.5, 52.0, 1 13.59, 1 18.1 , 123.9, 125.3, 127.7, 129.0 (2C), 129.2, 129.6 (2C), 130.1 , 133.6, 137.2, 141 .6, 144.7, 154.7, 167.1 , 168.8, 184.7. LC-MS (ESI) m / z [M+H]+= 364.2.

[0082] Methyl 3-(2-benzoyl-3-acetamido-1-benzofuran-5-yl)propanoate (7). Compound 7 was prepared according to general procedure A starting from methyl 3-(3-amino-2-benzoyl-1 -benzofuran- 5-yl)propanoate (130 mg, 0.40 mmol) and acetyl chloride (86 pL, 1 .21 mmol), and obtained as a yellow powder (100 mg, 68%).1H NMR (300 MHz, CDCI3) 6 2.39 (s, 3H), 2.72 (t, J = 15.6 Hz, 2H), 3.10 (t, J= 15.6 Hz, 2H), 3.70 (s, 3H), 7.28-7.65 (m, 5H), 8.23 (m, 2H), 8.39 (s, 1 H), 10.72 (br s, 1 H).13C NMR (75 MHz, CDCI3) <524.6, 30.9, 36.1 , 51 .7, 1 12.1 , 121 .2, 126.7, 128.5, 129.7, 130.9, 133.0, 133.3, 135.7, 136.8, 138.5, 153.7, 168.6, 173.2, 185.8. LC-MS (ESI) m / z [M+H]+= 366.2.

[0083] Methyl 2-(2-benzoyl-3-acetamido-1-benzofuran-5-yl)cyclopropane-1-carboxylate (8). To a solution of trimethylsulfoxonium iodide (303 mg, 1.38 mmol) in DMSO (4 mL) was added NaH (56 mg, 1 .38 mmol). The mixture was stirred for 1 h at rt and added to a solution of methyl (2E)-3-(2- benzoyl-3-acetamido-1 -benzofuran-5-yl)prop-2-enoate (200 mg, 0.55 mmol) in DMSO (3 mL). The resulting mixture was cooled to rt and hydrolyzed with water. The aqueous layer was extracted with DCM, dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by flash column chromatography (10-30 % EtOAc in cyclohexane) to give a yellow powder (5 mg, 2%).1H NMR (300 MHz, CDCI3) <5 1 .46 (m, 1 H), 1 .67 (m, 1 H), 1 .99 (m, 1 H), 2.39 (s, 3H), 2.70 (m, 1 H), 3.75 (s, 3H), 7.34 (dd, J= 8.7, 1 .8 Hz, 1 H), 7.44 (d, J = 8.7 Hz, 1 H), 7.61 (m, 3H), 8.23 (m, 2H),8.31 (d, J= 1 .7 Hz, 1 H), 10.71 (s, 1 H). NMR13C (75 MHz, CDCI3) <5 16.9, 24.1 , 24.4, 26.2, 29.7, 51 .9, 1 12.0, 121 .0, 124.7, 128.5 (2C), 129.0, 129.7 (2C), 133.0, 135.1 , 136.6, 138.5, 148.2, 168.6, 173.7, 185.7. LC-MS (ESI) m / z [M+H]+= 378.2.

[0084] A / -[5-Bromo-2-(3-methoxybenzoyl)-1-benzofuran-3-yl]acetamide (9). Compound 9 was prepared according to general procedure A starting from 5-bromo-2-(4-methoxybenzoyl)-1 - benzofuran-3-amine (150 mg, 0.43 mmol) and acetyl chloride (93 pL, 1 .3 mmol), and obtained as a yellow powder (1 19 mg, 71 %).1H NMR (300 MHz, CDCI3) <52.38 (s, 3H), 3.93 (s, 3H), 7.21 (ddd, J = 8.3, 2.6, 0.8 Hz, 1 H), 7.41 (d, J = 8.9 Hz, 1 H), 7.50 (t, J = 8.0, 1 H), 7.64 (dd, J = 8.9, 2.1 Hz, 1 H), 7.71 (m, 1 H), 7.87 (td, J = 7.7, 1 .0 Hz, 1 H), 8.77 (d, J = 1 .9 Hz, 1 H), 10.66 (br s, 1 H). LC-MS (ESI) m / z [M+H]+= 386.0, 388.1 .

[0085] A / -[5-Bromo-2-[3-(trifluoromethyl)benzoyl]-1-benzofuran-3-yl]acetamide (10).Compound 10 was prepared according to general procedure A starting from 5-Bromo-2-[3- (trifluoromethyl)benzoyl]-1 -benzofuran-3-amine (200 mg, 0.52 mmol), acetyl chloride (0.1 1 mL, 1 .56 mmol) and obtained as a yellow powder (216 mg, 97%).1H NMR (300 MHz, CDCI3) <5 2.40 (s, 3H), 7.42 (d, J = 8.9 Hz, 1 H), 7.68 (dd, J = 8.9, 2.1 Hz, 1 H), 7.73 (t, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 8.44 (d, J = 7.9 Hz, 1 H), 8.49 (m, 1 H), 8.80 (d, J = 1 .9 Hz, 1 H), 10.63 (s, 1 H). LC-MS (ESI) m / z [M-H]- = 424.0, 426.0.

[0086] A / -(2-Benzoyl-5-bromo-1-benzofuran-3-yl)-A / -methylacetamide (11). To a solution of A / -(2- benzoyl-5-bromo-1 -benzofuran-3-yl)acetamide (200 mg, 0.56 mmol) in 5 mL of THF, NaH (40 mg, 1 .68 mmol) was added at 0°C. The mixture was stirred 45 min at rt. Dimethyl sulfate (0.16 mL, 1 .68 mmoll) was added and the mixture was stirred during 3 h. The resulting mixture was cooled to rt and hydrolyzed with water. The aqueous layer was extracted three times with EtAOc. Organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by flash column chromatography (1 -20% EtAOc in cyclohexane) to give a beige powder (99 mg, 48%).1H NMR (300 MHz, DMSO-d6) < 1 .82 (s, 2H), 2.00 (s, 1 H), 3.14 (s, 2H), 3.25 (s, 1 H), 7.57-7.64 (m, 2H), 7.69-7.78 (m, 2H), 7.82 (m, 2H), 7.87 (m, 0.7H), 7.95 (m, 0.3H), 8.03 (m, 1 .3H), 8.10 (m, 0.7H). LC- MS (ESI) m / z [M+H]+= 374.0.

[0087] A / -[2-Benzoyl-5-(4-fluorophenyl)-1-benzofuran-3-yl]acetamide (12). To a sealed tube were added 2-benzoyl-5-bromo-1 -benzofuran-3-amine (1 .0 g, 2.79 mmol), 4-fluorophenylboronic acid (879 mg, 6.28 mmol), CS2CO3 (4.1 g, 12.56 mmol) and TBAB (90 mg, 0.28 mmol) in dioxane (20 mL) and water (5 mL). The solution was degassed with nitrogen during 5 minutes and tetrakis(triphenyiphosphine)pailadium(0) (130 mg, 0.1 1 mmol) was added. The solution was stirred and heated at 100°C overnight. The mixture was cooled to rt., hydrolyzed with water and acidified with a 6N HCI solution. Aqueous layer was extracted three times with EtOAc. Combined organic layers were dried over MgSCk, discolored with charcoal, filtered and concentrated in vacuo. Solid was taken up in PE and filtered to give a yellow powder (1 .0 g, 65%).1H NMR (300 MHz, CDCI3) <5 2.41 (s, 3H) 7.16 (m, 2H), 7.62 (m, 6H), 7.75 (dd, J = 8.8, 1 .9, Hz, 1 H), 8.26 (m, 2H), 8.75 (d, J = 1 .9 Hz, 1 H), 10.76 (s, 1 H). LC-MS (ESI) m / z [M+H]+= 374.0.

[0088] Methyl (2E)-3-(2-benzoyl-3-propanamido-1 -benzofuran-5-yl)prop-2-enoate (13). Compound 13 was prepared according to general procedure B starting from methyl acrylate (62 pL, 0.69 mmol) and A / -(2-benzoyl-5-bromo-1 -benzofuran-3-yl)propanamide (85 mg, 0.23 mmol), and obtained as a white solid (42 mg, 48%).1H NMR (300 MHz, CDCI3) <5 1 .03 (t, J = 7.6 Hz, 3H), 2.39 (q, J = 7.5 Hz, 2H), 3.76 (s, 3H), 6.66 (d, J = 16.0 Hz, 1 H), 7.58 (m, 2H), 7.69 (m, 1 H), 7.79 (m, 2H), 7.98 (m, 3H), 8.59 (d, J = 1 .2 Hz, 1 H). LC-MS (ESI) m / z [M+H]+= 378.2.

[0089] A / -(2-Benzoyl-5-bromo-1-benzofuran-3-yl)acetamide (14). Compound 14 was prepared according to general procedure A starting from 2-benzoyl-5-bromo-1 -benzofuran-3-amine (5.0 g, 15.82 mmol), acetyl chloride (3.4 mL, 47.45 mmol) and obtained as a yellow powder (4.2 g, 74%).1H NMR (300 MHz, CDCI3) 5 2.38 (s, 3H), 7.40 (d, J = 8.2 Hz, 1 H), 7.62 (m, 4H), 8.22 (m, 2H), 8.75 (d, J= 1 .9 Hz, 1 H), 10.66 (s, 1 H).13C NMR (75 MHz, CDCI3) <524.5, 1 13.6, 1 16.3, 122.7, 128.6 (2C), 129.7 (2C), 130.2, 132.4, 132.9, 133.3, 136.5, 138.7, 153.3, 168.7, 185.8. LC-MS (ESI) m / z [M+H] = not detected.

[0090] Ethyl (E)-3-(3-acetamido-2-benzoylbenzofuran-5-yl)acrylate (15). Compound 15 was prepared according to general procedure B starting from A / -(2-benzoyl-5-bromo-1 -benzofuran-3- yl)acetamide (2.0 g, 5.58 mmol) and ethyl acrylate (0.91 mL, 8.38 mmol), and obtained as a beige solid (1 .35 g, 64%).1H NMR (300 MHz, DMSO-d6) <5 1 .28 (t, J = 7.0 Hz, 3H), 2.1 (s, 3H), 4.22 (q, J = 7.0 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1 H), 7.60 (m, 2H), 7.67-7.78 (m, 2H), 7.78 (d, J = 16.0 Hz, 1 H), 7.95-8.02 (m, 3H), 8.26 (d, J= 1 .8 Hz, 1 H), 10.36 (s, 1 H).13C NMR (75 MHz, DMSO-d6) <5 14.3, 24.5, 60.5, 1 12.8, 1 18.3, 121 .5, 128.5, 128.6 (2C), 129.1 , 129.7 (2C), 130.2, 133.2, 133.4, 136.6, 144.3,155.4, 166.9, 168.7, 185.8. LC-MS (ESI) m / z [M+H]+= 378.31

[0091] A / -[2-(2-Chlorobenzoyl)-1-benzofuran-3-yl]acetamide (16). Compound 16 was prepared according to general procedure A starting from (3-aminobenzofuran-2-yl)(2-chlorophenyl)methanone (150 mg, 0.55 mmol) and acetyl chloride (0.12 mL, 1 .66 mmol), and obtained as a yellow solid (63 mg, 36 %).1H NMR (300 MHz, CDCI3) <52.40 (s, 3H), 7.33 (m, 1 H), 7.40 (m, 1 H), 7.46 (m, 1 H), 7.55 (m, 4H), 8.60 (d, J = 8.3 Hz, 1 H), 10.44 (s, 1 H).13C NMR (75 MHz, CDCI3) <5 24.6, 1 12.3, 121 .0,123.4, 126.7, 128.1 , 129.5, 130.4 (2C), 131 .9, 131 .9, 133.3, 136.9, 137.5, 155.3, 168.6, 186.7. LC- MS (ESI) m / z [M+H]+= 314.1 , 316.2.

[0092] A / -[5-Bromo-2-(2-chlorobenzoyl)-1-benzofuran-3-yl]acetamide (17). Compound 17 was prepared according to general procedure A starting from (3-amino-5-bromobenzofuran-2-yl)(2- chlorophenyl)methanone (150 mg, 0.43 mmol) and acetyl chloride (0.092 mL, 1 .28 mmol) and obtained as orange solid (89 mg, 53 %).1H NMR (300 MHz, CDCI3) <52.39 (s, 3H), 7.28 (dd, J= 0.4, 8.9 Hz, 1 H), 7.41 -7.49 (m, 1 H), 7.51 -7.57 (m, 3H), 7.62 (dd, J = 2.1 , 8.9 Hz, 1 H), 8.79 (d, J = 2.1 , 1 H), 10.34 (br s, 1 H). LC-MS (ESI) m / z [M+H]+= 390.0, 392.0.

[0093] Methyl (2E)-3-[3-acetamido-2-(2-methylbenzoyl)-1-benzofuran-5-yl]prop-2-enoate (18).Compound 18 was prepared according to general procedure B starting from A / -[5-bromo-2-(2- chlorobenzoyl)-1 -benzofuran-3-yl]acetamide (200 mg, 0.537 mmol). The resulting mixture requiredfurther purification and was purified by flash column chromatography (30-50 % cyclohexane in DCM) to obtain the final product as a white solid (1 15 mg, 57 %).1H NMR (300 MHz, CDC ) <52.41 (s, 3H), 3.84 (s, 3H), 6.51 (d, J = 15.9 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.44 - 7.58 (m, 4H), 7.72 (dd, J =1 .7, 8.8 Hz, 1 H), 7.84 (d, J = 16.1 Hz, 1 H), 8.81 (d, J = 1 .5 Hz, 1 H), 10.42 (br s, 1 H).13C NMR (75 MHz, CDCI3) <524.5, 51 .8, 1 13.0, 1 17.9, 121 .6, 126.8, 128.9, 129.4, 129.5, 130.1 , 130.4, 131 .9, 132.1 , 133.1 , 136.6, 138.1 , 144.5, 155.9, 167.4, 168.6, 186.6. LC-MS (ESI) m / z [M+H]+= 398.2, 400.2.

[0094] A / -(5-Bromo-2-(2-methylbenzoyl)benzofuran-3-yl)acetamide (19). Compound 19 was prepared according to general procedure A starting from (3-amino-5-bromobenzofuran-2-yl)(o- tolyl)methanone (800 mg, 2.42 mmol) and acetyl chloride (0.52 mL, 7.27 mmol) and obtained as a pale yellow solid (525 mg, 58 %).1H NMR (300 MHz, CDC ) <5 2.39 (s, 3H), 2.45 (s, 3H), 7.30-7.53 (m, 4H), 7.61 (d, J = 8.3 Hz, 2H), 8.77 (d, J = 1 .4 Hz, 1 H), 10.47 (s, 1 H). LC-MS (ESI) m / z [M+H]+= 372.3-374.2.

[0095] Methyl (2E)-3-[3-acetamido-2-(2-methylbenzoyl)-1-benzofuran-5-yl]prop-2-enoate (20).Compound 20 was prepared according to general procedure B starting from A / -(5-bromo-2-(2- methylbenzoyl)benzofuran-3-yl)acetamide (200 mg, 0.537 mmol). The resulting mixture required further purification and was purified by flash column chromatography (30-50 % cyclohexane in DCM) to obtain the final product as a white solid (1 15 mg, 57 %).1H NMR (300 MHz, CDCb) <52.41 (s, 3H), 2.46 (s, 3H), 3.85 (s, 3H), 6.50 (d, J = 16.0 Hz, 1 H), 7.37 (m, 2H), 7.43 (d, J = 8.7 Hz, 1 H), 7.49 (m, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.71 (dd, J =, 8.8, 1 .6 Hz, 1 H), 7.85 (d, J = 16.1 Hz, 1 H), 8.79 (d, J = 1 .8 Hz, 1 H), 10.56 (s, 1 H).13C NMR (75 MHz, CDCb) <5 19.9, 24.5, 51 .7, 1 12.8, 1 17.7, 121 .7, 125.4,128.7, 128.8, 129.0, 130.0, 131 .2, 131 .3, 132.5, 136.7, 137.2, 138.6, 144.5, 155.5, 167.3, 168.6,189.8, LC-MS (ESI) m / z [M+H]+= 378.3.

[0096] ACSL4 activityTablel : The results presented in Table 1 above demonstrate that the tested compounds of the invention have a high inhibitory activity on ACSL4. Indeed their IC50 values are below 50 pM, most of the compounds having IC50 below 10 pM. A large number of compounds have IC50 below 1 pM.

[0097] The antiferroptotic potential of compounds 2 and 6 was evaluated in Lund human mesencephalic cells (LUHMES), The results are shown in Figure 1. Figure 1 A shows that the combination of arachidonic acid and iron induces ferroptosis. Figure 1 B shows that compounds 2 and 6 are not toxic for the cells. Moreover, the addition of compounds 2 or 6 to LUHMES cells initially treated with arachidonic acid and iron protects the cell against ferroptosis, therefore showing interesting anti-ferroptotic properties of the compounds of the disclosure.Citation List

[0098] 1 . T. J. Grevengoed, E. L. Klett, R.A Coleman, Annu. Rev. Nutr. 2014, 34, 1 -30.2. P. A. Watkins, D. Maiguel, Z. Jia, J. Pevsner, J. Lipid. Res. 2007, 48, 2736-2750.3. E. Soupene, F. A. Kuypers, Exp. Biol. Med. (Maywood). 2008, 233, 507-521.4. Klett EL, Chen S, Yechoor A, Lih FB, Coleman RA. J Lipid Res. 2017, 58, 884-894.5. Quan J, Bode AM, Luo X. Eur J Pharmacol. 2021 Oct 15;909:174397.6.Wu Z, Sun J, Liao Z, Qiao J, Chen C, Ling C, Wang H. Front Neurosci. 2022 Nov 24;16:1030512.7. Grube J, Woitok MM, Mohs A, Erschfeld S, Lynen C, Trautwein C, Otto T. Cell Death Dis. 2022 Aug 13;13(8):704.8. Monaco ME. Oncotarget. 2023 Jun 12;14:563-575.9. Castillo AF, Orlando UD, Maloberti PM, Prada JG, Dattilo MA, Solano AR, Bigi MM, Rios Medrano MA, Torres MT, Indo S, Caroca G, Contreras HR, Marelli BE, Salinas FJ, Salvetti NR, Ortega HH, Lorenzano Menna P, Szajnman S, Gomez DE, Rodriguez JB, Podesta EJ. Cell Mol Life Sci. 2021 Mar;78(6):2893-2910.10. Ma Y, Zhang X, Alsaidan OA, Yang X, Sulejmani E, Zha J, Beharry Z, Huang H, Bartlett M, Lewis Z, Cai H. Mol Cancer Res. 2021 Jan;19(1 ):124-135.1 1 . Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G, Stockwell BR. ACS Chem Biol. 2015 Jul 17;10(7):1604-9.12. Yuan H, Li X, Zhang X, Kang R, Tang D. Biochem Biophys Res Commun. 2016 Sep 23;478(3):1338-43.13. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trumbach D, Mao G, Qu F, Bayir H, Fullekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP, Conrad M. Nat Chem Biol. 2017 Jan;13(1 ):91 -98.14. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Cell. 2012 May 25;149(5):1060-72.15. Stockwell BR. Cell. 2022 Jul 7;185(14):2401 -2421 .16. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, Kapralov AA, Amoscato AA, Jiang J, Anthonymuthu T, Mohammadyani D, Yang Q, Proneth B, Klein- Seetharaman J, Watkins S, Bahar I, Greenberger J, Mallampalli RK, Stockwell BR, Tyurina YY, Conrad M, Bayir H. Nat Chem Biol. 2017 Jan;13(1 ):81 -90.17. Kim JH, Lewin TM, Coleman RA. J Biol Chem. 2001 Jul 6;276(27):24667-73.18. Do Van B, Gouel F, Jonneaux A, Timmerman K, Gele P, Petrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian JC. Neurobiol Dis. 2016 Oct;94:169-78.19. Mahoney-Sanchez L, Bouchaoui H, Boussaad I, Jonneaux A, Timmerman K, Bordeaux O, Ayton S, Kruger R, Duce JA, Devos D, Devedjian JC. Cell Rep. 2022 Aug 23;40(8):1 1 1231 .20. Bouchaoui H, Mahoney-Sanchez L, Gargon G, Bordeaux O, Alleman LY, Devos D, Duce JA, Devedjian JC. Free Radic Biol Med. 2023 Feb 1 ;195:145-157.

Claims

1. Claims

1. Compound of formula (I)a pharmaceutically acceptable salt or a solvate thereof, wherein each R1 is independently selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; m is an integer between 0 and 5, preferably m is 0 or 1 ;R2 is H or C1-6 alkyl;R3 is selected from C1-6 alkyl and optionally substituted cycloalkyl;R4 is selected from H, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, - (CH2)P-X-R’, -(CH=CH)-X-R’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R5 is selected from H, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; preferably R5 is H; p is 0 to 6;X is selected from the group consisting of -O-, -NR’-, -O-(CO)-, -(CO)-O-, -NR’-(CO)-, -(CO)-NR’-, - SO2-, -O-(SO2)-, -(SO2)-O-, -NR’-(SO2)-, -(SO2)-NR’-, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; provided that- at least one of R4 and R5 is different from H;- when R4 is Cl or Br, m is an integer from 1 to 5; and- when m is 0, R2 is H, R3 is methyl, R5 is H and R4 is -(CH=CH)-(CO)-O-R’, R’ represents H, Me or a C3-6 alkyl.

2. The compound of claim 1 , wherein said compound is a compound of formula (II)wherein L is a linker selected from C1-6 alkyl, C2-6 alkenyl, cycloalkyl and any combinations thereof;R7 is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, preferably R7 is H or C1-6 alkyl; provided that when m is 0, R2 is H, R3 is methyl and L is C2 alkenyl, R7 represents H, Me or a C3-6 alkyl.

3. The compound of claim 2, wherein said compound is a compound of formula (III)Wherein = represents a single bond or a double bond.

4. The compound of claim 1 , wherein said compound is a compound of formula (IV)whereinA represents a cycloalkyl, an aryl, or a heterocycle; R6 is selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; and n is an integer between 0 and 5, preferably n is 0 or 1 .

5. The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of:

6. The compound according to any one of claims 1 to 5, wherein the compound is selected

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and at least one other ingredient selected from a pharmaceutically acceptable excipient.

8. The compound according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 7 for use in a method of therapeutic treatment of a subject.

9. The compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 for use according to claim 8 in a method of therapeutic treatment of a disease selected from cancers, neurodegenerative diseases and infectious diseases.

10. Compound or pharmaceutical composition for use in a method according to claim 8 or 9, wherein said compound or composition is administered orally, enterally, intravenously, or intramuscularly to said subject.

11. A compound of formula (la) for use in a method of therapeutic treatment of a disease selected from cancers, neurodegenerative diseases and infectious diseases:a pharmaceutically acceptable salt or a solvate thereof, wherein each R1 a is independently selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, and C1-6 haloalkyl; m’ is an integer between 0 and 5, preferably m’ is 0 or 1 ;R2a is H or C1-6 alkyl;R3a is selected from C1-6 alkyl and optionally substituted cycloalkyl;R4a is selected from H, Cl, Br, F, I, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, -(CH2)r-Xa-Ra’, -(CH=CH)-Xa-Ra’, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle;R5a is selected from H, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; preferably R5a is H,; r is 0 to 6;Xa is selected from the group consisting of -O-, -NRa’-, -O-(CO)-, -(CO)-O-, -NRa’-(CO)-, -(CO)- NRa’-, -SO2-, -O-(SO2)-, -(SO2)-O-, -NRa’-(SO2)-, -(SO2)-NRa’-, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle; andRa' is selected from H, C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle.

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