Novel inhibitors of ACSL4 and their use as medicines

Abstract

The present invention pertains to novel inhibitors of ACSL4 and their use as medicines. The inventors have designed and studied novel compounds that inhibit selectively ACSL4 activity at sub-micromolar concentrations while having no or minimized activity on PPAR-γ. 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 disease.

Description

-1- Description Title: Novel inhibitors of ACSL4 and their use as medicines Technical Field

[0001] This disclosure pertains to novel inhibitors of ACSL4 and their use as medicines. 5 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- 10 CoA esters. Once activated, fatty acids (FAs) participate in various cellular pathways including the synthesis of phospholipids, triacylglycerol and cholesterol esters, β-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.5,6More specifically, ACSL4 recently emerged as an 15 attractive target in some cancers including hepatocellular carcinoma,7estrogen receptor-negative breast cancer,8,9colorectal 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 20 PUFAs, which are highly prone to peroxidation.16Moreover, its phosphorylation by PKCβII (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. 25

[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-γ), a nuclear receptor strongly involved in lipid metabolism constitutes an important limitation. 30

[0004] Therefore, the development of potent and selective ACSL4 inhibitors with a minimized activity on PPAR-γ appears highly valuable. Summary

[0005] In this context, the inventors have designed and studied novel compounds that inhibit selectively ACSL4 activity at sub-micromolar concentrations while having no or minimized activity on 35 PPAR-γ.-2-

[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.

[0007] The first object of the invention is thus a compound of formula (II) 5a pharmaceutically acceptable salt or a solvate thereof, wherein R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, C1-6 alkyl-optionally substituted aryl, C1-6 alkyl- 10 optionally substituted heteroaryl, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally 15 substituted aryl, and optionally substituted heteroaryl, W is selected from O and NH, X and Y are independently selected from H, CH, N and (CH2)n, Z is selected from CH, CH2 and N, m is an integer selected from 1 or 2, 20 n is an integer selected from 1, 2, 3, 4 or 5, represents a single bond or a double bond, represents no bond, a single bond, or a double bond.

[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 25 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. Detailed Description

[0010] A first object of the invention is thus a compound of formula (II) 30-3- a pharmaceutically acceptable salt or a solvate thereof, wherein R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, C1-6 alkyl-optionally substituted aryl, C1-6 alkyl- 5 optionally substituted heteroaryl, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally 10 substituted aryl, and optionally substituted heteroaryl, W is selected from O and NH, X and Y are independently selected from H, CH, N and (CH2)n, Z is selected from CH, CH2 and N, m is an integer selected from 1 or 2, 15 n is an integer selected from 1, 2, 3, 4 or 5, represents a single bond or a double bond, represents no bond, a single bond, or a double bond.

[0011] According to a particular embodiment, the compound of the invention can have the formula 20a pharmaceutically acceptable salt or a solvate thereof, wherein R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, optionally substituted heterocycle, C1-6 alkyl-optionally substituted aryl, and C1-6 alkyl- 25 optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally 30 substituted aryl, and optionally substituted heterocycle, m is an integer selected from 1 or 2, n is an integer selected from 1, 2, 3, 4 or 5,-4- X and Y are independently selected from H, CH, N and (CH2)n, Z is selected from CH, CH2 and N, represents a single bond or a double bond, represents no bond, a single bond, or a double bond. 5

[0012] According to a particular embodiment, the compound of the invention can have the formula (III)a pharmaceutically acceptable salt or a solvate thereof, wherein 10 R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, optionally substituted heterocycle, C1-6 alkyl-optionally substituted aryl, and C1-6 alkyl- optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- 15 OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4is selected from H, C1-6alkyl, -O-C1-6alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, m is an integer selected from 1 or 2, n is an integer selected from 1, 2, 3, 4 or 5, 20 X and Y are independently selected from H, CH, N and (CH2)n, Z is selected from CH, CH2 and N, represents a single bond or a double bond, represents no bond, a single bond, or a double bond.

[0013] The inventors demonstrated that compounds of formula (I), (II) and (III) have a significative 25 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 and infectious diseases.

[0014] In the context of the invention, the term “C1-6alkyl” refers to C1-6linear (i.e., "straight-chain"), branched, or cyclic, saturated hydrocarbon chains, including for example, methyl, ethyl, propyl, 30 isopropyl, butyl, isobutyl groups. The term “cycloalkyl” refers to a cyclic saturated hydrocarbon chain, including for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups.-5-

[0015] 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 be unsubstituted or substituted with at least one suitable substituent, for example with an optionally substituted C1-C6 alkyl, or -O-C1-6 alkyl, -NO2, - 5 CN, halogen, or an amino group.

[0016] 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). 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 10 monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, or may be an “heteroaromatic”, 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 15 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 C1-C6 alkyl.

[0017] In the context of the invention, the term “halogen” refers to fluorine, chlorine, bromine, iodine. 20

[0018] According to a particular embodiment, the compound of the invention can have the formula (IIa) below:wherein R1, R2, R3, R4, W, X, Y, Z and m are as previously defined.

[0019] According to a particular embodiment, the compound of the invention can have the formula 25 (IIb) below:wherein R1, R2, R3, R4, W, X, Y, Z and m are as previously defined.

[0020] According to a particular embodiment, the compound of the invention can have the formula (IIc) below: 30wherein R1, R2, R3, R4, W, X, Y, Z and m are as previously defined.-6-

[0021] According to a particular embodiment, the compound of the invention can have the formula (IId) below:wherein R1, R2, R3, R4, W, X, Y, Z and m are as previously defined. 5

[0022] According to a particular embodiment, the compound of the invention can have the formula (IIe) below:wherein R1, R2, R3, R4, W, X, Y, Z and m are as previously defined.

[0023] According to a particular embodiment, the compound of the invention can have the formula 10 (IIf) below:wherein R1, R2, R3, R4, W, X, Y, Z and m are as previously defined.

[0024] According to a particular embodiment, the compound of the invention can have the formula (Ia) below: 15wherein R1, R2, R3, R4, X, Y, Z and m are as previously defined.

[0025] According to a particular embodiment, the compound of the invention can have the formula (Ib) below:20 wherein R1, R2, R3, R4, X, Y, Z and m are as previously defined.

[0026] According to a particular embodiment, the compound of the invention can have the formula (Ic) below:wherein R1, R2, R3, R4, X, Y, Z and m are as previously defined. 25

[0027] According to a particular embodiment, the compound of the invention can have the formula (Id) below:-7-wherein R1, R2, R3, R4, X, Y, Z and m are as previously defined.

[0028] According to a particular embodiment, the compound of the invention can have the formula (Ie) below: 5wherein R1, R2, R3, R4, X, Y, Z and m are as previously defined.

[0029] According to a particular embodiment, the compound of the invention can have the formula (If) below:10 wherein R1, R2, R3, R4, X, Y, Z and m are as previously defined.

[0030] According to a particular embodiment, the compound of the invention can have the formula (Ia1) below:wherein R1, R2, R3, R4, X and m are as previously defined. 15

[0031] According to a particular embodiment, the compound of the invention can have the formula (Ic1) below:wherein R1, R2, R3, R4, X and m are as previously defined.

[0032] According to a particular embodiment, when m = 1, the compound of the invention has the 20 formula (Ig) below: wR , R,R3, R , , , X, Y and Z are as previously defined.

[0033] According to a particular embodiment, when m = 2, the compound of the invention has the formula (Ih) below:-8-wherein R1, R2, R3, R4, , , X, Y and Z are as previously defined.

[0034] According to a particular embodiment, when m = 1, the compound of the invention can have the formula (Ig1) below: 5wherein R1, R2, R3, R4, X and Z are as previously defined.

[0035] According to a particular embodiment, when m = 2, the compound of the invention can have the formula (Ih1) below:10 wherein R1, R2, R3, R4 X and Z are as previously defined.

[0036] According to a particular embodiment, when m = 1, the compound of the invention can have the formula (Ig2) below:wherein R1, R2, R3, R4, X and Z are as previously defined. 15

[0037] According to a particular embodiment, when m = 2, the compound of the invention can have the formula (Ih2) below:whereinR1, R2, R3, R4, X and Z are as previously defined.

[0038] According to a particular embodiment, the compound of the invention can have one of the 20 formulas (Ig3), (Ih3), (Ig4), or (Ih4) below:-9-wherein R1, R2, R3, R4, X and n are as previously defined.

[0039] According to a particular embodiment, the compound of the invention can have one of the formulas (Ii), or (Ij) below:wherein R1, R2, R3, R4, , , X, Y, Z, m and n are as previously defined,R5 is selected from H, -C1-C6 alkyl, C1-8 alkoxy, -NO2, -CN, halogen, or an amino group.

[0040] According to a particular embodiment, the compound of the invention can have one of the formulas (Ii1), or (Ij1) below:wherein R1, R2, R3, R4, X, m and n are as previously defined, R5 is selected from H, -C1-C6 alkyl, C1-8 alkoxy, -NO2, -CN, halogen, or an amino group.

[0041] According to a particular embodiment, the compound of the invention can be selected from the group consisting of:-12-

[0042] According to a particular embodiment, the compound of the invention can be selected from 5.

[0043] The compounds represented by Formula (I), (II) and (III) of the present disclosure may exist 10 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. 15

[0044] The compounds represented by Formula (I), (II) and (III) 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.

[0045] Particularly, the pharmaceutically acceptable salt may be an acid addition salt formed by a 20 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, phenyl- substituted alkanoates, hydroxy alkanoates, and alkanedioates, aromatic acids, and aliphatic and-13- 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 5 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,10 xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- 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), (II) or (III) or (Ia) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, or acetonitrile, adding an 15 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 20 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).

[0046] The compounds of the present disclosure and their pharmaceutically acceptable salts or 25 solvates thereof may contain one or more asymmetric centers, chiral axes and chiral planes and may thus 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.

[0047] Another object of the invention is a pharmaceutical composition comprising a compound of 30 the invention or a pharmaceutically acceptable salt or a solvate thereof and at least one other ingredient selected from a pharmaceutically acceptable excipient.

[0048] 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 35 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.-14-

[0049] 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 formula (I), (II) or (III) or of a pharmaceutically acceptable salt thereof. 5

[0050] 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. 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 10 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 15 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. 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 20 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 the 25 incidence 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.

[0051] In the context of the invention, the term “administration”, or a variant thereof (e.g., 30 “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.

[0052] 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 35 of a medical procedure.

[0053] 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.-15-

[0054] 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, 5 myocardial Infarction, infectious diseases, inflammatory bowel disease, psoriasis, atopic dermatitis, multiple sclerosis, rheumatoid arthritis, adrenoleukodystrophy.

[0055] 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. 10

[0056] 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).

[0057] In a particular embodiment, the patient suffers from a solid cancer selected from the group 15 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, 20 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 carcinoid 25 tumors (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 30 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. 35 uterine leiomyosarcoma).

[0058] 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-16- amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases.

[0059] 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 5 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.

[0060] According to a particular embodiment, the compound or composition for use in a method of 10 therapeutic treatment according to the invention can be administered orally, enterally, intravenously, or intramuscularly.

[0061] The compounds of formula (I), (II) and (III) may be prepared by known methods, such as nucleophilic substitutions, Mitsunobu reactions, amine protection and deprotection, amide coupling reactions, Suzuki reactions, Heck reactions, cyclization reactions, condensations, reduction 15 reactions, from commercial products, starting for example from aniline, naphtol, cinnamic derivatives. Brief Description of Drawings Fig.1

[0062] [Fig.1] Cytotoxicity of compound 15 across different cell lines. Cytotoxic Concentration 50% (CC50) curves of compound 15 in HEK293 (A), HT-1080 (B), SiHa (C), HCT-116 (D) and MDA- 20 MB-231 (E) cell lines after 72 h. Data represent CC50 ± SD (n = 3). F) Percentage of LUHMES cell viability following 48 h of treatment with compound 15 at concentrations of 10, 20, and 50 μM. Data represent mean ± SD (n = 2).. Fig.2

[0063] [Fig.2] Compound 15 protects cells from ferroptosis. A) Cell viability analysis of HEK293 25 cells pretreated with 2.5 µM of 15 for 24 h, followed by treatment with RSL3 for 48 h. Data represent mean and SD (n = 4). Statistical analysis was performed using Tukey’s multiple comparisons test. **** p < 0.001. B) Cell viability analysis of HT-1080 cells pretreated with 2.5 µM of 15 for 24 h, followed by treatment with RSL3 for 48 h. Data represent mean and SD (n = 4). Statistical analysis was performed using Tukey’s multiple comparisons test. **** p < 0.001. C) Cell viability analysis of 30 LUHMES cells transfected with ACSL4 siRNA or pretreated with 2.5 µM of 15 for 4 h, followed by treatment with AA+Fe for 48 h. Data represent mean and SD (n = 3). Statistical analysis was performed using Tukey’s multiple comparisons test. **** p < 0.001. D) Percentage of lipid peroxidation in LUHMES cells transfected with ACSL4 siRNA or pretreated with 2.5 µM of 15 for 4 h, followed by treatment with AA+Fe for 24 h. Lipid peroxidation in cells was measured by flow 35 cytometry using the C11 BODIPY 581 / 591 probe. The staining data obtained at 530 nm (oxidized C11 BODIPY 581 / 591) are plotted as a histogram. Data represents mean and SEM (n = 4). Statistical analysis was performed using Tukey’s multiple comparisons test. **** p < 0.001..-17- Fig.3

[0064] [Fig.3] Compound 45 protects LUHMES cells from ferroptosis. (A) Cell viability analysis of LUHMES cells transfected with ACSL4 siRNA or pretreated with 2.5 µM of 45 for 4 h, followed by treatment with AA+Fe for 48 h. Data represent mean and SEM (n = 3). Statistical analysis was 5 performed using Tukey’s multiple comparisons test. **** p < 0.001. (B) Percentage of lipid peroxidation in LUHMES cells transfected with ACSL4 siRNA or pretreated with 2.5 µM of 45 for 4 h, followed by treatment with AA+Fe for 24 h. Lipid peroxidation in cells was measured by flow cytometry using the C11 BODIPY 581 / 591 probe. The staining data obtained at 530 nm (oxidized BODIPY 581 / 591-C11) are plotted as a histogram. Data represent mean and SEM (n = 3). Statistical 10 analysis was performed using Tukey’s multiple comparisons test. **** p < 0.001. Examples

[0065] Material and Methods

[0066] Chemical synthesis: Starting materials, reagents, and solvents were purchased from commercial vendors and used without further purification. Analytical liquid chromatography−mass 15 spectrometry (UPLC / MS) was conducted using a Waters AcQuity UPLC I-Class with UV detection and an electrospray mode (ESI). Purification of intermediates and final products was carried out on normal phase using a Reveleris X2 Grade. NMR spectra were recorded on a Bruker NEO 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. Data sets were processed using Bruker Topspin 4.2 20 software. Chemical shifts (δ) are reported in parts per million (ppm) relative to a deuterated solvent as the internal standard and coupling constants (J) are in hertz (Hz). The data are reported as follows: chemical shifts (δ) 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. Unless otherwise noted, the purity for compounds was 25 judged to be > 98% as determined by UPLC.

[0067] ACSL3 and ACSL4 Production and Purification: The plasmid pET-28(a)+ coding for both isoforms as well as their mutants were purchased from GeneCustTMand transformed into E. Coli BL21 (DE3). First 42 amino acids corresponding to the N-terminal transmembrane helix were truncated for all enzymes and replaced by a N-terminal His-tag. Production, purification & 30 characterization were performed as previously described (R. Marteau, S. Ravez, D. Mazhari Dorooee, H. Bouchaoui, K. Porte, J. C. Devedjian, P. Melnyk, D. Devos, R. Frédérick, J. El Bakali, Biochem. Pharmacol.2022, 204, 115239).

[0068] ACSL4 activity assay: Inorganic pyrophosphate (PPi) production was monitored with a Varioskan Flash spectrophotometer (Thermo Scientific) using the EnzChek® pyrophosphate assay 35 kit (E-6645). Each condition was measured in triplicate at 25°C. The total reaction volume was 100 µL and activity was assayed in buffer containing 50 mM Tris pH 7.5, 200 mM NaCl, 1 mM MgCl2, 200 µM MESG, 50 µM ATP, 100 µM 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-18- addition of a palmitate solution, typically to a final concentration of 100 µM (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 5 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 GraphPad Prism®.

[0069] ACSL3 Activity Assay: The ACSL3 activity assay was performed as previously described, following a protocol similar to that used for ACSL4.[1] Inorganic pyrophosphate (PPi) production was 10 monitored with a Varioskan Flash spectrophotometer (Thermo Scientific) using the EnzChek® pyrophosphate assay kit (E-6645). Each condition was measured in duplicate at 25°C. The total reaction volume was 100 µL and activity was assayed in buffer containing 50 mM Tris pH 7.5, 200 mM NaCl, 1 mM MgCl2, 200 µM MESG, 50 µM ATP, 100 µM CoA, 1 mM DTT, 10% DMSO (or tested compound), 1 U / mL PNP, 0.03 U / mL pyrophosphatase, and 600 nM purified human ACSL3. 15 Reactions were initiated by the addition of a palmitate solution, to a final concentration of 100 µM (final concentration: 0.06% triton, 1% EtOH). A control experiment was performed in which a solution (0.06% triton, 1% EtOH) was added instead of a palmitate solution. The plate was mixed manually, and the absorption change was recorded every 30 s for 30 min at 360 nm. Reaction rates were determined from the linear phase, typically using 10 data points between 2 and 10 minutes of the 20 reaction. The slope of the control experiment was subtracted from each measured slope to obtain corrected values, which were then expressed as a percentage of the enzyme's activity relative to the uninhibited control. Compounds were screened at 10 and 50 µM. Because none of the compounds inhibited ACSL3 at these concentrations, IC50 values were not determined.

[0070] Cell Culture: HEK293, HT-1080, SiHa, HCT-116 and MDA-MB-231 cells were cultivated in 25 DMEM media (GibcoTM, 41965-062) supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Sigma-Aldrich, F7524), and penicillin / streptomycin (50 U / mL / 50 μg / mL) (GibcoTM, 151140122). The cells were cultured in a humid atmosphere of 5% CO2 at 37 °C. All procedures with LUHMES cells were carried out in flasks or well plates (Nunclon™) pre-coated with 50 μg / mL poly-L-ornithine and 1 μg / mL fibronectin in distilled water overnight before washing twice. 30 Proliferating LUHMES were maintained in proliferative media (Advanced Dulbecco modified Eagle’s Medium / F12 supplemented; 1X N-2 supplement; 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 (B. Do Van, F. Gouel, A. Jonneaux, K. Timmerman, P. Gelé, M. Pétrault, M. Bastide, C. Laloux, C. Moreau, R. Bordet, D. Devos, J. C. Devedjian, Neurobiol. Dis.2016, 94, 169– 35 178.).

[0071] Anti-Ferroptotic Assays: HEK293 and HT-1080 cells were seeded in 96 well plates at densities of 6,000 and 7,000 cells per well, respectively, in 200 μL of medium. The cells were incubated for 24 h. After incubation, the cell culture medium was gently removed and replaced with 100 μL of fresh medium containing 2.5 µM of compound 15 (final DMSO concentration: 0.8%). Cells-19- were further incubated for 24 h with 15. Ferroptosis was induced by adding 100 μL of RSL3 (Sigma- Aldrich) solutions containing 2.5 µM of 15. The final RSL3 concentrations were 1.25 µM for HEK293 cells and 500 nM for HT-1080 cells, with a final DMSO concentration of 0.8%. After 48 h of incubation, cell density was determined using the PrestoBlue™ Assay (ThermoFisher Scientific) following the 5 manufacturer’s instructions. LUHMES cells were seeded on day 2 (d2) in 24 well plates at a density of 250,000 cells per well. Cells were differentiated until day 5 (d5). At d5, cells were pre-treated with 2.5 µM of compound 15 or 45 for 4 h (final DMSO concentration: 0.5%). Ferroptosis was induced by supplementing the medium with arachidonic acid (AA) and FeCl3-NTA. Arachidonic acid (0 or 20 μM) was added for 2 10 h, followed by the addition of FeCl3-NTA (final Fe³⁺ concentration: 20 μM) prepared as previously described (H. Bouchaoui, L. Mahoney-Sanchez, G. Garçon, O. Berdeaux, L. Y. Alleman, D. Devos, J. A. Duce, J. C. Devedjian, Free Radic. Biol. Med.2023, 195, 145–157.). After 48 h of incubation, cells were harvested by trypsinization, pelleted (5 min, 300 g, 4°C), and resuspended in 200 μL of PBS containing LIVE / DEAD™ Violet stain (0.5 µL). Staining was performed for 15 min at 37°C. A 15 total of 15,000 cells per sample was acquired using the CytoFLEX Flow Cytometer (Beckman Coulter, USA), and quantification was conducted using Kaluza Analysis Software (Beckman Coulter). Cell viability was calculated as a percentage relative to untreated control cells and analyzed using GraphPad Prism (version 10.0). All experiments were performed at least in triplicate.

[0072] Lipid Peroxidation Evaluation: LUHMES were seeded on d2 in 24 well plates at a density 20 of 250,000 cells per well and left to fully differentiate (d5). Cells were pre-treated with compound 15 or 45 (2.5 µM) for 4 h (DMSO final concentration of 0.5%) before the induction of ferroptosis by supplementation with arachidonic acid (AA) + Fe. Arachidonic acid and FeCl3-NTA solutions were prepared as previously described (H. Bouchaoui, L. Mahoney-Sanchez, G. Garçon, O. Berdeaux, L. Y. Alleman, D. Devos, J. A. Duce, J. C. Devedjian, Free Radic. Biol. Med.2023, 195, 145–157). The 25 cells were treated with AA (0 or 20 μM) for 2 h before the addition of FeCl3-NTA (20 μM Fe3+). Lipid peroxidation was measured by C11-BODIPY 581 / 591 probe (Thermo Fisher, D3861) 24 h after AA + Fe supplementation in the living cell population (unlabeled with the LIVE / DEAD probe). LUHMES were harvested by trypsinization and pelleted (5 min, 300 g, 4 °C) before resuspending in 200 μL PBS containing C11-BODIPY 581 / 591 probe (1 μM) and LIVE / DEAD VIOLET (0.5 μL) for 15 min at 30 37 °C. A total of 10,000 cells was acquired using cytoFLEX (Beckman Coulter, California, USA) and quantification was performed with Kaluza Analysis software (Beckman) and analyzed using GraphPad Prism® (version 10.0). All experiments were performed in triplicate.

[0073] Cytotoxicity Assays: HEK293 and HT-1080 cells were seeded as described in the anti- ferroptotic assay protocol. SiHa, HCT-116, and MDA-MB-231 cells were seeded similarly in 96 well35 plates at densities of 4,000 cells per well for SiHa and HCT-116, and 7,000 cells per well for MDA- MB-231. All cell lines were incubated for 24 h. After incubation, cells were treated with concentrations ranging from 1 to 50 µM of compound 15 (final DMSO concentration 0.8%) for 72 h. Cytotoxicity was assessed using the PrestoBlue™ Assay (ThermoFisher Scientific) as described in the anti-ferroptotic assay protocol. LUHMES were seeded on d2 in 24 well plates at a density of 250,000 cells per well 40 and left to fully differentiate (d5). Cells were treated with compound 15 (10, 20 and 50 µM) for 48 h-20- (DMSO final concentration of 0.5%). LUHMES were harvested by trypsinization and pelleted (5 min, 300 g, 4 °C) before resuspending in 200 μL PBS LIVE / DEAD VIOLET (0.5 μL) for 15 min at 37 °C. A total of 10,000 cells was acquired using cytoFLEX (Beckman Coulter, California, USA) and quantification was performed with Kaluza Analysis software (Beckman). Cell viability was calculated 5 as a percentage relative to untreated control cells and analyzed using GraphPad Prism (version 10.0). All experiments were performed in triplicate in at least two independent experiments.

[0074] General procedures General procedure A To a solution of dibromoalkyl derivative (5-10 equiv) and K2CO3 (2 equiv) in ACN (10 mL), the 10 corresponding amine (1 equiv) was added. The mixture was refluxed for 40 h. After cooling to room temperature, ACN was evaporated and the resulting oil was taken up in DCM, washed with water, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by flash column chromatography (1-20% DCM in PE). General procedure B 15 A solution of methyl (2E)-3-[4-(2-bromoethoxy)phenyl]prop-2-enoate (1 equiv), K2CO3 (2 equiv), and appropriate starting material (1-4 equiv) in 10 mL of ACN was refluxed overnight. The resulting mixture was filtered and ACN was removed under reduced pressure. The resulting residue was taken up in DCM and washed with water. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Compounds were purified by flash column chromatography. 20 General procedure C To a solution of appropriate bromine derivative (1 equiv.) in acetonitrile, K2CO3 (2 equiv.) and corresponding phenol (1 equiv.) was added. The mixture was stirred at reflux for 16 h. ACN was removed under reduced pressure, and the resulting residue was taken in DCM and washed with water. The organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue 25 was either triturated in PE to give pure product or purified by flash column chromatography. General procedure D To neutral Al2O3 (1.5 equiv) was added the amine derivative (1 equiv). (Boc)2O (1.1 equiv) was added provoking a gaz release and the melting of (Boc)2O. After 10 min, the resulting mixture was diluted with EtOAc, filtered and washed with EtOAc. The solvent was then removed under reduced pressure 30 to give the desired product. General procedure E To a solution of primary alcohol (1.2 equiv), suitably substituted phenol or naphtol (1 equiv) and PPh3 (1.5 equiv) in THF (15 mL) was added, dropwise, at 0°C, DEAD (1.5 equiv). The mixture was stirred 12 h at rt. THF was then removed under reduced pressure, and the resulting residue was taken in 35 EtOAc, washed with 1N NaOH, water, and brine. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude was purified by flash column chromatography.-21- General procedure F A solution of appropriate tert-butyloxycarbonyl in a 4N HCl dioxane solution (5 mL) was stirred at rt for 4 h. Dioxane was then removed under reduced pressure and and the resulting residue was taken in Et2O. The precipitate was filtered and dried. 5 General procedure G A solution of acyl chloride (1 equiv), methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (1 equiv) or methyl (2E)-3-[4-(2-aminoethoxy)phenyl]prop-2-enoate hydrochloride (1 equiv) and Et3N (5 equiv) in 10 mL of DCM was stirred at rt for 4 h. The resulting mixture was washed with water and brine, and extracted 2 times with DCM. The organic layers were combined, dried 10 (MgSO4), and concentrated under reduced pressure. General procedure H A solution of the amino derivative 60 or 61 (1 equiv), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.2 equiv), HOBt (1.2 equiv), and Et3N (5 equiv) in 10 mL of DCM was stirred at rt for 24 h. The resulting mixture was washed with NaHCO3 sat. and brine. The organic layer was dried (MgSO4), 15 and concentrated under reduced pressure. The crude was purified by flash column chromatography. General procedure I 6-Hydroxy-2-naphtoic acid (1 equiv, 5.3 mmol) was solubilized in appropriate alcohol. This solution was cooled to 0°C and SOCl2 (2 equiv, 10.6 mmol) was added dropwise. The reaction mixture was stirred at rt overnight. Solvent was removed under reduced pressure. The resulting residue was 20 dissolved in EtOAc and the organic layer was washed with water and NaHCO3sat. The desired product was obtained with good purity after drying the organic layer (MgSO4) and evaporation of EtOAc. General procedure J

[0075] N-(2-Hydroxyethyl)-N-methylbenzamide (1.2 equiv), naphtol derivative (1 equiv) and 25 triphenylphosphine (1.5 equiv) were solubulized in 10 mL of THF. The solution was cooled to 0°C and DIAD (2 equiv) was added dropwise and the mixture was stirred at rt overnight. Solvent was removed under reduced pressure. The resulting residue was dissolved in 50 mL of EtOAc. The organic layer was washed with a 1N NaOH solution, brine, dried over MgSO4, filtered and evaporated. Product was purified by flash column chromatography (10-60 % EtOAc in cyclohexane) to give the 30 final product. General procedure M

[0076] To a sealed tube were added the corresponding boronic acid (1.5 equiv), compound 38 (1 equiv), and Cs2CO3 (1.1 equiv) in a toluene / MeOH mixture (4:1). The suspension was stirred and degassed under nitrogen for 5 minutes, then Pd(PPh3)4 (0.1 equiv) was added. The reaction mixture 35 was stirred at 100^°C for 16 h. The solvent was then removed under reduced pressure, and the residue was dissolved in DCM. The organic phase was then washed with water, dried over MgSO4,-22- filtered, and concentrated. The crude product was purified by flash column chromatography (0-10% MeOH in DCM) to afford the desired compound.

[0077] Synthesis 5 10 15 20(Int4). To a solution of 1,2-dibromoethane (4.8 mL, 56.1 mmol) and K2CO3 (3.1 g, 22.4 mmol) in ACN (80 mL), was added, dropwise, a solution of methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (2.0 g, 11.2 mmol) in ACN (20 mL). The resulting mixture was refluxed for 30 h. K2CO3 was then filtered and ACN removed under reduced pressure. The residue was triturated in cyclohexane and filtered to give 25 a pale yellow powder (2.65 g, 83 %).1H NMR (300 MHz, CDCl3) δ 3.72 (s, 3H), 3.82 (t, J = 5.4 Hz, 2H), 4.38 (t, J = 5.4 Hz, 2H), 6.55 (d, J = 16.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 16.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H). LC-MS (ESI) m / z [M+H]+= 286.1.-23-Methyl (2E)-3-{4-[2-(piperidin-1- yl)ethoxy]phenyl}prop-2-enoate (Int5). A solution of methyl (2E)-3-[4-(2- bromoethoxy)phenyl]prop-2-enoate (Int4, 0.20 g, 0.70 mmol) and piperidine (0.21 mL, 2.1 mmol) in 10 mL of ACN was refluxed overnight. The resulting mixture was filtered and ACN was removed 5 under reduced pressure. The crude was purified by flash column chromatography (0-5% EtOAc in cyclohexane) to give the product as a white powder (30 mg, 15%).1H NMR (300 MHz, CDCl3) δ 1.48 (m, 2H), 1.64 (m, 4H), 2,55 (m, 4H), 2.82 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 4.16 (t, J = 6.0 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 16.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 24.0, 25.7, 51.6, 55.0, 57.7, 66.0, 114.9, 115.3, 127.2, 129.7, 144.5, 10 160.6, 167.7. LC-MS (ESI) m / z [M+H]+= 290.4.Methyl (2E)-3-{4-[2-(1H-imidazol-1- yl)ethoxy]phenyl}prop-2-enoate (4). Compound 4 was prepared according to general procedure B using imidazole (48 mg, 0.70 mmol) as starting material. 4 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a white powder (83 mg, 43%).1H NMR (300 15 MHz, CDCl3) δ 3.78 (s, 3H), 4.23 (t, J = 6.0 Hz, 2H), 4.34 (t, J = 6.0 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.04 (m, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7,59 (s, 1H), 7.61 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 46.3, 51.6, 67.3, 114.8, 115.9, 119.3, 127.9, 129.6, 127.8, 137.5, 144.1, 159.6. LC-MS (ESI) m / z [M+H]+= 273.30.Methyl (2E)-3-{4-[2-(1H-pyrazol-1- 20 yl)ethoxy]phenyl}prop-2-enoate (5). Compound 5 was prepared according to general procedure B using 1H-pyrazole (48 mg, 0.70 mmol) as starting material. 5 was purified by flash column chromatography (5-30% EtOAc in cyclohexane) and isolated as a white powder (49 mg, 26%).1H NMR (300 MHz, CDCl3) δ 3.81 (s, 3H), 4.38 (t, J = 6.0 Hz, 2H), 4.56 (t, J = 6,0 Hz, 2H), 6.28 (t, J = 2.1 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 25 1.6 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 46.3, 51.6, 67.3, 114.8, 115.9, 119.3, 127.9, 129.6, 127.8, 137.5, 144.1, 159.6. LC-MS (ESI) m / z [M+H]+= 273.3.-24-Methyl (2E)-3-{4-[2- (phenylamino)ethoxy]phenyl}prop-2-enoate (6). Compound 6 was prepared according to general procedure B using aniline (64 µL, 0.70 mmol) as starting material and potassium iodide (233 mg, 1.40 mmol). 6 was purified by flash column chromatography (5-20% EtOAc in cyclohexane) and 5 isolated as a white powder (42 mg, 20%).1H NMR (300 MHz, CDCl3) δ 3.58 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 4.22 (t, J = 6.0 Hz, 2H), 6.33 (d, J = 16.0 Hz, 1H), 6.70 (m, 2H), 6.77 (t, J =7.3 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.23 (m, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3): δ 43.2, 51.6, 66.6, 113.2, 114.9, 115.5, 118.02, 127.5, 129.4, 129.8, 144.4, 147.7, 160.4, 167.7. LC-MS (ESI) m / z [M+H]+= 298.3. 10Methyl (2E)-3-{4-[2-(1H-1,3-benzodiazol-1- yl)ethoxy]phenyl}prop-2-enoate (10). Compound 10 was prepared according to general procedure B using 1H-benzo[d]imidazole (83 mg, 0.70 mmol) as starting material. 10 was purified by flash column chromatography (1-5% EtOAc in cyclohexane) and isolated as a white powder (100 mg, 43%).1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.34 (t, J = 6.0 Hz, 2H), 460 (t, J = 6.0 Hz, 2H), 6.31 15 (d, J = 16.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.33 (m, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.49 (m, 1H), 7.63 (d, J = 16.0 Hz, 1H), 7.84 (m, 1H), 8.05 (s, 1H).13C NMR (75 MHz, CDCl3) δ 44.3, 51.6, 66.2, 109.4, 114.8, 115.9, 120.6, 122.3, 123.1, 128.0, 129.7, 133.7, 143.5, 143.8, 144.1, 159.5, 167.6. LC- MS (ESI) m / z [M+H]+= 323.4.Methyl (2E)-3-{4-[2-(2,3-dihydro-1H-indol-1- 20 yl)ethoxy]phenyl}prop-2-enoate (8). Compound 8 was prepared according to general procedure B using indoline (80 µL, 0.70 mmol) as starting material and potassium iodide (233 mg, 1.40 mmol).8 was purified by flash column chromatography (1-5% EtOAc in cyclohexane) and isolated as a light brown oil (76 mg, 34%).1H NMR (300 MHz, CDCl3) δ 3.02 (t, J = 8.3 Hz, 2H), 3.54 (m, 4H), 3.82 (s, 3H), 4.24 (t, J = 6.0 Hz, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 6.69 (m, 1H), 6.94 25 (d, J = 8.8 Hz, 2H), 7.10 (m, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 28.7, 48.7, 51.6, 54.1, 66.4, 106.7, 114.9, 115.4, 117.8, 124.6, 127.3, 129.7, 144.5, 152.1, 160.5, 167.8. LC-MS (ESI) m / z [M+H]+= 324.4.-25-Methyl (2E)-3-{4-[2-(1H-indol-1- yl)ethoxy]phenyl}prop-2-enoate (11). Compound 11 was prepared according to general procedure B using indole (82 mg, 0.70 mmol) as starting material. NaH (0.84 mmol, 34 mg) was used in place of K2CO3. 11 was purified by flash column chromatography (1-20% EtOAc in cyclohexane) and 5 isolated as a white powder (65 mg, 29%).1H NMR (300 MHz, CDCl3): δ 3.81 (s, 3H), 4.33 (t, J = 5.6 Hz, 2H), 4.57 (t, J = 5.6 Hz, 2H), 6.31 (d, J = 16.0 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.12 (m, 1H), 7.25 (m, 2H) 7.43 (m, 3H), 7.66 (m, 2H).13C NMR (75 MHz, CDCl3) δ 45.6, 51.6, 66.9, 101.8, 109.1, 114.8, 115.0, 115.6, 115.6, 119.6, 121.1, 121.7, 127.6, 128.3, 128.7, 129.7, 136.0, 144.3, 160.0, 167.7. LC-MS (ESI) m / z [M+H]+= 322.4. 10Methyl (2E)-3-[4-(2-{1H-pyrrolo[2,3-b]pyridin-1- yl}ethoxy)phenyl]prop-2-enoate (12). Compound 12 was prepared according to general procedure B using 7-azaindole (83 mg, 0.70 mmol) as starting material. NaH (0.84 mmol, 34 mg) was used in place of K2CO3.12 was purified by flash column chromatography (1-20% EtOAc in cyclohexane) and isolated as a white powder (60 mg, 27%).1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.39 (t, J = 5.2 15 Hz, 2H), 4.73 (t, J = 5.2 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.09 (dd, J = 7.8, 4.2 Hz, 1H), 7.39 (d, J = 3.5 Hz, 1H) 7.45 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1H), 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 8.34 (dd, J = 4.2, 1.6 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 43.9, 51.6, 67.1, 99.7, 114.9, 115.5, 115.9, 120.8, 127.5, 128.9, 129.0, 129.7, 142.7, 144.3, 147.3, 160.1, 167.6. LC-MS (ESI) m / z [M+H]+= 323.4. 20Methyl (2E)-3-{4-[2- (dimethylamino)ethoxy]phenyl}prop-2-enoate (54). Compound 54 was prepared according to general procedure B using dimethylamine, HCl (86 mg, 1.0 mmol) as starting material. 54 was purified by flash column chromatography (1-10% MeOH in DCM) and isolated as a white powder (70 mg, 40%).1H NMR (300 MHz, CDCl3) δ 2.36 (s, 6H), 2.77 (t, J = 5.4 Hz, 2H), 3.80 (s, 3H), 4.11 (t, J 25 = 5.4 Hz, 2H), 6.31 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 16.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H). NMR13C (75 MHz, CDCl3) δ 45.8, 51.6, 58.1, 66.0, 114.9, 115.3, 127.2, 129.7, 144.5, 160.6, 167.7. LC-MS (ESI) m / z [M+H]+= 250.3.-26-Methyl (2E)-3-(4-{2- [benzyl(methyl)amino]ethoxy}phenyl)prop-2-enoate (14). Compound 14 was prepared according to general procedure B using N-methylbenzylamine (0.11 mL, 0.84 mmol) as starting material.14 was purified by flash column chromatography (1-20% EtOAc in cyclohexane) and isolated as a 5 colorless oil (180 mg, 80%).1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.87 (t, J = 5.8 Hz, 2H), 3.66 (s, 2H), 3.82 (s, 3H) 414 (t, J = 5.8 Hz, 2H), 6.33 (d, J = 16.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.35 (m, 5H), 7.47 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 43.0, 51.6, 55.6, 62.7, 66.4, 114.9, 115.2, 127.1, 127.2, 128.3, 129.1, 129.7, 144.5, 160.6, 167.8. LC-MS (ESI) m / z [M+H]+= 326.4. 10Methyl (2E)-3-{4-[2-(1,2,3,4-tetrahydroquinolin- 1-yl)ethoxy]phenyl}prop-2-enoate (9). Compound 9 was prepared according to general procedure C starting from 1-(2-bromoethyl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.83 mmol) and methyl (2E)- 3-(4-hydroxyphenyl)prop-2-enoate (148 mg, 0.83 mmol).9 was obtained as a white powder (80 mg, 28%) after trituration in PE.1H NMR (300 MHz, CDCl3) δ 1.98 (qt, J = 6.0 Hz, 2H), 2.79 (t, J = 6.3 15 Hz, 2H), 3.45 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 6,0 Hz, 2H), 6.34 (s, 3H), 4.20 (t, J = 6.0 Hz, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.62 (m, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.99 (m, 1H), 7.09 (m, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 16.0 Hz, 1H). NMR13C (75 MHz, CDCl3) δ 22.2, 28.1, 50.6, 51.6, 65.1, 110.3, 114.9, 115.4, 116.0, 122.5, 127.1, 127.3, 129.4, 129.7, 144.5, 144.8, 160.6, 167.7. LC-MS (ESI) m / z [M+H]+= 338.4. 20Methyl 4-(4-{2- [methyl(phenyl)amino]ethoxy}phenyl)butanoate (55). Compound 55 was prepared according to general procedure C starting from N-(2-bromoethyl)-N-methylaniline (109 mg, 0.51 mmol) and methyl 4-(4-hydroxyphenyl)butanoate (111 mg, 0.51 mmol). 55 was purified by flash column chromatography (1-10% EtOAc in cyclohexane) and isolated as a colorless oil (20 mg, 12%).1H NMR 25 (400 MHz, MeOD) δ 7.19 (t, J = 8.0 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.81 (m, 4H), 6.67 (t, J = 7.3 Hz, 1H), 4.13 (t, J = 5.7 Hz, 2H), 3.74 (t, J = 5.7 Hz, 2H), 3.65 (s, 3H), 3.03 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.89 (qt, J = 7.5 Hz, 2H).13C NMR (100 MHz, MeOD) δ 26.6, 32.6, 33.7, 38.0, 50.6, 51.7, 65.3, 112.2 (2C), 114.1 (2C), 116.2, 128.7 (2C), 129.0 (2C), 133.6, 149.3, 157.2, 174.6. LC-MS (ESI) m / z [M+H]+= 328.2.-27-Methyl 3-(4-{2- [methyl(phenyl)amino]ethoxy}phenyl)propanoate (56). Compound 56 was prepared according to general procedure C starting from N-(2-bromoethyl)-N-methylaniline (250 mg, 1.17 mmol) and methyl 3-(4-hydroxyphenyl)propionate (210 mg, 1.17 mmol). 56 was purified by flash column 5 chromatography (20-60% EtOAc in cyclohexane) and isolated as a white powder (278 mg, 76%). NMR1H (300 MHz, CDCl3) δ 2.62 (t, J = 7.5 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 3.08 (s, 3H), 3.68 (s, 3H), 3.78 (t, J = 6.1 Hz, 2H), 4.14 (t, J = 6.1 Hz, 2H), 6.72-6.85 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 7.30 (m, 2H).13C NMR (75 MHz, CDCl3) δ 30.1, 36.0, 39.1, 51.6, 51.9, 65.2, 112.1 (2C), 114.5 (2C), 116.5, 129.3 (4C), 132.8, 148.9, 157.2, 173.4. LC-MS (ESI) m / z [M+H]+= 314.1. 10Methyl 2-(4-{2- [methyl(phenyl)amino]ethoxy}phenyl)acetate (57). Compound 57 was prepared according to general procedure C starting from N-(2-bromoethyl)-N-methylaniline (386.5 mg, 1.80 mmol) and 4- hydroxyphenylacetate (300 mg, 1.80 mmol).57 was purified by flash column chromatography (5- 20% EtOAc in cyclohexane) and isolated as a bright yellow oil (461 mg, 85 %).1H NMR (300 MHz, 15 CDCl3) δ 3.07 (s, 3H), 3.58 (s, 2H), 3.70 (s, 3H), 3.78 (t, J = 6.1 Hz, 2H), 4.14 (t, J = 6.1 Hz, 2H), 6.76 (m, 3H), 6.86 (d, J = 8.5 Hz,2H), 7.20 (d, J = 8.5 Hz, 2H), 7.27 (m, 2H).13C NMR (75 MHz, DMSO-d6) δ 39.2, 40.3, 51.9, 52.0, 65.2, 112.1, 114.6 (3C), 116.5, 126.3, 129.3 (2C), 130.3 (3C), 157.9, 172.3. LC-MS (ESI) m / z [M+H]+= 300.3.Methyl (2E)-3-(4-{2- 20 [methyl(phenyl)amino]ethoxy}phenyl)prop-2-enoate (3). Compound 3 was prepared according to general procedure C starting from N-(2-bromoethyl)-N-methylaniline (250 mg, 1.17 mmol) and methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (208 mg, 1.17 mmol).3 was purified by flash column chromatography (20-60% EtOAc in cyclohexane) and isolated as a white powder (294 mg, 81%). NMR1H (300 MHz, CDCl3) δ 3.08 (s, 3H), 3.80 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 4.19 (t, J = 6.0 Hz, 25 2H), 6.37 (d, J = 16.0 Hz, 1H), 6.74-6.81 (m, 3H), 6.92 (d, J = 8.7 Hz, 2H), 7.29 (m, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 16.0 Hz, 1H). NMR13C (75 MHz, CDCl3) δ 39.2, 51.6, 51.8, 65.5, 112.2 (2C), 114.9 (2C), 115.4, 116.7, 127.3, 129.3 (2C), 129.7 (2C), 144.5, 148.8, 160.5, 167.7. LC-MS (ESI) m / z [M+H]+= 312.2.-28-Methyl (2E)-3-(4-(3- (methyl(phenyl)amino)propoxy)phenyl)prop-2-enoate (13). Compound 13 was prepared according to general procedure C starting from N-(3-bromopropyl)-N-methylaniline (250 mg, 1.10 mmol) and methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (195 mg, 1.10 mmol).13 was purified by 5 flash column chromatography (1-10% EtOAc in cyclohexane) and isolated as a colorless oil (290 mg, 81%). NMR1H (300 MHz, CDCl3) δ 2.11 (qt, J = 6.0 Hz, 2H), 2.98 (s, 3H), 3.59 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 4.07 (t, J = 6.0 Hz, 2H), 6.37 (d, J = 16.0 Hz, 1H), 6.71-6.79 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H), 7.29 (m, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 16.0 Hz, 1H). NMR13C (75 MHz, CDCl3) δ 26.8, 38.6, 49.3, 51.6, 65.5, 112.1 (2C), 114.9 (2C), 115.4, 116.3, 127.2, 129.3 (2C), 129.8 (2C), 10 144.5, 149.2, 160.7, 167.8. LC-MS (ESI) m / z [M+H]+= 326.1.

[0098] tert-Butyl N-(2-hydroxyethyl)carbamate (Int6). Compound Int6 was prepared according to general procedure D starting from ethanolamine (4 mL, 66.6 mmol). Int6 was obtained as a colorless oil (10.7 g, 100%).1H NMR (300 MHz, DMSO-d6) δ 1.47 (s, 9H), 3.31 (q, J = 5.5 Hz, 2H), 3.72 (q, J = 5.2 Hz, 2H), 4.97 (s, 1H). LC-MS (ESI) m / z [M+H]+= 105.2. 15 20butoxy)carbonyl]amino}ethoxy)phenyl]prop-2-enoate (58). Compound 58 was prepared according to general procedure E starting from tert-butyl N-(2-hydroxyethyl)carbamate (1.8 g, 11.4 mmol) and methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (1.7 g, 9.5 mmol).58 was purified by flash column chromatography (1-20% EtOAc in cyclohexane) and isolated as a colorless oil (2.0 g, 65%). 251H NMR (300 MHz, DMSO-d6) δ 1.48 (s, 9H), 3.63 (m, 2H), 3.82 (s, 3H), 4.14 (m, 2H), 5.00 (s, 1H), 6.33 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H). LC-MS (ESI) m / z [M+H]+= 266.4.-29-Methyl (2E)-3-[4-(2-{[(tert- butoxy)carbonyl](methyl)amino}ethoxy)phenyl]prop-2-enoate (59). Compound 59 was prepared according to general procedure E starting from tert-butyl N-(2-hydroxyethyl)-N- methylcarbamate (3.5 g, 20.2 mmol) and methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (3 g, 16.8 5 mmol).59 was purified by flash column chromatography (1-20% EtOAc in cyclohexane) and isolated as a colorless oil (2.9 g, 51%).1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.00 (s, 3H), 3.63 (m, 2H), 3.82 (s, 3H), 4.14 (m, 2H), 6.33 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H). LC-MS (ESI) m / z [M+H]+= 277.4.Methyl (2E)-3-[4-(2-aminoethoxy)phenyl]prop-2- 10 enoate hydrochloride (60). Compound 60 was prepared according to general procedure E starting from methyl (2E)-3-[4-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)phenyl]prop-2-enoate (2 g, 6.22 mmol).60 was isolated as a white powder (1,5 g, 95%).1H NMR (300 MHz, DMSO-d6) δ 3.40 (t, J = 4.7 Hz, 2H), 3.80 (s, 3H), 4.29 (t, J = 5.1 Hz, 2H), 6.44 (d, J = 16.0 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 16.0 Hz, 1H). LC-MS (ESI) m / z [M+H]+= 222.0. 15Methyl (2E)-3-{4-[2- (methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61). Compound 61 was prepared according to general procedure E starting from methyl (2E)-3-[4-(2-{[(tert- butoxy)carbonyl](methyl)amino}ethoxy)phenyl]prop-2-enoate (2.5 g, 7.4 mmol).61 was isolated as a white powder (1.9 g, 92%).1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 3.00 (t, J = 6.0 Hz,2H), 3.80 20 (s, 3H), 4.11 (t, J = 6.0 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H). LC-MS (ESI) m / z [M+H]+= 236.1(2E)-3-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}phenyl)prop-2-enoate (2). A solution of 2-bromopyridine (68 µL, 0.71 mmol), methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate (200 mg, 0.85 mmol), potassium 25 tert-butoxide (111 mg, 1.0 mmol), 1,3-bis(diphenylphosphino)propane (11.7 mg, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.01 mmol) in 10 ml of toluene was stirred-30- overnight under a nitrogen atmosphere. The resulting mixture was cooled to rt and tolene was removed under reduced pressure.2 was purified by flash column chromatography (5-20% EtOAc in cyclohexane) and isolated as a white solid (19 mg, 9%).1H NMR (300 MHz, CDCl3) δ 3.16 (s, 3H), 3.81 (s, 3H), 4.02 (t, J = 6.0 Hz, 2H), 4.25 (t, J = 6.0 Hz, 3H), 6.32 (d, J = 16.0 Hz, 1H), 6.56 (m, 2H), 5 6.92 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.48 (m, 1H), 7.64 (d, J = 16.0 Hz, 1H), 8.18 (d, J = 3.5 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 37.9, 49.4, 51.6, 66.5, 105.7, 111.8, 114.8, 115.2, 127.1, 129.7, 132.2, 137.3, 144.5, 147.9, 158.3, 160.7, 167.7. LC-MS (ESI) m / z [M+H]+= 313.4.Methyl (E)-3-(4-(2-(isoquinolin-1- yl(methyl)amino)ethoxy)phenyl)prop-2-enoate (7). A solution of 1-chloroisoquinoline (417 mg, 2.5 10 mmol) and methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 200 mg, 0.85 mmol) in DMF (3 mL) was stirred at 120°C during 48 h. After cooling to rt, the reaction medium was concentrated and water was added. The aqueous layer was extracted twice with DCM. Combined organic layers were washed with brine, dried over MgSO4 and evaporated.7 was purified by flash column chromatography (5-20% EtOAc in cyclohexane) and isolated as a colorless oil (20 15 mg, 6%).1H NMR (300 MHz, CDCl3) δ 3.22 (s, 3H), 3.82 (s, 3H), 3.90 (t, , J = 5.7 Hz 2H), 4.35 (t, J = 5.7 Hz, 2H), 6.32 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 5.7 Hz, 1H), 7.53 (m, 3H), 7.62 (m, 2H), 7.75 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 5.7 Hz, 1H) 8.24 (d, J = 8.1 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 41.6, 51.6, 50.7, 66.1, 115.0, 115.3, 115.4, 121.7, 125.8, 125.9, 127.0, 127.2, 129.6, 129.7, 138.4, 140.3, 144.5, 160.6, 161.3, 167.8. LC-MS (ESI) m / z [M+H]+= 363,1. 20Methyl (2E)-3-{4-[2- (phenylformamido)ethoxy]phenyl}prop-2-enoate (19). Compound 19 was prepared according to general procedure G starting from benzoyl chloride (170 µL, 1.42 mmol) and methyl (2E)-3-[4-(2- aminoethoxy)phenyl]prop-2-enoate hydrochloride (60, 366 mg, 1.42 mmol).19 was triturated in Et2O to give a white powder (261 mg, 56%).1H NMR (300 MHz, DMSO-d6) δ 3.82 (s, 3H), 3.92 (q, J = 5.5 25 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.59 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.49 (m, 5H), 7.67 (d, J = 16.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H).13C NMR (300 MHz, DMSO-d6) δ 39.2, 51.8, 66.2, 115.3 (2C), 115.6, 127.2, 127.7 (2C), 128.7 (2C), 130.6 (2C), 131.7, 134.7, 144.8, 160.8, 167.0, 167.4. LC-MS (ESI) m / z [M+H]+= 326.4.-31-Methyl (2E)-3-{4-[2-(N-methyl-1- phenylformamido)ethoxy]phenyl}prop-2-enoate (15). Compound 15 was prepared according to general procedure G starting from benzoyl chloride (86 µL, 0.74 mmol) and methyl (2E)-3-{4-[2- (methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 200 mg, 0.74 mmol).15 was purified 5 by flash column chromatography (5-20% EtOAc in cyclohexane) and isolated as a white powder (200 mg, 80%).1H NMR (300 MHz, CDCl3) δ 3.02 (s, 3H), 3.73 (m, 5H), 4.24 (t, J = 5.6 Hz, 2H), 6.43 (d, J = 16.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 7.41 (m, 5H), 7.63 (m, 3H).13C NMR (125 MHz, CDCl3) δ 29.7, 31.9, 33.5, 39.7, 47.6, 50.2, 51.6, 65.2, 66.5, 114.8, 115.5, 115.7, 127.0 (2C), 127.4, 127.7, 128.4, 129.5, 129.7, 129.8 (2C), 136.1, 136.4, 144.4, 159.9, 160.4, 167.7, 171.7, 172.5. LC-MS (ESI) 10 m / z [M+H]+= 340.1.Methyl (2E)-3-(4-{2-[1-(2-chlorophenyl)-N- methylformamido]ethoxy}phenyl)prop-2-enoate (23). Compound 23 was prepared according to general procedure G starting from 2-chlorobenzoyl chloride (129 mg, 0.74 mmol) and methyl (2E)-3- {4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 200 mg, 0.74 mmol). 23 was 15 purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a white powder (240 mg, 87%).1H NMR (300 MHz, DMSO-d6) δ 2.88 (s, 1.6H), 3.08 (s, 1.4H), 3.48 (t, J = 5.3 Hz, 1H), 3.71 (s, 3H), 3.88 (m, 1H), 4.10 (m, 1H), 4.30 (t, J = 5.3 Hz, 1H), 6.48 (d, J = 4.2 Hz, 0.5H), 6.53 (d, J = 4.2 Hz, 0.5H), 6.91 (d, J = 8.8 Hz, 0.9H), 7.04 (d, J = 8.8 Hz, 1.1H), 7.32-7.53 (m, 4H), 7.58- 7.66 (m, 2H), 7.70 (d, J = 8.8 Hz, 1H).13C NMR (75 MHz, DMSO-d6) δ 15.6, 32.6, 37.4, 46.2, 49.3, 20 51.8, 65.1, 65.4, 65.8, 115.2, 115.4, 115.7, 115.7, 127.3, 127.4, 127.8, 128.1, 128.2, 129.1, 129.4, 129.6, 129.7, 129.8, 130.6, 130.7, 130.8, 130.9, 136.4, 136.7, 144.7, 144.7, 160.3, 160.7, 167.4, 167.4, 167.9, 167.9. LC-MS (ESI) m / z [M+H]+= 374.8, 376.8.Methyl (2E)-3-(4-{2-[1-(3-chlorophenyl)-N- methylformamido]ethoxy}phenyl)prop-2-enoate (24). Compound 24 was prepared according to25 general procedure G starting from 3-chlorobenzoyl chloride (95 µL, 0.74 mmol) and methyl (2E)-3- {4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 200 mg, 0.74 mmol). 24 was purified by flash column chromatography (20-50% EtOAc in cyclohexane) and isolated as a white powder (173 mg, 63%).1H NMR (300 MHz, CDCl3) δ 3.14 (brs, 3H), 3.72 (brs, 0.7H), 3.82 (s, 3H), 3.95 (brs, 1.3H), 4.08 (brs, 0.7H), 4.34 (brs, 1.3H), 6.34 (d, J = 16.0 Hz, 1H), 6.91 (m, 2H), 7.39-7.43-32- (m, 4H), 7.50 (m, 2H), 7.67 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 33.2, 39.6, 47.7, 50.2, 51.6, 64.8, 66.5, 114.8, 115.6, 125.1, 127.2, 127.6, 129.8, 134.5, 137.8, 144.3, 160.3, 167.7, 170.1. LC-MS (ESI) m / z [M+H]+= 374.8, 376.8.Methyl (2E)-3-(4-{2-[1-(4-chlorophenyl)-N- 5 methylformamido]ethoxy}phenyl)prop-2-enoate (25). Compound 25 was prepared according to general procedure H starting from 4-chlorobenzoic acid (121 mg, 0.77 mmol) and methyl (2E)-3-{4- [2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 140 mg, 0.52 mmol). 25 was triturated in Et2O to give a white powder (60 mg, 31%).1H NMR (300 MHz, CDCl3) δ 3.02 (m, 3H), 3.62 (brs, 1H), 3.72 (s, 3H), 3.84 (brs, 1H), 4.14 (brs, 1H), 4.30 (brs, 1H), 6.51 (d, J = 16.0 Hz, 1H), 10 6.99 (m, 2H), 7.47 (m, 4H), 7.62-7.69 (m, 3H).13C NMR (75 MHz, CDCl3) δ 32.9, 38.8, 46.8, 50.0, 51.8, 65.1, 65.8, 115.3, 115.4, 115.7, 127.4, 128.9, 129.3, 130.6, 130.7, 134.2, 134.6, 135.6, 135.9, 144.7, 160.3, 160.7, 167.4, 169.8, 170.6. LC-MS (ESI) m / z [M+H]+= 374.8, 376.8.Methyl (2E)-3-(4-{2-[1-(4-fluorophenyl)-N- methylformamido]ethoxy}phenyl)prop-2-enoate (22). Compound 22 was prepared according to15 general procedure H starting from 4-fluorobenzoic acid (77 mg, 0.55 mmol) and methyl (2E)-3-{4-[2- (methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 100 mg, 0.37 mmol).22 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a white powder (91 mg, 69%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.00 (s, 3H), 3.73 (m, 5H), 4.24 (m, 2H), 6.45 (d, J = 16.0 Hz, 1H), 6.99 (d, 2H), 7.22 (m, 2H), 7.45 (m, 2H), 7.61 (m, 3H).13C NMR (75 MHz, DMSO-d6) 20 δ 33.0, 38.9, 46.8, 50.0, 51.8, 65.1, 65.8, 115.3, 115.6, 115.7, 115.8, 127.3, 129.8, 129.9, 130.6, 133.2, 144.7, 160.4, 161.2, 164.4, 167.4, 169.9, 170.8. LC-MS (ESI) m / z [M+H]+= 358.4.Methyl (2E)-3-(4-{2-[1-(4- methoxyphenyl)-N-methylformamido]ethoxy}phenyl)prop-2-enoate (21). Compound 21 was prepared according to general procedure H starting from 4-methoxybenzoic acid (84 mg, 0.55 mmol) 25 and methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 100 mg, 0.37 mmol).21 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a white powder (115 mg, 85%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.00 (s, 3H), 3.73 (m, 5H), 3.8 (s, 3H), 4.24 (t, J = 5.5 Hz, 2H), 6.45 (d, J = 16.0 Hz, 1H), 6.96 (m, 4H), 7.36 (d, J = 8.7 Hz, 2H), 7.60-33- (m, 2H).13C NMR (75 MHz, DMSO-d6) δ 33.2, 47.1, 50.0, 51.8, 55.6, 65.6, 112.0, 115.3, 115.7, 127.3, 128.9, 129.3, 130.6, 144.7, 160.4, 160.6, 167.4. LC-MS (ESI) m / z [M+H]+= 370.4.Methyl (2E)-3-(4-{2-[(pyridin-3- yl)formamido]ethoxy}phenyl)prop-2-enoate (20). Compound 20 was prepared according to 5 general procedure H starting from nicotinic acid (95 mg, 0.78 mmol) and methyl (2E)-3-[4-(2- aminoethoxy)phenyl]prop-2-enoate hydrochloride (60, 200 mg, 0.74 mmol).20 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a yellow powder (100 mg, 20%).1H NMR (300 MHz, CDCl3) δ 3.82 (s, H1), 3.92 (q, J = 5.5 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.62 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.42 (m, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.67 (d, J 10 = 16.0 Hz, 1H), 8.14 (td, J = 8.0, 2.0 Hz, 1H) 8.77 (dd, J = 4.8, 1.7 Hz, 1H), 9.2 (d, J = 1.9 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 39.5, 51.6, 66.7, 114.8, 115.8, 123.6, 129.8, 135.1, 144.2, 147.9, 152.5, 160.1, 165.8, 167.6. LC-MS (ESI) m / z [M+H]+= 327.3.Methyl (2E)-3-(4-{2-[N-methyl-1-(pyridin-4- yl)formamido]ethoxy}phenyl)prop-2-enoate (18). Compound 18 was prepared according to15 general procedure H starting from isonicotinic acid (102 mg, 0.83 mmol) and methyl (2E)-3-{4-[2- (methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 150 mg, 0.55 mmol).18 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a yellow powder (119 mg, 63%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.02 (s, 3H), 3.73 (m, 5H), 4.24 (brs, 2H), 6.44 (d, J = 16.0 Hz, 1H), 7.0 (d, J = 7.4 Hz, 2H), 7.35 (d, J = 6.0 Hz, 2H), 7.61 (m, 3H), 8.64 (d, J = 6.0 Hz, 2H). 2013C NMR (75 MHz, DMSO-d6) δ 32.7, 38.4, 46.5, 49.8, 51.8, 64.9, 65.7, 115.2, 115.4, 115.8, 121.5, 121.8, 127.4, 130.6, 130.7, 144.2, 144.5, 144.7, 150.3, 150.5, 160.3, 160.6, 167.4, 168.7, 169.4. LC- MS (ESI) m / z [M+H]+= 341.4.Methyl (2E)-3-(4-{2-[N-methyl-1-(pyridin-3- yl)formamido]ethoxy}phenyl)prop-2-enoate (17). Compound 17 was prepared according to25 general procedure H starting from nicotinic acid (102 mg, 0.83 mmol) and methyl (2E)-3-{4-[2- (methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 150 mg, 0.55 mmol).17 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a yellow oil (138 mg, 73%). NMR1H (300 MHz, DMSO-d6, 80°C) δ 3.05 (s, 3H), 3.73 (s, 3H), 3.75 (m, 2H), 4.24 (m, 2H), 6.44 (d, J = 15.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 7.44 (ddd, J = 7.8, 4.9, 0.8 Hz, 1H), 7.61 (m, 3H), 7.80 (td,-34- J =7.8, 2.0 Hz, 1H), 8.62 (m, 2H).13C NMR (75 MHz, DMSO-d6) δ 32.9, 38.8, 46.8, 50.1, 51.8, 65.0, 65.7, 115.2, 115.4, 115.7, 123.9, 127.4, 130.6, 130.3, 133.0, 135.2, 144.7, 147.9, 150.4, 150.8, 160.3, 160.7, 167.4, 168.6, 169.4. LC-MS (ESI) m / z [M+H]+= 341.4.Methyl (2E)-3-(4-{2-[N-methyl-1-(pyridin-2- 5 yl)formamido]ethoxy}phenyl)prop-2-enoate (16). Compound 16 was prepared according to general procedure H starting from picolinic acid (102 mg, 0.83 mmol) and methyl (2E)-3-{4-[2- (methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (61, 150 mg, 0.55 mmol).16 was purified by flash column chromatography (0-10% MeOH in DCM) and isolated as a yellow powder (100 mg, 53%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.05 (s, 3H), 3.73 (s, 3H), 3.75 (m, 2H), 4.24 (m, 2H), 10 6.44 (d, J = 15.0 Hz, 1H), 6.99 (m, 2H), 7.43 (m, 1H), 7.60 (m, 4H), 7.88 (t, J = 7.3 Hz, 1H), 8.56 (s, 1H).13C NMR (75 MHz, DMSO-d6) δ 33.9, 38.3, 47.0, 49.5, 51.8, 65.8, 65.9, 115.2, 115.4, 115.7, 123.3, 124.0, 124.9, 125.0, 127.2, 127.3, 130.5, 130.7, 137.7, 137.8, 144.7, 148.4, 148.7, 154.7, 154.8, 160.3, 160.6, 167.4, 168.8, 169.3. LC-MS (ESI) m / z [M+H]+= 341.4.Methyl (2E)-3-{4-[2-(N- 15 methylacetamido)ethoxy]phenyl}prop-2-enoate (62). Compound 62 was prepared according to general procedure G starting from methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (200 mg, 0.74 mmol) and acetyl chloride (0.063 mL, 0.88 mmol).62 was purified by flash column chromatography (20-50% EtOAc in cyclohexane) and isolated as a white powder (200 mg, 98%).1H NMR (500 MHz, CDCl3) δ 2.11 (s, 2.1H), 2.22 (s, 0.9H), 3.03 (s, 0.9H), 3.1 (s, 1H), 20 3.76 (m, 2H), 3.81 (s, 3H), 4.17 (m, 2H), 6.30-6.35 (2d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 16.0 Hz, 1H).13C NMR (125 MHz, CDCl3) δ 14.2, 21.1, 21.5, 21.9, 33.7, 38.3, 47.6, 49.9, 51.6, 51.7, 60.4, 65.3, 66.8, 114.7, 115.4, 115.8, 127.3, 127.8, 129.8, 129.8, 144.2, 144.4, 159.9, 160.4, 167.7, 167.8, 171.2. LC-MS (ESI) m / z [M+H]+= 278.1.Methyl (2E)-3-{4-[2-(N-25 methylpropanamido)ethoxy]phenyl}prop-2-enoate (26). Compound 26 was prepared according to general procedure H starting from methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (150 mg, 0.55 mmol) and propanoic acid (83 µL, 1.10 mmol).26 was purified by flash column chromatography (10-40% EtOAc in cyclohexane) and triturated in Et2O to give a white powder (122 mg, 76 %).1H NMR (300 MHz, CDCl3) δ 1.16 (t, J = 7.4 Hz, 3H), 2.4 (q, J = 7.4 Hz, 1H),-35- 2.49 (q, J = 7.4 Hz, 1H), 3.04 (s, 0.8H), 3.16 (s, 2.2H), 3.78 (m, 2H), 3.81 (s, 3H), 4.13 (t, J = 5.4 Hz, 0.5H), 4.19 (t, J = 5.4 Hz, 1.5H), 6.33 (m, 1H), 6.90 (m, 2H), 7.49 (m, 2H), 7.66 (d, J = 16.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 9.1, 9.6, 26.2, 26.8, 33.9, 37.4, 47.9, 48.9, 51.6, 65.4, 66.8, 114.8 (2C), 115.4, 115.8, 127.3, 129.8 (2C), 144.2, 144.4, 160.4, 167.8, 174.2. LC-MS (ESI) m / z [M+H]+= 292.2. 5Methyl (2E)-3-[4-(2-{N-methyl-1-[3-(prop-2-enamido)phenyl]formamido}ethoxy)phenyl]prop-2-enoate (29). To a stirred suspension of K2CO3 (229 mg, 1.66 mmol) in distilled water (1 mL) and acetone (10 mL) was added, at 0 °C, prop- 2-enoyl chloride (100 mg, 1.10 mmol) and methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2- enoate hydrochloride (150 mg, 0.55 mmol). Reaction medium was stirred for 1 h at 0 °C. The solvant 10 was removed under reduced pressure and the residue was taken up in water. The aqueous layer was then extracted 3 times with DCM. Combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by flash column chromatography (0-5 % MeOH in DCM) to give 29 as a white powder (144 mg, 90%).1H NMR (500 MHz, CDCl3) δ 2.96 (s, 1.5H), 3.15 (s, 1.5H), 3.71 (s, 3H), 3.72 (t, J = 5.3 Hz, 1H), 3.82 (t, J = 5.3 Hz, 1H), 4.17 (t, J = 5.3 15 Hz, 2H), 5.68 (ddd, J = 10.3, 10.2, 2.4 Hz, 1H), 6.13 (ddd, 1H, J = 16.7, 12.2, 2.5 Hz), 6.50 (d, J = 16.0 Hz, 1H), 6.81 (ddd, 1H, J = 16.7, 14.5, 10.4 Hz), 6.95 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 16.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H).13C NMR (125 MHz, CDCl3) δ 15.6, 34.3, 36.9, 47.2, 48.6, 51.8, 55.4, 65.4, 66.0, 66.2, 79.6, 115.3, 115.3, 115.7, 115.7, 127.2, 127.3, 127.4, 128.0, 128.9, 129.1, 130.7, 144.7, 144.8, 160.5, 160.6, 166.2, 167.4. LC-MS (ESI) m / z [M+H]+= 20 290.2.Methyl (2E)-3-(4-{2-[1-(3-aminophenyl)- N-methylformamido]ethoxy}phenyl)prop-2-enoate (28). Compound 28 was prepared according to general procedure H strating from methyl (2E)-3-{4-[2-(methylamino)ethoxy]phenyl}prop-2-enoate hydrochloride (300 mg, 1.10 mmol) and 3-aminobenzoic acid (227 mg, 1.66 mmol).28 was purified 25 by flash column chromatography (0-5% MeOH in DCM) and by Et2O washing to give the titled compound as a white powder (290.0 mg, 75%).1H NMR (300 MHz, CDCl3) δ 2.99 (s, 3H), 3.70 (m,2H), 3.71 (s, 3H), 4.18 (m, 2H), 5.25 (s, 2H), 6.48-6.61 (m, 4H), 6.94 (m, 1H), 7.04 (t, J = 7.7 Hz, 2H), 7.60-7.70 (m, 3H). LCMS (ESI) m / z [M+H]+= 355.2.-36-Methyl (2E)-3-[4-(2-{N-methyl-1-[3- (prop-2-enamido)phenyl]formamido}ethoxy)phenyl]prop-2-enoate (27). To a stirred suspension of K2CO3 (175 mg, 1.27 mmol) in distilled water (1 mL) and acetone (10 mL) was added, at 0 °C, prop-2-enoyl chloride (77 mg, 0.85 mmol) and methyl (2E)-3-(4-{2-[1-(3-aminophenyl)-N- 5 methylformamido]ethoxy}phenyl)prop-2-enoate (150 mg, 0.42 mmol). Reaction medium was stirred for 1 h at 0 °C. The solvant was removed under reduced pressure and the residue taken up in water. The aqueous layer was then extracted 3 times with DCM. Combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by flash column chromatography (0-5% MeOH in DCM) to give the titled compound as a colorless oil (173 mg, 100%). 101H NMR (300 MHz, CDCl3) δ 3.02 (brs, 3H), 3.63 (brs, 1H), 3.71 (s, 3H), 3.84 (brs, 1H), 4.13 (brs, 1H), 4.30 (brs, 1H), 5.79 (m, 1H), 6.28 (m, 1H), 6.39-6.53 (m, 2H), 7.01 (m, 3H), 7.38 (t, 1H, J = 7.3 Hz), 7.56-7.80 (m, 5H), 10.27 (s, 1H).13C NMR (75 MHz, CDCl3) δ 33.7, 39.6, 47.7, 50.3, 51.6, 65.4, 66.3, 114.8, 115.6, 118.7, 121.4, 122.5, 127.5, 127.9, 29.2, 129.8, 131.1, 136.5, 138.2, 144.4, 160.3, 163.8, 167.7, 171.5, 172.3. LC-MS (ESI) m / z [M+H]+= 409.3. 15N-(2-Hydroxyethyl)-N-methylbenzamide (Int8). 2- Methylaminoethanol (0.7 mL, 7.80 mmol) and triethylamine (1.5 mL, 10.7 mmol) were solubilized in 20 mL of dry DCM under nitrogen. The mixture was cooled to 0°C and benzoyl chloride (0.8 mL, 7.1 mmol) was added dropwise. After stirring for 30 min at rt, the mixture was diluted with 10 mL of DCM. The organic layer was washed with a 1N HCl solution, dried over MgSO4, filtered and evaporated to 20 give Int8 as a yellow oil (1.0 g, 80%).1H NMR (300 MHz, DMSO-d6): δ 2.95 (Brs, 1.5H), 2.98 (Brs, 1.5H), 3.28 (Brs, 1H), 3.50 (Brs, 1H), 3.50 (Brs, 1H), 3.62 (Brs, 1H), 4.79 (t, J = 5.4 Hz, 1H), 7.41 (m, 5H, HAr). LC-MS (ESI) m / z [M+H]+= 179.2.Methyl 6-hydroxynaphthalene-2-carboxylate (Int10). Int10 was obtained as a white powder (1.5 g, 71%).1H NMR (300 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.17 (Dd, J 25 = 10.9, 2.5 Hz, 1H), 7.19 (s, 1H), 7.74 (d, J = 10.9 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.88 (dd, J = 8.7, 1.6 Hz, 1H), 7.99 (s, 1H), 10.20 (Brs, 1H). LC-MS (ESI) m / z [M+H]+= 202.2.-37- [Ethyl 6-hydroxynaphthalene-2-carboxylate (Int11). Int11 was obtained as a white powder (0.78 g, 71%).1H NMR (300 MHz, CDCl3) δ 1.46 (t, J = 7.1 Hz, 3H), 4.46 (q, J = 7.5 Hz, 2H), 7.17 (dd, J = 10.9, 2.5 Hz, 1H), 7.20 (s, 1H), 7.74 (d, J = 10.9 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 8.03 (dd, J = 8.7, 1.6 Hz, 1H), 8.56 (s, 1H). LC-MS (ESI) m / z [M+H]+= 5 216.2. 10Int13 was obtained as a yellow powder (0.96 g, 79%).1H NMR (300 MHz, DMSO-d6) δ 1.36 (d, J = 5.9 Hz, 6H), 5.18 (sept, J = 6.6 Hz, 1H), 7.15 (dd, J = 10.6, 2.5 Hz, 1H), 7.18 (s, 1H) 7.78 (d, J = 8.7 Hz, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 8.46 (s, 1H), 10.18 (Brs, 1H). LC- 15 MS (ESI) m / z [M+H]+= 230.2.Methyl 6-[2-(N-methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxylate (33). Compound 33 was prepared according to general procedure J strating from methyl 6-hydroxynaphthalene-2-carboxylate (Int10, 470 mg, 2.32 mmol).33 was obtained as a white powder (358 mg, 42%).1H NMR (300 MHz, DMSO-20 d6) δ 1.39 (s, 3H), 3.05 (Brs, 3H), 3.63-3.99 (2Brs, 2H), 4.16-4.51 (2Brs, 2H), 7.17-7.59 (m, 7H), 7.81- 8.11 (m, 3H), 8.51-8.62 (m, 1H).13C NMR (75 MHz, DMSO-d6) δ 14.8, 52.3, 60.8, 66.2, 107.9, 119.9, 125.4, 127.3, 127.7, 128.0, 128.6, 129.1-130.2, 130.8, 131.5, 137.5, 167.0, 171.6. LC-MS (ESI) m / z [M+H]+= 363.3.Ethyl 6-[2-(N-methyl-1- 25 phenylformamido)ethoxy]naphthalene-2-carboxylate (35). Compound 35 was prepared-38- according to general procedure J strating from ethyl 6-hydroxynaphthalene-2-carboxylate (Int11, 480 mg, 2.22 mmol).35 was obtained as a white powder (218 mg, 26%).1H NMR (300 MHz, DMSO- d6) δ 1.37 (t, J = 7.1 Hz, 3H), 3.06 (Brs, 3H), 3.63-3.98 (2Brs, 2H), 4.20-4.48 (2Brs, 2H), 4.35 (q, J = 7.1 Hz, 2H), 7.18-7.61 (m, 7H), 7.82-8.00 (m, 2H), 8.00-8.12 (m, 1H), 8.52-8.60 (m, 1H).13C NMR 5 (75 MHz, DMSO-d6) δ 14.9, 33.1, 46.8, 49.9, 61.1, 107.4, 120.2, 125.4, 127.2, 127.7, 128.0, 128.8, 129.1-130.2, 130.8, 131.6, 136.6-137.4, 158.5, 166.3. LC-MS (ESI) m / z [M+H]+= 377.2.Propan-2-yl 6-[2-(N-methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxylate (37). Compound 37 was prepared according to general procedure J strating from propan-2-yl 6-hydroxynaphthalene-2-carboxylate 10 (Int13, 540 mg, 2.32 mmol). After flash column chromatography, 37 was triturated in 1N NaOH solution, filtered and washed with Et2O to give a white powder (47 mg, 5%).1H NMR (300 MHz, DMSO-d6) δ 1.37 (d, J = 6.4 Hz, 6H), 3.06 (Brs, 3H), 3.62-4.04 (2Brs, 2H), 4.16-4.52 (2Brs, 2H), 5.19 (sept, J = 6.4 Hz, 1H), 7.16-7.65 (m, 7H), 7.81-7.99 (m, 2H), 7.99-8.13 (m, 1H), 8.47-8.60 (m, 1H). 13C NMR (75 MHz, DMSO-d6) δ 22.3, 33.0, 46.8, 50.2, 68.6, 107.3, 120.2, 125.7, 126.0, 127.3, 127.5, 15 128.2, 128.8, 129.4-130.3, 130.6, 131.6, 136.6-137.6, 158.7, 165.9. LC-MS (ESI) m / z [M+H]+= 391.3.N-{2-[(6-Bromonaphthalen-2-yl)oxy]ethyl}-N- methylbenzamide (38). Compound 38 was prepared according to general procedure J strating from 6-bromo-2-naphthol (490 mg, 2.22 mmol). After flash column chromatography, 38 was triturated in 1N NaOH solution, filtered and washed with Et2O to give a white powder (483 mg, 58%).1H NMR 20 (300 MHz, DMSO-d6) δ 3.05 (Brs, 3H), 3.61-3.98 (2Brs, 2H), 4.15-4.43 (2Brs, 2H), 7.14-7.52 (m, 7H), 7.52-7.66 (m, 1H), 7.66-7.90 (m, 2H), 8.06-8.17 (m, 1H).13C NMR (75 MHz, DMSO-d6): δ 33.4, 46.6, 50.0, 107.3, 116.8, 120.3, 127.3, 128.7, 129.1-130.2, 130.4, 133.4, 136.6-137.5, 157.1. LC-MS (ESI) m / z [M+H]+= 384.3. [N-{2-[(6-Methoxynaphthalen-2-yl)oxy]ethyl}-N- 25 methylbenzamide (39). Compound 39 was prepared according to general procedure J strating from 6-methoxy-2-naphthol (405 mg, 2.32 mmol). After flash column chromatography, 39 was triturated in 1N NaOH solution, filtered and washed with Et2O to give a white powder (38 mg, 5%).1H NMR (300 MHz, DMSO-d6) δ 3.05 (Brs, 3H), 3.84 (s, 3H), 3.58-3.95 (2Brs, 2H), 4.11-4.39 (2Brs, 2H), 7.05-7.52 (m, 9H), 7.64-7.81 (m, 2H).13C NMR (75 MHz, DMSO-d6): δ 32.9, 46.9, 50.2, 106.6, 107.5, 119.2, 30 127.3, 128.5-130.0, 136.7, 154.9, 156.2. LC-MS (ESI) m / z [M+H]+= 335.2.-39- [N-{2-[(6-Cyanonaphthalen-2-yl)oxy]ethyl}-N- methylbenzamide (40). Compound 40 was prepared according to general procedure J strating from 6-methoxy-2-naphthol (393 mg, 2.32 mmol). After flash column chromatography, 40 was triturated in 1N NaOH solution, filtered and washed with Et2O to give a white powder (69 mg, 9%).1H NMR (300 5 MHz, DMSO-d6) δ 3.05 (Brs, 3H), 3.63-3.99 (2Brs, 2H), 4.17-4.50 (2Brs, 2H), 7.24-8.06 (m, 11H). 13C NMR (75 MHz, DMSO-d6) δ 32.9, 46.8, 46.9, 106.3, 107.5, 126.8-130.3, 130.7, 132.0, 132.6, 134.5, 136.2-139.5, 158.9, 170.9. LC-MS (ESI) m / z [M+H]+= 330.2. [6-[2-(N-Methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxylic acid (41). To a solution of 1N NaOH (10 mL,10 10.0 mmol) in MeOH (10 mL) was added methyl 6-[2-(N-methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxylate (450 mg, 1.24 mmol). The reaction was refluxed for 24 h. The solvant was removed under reduced pressure and the residue dissolved in water and acidified with 1N HCl solution (pH 2-3). The precipitate formed was filtered and dried in a desiccator to give 41 as a white powder (294 mg, 68%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.00 15 (s, 1H), 3.82 (m, 2H), 4.36 (m, 2H), 7.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.41 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 9.0, 1.9 Hz, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.53 (s, 1H).13C NMR (75 MHz, DMSO- d6) δ 32.9, 46.8, 49.9, 65.1, 65.9, 107.1, 119.9, 126.2, 127.2, 127.4, 128.0, 128.8, 129.1, 129.6, 129.7, 129.9, 130.8, 131.5, 137.0. LC-MS (ESI) m / z [M+H]+= 350.2.Propyl 6-[2-(N-methyl-1-20 phenylformamido)ethoxy]naphthalene-2-carboxylate (36). 6-[2-(N-Methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxylic acid (100 mg, 0.29 mmol) was solubilized in 10 mL of n-propanol. This solution was cooled to 0°C and SOCl2 (42 µL, 0.57 mmol) was added dropwise. The reaction mixture was stirred at rt overnight. Solvent was removed under reduced pressure. The resulting residue was dissolved in 20 mL of EtOAc. The organic layer was washed 25 with water and NaHCO3 sat. Organic layer was dried over MgSO4, filtered and evaporated under vacuum to give the final product as a white powder (61 mg, 55%).1H NMR (300 MHz, DMSO-d6) δ 1.01 (t, J = 7.4 Hz, 3H), 1.76 (sext, J = 7.1 Hz, 2H), 3.06 (Brs, 3H), 3.62-4.01 (2Brs, 2H), 4.15-4.49 (2Brs, 2H), 4.28 (t, J = 6.6 Hz, 2H) 7.17-8.17 (m, 10H), 8.56 (s, 1H).13C NMR (75 MHz, DMSO-d6) δ 11.0, 22.4, 33.4, 47.3, 50.3, 66.7, 107.4, 120.0, 125.4, 126.1, 127.7, 128.0, 128.8, 129.1-130.1, 30 130.8, 131.5, 131.7-133.2, 134.8, 158.8, 166.4. LC-MS (ESI) m / z [M+H]+= 391.4.-40-6-[2-(N-Methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxamide (42). A solution of methyl 6-[2-(N-methyl- 1-phenylformamido)ethoxy]naphthalene-2-carboxylate (33, 150 mg, 0.41 mmol) and formamide (52 µL, 1.31 mmol) in anhydrous DMF (5 mL) was heated at 100 °C under nitrogen. NaOMe (15 mg, 5 0.28 mmol) was added and stirring was continued for 48 h. The resulting mixture was cooled to room temperature and water was added. The aqueous layer was then extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by flash column chromatography (0-5% MeOH in DCM) to give the 42 as a light brown oil (43 mg, 30%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.00 (s, 1H,), 3.82 (m, 2H), 4.36 (m, 2H), 7.26 (dd, J = 10 8.9, 2.5 Hz, 1H), 7.41 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H), 7.92 (m, 2H), 8.40 (s, 1H).13C NMR (75 MHz, DMSO-d6) δ 48.4, 60.9, 66.0, 107.7, 119.6, 125.4, 127.0, 127.2, 128.1, 128.2, 128.7, 129.6, 130.2, 130.9, 136.2, 137.2, 158.0, 168.6, 171.3. LC-MS (ESI) m / z [M+H]+= 349.2.(Hydrazinecarbonyl)naphthalen-2- yl]oxy}ethyl)-N-methylbenzamide (43). Methyl 6-[2-(N-methyl-1- 15 phenylformamido)ethoxy]naphthalene-2-carboxylate (300 mg, 0.83 mmol), hydrazine monohydrate (5.0 mL, 103.19 mmol) were in 20 mL of MeOH and heated at reflux for 5 h. Volatils were removed under reduced pressure. The resulting residue was solubilized in DCM and washed with water and brine. The organic layer was dried over MgSO4, filtered and evaporated under vacuum to give 43 as a yellow oil (272 mg, 91%).1H NMR (300 MHz, DMSO-d6): δ 3.06 (Brs, 3H), 3.63-3.96 (2Brs, 2H), 20 4.15-4.45 (2Brs, 2H), 4.53 (Brs, 2H), 7.07-7.99 (m, 11H), 8.36 (Brs, 1H). LC-MS (ESI) m / z [M+H]+= 363.2.N-[2-({6-[(E)-N'- Hydroxycarbamimidoyl]naphthalen-2-yl}oxy)ethyl]-N-methylbenzamide (63). To a solution of hydroxylamine hydrochloride (41 mg, 1.24 mmol) and Et3N (0.34 mL, 2.48 mmol), in EtOH (10 mL), 25 N-{2-[(6-cyanonaphthalen-2-yl)oxy]ethyl}-N-methylbenzamide (40, 205 mg, 0.62 mmol) was added and the reaction mixture was refluxed for 48 h. The mixture was then cooled to rt. The white solid was filtered and washed with Et2O to give 63 as a white powder (122 mg, 54%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 3.00 (s, 3H), 3.8 (t, J = 5.5 Hz, 2H), 4.33 (t, J = 5.5 Hz, 2H), 5.68 (s, 2H), 7.19-41- (dd, J = 8.9, 2.5 Hz, 1H), 7.33 (s, 1H), 7.40 (s, 5H), 7.78 (m, 3H), 8.12 (s, 1H). LC-MS (ESI) m / z [M+H]+= 364.1.N-Methyl-N-(2-{[6-(5-methyl-1,2,4- oxadiazol-3-yl)naphthalen-2-yl]oxy}ethyl)benzamide (44). To a solution of N-[2-({6-[(E)-N'- 5 hydroxycarbamimidoyl]naphthalen-2-yl}oxy)ethyl]-N-methylbenzamide (63, 100 mg, 0.28 mmol) in pyridine (4 mL) at 0 °C was added acetyl chloride (0.24 µL, 0.33 mmol) and the reaction mixture was refluxed for 16 h. The solvant was removed under reduced pressure and the residue taken up in water. Then, the aqueous layer was extracted 3 times with ethyl acetate, dried over MgSO4. The solution was filtered and evaporated under reduced pressure. The crude was purified by flash column 10 chromatography (5-40% EtOAc in cyclohexane) to give 44 as a yellow powder (387 mg, 47%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 2.44 (s, 3H), 3.00 (s, 1H), 3.82 (m, 2H), 4.36 (m, 2H), 7.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.41 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 9.0, 1.90 Hz, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.53 (s, 1H).13C NMR (75 MHz, DMSO-d6) δ 12.5, 33.0, 38.9, 46.7, 50.0, 65.2, 65.9,107.5, 120.0, 121.9, 124.3, 127.3, 127.7, 128.2, 128.5, 128.8, 129.5, 129.8, 131.0, 136.2, 137.1, 15 157.8, 158.1, 168.2, 177.8. LC-MS (ESI) m / z [M+H]+= 388.2.N-methyl-N-(2-{[6-(3-methyl-1,2,4- oxadiazol-5-yl)naphthalen-2-yl]oxy}ethyl)benzamide (45). To a solution of 6-[2-(N-methyl-1- phenylformamido)ethoxy]naphthalene-2-carboxylic acid (41, 100 mg, 0.29 mmol) and acetylamidoxime (21 mg, 0.29 mmol) in EtOAc (10 mL) was added, Et3N (0.32 mL, 2.29 mmol) 20 followed by dropwise addition of T3P (0.43 mL, 0.72 mmol, 50% solution in EtOAc). The mixture was refluxed under nitrogen atmosphere for 12 h. The mixture was cooled to rt, and poured into ice-water. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with NaHCO3 sat. and brine. The organic layer was then dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude was purified by silica gel chromatography (10-40% 25 AcOEt in cyclohexane) to give 45 a light yellow powder (10 mg, 9%).1H NMR (300 MHz, DMSO-d6, 80°C) δ 2.44 (s, 3H), 3.00 (s, 1H), 3.82 (m, 2H), 4.36 (m, 2H), 7.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.41 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 9.0, 1.9 Hz, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.53 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 12.5, 33.0, 38.9, 46.7, 50.0, 65.2, 65.9, 107.5, 120.0, 121.9, 124.3, 127.3, 127.7, 128.2, 128.5, 128.8, 129.5, 129.8, 131.0, 136.2, 137.1, 157.8, 158.1, 168.2, 177.8. LC- 30 MS (ESI) m / z [M+H]+= 388.1.-42-N-(2-{[6-(Furan-2-yl)naphthalen-2- yl]oxy}ethyl)-N-methylbenzamide (48). 2-Furanboronic acid (88 mg, 0.78 mmol), N-{2-[(6- bromonaphthalen-2-yl)oxy]ethyl}-N-methylbenzamide (200 mg, 0.52 mmol), Pd(PPh3)4 (60.0 mg, 0.05 mmol) and Cs2CO3 (187.0 mg, 0.57 mmol) were solubilized in 10 mL of toluene / MeOH (4:1), 5 under nitrogen. The mixture was stirred at 100°C overnight. Solvent was removed under reduced pressure. The resulting residue was solubilized in 50 mL of EtOAc and washed with brine, dried over MgSO4, filtered and evaporated under vacuum.48 was triturated in Et2O to give the final product as an orange solid (132 mg, 68%).1H NMR (300 MHz, DMSO-d6): δ 3.06 (Brs, 3H), 3.62-3.98 (2Brs, 2H), 4.14-4.44 (2Brs, 2H), 6.60-6.69 (m, 1H), 6.95-7.08 (m, 1H), 7.08-7.71 (m, 7H), 7.71-7.98 (m, 10 4H), 8.11-8.20 (m, 1H).13C NMR (75 MHz, DMSO-d6): δ 33.1, 46.9, 50.1, 106.3, 107.7, 112.7, 119.8, 122.0, 123.2, 125.3-131.2, 131.2-138.4, 143.5, 153.9, 156.9. LC-MS (ESI) m / z [M+H]+= 371.3.N-Methyl-N-(2-{[6-(1H-1,2,3,4-tetrazol-5- yl)naphthalen-2-yl]oxy}ethyl)benzamide (47). Trimethylsilyl azide (100 µL, 0.76 mmol), Cu2O (2.0 mg, 0.01 mmol) and N-{2-[(6-cyanonaphthalen-2-yl)oxy]ethyl}-N-methylbenzamide (40, 167 mg, 0.50 15 mmol) were solubilized in 10 mL of DMF / MeOH (9:1). The mixture was stirred at 80°C overnight. The resulting solution was diluted in 30 mL of EtOAc and washed with a solution of 1N HCl and brine. The organic layer was dried over MgSO4, filtered and evaporated under vacuum. Product was purified by flash column chromatography (0-10% MeOH in DCM) to give the final product as a white powder (21 mg, 12%).1H NMR (300 MHz, DMSO-d6) δ 3.04 (Brs, 3H), 3.62-4.02 (2Brs, 2H), 4.16-4.54 (2Brs, 20 2H), 7.17-8.18 (m, 11H).13C NMR (75 MHz, DMSO-d6) δ 33.0, 46.8, 50.0, 106.3, 107.4, 120.1, 121.3, 124.8, 126.1-130.2, 130.8, 135.5, 137.0, 138.9, 156.9, 157.8. LC-MS (ESI) m / z [M+H]+= 373.2.2-bromo-5-{2- [methyl(phenyl)amino]ethoxy}benzaldehyde (Int23). Compound Int23 was prepared according to general procedure C starting from 2-bromo-5-hydroxybenzaldehyde (3 g, 14.9 mmol) and Int1 (2.9 25 g, 14.9 mmol). The resulting residue was taken in EtOAc and washed with 1N NaOH to afford an orange oil (2.2 g, 48%).1H NMR (300 MHz, CDCl3) δ 3.06 (s, 3H), 3.78 (t, J = 5.8 Hz, 2H), 4.18 (t, J = 5.8 Hz, 2H), 6.70-6.81 (m, 3H), 7.02 (dd, J = 8.8, 0.5 Hz 1H), 7.20-7.32 (m, 2H), 7.39 (d, J = 3.2 Hz, 1H), 7.50 (d, J = 8.8 Hz 1H), 10.29 (s, 1H). LC-MS (ESI) m / z [M+H]+= 334.1, 336.1.-43-Methyl 7-{2- [methyl(phenyl)amino]ethoxy}isoquinoline-3-carboxylate (54). To a stirred solution of Int23 (400 mg, 1.2 mmol) in dry DMSO (5 mL) were added methyl 2-acetamidoprop-2-enoate (257 mg, 1.8 mmol), Et3N (2.0 mL, 14.4 mmol) and tri(o-tolyl)phosphine (73 mg, 0.2 mmol). The solution was 5 degassed for 5 minutes, then Pd(OAc)2 (24^mg, 0.1^mmol) was added. The mixture was stirred at 110^°C for 15^h. After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (40-100% EtOAc in cyclohexane) and washed with diethyl ether to afford the final product as a brown solid (140^mg, 35%).1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 3.88 (t, J = 5.8 10 Hz, 2H), 4.06 (s, 3H), 4.33 (t, J = 5.8 Hz, 2H), 6.62-6.90 (m, 4H), 7.23-7.32 (m, 2H), 7.44 (dd, J = 9.0, 2.6 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 8.54 (s, 1H), 9.17 (s, 1H).13C NMR (75 MHz, CDCl3) δ 39.2, 51.8, 52.7, 65.8, 105.9, 112.2, 116.9, 123.8, 124.4, 129.4 (2C), 129.6, 130.9, 131.5, 139.9, 148.7, 151.1, 159.5, 166.4. LC-MS (ESI) m / z [M+H]+= 337.3.2-chloro-4-{2- 15 [methyl(phenyl)amino]ethoxy}benzaldehyde (Int24). Compound Int24 was prepared according to general procedure C starting from 2-chloro-4-hydroxybenzaldehyde (2.9 g, 18.5 mmol) and Int1 (3.9 g, 14.9 mmol). The resulting residue was taken in EtOAc and washed with 1N NaOH to afford a brown solid (5.2 g, 97%).1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 3.81 (t, J = 5.8 Hz, 2H), 4.22 (t, J = 5.8 Hz, 2H), 6.73-6.82 (m, 3H), 6.89 (dd, J = 2.4, 0.8 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 7.28 (t, J 20 = 7.7 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 10.34 (s, 1H). LC-MS (ESI) m / z [M+H]+= 290.1, 292.1.N-[(2-chloro-4-{2- [methyl(phenyl)amino]ethoxy}phenyl)methylidene]-4-methylbenzene-1-sulfonamide (Int25). To a solution of Int24 (4.5 g, 15.5 mmol) in 150 mL of toluene, were added tosylamide (4.0 g, 23.3 mmol) and molecular sieves (4 Å powder), and the mixture was refluxed overnight. The sieves were 25 removed by filtration, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was filtered to afford Int25 as a yellow solid (6.2 g, 90%).1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.05 (s, 3H), 3.80 (t, J = 5.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 6.73-6.80 (m, 2H), 6.85 (dd, J = 8.8, 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 7.24-7.33 (m,-44- 5H), 7.88 (d, J = 8.3 Hz, 2H), 8.10 (d, J = 8.8 Hz, 1H), 9.39 (s, 1H). LC-MS (ESI) m / z [M+H]+= 443.3, 445.3.Methyl 2-[(2-chloro-4-{2- [methyl(phenyl)amino]ethoxy}phenyl)(4-methylbenzenesulfonamido)methyl]prop-2-enoate 5 (Int26). To a solution of Int25 (2.0^g, 4.5^mmol) in THF (30^mL) were added DABCO (203^mg, 1.8^mmol) and methyl acrylate (3.3^mL, 36.1^mmol), and the mixture was refluxed for 72^h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM. The organic layer was washed with 1N HCl, dried over MgSO4, filtered, and concentrated. The product was purified by flash column chromatography (5-30% EtOAc in cyclohexane) to afford the final product 10 as a white powder (1.2^g, 48%).1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.45 (s, 1H), 3.04 (s, 3H), 3.63 (s, 3H), 3.74 (t, J = 5.9 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 5.67 (s, 2H), 5.90 (s, 1H), 6.29 (s, 1H), 6.63 (dd, J = 8.8, 2.6 Hz, 1H), 6.70-6.81 (m, 4H), 7.22-7.38 (m, 4H), 7.15-7.39 (m, 6H). LC-MS (ESI) m / z [M+H]+= 529.2, 531.2.Methyl 7-{2- 15 [methyl(phenyl)amino]ethoxy}isoquinoline-3-carboxylate (55). To a solution of Int26 (840^mg, 1.6^mmol) in DMF (15^mL) were added tosylamide (136^mg, 0.8^mmol) and K2CO3 (878^mg, 6.4^mmol), and the mixture was stirred at 90^°C overnight. The solvent was removed under reduced pressure, and the residue was taken up in water. The organic layer was extracted with DCM, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (2-30% EtOAc 20 in cyclohexane) to afford the desired product as a white powder (192 mg, 36%).1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 3.87 (t, J = 5.8 Hz, 2H), 4.02 (s, 3H), 4.36 (t, J = 5.8 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.27 (t, J = 7.5 Hz, 3H), 7.45 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 7.0 Hz, 2H).13C NMR (75 MHz, CDCl3) δ 39.2, 51.8, 52.4, 66.0, 108.1, 112.3 (2C), 116.8, 121.0, 121.0, 122.1, 129.3, 130.3, 138.3, 148.9, 150.5, 151.7, 161.8, 166.1. LC-MS (ESI) m / z [M+H]+= 337.3. 25N-methyl-N-(2-{[6-(pyridin-4-yl)naphthalen- 2-yl]oxy}ethyl)benzamide (56). Compound 56 was prepared according to general procedure M starting from compound 38 (150 mg, 0.4 mmol) and pyridine-4-boronic acid (72 mg, 0.6 mmol). The-45- product was washed and filtered with diethyl ether, and obtained as a white powder (113 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 3.24 (m, 3H, H), 3.81 (brs, 0.7H), 4.04 (brs, 1.3H), 4.20 (brs, 0.7H), 4.48 (brs, 1.3H), 7.19 (m, 2H), 7.46 (m, 5H), 7.65 (dd, J = 4.6, 1.6 Hz, 2H), 7.76 (dd, J = 8.5, 1.7 Hz, 1H), 7.87 (m, 2H), 8.09 (d, J = 1.3 Hz, 1H), 8.71 (dd, J = 4.6, 1.5 Hz, 2H).13C NMR (75 MHz, CDCl3) 5 δ 39.7, 47.7, 50.3, 65.3, 66.6, 106.6, 119.6, 121.6, 125.1, 126.2, 127.0, 127.8, 128.4, 129.1, 130.2, 131.9, 132.0 (2C), 132.2, 133.3, 148.3, 150.3, 157.4. LC-MS (ESI) m / z [M+H]+= 383.4.N-methyl-N-(2-{[6-(pyridin-3-yl)naphthalen- 2-yl]oxy}ethyl)benzamide (57). Compound 57 was prepared according to general procedure M starting from compound 38 (146 mg, 0.4 mmol) and pyridin-3-boronic acid (70 mg, 0.6 mmol). The 10 product was washed and filtered with diethyl ether, and obtained as a white powder (67 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 3.22 (m, 3H), 3.81 (brs, 0.7H), 4.05 (brs, 1.3H), 4.20 (brs, 0.7H), 4.48 (brs, 1.3H), 7.18 (m, 2H), 7.45 (m, 6H), 7.71 (m, 1H), 7.86 (m, 2H), 8.00 (m, 1H), 8.63 (dd, J = 4.9, 1.5 Hz, 1H), 8.99 (d, J = 1.9 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 39.7, 47.7, 50.2, 65.2, 66.7, 106.6, 119.5, 123.8, 125.6, 126.0, 127.8, 128.4, 128.6, 129.6, 129.9, 132.0, 132.2, 134.7, 147.9, 148.1, 15 171.7. LC-MS (ESI) m / z [M+H]+= 383.4.N-methyl-N-(2-{[6-(pyrimidin-5- yl)naphthalen-2-yl]oxy}ethyl)benzamide (58). Compound 58 was prepared according to general procedure M starting from compound 38 (200 mg, 0.5 mmol) and pyrimidin-5-boronic acid (97 mg, 0.8 mmol). The product was washed and filtered with diethyl ether, and obtained as a white powder 20 (105 mg, 53%).1H NMR (300 MHz, CDCl3) δ 3.22 (m, 3H), 3.82 (brs, 0.7H), 4.05 (brs, 1.3H), 4.20 (brs, 0.7H), 4.48 (brs, 1.3H), 7.19 (m, 2H), 7.46 (m, 5H), 7.69 (dd, J = 8.6, 1.6 Hz, 1H), 7.88 (m, 2H), 8.01 (brs, 1H), 9.05 (brs, 2H), 9.24 (s, 1H).13C NMR (75 MHz, CDCl3) δ 39.7, 47.7, 50.2, 65.3, 66.6, 106.6, 119.8, 124.9, 126.1, 127.0, 126.98, 128.3, 128.4, 129.2, 129.6, 130.0, 132.0, 132.2, 134.3, 134.5, 136.2, 154.9 (2C), 157.3. LC-MS (ESI) m / z [M+H]+= 384.2. 25-hydroxyethyl)-N-propylbenzamide (Int30). To a solution of 2- aminoethan-1-ol (0.49 mL, 8.2 mmol) and K₂CO₃ (1.7 g, 12.3 mmol) in ACN was added dropwise 1- bromopropane (1.1 mL, 12.3 mmol). The reaction mixture was stirred at reflux for 2 h. The solvent was removed under reduced pressure, and the residue was dissolved in water. Then, the aqueous layer was extracted with AcOEt. The organic layer was dried over MgSO4, filtered, and concentrated-46- under reduced pressure. The resulting product was dissolved in DCM and benzoyl chloride (0.95 mL, 8.2 mmol) and Et3N (5.7 mL, 40.9 mmol) were added. The reaction was stirred at rt for 4 h. The mixture was then washed with water and brine, and extracted with DCM. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by flash column 5 chromatography (0-5 % MeOH in DCM) to give a yellow oil (1.37 g, 81 %).1H NMR (300 MHz, CDCl3) δ 0.78 (t, J = 7.15 Hz, 2.3H), 0.98 (brs, 0.7H), 1.59 (q, J = 7.1 Hz, 1.6H), 1.68 (brs, 0.4H), 3.25 (t, J = 7 Hz, 1.6H), 3.41 (brs, 0.4H), 3.65 (brs, 0.4H), 3.71 (brs, 1.6H), 3.83 (brs, 0.4H), 3.89 (brs, 1.6 H), 7.41 (brs, 5H). LC-MS (ESI) m / z [M+H]+= 208.3.Methyl (2E)-3-{4-[2-(1-phenyl-N- 10 propylformamido)ethoxy]phenyl}prop-2-enoate (59). Compound 59 was prepared according to general procedure E starting from N-(2-hydroxyethyl)-N-propylbenzamide (Int30, 279 mg, 1.3 mmol) and methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (200 mg, 1.1 mmol). The crude was purified by flash column chromatography (20-40 % AcOEt in cyclohexane) to give a white powder (210 mg, 51 %).1H NMR (300 MHz, DMSO-d6) δ 0.67 (brs, 1.5H), 0.92 (brs, 1.5H), 1.54 (brs, 2H), 3.22 (brs, 15 1H), 3.46 (brs, 1H), 3.60 (brs, 1H), 3.72 (s, 3H), 3.80 (brs, 1H), 4.10 (brs, 1H), 4.28 (brs, 1H), 6.51 (d, J = 16.0 Hz, 1H), 6.92 (brs, 1H), 7.05 (brs, 1H), 7.33-7.43 (m, 5H), 7.65 (m, 3H).13C NMR (75 MHz, DMSO-d6) δ 11.3, 11.7, 20.8, 21.9, 44.3, 46.4, 48.0, 51.7, 51.8, 65.7, 115.3, 115.7 (2C), 126.8, 127.1, 127.3, 128.8 (2C), 129.6, 130.7 (2C), 137.5, 144.7 (2C), 160.4, 160.7, 167.4, 171.5. LC-MS (ESI) m / z [M+H]+= 368.3. 20Methyl (2E)-3-(4-{2-[1-(4-aminophenyl)- N-methylformamido]ethoxy}phenyl)prop-2-enoate (60). Compound 60 was prepared according to general procedure H starting from p-aminobenzoic acid (113 mg, 0.8 mmol).1H NMR (300 MHz, CDCl3) δ 3.19 (s, 3H), 3.82 (s, 3H), 3.88 (brs, 2H), 4.26 (brs, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.67 (d, J 25 = 16.à Hz, 1H). LC-MS (ESI) m / z [M+H]+= 355.2.2-[methyl(phenyl)amino]acetonitrile (Int28). N,N-Dimethylaniline (2.0^mL, 15.7^mmol), FeCl₂ (0.2^g, 1.6^mmol), tert-butyl hydroperoxide (3.8^mL, 39.2^mmol), and trimethylsilanecarbonitrile (4.2^mL, 31.4^mmol) were dissolved in MeOH (60^mL), and the mixture was heated at reflux overnight. The solvent was removed under reduced pressure, and the residue was 30 dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and-47- concentrated to afford the desired product as a black liquid (1.9^g, 84%).1H NMR (300 MHz, CDCl3) δ 3.04 (s, 3H), 4.21 (s, 2H), 6.71-6.84 (m, 3H), 6.87-7.01 (m, 3H), 7.30-7.39 (m, 2H). LC-MS (ESI) m / z not detected.

[0155] N-(2-aminoethyl)-N-methylaniline (Int29). To solution of Int28 in 5 diethyl ether (40^mL) at 0 °C, LiAlH₄ (0.5^g, 14.0^mmol) was added portion-wise over 15 minutes. The mixture was then stirred at rt for 15^h. The solvent was removed under reduced pressure, and 0.5^mL of water was added to the residue, followed by 0.5^mL of NaOH 15% and 1.5^mL of water. The mixture was stirred at rt for 30 minutes, then filtered through Celite. The filtrate was concentrated under reduced pressure to afford the desired Int29 as a brown oil (1.9 g, 84%).1H NMR (300 MHz, CDCl3) 10 δ 2.47 (sl, 2H), 2.90-2.97 (m, 2H), 2.98 (s, 3H), 3.42 (t, J = 6.6 Hz, 2H).Methyl (2E)-3-[4-({2- [methyl(phenyl)amino]ethyl}amino)phenyl]prop-2-enoate (61). To a solution of methyl (2E)-3-(4- bromophenyl)prop-2-enoate (188 mg, 0.78 mmol) in dry dioxane (3 mL) was added Int29 (352 mg, 2.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (72 mg, 0.078 mmol), xantphos (91 mg, 0.16 15 mmol), and Cs2CO3 (764 mg, 2.34 mmol) under nitrogen, and the mixture was stirred at reflux for 12 h. The reaction solution was filtered on Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10 % MeOH in DCM) to give the desired product as a yellow solid (153 mg, 63%).1H NMR (300 MHz, CDCl3) δ 2.97 (s, 3H), 3.44 (brs, 2H), 3.58 (brs, 2H), 3.80 (s, 3H), 6.22 (d, J = 16.0 Hz, 1H), 6.61 (m, 2H), 6.79 (m, 2H), 7.21- 20 7.50 (m, 4H), 7.61 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 38.5, 40.9, 51.5, 52.0, 112.6, 112.6, 112.6, 112.9, 112.9, 117.3, 123.7, 129.4, 129.4, 130.0, 130.0, 145.3, 149.6, 149.9, 168.3. LC- MS (ESI) m / z [M+H]+= 311.2.

[0157] ACSL4 activity Table1:-48--49- 10 21 M-50--51--52- 34 4.0 µM-53--54--55-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 µM, most of the compounds having IC50 below 10 µM. A large number of compounds have IC50 below 1 µM.

[0158] PPAR activity 5 Evaluation of PPAR activity by luciferase reporter gene assay Cos-7 cells were seeded in 60-mm dishes at a density of 5.5 x 105 cells / dish in Dulbecco’s modified Eagle’s minimal essential medium (DMEM) supplemented with 10% fetal calf serum (FCS) at 37 °C for 16 h before transfection. Cells were transfected in DMEM with the jetPEI transfection reagent (Polyplus-Transfection S.A., Strasbourg, France) using the reporter plasmid pG5-TK-pGL3 in 10 combination with one of the expression plasmids, pGal4hPPARα, pGal4hPPARγ or pGal4hPPARβ / δ. The pCMV-β-galactosidase expression plasmid was included as a control of transfection efficiency. Transfected cells were seeded in 96-well plates and then incubated overnight in DMEM containing 0.2% FCS and increasing concentrations of the compound tested or vehicle (DMSO, 0.1% final concentration). At the end of the experiment, cells were washed once with ice-cold phosphate 15 buffered saline (PBS) and lysed, and luciferase and β-galactosidase activity were measured. Luciferase activity was then normalized to internal control β-galactosidase activity. Each experiment was achieved in triplicate. Data were expressed as the percentage of positive reference value (Wy14,643 at 10 µM, rosiglitazone at 1 µM or GW501516 at 1 µM were used as a positive reference compound for PPARalpha, gamma or delta respectively). Dose-response curves were fitted by a 20 nonlinear regression analysis and half maximal effective concentration (EC50) was calculated using GraphPad Prism 9 Software. Table 2:-56-

[0159] The results presented in Table 2 above demonstrate that the tested compounds of the invention are inactive on PPAR gamma, alpha and delta at 10 µM. Thus, the compounds of the invention have no or minimized activity on PPAR, which constitutes a highly valuable advantage compared to the previously described ASCL4 inhibitors such as rosiglitazone (EC50 = 36 nM under 5 tested conditions).

[0160] Selectivity of ACSL4 Inhibitors Over ACSL3 The most promising ACSL4 inhibitors, including compounds 15 and 45, were evaluated against hACSL3 and showed no inhibitory activity at 50^µM, highlighting the selectivity of this series for ACSL4. 10

[0161] Cell evaluations

[0162] Cytotoxicity of compound 15 across six different cell lines (SiHa, HCT-116, MDA-MB-231, HEK293, HT-1080, and LUHMES) was evaluated. Compound 15 demonstrated minimal toxicity at concentrations up to 10 µM (Figure 1).

[0163] The anti-ferroptotic potential of compound 15 was evaluated in HEK293, HT-1080, and 15 LUHMES cell lines, which are commonly used to study ACSL4 in the context of ferroptosis. RSL3 was used to induce ferroptosis in HEK293 and HT-1080 cells. LUHMES cells, a non-oncogenic model of human dopaminergic neurons widely used in Parkinson's disease research and highly sensitive to ferroptosis, were treated with a combination of arachidonic acid (AA) and iron (Fe), which better-57- mimics the neuropathological environment (H. Bouchaoui, L. Mahoney-Sanchez, G. Garçon, O. Berdeaux, L. Y. Alleman, D. Devos, J. A. Duce, J. C. Devedjian, Free Radic. Biol. Med.2023, 195, 145–157). Compound 15 at 2.5 µM significantly prevented RSL3-induced cell death in both HEK293 (Figure 2A) and HT-1080 cells (Figure 2B). Additionally, in LUHMES cells, compound 15 (2.5 µM) 5 effectively inhibited cell death caused by AA+Fe treatment, comparable to the protective effect seen with ACSL4 knockdown (Figure 2C). The protective effect of compound 15 was correlated to a significant decrease in lipid peroxidation to a similar level to ACSL4 siRNA (Figure 2D). Similar results were obtained with compound 45 (Figure 3). Citation List 10

[0164] 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. 15 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, Ríos Medrano 20 MA, Torres MT, Indo S, Caroca G, Contreras HR, Marelli BE, Salinas FJ, Salvetti NR, Ortega HH, Lorenzano Menna P, Szajnman S, Gomez DE, Rodríguez 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. 25 11. 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 30 M, Walch A, Prokisch H, Trümbach D, Mao G, Qu F, Bayir H, Füllekrug 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.-58- 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, Bayır H. Nat Chem Biol.2017 Jan;13(1):81-90. 5 17. Kim JH, Lewin TM, Coleman RA. J Biol Chem.2001 Jul 6;276(27):24667-73.

Claims

-59- Claims

1. Compound of formula (II)a pharmaceutically acceptable salt or a solvate thereof, wherein 5 R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, optionally substituted heterocycle, C1-6 alkyl-optionally substituted aryl, and C1-6 alkyl- optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- 10 OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, m is an integer selected from 1 or 2, W is selected from O and NH, 15 X and Y are independently selected from H, CH, N and (CH2)n, n is an integer selected from 1, 2, 3, 4 or 5, Z is selected from CH, CH2 and N, represents a single bond or a double bond, represents no bond, a single bond, or a double bond. 20

2. The compound of claim 1, wherein said compound is a compound of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf)25 a pharmaceutically acceptable salt or a solvate thereof, wherein-60- R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, optionally substituted heterocycle, C1-6 alkyl-optionally substituted aryl, and C1-6 alkyl- optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, 5 R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, m is an integer selected from 1 or 2, 10 W is selected from O and NH, X and Y are independently selected from H, CH, N and (CH2)n, n is an integer selected from 1, 2, 3, 4 or 5, Z is selected from CH, CH2 and N.

3. The compound of claim 1 or 2, wherein said compound is a compound of formula (Ia), 15 (Ib), (Ic), (Id), (Ie) or (If)20 a pharmaceutically acceptable salt or a solvate thereof, wherein R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, optionally substituted heterocycle, C1-6 alkyl-optionally substituted aryl, and C1-6 alkyl- optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, 25 R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, m is an integer selected from 1 or 2,-61- X and Y are independently selected from H, CH, N and (CH2)n, n is an integer selected from 1, 2, 3, 4 or 5, Z is selected from CH, CH2 and N.

4. The compound according to any one of claims 1 to 3, wherein said compound is a 5 compound of formula (Ig3), (Ih3), (Ig4), or (Ih4)wherein R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally10 substituted aryl, optionally substituted heterocycle, C1-6 alkyl-optionally substituted aryl, and C1-6 alkyl- optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6 alkyl, halogen, and optionally substituted heterocycle, 15 R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, X is selected from H, CH, N and (CH2)n, n is an integer selected from 1, 2, 3, 4 or 5.

5. The compound according to any one of claims 1 to 4, wherein said compound is a 20 compound of formula (Ii) or (Ij)wherein R1 and R2 are independently selected from H, C1-6 alkyl, -C(O)R4, -COOH, -COOC1-6 alkyl, optionally substituted aryl, optionally substituted heterocycle, C1-6alkyl-optionally substituted aryl, and C1-6alkyl- 25 optionally substituted heterocycle, or R1 and R2 form together a monocyclic or bicyclic heterocycle, R3 is selected from H, -COOH, -COOC1-6 alkyl, -CONH2, -CON(C1-6 alkyl)2, -C(O)NHNH2, -C(N- OH)(NH2), -CN, -OC1-6alkyl, halogen, and optionally substituted heterocycle,-62- R4 is selected from H, C1-6 alkyl, -O-C1-6 alkyl, -CH=CH2, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle, m is an integer selected from 1 or 2, X and Y are independently selected from H, CH, N and (CH2)n, 5 n is an integer selected from 1, 2, 3, 4 or 5, Z is selected from CH, CH2 and N, R5 is selected from H, -C1-C6 alkyl, C1-8 alkoxy, -NO2, -CN, halogen, or an amino group, represents a single bond or a double bond, represents no bond, a single bond, or a double bond. 10

6. The compound according to any one of claims 1 to 5, wherein the compound is selected15-64-10

7. The compound according to any one of claims 1 to 6, wherein the compound is selected fromgroup consisting of:-65- 5.

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

9. The compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 for use in a method of therapeutic treatment of a subject. 10

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

11. Compound or pharmaceutical composition for use in a method according to claim 9 or 10, wherein said compound or composition is administered orally, enterally, intravenously, or 15 intramuscularly to said subject. .

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